European Heart Journal

European Heart Journal 2006 27(16):1979-2030; doi:10.1093/eurheartj/ehl176

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© 2006 by the American College of Cardiology Foundation, the American Heart Association, Inc, and the European Society of Cardiology. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation–executive summary

A report 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

Authors/Task Force Members, Valentin Fuster, MD, PhD, FACC, FAHA, FESC, Co-Chair, Lars E. Rydén, MD, PhD, FACC, FESC, FAHA, Co-Chair, David S. Cannom, MD, FACC, Harry J. Crijns, MD, FACC, FESC^*, Anne B. Curtis, MD, FACC, FAHA, Kenneth A. Ellenbogen, MD, FACC, Jonathan L. Halperin, MD, FACC, FAHA, Jean-Yves Le Heuzey, MD, FESC, G. Neal Kay, MD, FACC, James E. Lowe, MD, FACC, S. Bertil Olsson, MD, PhD, FESC, Eric N. Prystowsky, MD, FACC, Juan Luis Tamargo, MD, FESC and Samuel Wann, MD, FACC, FESC

ESC Committee for Practice Guidelines, Silvia G. Priori, MD, PhD, FESC, Chair, Jean-Jacques Blanc, MD, FESC, Andrzej Budaj, MD, FESC, A. John Camm, MD, FESC, FACC, FAHA, Veronica Dean, Jaap W. Deckers, MD, FESC, Catherine Despres, Kenneth Dickstein, MD, PhD, FESC, John Lekakis, MD, FESC, Keith McGregor, PhD, Marco Metra, MD, Joao Morais, MD, FESC, Ady Osterspey, MD, Juan Luis Tamargo, MD, FESC and José Luis Zamorano, MD, FESC

France
Poland
United Kingdom
France
The Netherlands
France
Norway
Greece
France
Italy
Portugal
Germany
Spain
Spain

ACC/AHA (Practice Guidelines) Task Force Members, Sidney C. Smith, Jr, MD, FACC, FAHA, FESC, Chair, Alice K. Jacobs, MD, FACC, FAHA, Vice-Chair, Cynthia D. Adams, MSN, APRN-BC, FAHA, Jeffery L. Anderson, MD, FACC, FAHA, Elliott M. Antman, MD, FACC, FAHA, Jonathan L. Halperin, MD, FACC, FAHA, Sharon Ann Hunt, MD, FACC, FAHA, Rick Nishimura, MD, FACC, FAHA, Joseph P. Ornato, MD, FACC, FAHA, Richard L. Page, MD, FACC, FAHA and Barbara Riegel, DNSc, RN, FAHA

Key Words: ACC/AHA/ESC Guidelines • atrial fibrillation • arrhythmia • heart rate • anticoagulants • antiarrhythmia agents • electrophysiology • pharmacology

	Preamble

Top Preamble I. Introduction Recommendations II. Definition III. Classification IV. Epidemiology and... V. Pathophysiological... VI. Causes, associated... VII. Clinical evaluation VIII. Management IX. Proposed management... References

 
It is important that the medical profession play a significant role in critically evaluating the use of diagnostic procedures and therapies as they are introduced and tested in the detection, management, or prevention of disease states. Rigorous and expert analysis of the available data documenting absolute and relative benefits and risks of those procedures and therapies can produce helpful guidelines that improve the effectiveness of care, optimize patient outcomes, and favorably affect the overall cost of care by focusing resources on the most effective strategies.

The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of such guidelines in the area of cardiovascular disease since 1980. The ACC/AHA Task Force on Practice Guidelines, whose charge is to develop, update, or revise practice guidelines for important cardiovascular diseases and procedures, directs this effort. The Task Force is pleased to have this guideline developed in conjunction with the European Society of Cardiology (ESC). Writing committees are charged with the task of performing an assessment of the evidence and acting as an independent group of authors to develop or update written recommendations for clinical practice.

Experts in the subject under consideration have been selected from all 3 organizations to examine subject-specific data and to write guidelines. The process includes additional representatives from other medical practitioner and specialty groups when appropriate. Writing committees are specifically charged to perform a formal literature review, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that might influence the choice of particular tests or therapies are considered as well as frequency of follow-up and cost-effectiveness. When available, information from studies on cost will be considered; however, review of data on efficacy and clinical outcomes will constitute the primary basis for preparing recommendations in these guidelines.

The ACC/AHA Task Force on Practice Guidelines and the ESC Committee for Practice Guidelines make every effort to avoid any actual, potential, or perceived conflict of interest that might arise as a result of an outside relationship or personal interest of the Writing Committee. Specifically, all members of the Writing Committee and peer reviewers of the document are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. Writing Committee members are also strongly encouraged to declare a previous relationship with industry that might be perceived as relevant to guideline development. If a Writing Committee member develops a new relationship with industry during his or her tenure, he or she is required to notify guideline staff in writing. The continued participation of the Writing Committee member will be reviewed. These statements are reviewed by the parent Task Force, reported orally to all members of the Writing Committee at each meeting, and updated and reviewed by the Writing Committee as changes occur. Please refer to the methodology manuals for further description of the policies used in guideline development, including relationships with industry, available on the ACC, AHA, and ESC World Wide Web sites (http://www.acc.org/clinical/manual/manual_introltr.htm, http://circ.ahajournals.org/manual/ and http://www.escardio.org/knowledge/guidelines/Rules/). Please see Appendix I for author relationships with industry and Appendix II for peer reviewer relationships with industry that are pertinent to these guidelines.

These practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches for the diagnosis, management, and prevention of specific diseases and conditions. These guidelines attempt to define practices that meet the needs of most patients in most circumstances. These guideline recommendations reflect a consensus of expert opinion after a thorough review of the available, current scientific evidence and are intended to improve patient care. If these guidelines are used as the basis for regulatory/payer decisions, the ultimate goal is quality of care and serving the patient's best interests. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and the patient in light of all of the circumstances presented by that patient. There are circumstances in which deviations from these guidelines are appropriate.

The guidelines will be reviewed annually by the ACC/AHA Task Force on Practice Guidelines and the ESC Committee for Practice Guidelines and will be considered current unless they are updated, revised, or sunsetted and withdrawn from distribution. The executive summary and recommendations are published in the August 15, 2006, issue of the Journal of the American College of Cardiology, August 15, 2006, issue of Circulation, and August 16, 2006, issue of the European Heart Journal. The full-text guidelines are e-published in the same issues of the Journal of the American College of Cardiology and Circulation, published in September 9, 2006, issue of Europace, as well as posted on the ACC (www.acc.org), AHA (www.americanheart.org), and ESC (www.escardio.org) World Wide Web sites. Copies of the full text and the executive summary are available from all 3 organizations.

Sidney C. Smith, Jr., MD, FACC, FAHA, FESC, Chair, ACC/AHA Task Force on Practice Guidelines

Silvia G. Priori, MD, PhD, FESC, Chair, ESC Committee for Practice Guidelines

	I. Introduction

Top Preamble I. Introduction Recommendations II. Definition III. Classification IV. Epidemiology and... V. Pathophysiological... VI. Causes, associated... VII. Clinical evaluation VIII. Management IX. Proposed management... References

 
A. Organization of committee and evidence review
Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, increasing in prevalence with age. AF is often associated with structural heart disease, although a substantial proportion of patients with AF have no detectable heart disease. Hemodynamic impairment and thromboembolic events related to AF result in significant morbidity, mortality, and cost. Accordingly, the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) created a committee to establish guidelines for optimum management of this frequent and complex arrhythmia.

The committee was composed of representatives of the ACC, AHA, ESC, the European Heart Rhythm Association (EHRA), and the Heart Rhythm Society (HRS). The document was reviewed by reviewers nominated by these organizations and will be reviewed annually by the Task Force and considered current unless the Task Force revises or withdraws it from distribution.

The ACC/AHA/ESC Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation conducted a comprehensive review of the relevant literature from 2001 to 2006 using the PubMed/MEDLINE and Cochrane Library databases. Searches focused on English-language sources and studies in human subjects. Articles related to animal experimentation were cited when important to understanding concepts pertinent to patient management.

Classification of recommendations

• Class I: Conditions for which there is evidence and/or general agreement that a given procedure/therapy is beneficial, useful, and effective.
  
• Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of performing the procedure/therapy.
  • Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.
    
  • Class IIb: Usefulness/efficacy is less well established by evidence/opinion.
    
  
  
• Class III: Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful or effective and in some cases may be harmful.
  

Level of evidence
The weight of evidence was ranked from highest (A) to lowest (C), as follows:

• Level of Evidence A: Data derived from multiple randomized clinical trials or meta-analyses.
  
• Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies.
  
• Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care.
  

B. Changes since the initial publication of these guidelines in 2001
The Writing Committee considered evidence published since 2001 and drafted revised recommendations to incorporate results from major clinical trials such as those that compared rhythm control and rate control approaches to long-term management. The text has been reorganized to reflect the implications for patient care, beginning with recognition of AF and its pathogenesis and the general priorities of rate control, prevention of thromboembolism, and methods available for use in selected patients to correct the arrhythmia and maintain normal sinus rhythm. Advances in catheter-based ablation technologies are incorporated in expanded sections and recommendations, with the recognition that such vital details as patient selection, optimum catheter positioning, absolute rates of treatment success, and the frequency of complications remain incompletely defined. Sections on drug therapy have been confined to human studies with compounds approved for clinical use in North America and/or Europe. As data on the management of patients prone to AF in special circumstances are more robust, recommendations are based on a higher level of evidence than in the first edition of these guidelines. Every effort was made to maintain consistency with other ACC/AHA and ESC practice guidelines.

C. Recommendations for management of patients with atrial fibrillation
Classification of Recommendations and Level of Evidence are expressed in the ACC/AHA/ESC format as follows and described in Table 1. Recommendations are evidence based and derived primarily from published data. The reader is referred to the full-text guidelines for a complete description of the rationale and evidence supporting these recommendations.

Table 1 Applying Classification of Recommendations and Level of Evidence^b

	Recommendations

Top Preamble I. Introduction Recommendations II. Definition III. Classification IV. Epidemiology and... V. Pathophysiological... VI. Causes, associated... VII. Clinical evaluation VIII. Management IX. Proposed management... References

 
1. Pharmacological rate control during atrial fibrillation
Class I

1. Measurement of the heart rate at rest and control of the rate using pharmacological agents (either a beta blocker or nondihydropyridine calcium channel antagonist, in most cases) are recommended for patients with persistent or permanent AF. (Level of Evidence: B)
   
2. In the absence of preexcitation, intravenous administration of beta blockers (esmolol, metoprolol, or propranolol) or nondihydropyridine calcium channel antagonists (verapamil, diltiazem) is recommended to slow the ventricular response to AF in the acute setting, exercising caution in patients with hypotension or heart failure (HF). (Level of Evidence: B)
   
3. Intravenous administration of digoxin or amiodarone is recommended to control the heart rate in patients with AF and HF who do not have an accessory pathway. (Level of Evidence: B)
   
4. In patients who experience symptoms related to AF during activity, the adequacy of heart rate control should be assessed during exercise, adjusting pharmacological treatment as necessary to keep the rate in the physiological range. (Level of Evidence: C)
   
5. Digoxin is effective following oral administration to control the heart rate at rest in patients with AF and is indicated for patients with HF, left ventricular (LV) dysfunction, or for sedentary individuals. (Level of Evidence: C)
   

Class IIa

1. A combination of digoxin and either a beta blocker or nondihydropyridine calcium channel antagonist is 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. (Level of Evidence: B)
   
2. It is reasonable to use ablation of the AV node or accessory pathway to control heart rate when pharmacological therapy is insufficient or associated with side effects. (Level of Evidence: B)
   
3. Intravenous amiodarone can be useful to control the heart rate in patients with AF when other measures are unsuccessful or contraindicated. (Level of Evidence: C)
   
4. When electrical cardioversion is not necessary in patients with AF and an accessory pathway, intravenous procainamide or ibutilide is a reasonable alternative. (Level of Evidence: C)
   

Class IIb

1. When the ventricular rate cannot be adequately controlled both at rest and during exercise in patients with AF using a beta blocker, nondihydropyridine calcium channel antagonist, or digoxin, alone or in combination, oral amiodarone may be administered to control the heart rate. (Level of Evidence: C)
   
2. Intravenous procainamide, disopyramide, ibutilide, or amiodarone may be considered for hemodynamically stable patients with AF involving conduction over an accessory pathway. (Level of Evidence: B)
   
3. When the rate cannot be controlled with pharmacological agents or tachycardia-mediated cardiomyopathy is suspected, catheter-directed ablation of the AV node may be considered in patients with AF to control the heart rate. (Level of Evidence: C)
   

Class III

1. Digitalis should not be used as the sole agent to control the rate of ventricular response in patients with paroxysmal AF. (Level of Evidence: B)
   
2. Catheter ablation of the AV node should not be attempted without a prior trial of medication to control the ventricular rate in patients with AF. (Level of Evidence: C)
   
3. In patients with decompensated HF and AF, intravenous administration of a nondihydropyridine calcium channel antagonist may exacerbate hemodynamic compromise and is not recommended. (Level of Evidence: C)
   
4. Intravenous administration of digitalis glycosides or nondihydropyridine calcium channel antagonists to patients with AF and a preexcitation syndrome may paradoxically accelerate the ventricular response and is not recommended. (Level of Evidence: C)
   

2. Preventing thromboembolism
(For recommendations regarding antithrombotic therapy in patients with AF undergoing cardioversion, see Section I.C.3.d.)

Class I

1. Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except those with lone AF or contraindications. (Level of Evidence: A)
   
2. The selection of the antithrombotic agent should be based upon the absolute risks of stroke and bleeding and the relative risk and benefit for a given patient. (Level of Evidence: A)
   
3. For patients without mechanical heart valves at high risk of stroke, chronic oral anticoagulant therapy with a vitamin K antagonist is recommended in a dose adjusted to achieve the target intensity international normalized ratio (INR) of 2.0 to 3.0, unless contraindicated. Factors associated with highest risk for stroke in patients with AF are prior thromboembolism (stroke, transient ischemic attack [TIA], or systemic embolism) and rheumatic mitral stenosis. (Level of Evidence: A)
   
4. Anticoagulation with a vitamin K antagonist is recommended for patients with more than 1 moderate risk factor. Such factors include age 75 y or greater, hypertension, HF, impaired LV systolic function (ejection fraction 35% or less or fractional shortening less than 25%), and diabetes mellitus. (Level of Evidence: A)
   
5. INR should be determined at least weekly during initiation of therapy and monthly when anticoagulation is stable. (Level of Evidence: A)
   
6. Aspirin, 81–325 mg daily, is recommended as an alternative to vitamin K antagonists in low-risk patients or in those with contraindications to oral anticoagulation. (Level of Evidence: A)
   
7. For patients with AF who have mechanical heart valves, the target intensity of anticoagulation should be based on the type of prosthesis, maintaining an INR of at least 2.5. (Level of Evidence: B)
   
8. Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF. (Level of Evidence: C)
   

Class IIa

1. For primary prevention of thromboembolism in patients with nonvalvular AF who have just 1 of the following validated risk factors, antithrombotic therapy with either aspirin or a vitamin K antagonist is reasonable, based upon an assessment of the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences: age greater than or equal to 75 y (especially in female patients), hypertension, HF, impaired LV function, or diabetes mellitus. (Level of Evidence: A)
   
2. For patients with nonvalvular AF who have 1 or more of the following less well-validated risk factors, antithrombotic therapy with either aspirin or a vitamin K antagonist is reasonable for prevention of thromboembolism: age 65 to 74 y, female gender, or CAD. The choice of agent should be based upon the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences. (Level of Evidence: B)
   
3. It is reasonable to select antithrombotic therapy using the same criteria irrespective of the pattern (i.e., paroxysmal, persistent, or permanent) of AF. (Level of Evidence: B)
   
4. In patients with AF who do not have mechanical prosthetic heart valves, it is reasonable to interrupt anticoagulation for up to 1 wk without substituting heparin for surgical or diagnostic procedures that carry a risk of bleeding. (Level of Evidence: C)
   
5. It is reasonable to reevaluate the need for anticoagulation at regular intervals. (Level of Evidence: C)
   

Class IIb

1. In patients 75 y of age and older at increased risk of bleeding but without frank contraindications to oral anticoagulant therapy, and in other patients with moderate risk factors for thromboembolism who are unable to safely tolerate anticoagulation at the standard intensity of INR 2.0 to 3.0, a lower INR target of 2.0 (range 1.6 to 2.5) may be considered for primary prevention of ischemic stroke and systemic embolism. (Level of Evidence: C)
   
2. When surgical procedures require interruption of oral anticoagulant therapy for longer than 1 wk 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. (Level of Evidence: C)
   
3. Following percutaneous coronary intervention or revascularization surgery in patients with AF, low-dose aspirin (less than 100 mg per d) and/or clopidogrel (75 mg per d) 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 of bleeding. (Level of Evidence: C)
   
4. In patients undergoing percutaneous coronary intervention, anticoagulation may be interrupted to 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 mo after implantation of a bare metal stent, at least 3 mo for a sirolimus-eluting stent, at least 6 mo for a paclitaxel-eluting stent, and 12 mo 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. (Level of Evidence: C)
   
5. In patients with AF younger than 60 y without heart disease or risk factors for thromboembolism (lone AF), the risk of thromboembolism is low without treatment and the effectiveness of aspirin for primary prevention of stroke relative to the risk of bleeding has not been established. (Level of Evidence: C)
   
6. In patients with AF who sustain ischemic stroke or systemic embolism during treatment with 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. (Level of Evidence: C)
   

Class III

Long-term anticoagulation with a vitamin K antagonist is not recommended for primary prevention of stroke in patients below the age of 60 y without heart disease (lone AF) or any risk factors for thromboembolism. (Level of Evidence: C)

3. Cardioversion of atrial fibrillation
a. Pharmacological cardioversion
Class I

Administration of flecainide, dofetilide, propafenone, or ibutilide is recommended for pharmacological cardioversion of AF. (Level of Evidence: A)

Class IIa

1. Administration of amiodarone is a reasonable option for pharmacological cardioversion of AF. (Level of Evidence: A)
   
2. A single oral bolus dose of propafenone or flecainide (‘pill-in-the-pocket’) can be administered to terminate persistent AF outside the hospital once treatment has proved safe in hospital for selected patients without sinus or AV node dysfunction, bundle-branch block, QT-interval prolongation, the 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 atrial flutter occurs. (Level of Evidence: C)
   
3. Administration of amiodarone can be beneficial on an outpatient basis in patients with paroxysmal or persistent AF when rapid restoration of sinus rhythm is not deemed necessary. (Level of Evidence: C)
   

Class IIb

Administration of quinidine or procainamide might be considered for pharmacological cardioversion of AF, but the usefulness of these agents is not well established. (Level of Evidence: C)

Class III

1. Digoxin and sotalol may be harmful when used for pharmacological cardioversion of AF and are not recommended. (Level of Evidence: A)
   
2. Quinidine, procainamide, disopyramide, and dofetilide should not be started out of hospital for conversion of AF to sinus rhythm. (Level of Evidence: B)
   

b. Direct-current cardioversion
Class I

1. When a rapid ventricular response does not respond promptly to pharmacological measures for patients with AF with ongoing myocardial ischemia, symptomatic hypotension, angina, or HF, immediate R-wave synchronized direct-current cardioversion is recommended. (Level of Evidence: C)
   
2. Immediate direct-current cardioversion is recommended for patients with AF involving preexcitation when very rapid tachycardia or hemodynamic instability occurs. (Level of Evidence: B)
   
3. Cardioversion is recommended in patients without hemodynamic instability when symptoms of AF are unacceptable to the patient. In case of early relapse of AF after cardioversion, repeated direct-current cardioversion attempts may be made following administration of antiarrhythmic medication. (Level of Evidence: C)
   

Class IIa

1. Direct-current cardioversion can be useful to restore sinus rhythm as part of a long-term management strategy for patients with AF. (Level of Evidence: B)
   
2. Patient preference is a reasonable consideration in the selection of infrequently repeated cardioversions for the management of symptomatic or recurrent AF. (Level of Evidence: C)
   

Class III

1. Frequent repetition of direct-current cardioversion is not recommended for patients who have relatively short periods of sinus rhythm between relapses of AF after multiple cardioversion procedures despite prophylactic antiarrhythmic drug therapy. (Level of Evidence: C)
   
2. Electrical cardioversion is contraindicated in patients with digitalis toxicity or hypokalemia. (Level of Evidence: C)
   

c. Pharmacological enhancement of direct-current cardioversion
Class IIa

1. Pretreatment with amiodarone, flecainide, ibutilide, propafenone, or sotalol can be useful to enhance the success of direct-current cardioversion and prevent recurrent AF. (Level of Evidence: B)
   
2. In patients who relapse to AF after successful cardioversion, it can be useful to repeat the procedure following prophylactic administration of antiarrhythmic medication. (Level of Evidence: C)
   

Class IIb

1. For patients with persistent AF, administration of beta blockers, disopyramide, diltiazem, dofetilide, procainamide, or verapamil may be considered, although the efficacy of these agents to enhance the success of direct-current cardioversion or to prevent early recurrence of AF is uncertain. (Level of Evidence: C)
   
2. Out-of-hospital initiation of antiarrhythmic medications may be considered in patients without heart disease to enhance the success of cardioversion of AF. (Level of Evidence: C)
   
3. Out-of-hospital administration of antiarrhythmic medications may be considered to enhance the success of cardioversion of AF in patients with certain forms of heart disease once the safety of the drug has been verified for the patient. (Level of Evidence: C)
   

d. Prevention of thromboembolism in patients with atrial fibrillation undergoing cardioversion
Class I

1. For patients with AF of 48-h duration or longer, or when the duration of AF is unknown, anticoagulation (INR 2.0 to 3.0) is recommended for at least 3 wk prior to and 4 wk after cardioversion, regardless of the method (electrical or pharmacological) used to restore sinus rhythm. (Level of Evidence: B)
   
2. For patients with AF of more than 48-h duration requiring immediate cardioversion because of hemodynamic instability, heparin should be administered concurrently (unless contraindicated) by 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 2.0 to 3.0) should be provided for at least 4 wk, as for patients undergoing elective cardioversion. Limited data support subcutaneous administration of low-molecular-weight heparin in this indication. (Level of Evidence: C)
   
3. For patients with AF of less than 48-h duration associated with hemodynamic instability (angina pectoris, myocardial infarction [MI], shock, or pulmonary edema), cardioversion should be performed immediately without delay for prior initiation of anticoagulation. (Level of Evidence: C)
   

Class IIa

(1) During the 48 h after onset of AF, the need for anticoagulation before and after cardioversion may be based on the patient's risk of thromboembolism. (Level of Evidence: C)

(2) As an alternative to anticoagulation prior to cardioversion of AF, it is reasonable to perform transesophageal echocardiography (TEE) in search of thrombus in the left atrium (LA) or left atrial appendage (LAA). (Level of Evidence: B)

(2a) For patients with no identifiable thrombus, cardioversion is reasonable immediately after 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 equal to or greater than 2.0). (Level of Evidence: B) Thereafter, continuation of oral anticoagulation (INR 2.0 to 3.0) is reasonable for a total anticoagulation period of at least 4 wk, as for patients undergoing elective cardioversion. (Level of Evidence: B) Limited data are available to support the subcutaneous administration of a low-molecular-weight heparin in this indication. (Level of Evidence: C)

(2b) For patients in whom thrombus is identified by TEE, oral anticoagulation (INR 2.0 to 3.0) is reasonable for at least 3 wk prior to and 4 wk after restoration of sinus rhythm, and a longer period of anticoagulation may be appropriate even after apparently successful cardioversion, because the risk of thromboembolism often remains elevated in such cases. (Level of Evidence: C)

(3) For patients with atrial flutter undergoing cardioversion, anticoagulation can be beneficial according to the recommendations as for patients with AF. (Level of Evidence: C)

4. Maintenance of sinus rhythm
Class I

Before initiating antiarrhythmic drug therapy, treatment of precipitating or reversible causes of AF is recommended. (Level of Evidence: C)

Class IIa

1. Pharmacological therapy can be useful in patients with AF to maintain sinus rhythm and prevent tachycardia-induced cardiomyopathy. (Level of Evidence: C)
   
2. Infrequent, well-tolerated recurrence of AF is reasonable as a successful outcome of antiarrhythmic drug therapy. (Level of Evidence: C)
   
3. Outpatient initiation of antiarrhythmic drug therapy is reasonable in patients with AF who have no associated heart disease when the agent is well tolerated. (Level of Evidence: C)
   
4. In patients with lone AF without structural heart disease, initiation of propafenone or flecainide can be beneficial on an outpatient basis in patients with paroxysmal AF who are in sinus rhythm at the time of drug initiation. (Level of Evidence: B)
   
5. Sotalol can be beneficial in outpatients in sinus rhythm with little or no heart disease, prone to paroxysmal AF, if the baseline uncorrected QT interval is less than 460 ms, serum electrolytes are normal, and risk factors associated with class III drug-related proarrhythmia are not present. (Level of Evidence: C)
   
6. Catheter ablation is a reasonable alternative to pharmacological therapy to prevent recurrent AF in symptomatic patients with little or no LA enlargement. (Level of Evidence: C)
   

Class III

1. Antiarrhythmic therapy with a particular drug is not recommended for maintenance of sinus rhythm in patients with AF who have well-defined risk factors for proarrhythmia with that agent. (Level of Evidence: A)
   
2. Pharmacological therapy is not recommended for maintenance of sinus rhythm in patients with advanced sinus node disease or atrioventricular (AV) node dysfunction unless they have a functioning electronic cardiac pacemaker. (Level of Evidence: C)
   

5. Special considerations
a. Postoperative atrial fibrillation
Class I

1. Unless contraindicated, treatment with an oral beta blocker to prevent postoperative AF is recommended for patients undergoing cardiac surgery. (Level of Evidence: A)
   
2. Administration of AV nodal blocking agents is recommended to achieve rate control in patients who develop postoperative AF. (Level of Evidence: B)
   

Class IIa

1. Preoperative administration of amiodarone reduces the incidence of AF in patients undergoing cardiac surgery and represents appropriate prophylactic therapy for patients at high risk for postoperative AF. (Level of Evidence: A)
   
2. It is reasonable to restore sinus rhythm by pharmacological cardioversion with ibutilide or direct-current cardioversion in patients who develop postoperative AF as advised for nonsurgical patients. (Level of Evidence: B)
   
3. It is reasonable to administer antiarrhythmic medications in an attempt to maintain sinus rhythm in patients with recurrent or refractory postoperative AF, as recommended for other patients who develop AF. (Level of Evidence: B)
   
4. It is reasonable to administer antithrombotic medication in patients who develop postoperative AF, as recommended for nonsurgical patients. (Level of Evidence: B)
   

Class IIb

Prophylactic administration of sotalol may be considered for patients at risk of developing AF following cardiac surgery. (Level of Evidence: B)

b. Acute myocardial infarction
Class I

1. Direct-current cardioversion is recommended for patients with severe hemodynamic compromise or intractable ischemia, or when adequate rate control cannot be achieved with pharmacological agents in patients with acute MI and AF. (Level of Evidence: C)
   
2. Intravenous administration of amiodarone is recommended to slow a rapid ventricular response to AF and improve LV function in patients with acute MI. (Level of Evidence: C)
   
3. Intravenous beta blockers and nondihydropyridine calcium antagonists are recommended to slow a rapid ventricular response to AF in patients with acute MI who do not display clinical LV dysfunction, bronchospasm, or AV block. (Level of Evidence: C)
   
4. For patients with AF and acute MI, administration of unfractionated heparin by 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. (Level of Evidence: C)
   

Class IIa

Intravenous administration of digitalis is reasonable to slow a rapid ventricular response and improve LV function in patients with acute MI and AF associated with severe LV dysfunction and HF. (Level of Evidence: C)

Class III

The administration of class IC antiarrhythmic drugs is not recommended in patients with AF in the setting of acute MI. (Level of Evidence: C)

c. Management of atrial fibrillation associated with the Wolff-Parkinson-White (WPW) preexcitation syndrome
Class I

1. Catheter ablation of the accessory pathway is recommended in symptomatic patients with AF who have WPW syndrome, particularly those with syncope due to rapid heart rate or those with a short bypass tract refractory period. (Level of Evidence: B)
   
2. Immediate direct-current cardioversion is recommended to prevent ventricular fibrillation in patients with a short anterograde bypass tract refractory period in whom AF occurs with a rapid ventricular response associated with hemodynamic instability. (Level of Evidence: B)
   
3. Intravenous procainamide or ibutilide is recommended to restore sinus rhythm in patients with WPW in whom AF occurs without hemodynamic instability in association with a wide QRS complex on the electrocardiogram (ECG) (greater than or equal to 120-ms duration) or with a rapid preexcited ventricular response. (Level of Evidence: C)
   

Class IIa

Intravenous flecainide or direct-current cardioversion is reasonable when very rapid ventricular rates occur in patients with AF involving conduction over an accessory pathway. (Level of Evidence: B)

Class IIb

It may be reasonable to administer intravenous quinidine, procainamide, disopyramide, ibutilide, or amiodarone to hemodynamically stable patients with AF involving conduction over an accessory pathway. (Level of Evidence: B)

Class III

Intravenous administration of digitalis glycosides or nondihydropyridine calcium channel antagonists is not recommended in patients with WPW syndrome who have preexcited ventricular activation during AF. (Level of Evidence: B)

d. Hyperthyroidism
Class I

1. Administration of a beta blocker is recommended to control the rate of ventricular response in patients with AF complicating thyrotoxicosis, unless contraindicated. (Level of Evidence: B)
   
2. In circumstances when a beta blocker cannot be used, administration of a nondihydropyridine calcium channel antagonist (diltiazem or verapamil) is recommended to control the ventricular rate in patients with AF and thyrotoxicosis. (Level of Evidence: B)
   
3. In patients with AF associated with thyrotoxicosis, oral anticoagulation (INR 2.0 to 3.0) is recommended to prevent thromboembolism, as recommended for AF patients with other risk factors for stroke. (Level of Evidence: C)
   
4. Once a euthyroid state is restored, recommendations for antithrombotic prophylaxis are the same as for patients without hyperthyroidism. (Level of Evidence: C)
   

e. Management of atrial fibrillation during pregnancy
Class I

1. Digoxin, a beta blocker, or a nondihydropyridine calcium channel antagonist is recommended to control the rate of ventricular response in pregnant patients with AF. (Level of Evidence: C)
   
2. Direct-current cardioversion is recommended in pregnant patients who become hemodynamically unstable due to AF. (Level of Evidence: C)
   
3. Protection against thromboembolism is recommended throughout pregnancy for all patients with AF (except those with lone AF and/or low thromboembolic risk). Therapy (anticoagulant or aspirin) should be chosen according to the stage of pregnancy. (Level of Evidence: C)
   

Class IIb

1. Administration of heparin may be considered during the first trimester and last month of pregnancy 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 h, adjusted to prolong the mid-interval (6 h after injection) activated partial thromboplastin time to 1.5 times control. (Level of Evidence: B)
   
2. Despite the limited data available, subcutaneous administration of low-molecular-weight heparin may be considered during the first trimester and last month of pregnancy for patients with AF and risk factors for thromboembolism. (Level of Evidence: C)
   
3. Administration of an oral anticoagulant may be considered during the second trimester for pregnant patients with AF at high thromboembolic risk. (Level of Evidence: C)
   
4. Administration of quinidine or procainamide may be considered to achieve pharmacological cardioversion in hemodynamically stable patients who develop AF during pregnancy. (Level of Evidence: C)
   

f. Management of atrial fibrillation in patients with hypertrophic cardiomyopathy (HCM)
Class I

Oral anticoagulation (INR 2.0 to 3.0) is recommended in patients with HCM who develop AF, as for other patients at high risk of thromboembolism. (Level of Evidence: B)

Class IIa

Antiarrhythmic medications can be useful to prevent recurrent AF in patients with HCM. Available data are insufficient to recommend one agent over another in this situation, but (a) disopyramide combined with a beta blocker or nondihydropyridine calcium channel antagonist or (b) amiodarone alone is generally preferred. (Level of Evidence: C)

g. Management of atrial fibrillation in patients with pulmonary disease
Class I

1. Correction of hypoxemia and acidosis is the recommended primary therapeutic measure for patients who develop AF during an acute pulmonary illness or exacerbation of chronic pulmonary disease. (Level of Evidence: C)
   
2. A nondihydropyridine calcium channel antagonist (diltiazem or verapamil) is recommended to control the ventricular rate in patients with obstructive pulmonary disease who develop AF. (Level of Evidence: C)
   
3. Direct-current cardioversion should be attempted in patients with pulmonary disease who become hemodynamically unstable as a consequence of AF. (Level of Evidence: C)
   

Class III

1. Theophylline and beta-adrenergic agonist agents are not recommended in patients with bronchospastic lung disease who develop AF. (Level of Evidence: C)
   
2. Beta blockers, sotalol, propafenone, and adenosine are not recommended in patients with obstructive lung disease who develop AF. (Level of Evidence: C)
   

	II. Definition

Top Preamble I. Introduction Recommendations II. Definition III. Classification IV. Epidemiology and... V. Pathophysiological... VI. Causes, associated... VII. Clinical evaluation VIII. Management IX. Proposed management... References

 
A. Atrial fibrillation
AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of mechanical function. On the ECG, rapid oscillations, or fibrillatory waves that vary in amplitude, shape, and timing, replace consistent P waves, and there is an irregular ventricular response that is rapid when conduction is intact.¹ The ventricular response depends on electrophysiological properties of the AV node and other conducting tissues, vagal and sympathetic tone, the presence or absence of accessory pathways, and the action of drugs.² When AV block or ventricular or AV junctional tachycardia is present, the cardiac cycles (R-R intervals) may be regular. In patients with pacemakers, diagnosis of AF may require pacemaker inhibition to expose fibrillatory activity. An irregular, sustained, wide-QRS-complex tachycardia suggests AF with conduction over an accessory pathway or AF with bundle-branch block. Atrial flutter is usually readily distinguished from AF. Extremely rapid rates (greater than 200 beats per minute) suggest an accessory pathway or ventricular tachycardia.

B. Related arrhythmias
AF may occur in association with atrial flutter or atrial tachycardia. The typical form of atrial flutter is characterized by a saw-tooth pattern of regular atrial activation called flutter (f) waves on the ECG, particularly visible in leads II, III, aVF, and V₁. If untreated, the atrial rate typically ranges from 240 to 320 beats per minute, with f waves inverted in ECG leads II, III, and aVF and upright in lead V₁. The direction of activation in the right atrium (RA) may be reversed, resulting in upright f waves in leads II, III, and aVF and inversion in lead V₁. Atrial flutter may degenerate into AF, and AF may convert to atrial flutter. Atrial flutter is usually readily distinguished from AF, but misdiagnosis may occur when fibrillatory atrial activity is prominent in more than 1 ECG lead.³

Focal atrial tachycardias, AV reentrant tachycardias, and AV nodal reentrant tachycardias may also trigger AF. In these tachycardias, distinct P waves are typically separated by an isoelectric baseline, and their morphology may localize the origin of the arrhythmia.

	III. Classification

Top Preamble I. Introduction Recommendations II. Definition III. Classification IV. Epidemiology and... V. Pathophysiological... VI. Causes, associated... VII. Clinical evaluation VIII. Management IX. Proposed management... References

 
Various classification systems have been proposed for AF based on the ECG pattern,¹ epicardial⁴ or endocavitary recordings, mapping of atrial electrical activity, or clinical features. Although the pattern of AF can change over time, it may be helpful to characterize the arrhythmia at a given moment. The classification scheme recommended here represents a consensus driven by a desire for simplicity and clinical relevance.

The clinician should distinguish a first-detected episode of AF, whether or not symptomatic or self-limited, recognizing the uncertainty about the actual duration of the episode and about previous undetected episodes (Figure 1). After 2 or more episodes, AF is considered recurrent. If the arrhythmia terminates spontaneously, recurrent AF is designated paroxysmal; when sustained beyond 7 d, it is termed persistent. Termination with pharmacological therapy or direct-current cardioversion does not alter the designation. First-detected AF may be either paroxysmal or persistent. The category of persistent AF also includes cases of long-standing AF (e.g., longer than 1 y), usually leading to permanent AF, in which cardioversion has failed or has been foregone.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Patterns of atrial fibrillation (AF). 1, Episodes that generally last 7 d or less (most less than 24 h); 2, episodes that usually last more than 7 d; 3, cardioversion failed or not attempted; and 4, both paroxysmal and persistent AF may be recurrent.

 
These categories are not mutually exclusive, and a particular patient may have several episodes of paroxysmal AF and occasional persistent AF, or the reverse, but it is practical to categorize a given patient by his or her most frequent presentation. The definition of permanent AF is often arbitrary, and the duration refers both to individual episodes and to how long the diagnosis has been present in a given patient. Thus, in a patient with paroxysmal AF, episodes lasting seconds to hours may occur repeatedly for years.

This terminology applies to episodes lasting longer than 30 s without a reversible cause. Secondary AF in the setting of acute MI, cardiac surgery, pericarditis, myocarditis, hyperthyroidism, or acute pulmonary disease is considered separately. In these situations, AF is not the primary problem, and concurrent treatment of the underlying disorder usually terminates the arrhythmia. Conversely, when AF occurs in the course of a concurrent disorder like well-controlled hypothyroidism, the general principles for management of the arrhythmia apply.

The term lone AF applies to individuals younger than 60 y without clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension.⁵ These patients have a favorable prognosis with respect to thromboembolism and mortality. Over time, patients move out of the lone AF category due to aging or development of cardiac abnormalities such as enlargement of the LA, and the risks of thromboembolism and mortality rise. The term nonvalvular AF refers to cases without rheumatic mitral valve disease, prosthetic heart valve, or valve repair.

	IV. Epidemiology and prognosis

Top Preamble I. Introduction Recommendations II. Definition III. Classification IV. Epidemiology and... V. Pathophysiological... VI. Causes, associated... VII. Clinical evaluation VIII. Management IX. Proposed management... References

 
AF is the most common arrhythmia in clinical practice, accounting for approximately one third of hospitalizations for cardiac rhythm disturbances. An estimated 2.3 million people in North America and 4.5 million people in the European Union have paroxysmal or persistent AF.⁹ During the past 20 y, hospital admissions for AF have increased by 66%⁷ due to the aging of the population, a rising prevalence of chronic heart disease, more frequent diagnosis through use of ambulatory monitoring devices, and other factors. AF is an extremely expensive public health problem (approximately 3000 [approximately U.S. $3600] annually per patient)⁸; the total cost burden approaches 13.5 billion (approximately U.S. $15.7 billion) in the European Union.

A. Prevalence
The estimated prevalence of AF is 0.4% to 1% in the general population,⁹ increasing with age to 8% in those older than 80 y.¹⁰ Among men, the age-adjusted prevalence has more than doubled over a generation,¹⁰ while the prevalence in women has remained constant.¹¹ The median age of patients with AF is about 75 y. The number of men and women with AF is about equal, but approximately 60% of those over 75 y old are female. Based on limited data, the age-adjusted risk of developing AF in blacks seems less than half that in whites.

In population-based studies, patients with no history of cardiopulmonary disease account for fewer than 12% of all cases of AF.¹⁰ In case series, however, the observed proportion of lone AF was sometimes greater than 30%.¹²

B. Incidence
In prospective studies, the incidence of AF increases from less than 0.1% per year in people younger than 40 y to over 1.5% per year among women and 2% among men older than 80 y.¹³ In patients treated for HF, the 3-y incidence of AF was almost 10%.¹⁴ Angiotensin inhibition may be associated with a reduced incidence of AF in patients with HF¹⁵ and hypertension.¹⁶

C. Prognosis
AF is associated with an increased long-term risk of stroke,¹⁷ HF, and all-cause mortality, especially among women.¹⁸ The mortality rate of patients with AF is about double that of patients in normal sinus rhythm and is linked to the severity of underlying heart disease.¹⁹ In the Etude en Activité Libérale sur la Fibrillation Auriculaire Study (ALFA), about two thirds of the 5% annualized mortality was attributed to cardiovascular causes.¹² In large HF trials (COMET [Carvedilol Or Metoprolol European Trial], Val-HeFT [Valsartan Heart Failure Trial]), AF was a strong independent risk factor for mortality and morbidity.^20,21 HF promotes AF, AF aggravates HF, and individuals with either condition who develop the alternate condition share a poor prognosis.²² Thus, managing patients with the associated conditions is a major challenge, and randomized trials are needed to investigate the impact of AF on prognosis in HF.

The rate of ischemic stroke among patients with nonvalvular AF averages 5% per year, 2 to 7 times that of people without AF.²³ One of every 6 strokes occurs in a patient with AF, and when TIAs and clinically ‘silent’ strokes detected by brain imaging are considered, the rate of brain ischemia accompanying nonvalvular AF exceeds 7% per year.²⁴ In patients with rheumatic heart disease and AF in the Framingham Heart Study, stroke risk was increased 17-fold compared with age-matched controls,²⁵ and attributable risk was 5 times greater than in those with nonrheumatic AF.²³ The risk of stroke increased with age; the annual risk of stroke attributable to AF was 1.5% in participants aged 50 to 59 y and 23.5% in those aged 80 to 89 y.²³

	V. Pathophysiological mechanisms

Top Preamble I. Introduction Recommendations II. Definition III. Classification IV. Epidemiology and... V. Pathophysiological... VI. Causes, associated... VII. Clinical evaluation VIII. Management IX. Proposed management... References

 
A. Atrial factors
1. Atrial pathology as a cause of atrial fibrillation
The most frequent histopathological changes in AF are atrial fibrosis and loss of atrial muscle mass, but it is difficult to distinguish changes due to AF from those due to associated heart disease. Atrial fibrosis may precede the onset of AF,²⁶ and juxtaposition of patchy fibrosis with normal atrial fibers may account for nonhomogeneity of conduction.²⁷ Interstitial fibrosis may result from apoptosis leading to replacement of atrial myocytes,²⁸ loss of myofibrils, accumulation of glycogen granules, disruption of cell coupling at gap junctions,²⁹ and organelle aggregates³⁰ and may be triggered by atrial dilation in any type of heart disease associated with AF.

Patients with valvular heart disease who have mild fibrosis respond more successfully to cardioversion than those with severe fibrosis, and fibrosis is thought to contribute to persistent AF.³¹ The concentration of membrane-bound glycoproteins that regulate cell–cell and cell–matrix interactions (disintegrin and metalloproteinases) in human atrial myocardium has been reported to double during AF, and these changes may contribute to atrial dilation in patients with longstanding AF. Dilation of the atria activates several molecular pathways, including the renin-angiotensin-aldosterone system (RAAS). Angiotensin II is upregulated in response to stretch,³² and atrial tissue from patients with persistent AF demonstrates increased expression of angiotensin-converting enzyme (ACE).³³ Angiotensin inhibition may prevent AF by reducing fibrosis.³⁴ Atrial dilation and interstitial fibrosis in HF facilitate sustained AF.³⁵ The regional electrical silence (suggesting scar), voltage reduction, and conduction slowing described in patients with HF are similar to changes in the atria that occur as a consequence of aging.³⁶

2. Mechanisms of atrial fibrillation
Available data support a ‘focal’ triggering mechanism involving automaticity or multiple reentrant wavelets, but these mechanisms are not mutually exclusive and may coexist (Figure 2).

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 Posterior view of principal electrophysiological mechanisms of atrial fibrillation. (A) Focal activation. The initiating focus (indicated by the star) often lies within the region of the pulmonary veins. The resulting wavelets represent fibrillatory conduction, as in multiple-wavelet reentry. (B) Multiple-wavelet reentry. Wavelets (indicated by arrows) randomly re-enter tissue previously activated by the same or another wavelet. The routes the wavelets travel vary. Reproduced with permission from Konings KT, Kirchhof CJ, Smeets JR, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665–1680.45 LA indicates left atrium; PV, pulmonary vein; ICV, inferior vena cava; SCV, superior vena cava; and RA, right atrium.

 
The important observation that a focal source for AF could be identified and ablation of this source could extinguish AF³⁷ supported a focal origin. While pulmonary veins (PVs) are the most frequent source of these rapidly atrial impulses, foci have also been found in the superior vena cava, ligament of Marshall, left posterior free wall, crista terminalis, and coronary sinus.^37–40 In histological studies, cardiac muscle with preserved electrical properties extends into the PVs,⁴¹ and the primacy of PVs as triggers of AF has prompted substantial research into the anatomical and electrophysiological properties of these structures. Atrial tissue in the PVs of patients with AF has shorter refractory periods than in control patients or other parts of the atria in patients with AF.^42,43 This heterogeneity of conduction may promote reentry and form a substrate for sustained AF.⁴⁴

The multiple-wavelet hypothesis as the mechanism of reentrant AF⁴⁶ involves fractionation of wave fronts propagating through the atria and self-perpetuating ‘daughter wavelets.’ In this model, the number of wavelets at any time depends on the refractory period, mass, and conduction velocity in different parts of the atria. A large atrial mass with a short refractory period and delayed conduction increases the number of wavelets, favoring sustained AF. Simultaneous recordings from multiple electrodes supported the multiple-wavelet hypothesis in human subjects.⁴⁷ Although the multiple-wavelet hypothesis was for years the dominant theory explaining the mechanism of AF, data from experimental^47a and clinical^47b,47c mapping studies challenge this notion. In patients with idiopathic paroxysmal AF, widespread distribution of abnormal electrograms in the RA predicts development of persistent AF,⁴⁸ suggesting the importance of an abnormal substrate in the maintenance of AF. Furthermore, in patients with persistent AF undergoing conversion to sinus rhythm, intra-atrial conduction is prolonged compared with a control group, especially among those who develop recurrent AF.⁴⁹ Among patients with HF, prolongation of the P wave on signal-averaged ECG analysis was more frequent in those prone to paroxysmal AF.⁵⁰ Because many of these observations were made prior to onset of clinical AF, the findings cannot be ascribed to atrial remodeling that occurs as a consequence of AF, and the degree to which changes in the atrial architecture contribute to the initiation and maintenance of AF is not known.

3. Atrial electrical remodeling
Pharmacological or direct-current cardioversion of AF has a higher success rate when AF has been present for less than 24 h,⁵¹ whereas more prolonged AF makes restoring and maintaining sinus rhythm less likely. These observations gave rise to the adage ‘atrial fibrillation begets atrial fibrillation.’ The notion that AF is self-perpetuating takes experimental support from a goat model using an automatic atrial fibrillator that detected spontaneous termination of AF and reinduced the arrhythmia by electrical stimulation.⁵² Initially, electrically induced AF terminated spontaneously. After repeated inductions, however, the episodes became progressively more sustained until AF persisted at a more rapid atrial rate.⁵² The increasing propensity to AF was related to progressive shortening of effective refractory periods with increasing episode duration, a phenomenon known as electrophysiological remodeling.

In addition to remodeling and changes in electrical refractoriness, prolonged AF disturbs atrial contractile function. After a period of persistent AF, recovery of atrial contraction can be delayed for days or weeks following the restoration of sinus rhythm, and this has important implications for the duration of anticoagulation after cardioversion. (See Section VIII.B.2, Preventing thromboembolism.)

4. Other factors contributing to atrial fibrillation
Data are accumulating on the importance of the RAAS in the genesis of AF.⁵³ Irbesartan plus amiodarone was associated with a lower incidence of recurrent AF after cardioversion than amiodarone alone,¹⁵ and treatment with angiotensin inhibitors and diuretics reduced the incidence of AF after catheter ablation of atrial flutter.⁵⁴ Inhibition of the RAAS, alone or in combination with other therapies, may prevent the onset or maintenance of AF through several mechanisms,⁵⁵ including lower atrial pressure and wall stress, prevention of structural remodeling (fibrosis, dilation, and hypertrophy) in both the LA and left ventricle (LV), inhibition of neurohumoral activation, reducing blood pressure, prevention or amelioration of HF, and avoidance of hypokalemia. Treatment with trandolapril reduced the incidence of AF in patients with LV dysfunction following acute MI,⁵⁶ but it remains to be clarified whether this effect is related to reversal of structural or electrical remodeling in the atria or to another mechanism.

Other factors potentially involved in the induction or maintenance of AF are outlined in Table 2. Among these is inflammation, and ongoing studies are exploring the use of statin-type lipid-lowering drugs with this mechanism in mind.

View this table: [in this window] [in a new window]   Table 2 Etiologies and factors predisposing patients to AF

 
B. Atrioventricular conduction
1. General aspects
In the absence of an accessory pathway or His-Purkinje dysfunction, the AV node limits conduction during AF.⁵⁷ Of the multiple atrial inputs to the AV node that have been identified, 2 seem dominant: one directed posteriorly via the crista terminalis and the other aimed anteriorly via the interatrial septum. Other factors affecting AV conduction are the intrinsic refractoriness of the AV node, concealed conduction, and autonomic tone. Concealed conduction plays a prominent role in determining the ventricular response during AF⁵⁸ by altering the refractoriness of the AV node and slowing or blocking atrial impulses and may explain the irregularity of ventricular response during AF.⁵⁹ When the atrial rate is relatively slow during AF, the ventricular rate tends to rise and, conversely, higher atrial rate is associated with slower ventricular rate.

Increased parasympathetic and reduced sympathetic tone exert negative dromotropic effects on AV nodal conduction, while the opposite is true in states of decreased parasympathetic and increased sympathetic tone.⁵⁸ Vagal tone also enhances the negative chronotropic effects of concealed conduction in the AV node.⁶⁰ Fluctuations in autonomic tone can produce disparate ventricular responses to AF, exemplified by a slow ventricular rate during sleep but accelerated ventricular response during exercise. Digitalis, which slows the ventricular rate during AF predominantly by increasing vagal tone, is more effective for controlling heart rate at rest in AF but less effective during activity.

2. Atrioventricular conduction in preexcitation syndromes
Conduction across an accessory pathway during AF can result in dangerously rapid ventricular rates.² Transition of AV reentry into AF in patients with the WPW syndrome can produce a rapid ventricular response that degenerates into lethal ventricular fibrillation.⁶¹ Drugs that lengthen refractoriness and slow conduction across the AV node (such as digitalis, verapamil, or diltiazem) do not block conduction over the accessory pathway and may accelerate the ventricular rate. Hence, these agents are contraindicated in this situation.⁶² Although the potential for beta blockers to potentiate conduction across the accessory pat