Atrial Fibrillation

Key Points

• AF is a common form of supraventricular tachyarrhythmia characterized on ECG by low-amplitude baseline oscillations (fibrillatory or f waves from the fibrillating atria) and an irregularly irregular ventricular rhythm. Often associated with hypertension, valvular heart disease, heart failure, or obstructive sleep apnea ^r1
• Some patients are asymptomatic or note only a vague sense of fatigue or decreased exercise tolerance. Others note palpitations, light-headedness, and dyspnea at rest or on exertion. Less commonly, a patient may come to medical attention with a complication of AF (eg, acute embolic stroke, tachycardia-mediated ventricular dysfunction) ^r1
• AF is episodic in nature in many patients and is termed paroxysmal when episodes terminate within 7 days of onset, persistent when episodes are continuous for more than 7 days, and long-standing persistent when episodes have been continuous for longer than 12 months ^r2
• Diagnosis is suspected based on history and compatible findings on physical examination (irregularly irregular pulse, usually with tachycardia) and is confirmed with ECG ^r2
• Management of AF is organized around 2 goals
  • Anticoagulation for stroke prevention in those at increased risk
  • Symptom management (rate or rhythm control) ^r3
• Anticoagulation recommendations vary based on stroke risk
  • For patients with nonvalvular AF, use the CHA₂DS₂-VASc score to determine stroke risk. Males with a score of 2 or higher and females with a score of 3 or higher are at elevated risk and should receive anticoagulation therapy, usually with a direct oral anticoagulant ^r4
  • Patients with valvular AF, regardless of CHA₂DS₂-VASc score, are considered high risk and should be given warfarin for anticoagulation ^r4
  • In the acute setting, when contemplating cardioversion, also consider duration of AF in determining stroke risk and need for anticoagulation. When the duration of AF is clearly no longer than 48 hours, stroke risk is presumed to be lower, and anticoagulation before cardioversion is often omitted ^r5r6
• Symptoms management is via either a rate control or rhythm control strategy; depending on individual patient factors, either strategy is reasonable and the chosen strategy may change over time ^r4r7
  • Initial emphasis should be on maintaining sinus rhythm and minimizing AF burden, meaning most patients with AF should undergo at least 1 attempt to achieve rhythm control
  • Patients with symptoms that are well controlled with rate control alone and with limited life expectancy or advanced age may opt to not receive rhythm control therapy
  • Rate control modalities include atrioventricular-nodal blocking drugs (β-blockers or nondihydropyridine calcium channel blockers for most patients) and atrioventricular-node ablation with implantation of a permanent pacemaker ^r4r8r9
  • Reversion to sinus rhythm may be achieved with electrical or pharmacologic cardioversion and maintained with antiarrhythmic drugs; alternatively, catheter or surgical ablation is an option for selected patients ^r1r4
• Complications of AF include embolic stroke, tachycardia-mediated ventricular dysfunction and heart failure, and increased risk for cognitive decline and dementia. Patients with AF have increased mortality risk
• AF tends to progress from paroxysmal to persistent over time and may eventually become irreversible. In general, outcomes for specific therapies are better for patients with paroxysmal AF than for those with persistent AF

Urgent Action

• Patients with hemodynamic compromise that occurs secondary to AF require urgent electrocardioversion ^r10
  • Use procedural sedation whenever possible ^r11
  • Place external electrode pads in an anteroposterior position across the chest wall (superior to anterolateral placement in some but not all studies) ^r2
  • Deliver a shock with 150 to 200 J on a biphasic machine or 200 to 300 J on a monophasic machine. May need to select lower energy for small patients or higher energy for large patients ^r11
  • With AF that has lasted more than 48 hours or of unknown duration, start anticoagulation as soon as possible and continue for at least 4 weeks ^r10

Pitfalls

• Anticoagulation reduces ischemic stroke risk by approximately 60%^r12 and must be considered based on CHA₂DS₂-VASc score, irrespective of whether the AF pattern is paroxysmal, persistent, or permanent ^r2
• In addition to stroke risk, consider bleeding risk before beginning anticoagulation, as this may, in some cases, temper the decision to start anticoagulation therapy
• Hemodynamic instability is uncommonly a direct result of AF and mandates a rapid search for underlying reversible conditions (eg, sepsis, gastrointestinal bleeding) that are contributing to the instability
• Electrocardioversion of AF and subsequent maintenance of sinus rhythm are more likely to be successful when AF duration is less than 6 months^r13. Pharmacologic cardioversion is most likely to be effective when initiated within 7 days of onset of an episode ^r2r13
• Consider presence or absence of structural heart disease, coronary artery disease, and potential to prolong the QT interval when choosing the specific maintenance antiarrhythmic drug. Consultation with a cardiologist is recommended

Clinical Clarification

• AF (atrial fibrillation) is a common form of supraventricular tachyarrhythmia (1 in 4 lifetime risk^r14) with rapid and disorganized atrial activation resulting in ineffective atrial contraction
• Characterized on ECG by low-amplitude baseline oscillations (fibrillatory or f waves from the fibrillating atria) and an irregularly irregular ventricular rhythm ^r1

Classification

• By stage
  • Paroxysmal ^r4
    • Terminates within 7 days of onset, spontaneously or with intervention
    • Accounts for 20% of AF diagnoses ^r15
  • Persistent ^r4
    • Continuous for more than 7 days
    • Often progresses from paroxysmal episodes to persistent episodes over a variable period
    • Both paroxysmal and persistent episodes may occur in the same patient
    • Accounts for 30% of AF diagnoses ^r15
  • Long-standing persistent ^r4
    • Continuous for more than 12 months
    • Accounts for 40% to 50% of AF diagnoses (percentages include those cases designated as permanent) ^r15
  • Permanent ^r4
    • Terminology used when the patient and clinician jointly decide to stop further attempts to restore and/or maintain sinus rhythm
      • Represents a therapeutic attitude as opposed to an inherent pathophysiologic attribute
      • This attitude may change as symptoms, efficacy of therapeutic interventions, and patient and clinician preferences evolve
  • Successfully ablated AF ^r4
    • Patient remains free of AF following percutaneous or surgical intervention to eliminate it
• By association with valvular heart disease
  • Classification of AF as ''valvular'' or "nonvalvular" is now considered obsolete. This distinction was intended to define eligibility for stroke prevention trials rather than etiological association with valvular heart disease. For these purposes the terms are defined as follows: ^r4
    • Valvular AF
      • AF in the setting of moderate to severe mitral stenosis or in the presence of a mechanical prosthetic heart valve ^r4r16
    • Nonvalvular AF
      • AF in the absence of moderate to severe mitral stenosis or a mechanical prosthetic heart valve ^r10
      • Does not imply the absence of other native valvular heart disease or bioprosthetic valve replacement ^r16
• Other descriptors
  • Subclinical AF ^r17
    • Term recently came into use based on widespread use of cardiac implantable electronic devices that detect asymptomatic AF in a substantial proportion of patients
  • Acute AF ^r18
    • American Heart Association recently introduced this term to describe AF detected in an acute care setting or during an acute illness; this new terminology is intended to replace the term secondary AF used in older literature

Clinical Presentation

Causes and Risk Factors

Diagnostic Procedures

Differential Diagnosis

Goals

• Stabilize the patient, which may require IV atrioventricular-nodal blocking agents or urgent cardioversion in some cases
• Identify and treat reversible causes
• Prevent embolic stroke with anticoagulation when indicated by risk stratification
• Relieve AF symptoms and improve quality of life ^r2
  • If rate-control management is elected, maintain heart rate that reduces symptoms, enables exercise, and prevents cardiovascular complications
  • If rhythm control strategy is elected, use pharmacologic or nonpharmacologic methods to restore and maintain sinus rhythm for improved quality of life

Disposition

Patients who have symptoms (ie, palpitations, chest pain, shortness of breath, diaphoresis, dizziness) require urgent evaluation in an emergency care setting ^r42

Patients who are hemodynamically unstable require urgent treatment in an emergency care setting, often with IV nodal blocking medication and, sometimes, urgent cardioversion

Patients who are hemodynamically stable with minimal or no symptoms may be managed as outpatients

Treatment Options

Treatment of AF is organized around 2 main issues:

• Anticoagulation to prevent embolic stroke if indicated based on risk stratification
• Symptom control with either a rate control or a rhythm control approach

Anticoagulation for stroke prevention

• Anticoagulation reduces ischemic stroke risk by approximately 60%^r12 and must be considered irrespective of whether the AF pattern is paroxysmal, persistent, or permanent ^r4
  • Decision to institute anticoagulation is based on risk stratification
  • For patients with nonvalvular AF, determine eligibility for anticoagulation using the CHA₂DS₂-VASc stroke clinical risk score
    • If CHA₂DS₂-VASc score is 2 or greater in males or 3 or greater in females, anticoagulation is recommended ^r4
    • If CHA₂DS₂-VASc score is 0 in males or 1 in females, it is reasonable to omit anticoagulant therapy ^r10
    • If CHA2DS2-VASc score is in intermediate range (1 in males and 2 in females), it is reasonable to consider anticoagulation based on individual risk-benefit shared decision-making ^r4
    • Reassess CHA₂DS₂-VASc score at least annually for patients with AF who were initially at low risk for stroke and prescribe anticoagulation once CHA₂DS₂‐VASc score increases ^r46

    • CHA₂DS₂-VASc stroke risk score.

      Add these points to determine the CHA₂DS₂-VASc stroke risk score, with score ranging from 0 through 9. Note that females cannot have a score of 0.

      Data from January CT et al: 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 74(1):104-32, 2019; January CT et al: 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 130(23):e199-267, 2014

      Component of CHA₂DS₂-VASc score	Points assigned
      Congestive heart failure	1
      Hypertension	1
      Age 75 years or older	2
      Diabetes mellitus	1
      Prior stroke (or transient ischemic attack)	2
      Vascular disease (eg, myocardial infarction, peripheral vascular disease)	1
      Age 65 to 74 years	1
      Sex category (female)	1

  • In addition to stroke risk, consider bleeding risk before initiating anticoagulation, as this may inform the decision to start anticoagulation therapy ^r47
    • Identify, and correct if modifiable, bleeding risk factors such as hypertension, severe kidney disease, severe liver disease, history of stroke, history of bleeding, presence of a labile INR, age older than 65 years, concomitant antiplatelet or NSAID therapy, and excessive alcohol intake ^r38r48
    • Review patients with nonmodifiable risk factors more frequently and consider management by multidisciplinary team ^r38
    • Use of specific bleeding risk scores is not recommended owing to uncertainty over accuracy and potential for under-use of anticoagulation ^r38
  • Oral anticoagulation is indicated for patients with hypertrophic cardiomyopathy or cardiac amyloidosis regardless of CHA₂DS₂-VASc stroke clinical risk score ^r38
• Pericardioversion anticoagulation is required when a rhythm control strategy (electrical or pharmacologic cardioversion) is planned for patient who is not already receiving anticoagulation therapy
  • With new-onset AF, precardioversion anticoagulation therapy is guided by both the duration of AF at presentation and the CHA₂DS₂-VASc score
    • With AF duration less than 48 hours
      • Patients with new-onset AF of less than 48 hours' duration are less likely to have embolic complications after cardioversion than those with longer duration of AF. However, recent large observational studies suggest that anticoagulation might improve outcomes for these patients and have led to controversy in management ^r5
        • Finnish CardioVersion, a series of 6 observational studies representing more than 10,000 patients with AF who underwent chemical or electrical cardioversion, found a non-negligible risk of embolic events among patients with AF duration of 12 to 48 hours versus duration of less than 12 hours (1.1% versus 0.33%) ^{r49r50r51r52r53r54}
        • Finnish CardioVersion studies also found that anticoagulation before cardioversion reduced the risk conferred by AF duration within the first 48 hours of onset
        • There is controversy regarding current recommendations for use of anticoagulation before and after cardioversion for patients presenting with AF duration of less than 48 hours
        • In cases of hemodynamic instability, when urgent cardioversion is indicated, cardioversion is often administered without anticoagulation ^r6
        • 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines recommend an aggressive anticoagulation strategy as follows: ^r43
          • For patients with AF duration less than 12 hours with no recent history of transient ischemic attack or stroke
            • Start anticoagulation therapy as soon as possible before cardioversion and continue for 4 weeks after cardioversion
          • For patients with AF duration of 12 to 48 hours with CHA₂DS₂-VASc of 0 to 1
            • Start anticoagulation therapy as soon as possible before cardioversion and continue for 4 weeks after cardioversion
          • For patients with AF duration of 12 to 48 hours with CHA₂DS₂-VASc of 2 or greater
            • Maintain anticoagulation therapy for 3 weeks or perform transesophageal echocardiography to exclude left atrial thrombus before cardioversion and continue anticoagulation after cardioversion
        • 2023 American College of Cardiology/American Heart Association guidelines recommend the following for patients with AF of less than 48-hour duration who are not receiving anticoagulation ^r4
          • Pericardioversion anticoagulation to achieve therapeutic level (before cardioversion and continued for at least 4 weeks following cardioversion) when the CHA₂DS₂-VASc score is 2 or higher for males or 3 or higher for females
          • Precardioversion imaging to exclude intracardiac thrombus in patients with CHA₂DS₂-VASc score of at least 2 in males or at least 3 in females (or equivalent) may be considered as an alternative
          • No recommendation is made regarding precardioversion imaging or pericardioversion anticoagulation for patients with low thromboembolic risks (CHA₂DS₂-VASc 0-1 or equivalent) and AF duration of less than 12 hours; benefit is uncertain given the incidence of pericardioversion thromboembolic events in this population is very low
    • With AF duration of 48 hours or longer (or of unknown duration)
      • Guidelines recommend anticoagulation for at least 3 weeks before and at least 4 weeks after cardioversion, regardless of the CHA₂DS₂-VASc score ^r4
      • For patients who have not been receiving anticoagulation therapy for the preceding 3 weeks but for whom earlier cardioversion is desired, precardioversion imaging to exclude intracardiac thrombus is an alternative to precardioversion anticoagulation ^r4
        • If no left atrial thrombus is identified, can initiate anticoagulation and proceed to cardioversion
        • If left atrial thrombus is identified, begin anticoagulation and postpone cardioversion for 3 to 6 weeks to allow for stabilization of the thrombus; repeat imaging before cardioversion
        • Maintain anticoagulation after cardioversion for at least 4 weeks
        • Randomized controlled trial (1222 patients) showed no difference between 3-week anticoagulation strategy and a transesophageal echocardiography–guided strategy in terms of embolic events or mortality ^r55
• Long-term anticoagulation is required for patients at elevated risk for embolic stroke
  • Patients with nonvalvular AF
    • Start anticoagulation therapy if CHA₂DS₂-VASc score is 2 or higher for males or 3 or higher for females ^r4
      • Direct oral anticoagulants are recommended (over warfarin) by most international guidelines ^r10r38r56r57
      • Direct oral anticoagulants have several advantages compared with vitamin K antagonists ^r58
        • Reduced risk of embolic stroke, hemorrhagic stroke, and major bleeding, even for older adults of advanced age^r60r59
        • More convenient; no requirement for routine laboratory monitoring
        • Fewer dietary and drug interactions ^r59
      • Apixaban, rivaroxaban, dabigatran, and edoxaban are approved for this indication. No prospective head-to-head clinical trial data are available
      • Based on observational data, apixaban may be safer and more effective than rivaroxaban for treating nonvalvular AF ^r61
        • Retrospective study compared patients with newly prescribed apixaban to patients with newly prescribed rivaroxaban (about 39,000 patients in each group)
        • Use of apixaban was associated with the following:
          • Lower rate of ischemic stroke/systemic embolism, corresponding to a hazard ratio of 0.82
          • Lower rate of gastrointestinal bleeding or intracranial hemorrhage, corresponding to a hazard ratio of 0.58
        • Higher rates of gastrointestinal bleeding have been observed among patients taking rivaroxaban (3.2/100 patient-years) compared with apixaban (2.5/100 patient years) and dabigatran (1.9/100 patient years) ^r62
      • For patients with end-stage renal disease or those undergoing dialysis, warfarin and apixaban are reasonable options for anticoagulation ^r57
  • Patients with valvular heart disease and AF
    • Recommendations for choice of anticoagulant differ based on whether the patient has rheumatic mitral stenosis or other forms of valvular heart disease
      • For patients with rheumatic mitral stenosis or a mechanical valve, risk of embolic complications is high; warfarin anticoagulation is indicated for all patients regardless of CHA₂DS₂-VASc score ^r10r57
        • Direct oral anticoagulants are not appropriate treatment owing to lack of favorable data for this indication ^r63
        • A large randomized controlled trial comparing rivaroxaban with warfarin therapy for patients with rheumatic heart disease–associated AF found that warfarin therapy led to a lower rate of a composite of cardiovascular events or death compared with rivaroxaban therapy; no significant difference in rate of major bleeding was noted ^r64
      • 2020 American College of Cardiology/American Heart Association guidelines recommend that direct oral anticoagulants or warfarin be considered for patients with AF with native valvular heart disease (not rheumatic mitral stenosis) or those who received a bioprosthetic valve more than 3 months earlier, based on the CHA₂DS₂-VASc score ^r65
• Left atrial appendage occlusion or obliteration is a nonpharmacologic option for stroke prevention in selected patients
  • Approximately 90% of thrombi in patients with nonvalvular AF and 57% of thrombi in those with valvular AF originate in the left atrial appendage ^r66
  • Percutaneous closure of left atrial appendage (Watchman device)
    • Watchman device prevents embolization of thrombi arising in the left atrial appendage, obviating need for oral anticoagulation for stroke prevention ^r4
    • Reasonable alternative for patients with a moderate to high risk of stroke (CHA2DS2-VASc score of at least 2) and a nonreversible contraindication to long-term oral anticoagulation ^r4
      • Also reasonable in patients with moderate to high risk of stroke and a high risk of major bleeding who are taking oral anticoagulation providing if patient prefers despite understanding there is procedural risk and less evidence for benefit than for oral anticoagulation
    • Meta-analysis of 2 randomized controlled trials (PROTECT AF^r68 and PREVAIL^r69 trials) and 2 nonrandomized registries published in 2015 found that for appropriate candidates, left atrial appendage closure resulted in the following: ^r67
      • Similar benefit in terms of all-cause stroke compared with warfarin but with different stroke pathophysiology between groups: more hemorrhagic strokes occurred with warfarin; more ischemic strokes occurred with the device
      • Decreased rates of cardiovascular/unexplained death and nonprocedural bleeding with the device compared with warfarin
    • Meta-analysis published in 2022 similarly found that left atrial appendage closure was associated with lower all-cause mortality; cardiovascular mortality; hemorrhagic stroke; major bleeding; and the composite of stroke, systemic embolism, and cardiovascular death compared with oral anticoagulation; but risk of all-cause stroke, ischemic stroke, and systemic embolism was similar between groups ^r70
    • Another meta-analysis found a high rate of peridevice leakage following percutaneous left atrial appendage occlusion. Peridevice leakage was detected in 26.1% of patients receiving transesophageal echocardiography and was associated with a higher risk of thromboembolism and higher all-cause mortality ^r71
      • Over half of patients had peridevice leakage visualized on CT, but this lacked prognostic significance
  • Surgical left atrial appendage obliteration
    • Surgical occlusion/obliteration of the left atrial appendage is recommended for patients with AF who are undergoing any first-time nonemergency cardiac surgery procedures; may be performed with or without concomitant surgical ablation of AF ^r4r72
      • American College of Cardiology/American Heart Association guidelines recommend specifically for patients with CHA2DS2-VASc score of at least 2 or equivalent stroke risk ^r4
    • Isolated surgical obliteration of the left atrial appendage may also be considered in patients with longstanding persistent AF, a high stroke risk, and contraindications to long-term oral anticoagulation ^r72
    • Surgical approaches to the left atrial appendage include resection, clipping, or endoatrial suture closure ^r72
    • American College of Cardiology/American Heart Association guidelines recommend continued anticoagulation following surgical left atrial appendage exclusion; data demonstrate left atrial appendage exclusion provides benefit over anticoagulation alone. However, it remains unclear whether anticoagulation can be safely discontinued after the procedure ^r4

Symptom management (control of rate and/or rhythm)

• Either a rate control or rhythm control strategy may be pursued; strategy may change over time
• Initial emphasis should be on maintaining sinus rhythm and minimizing AF burden; however, depending on individual patient factors, either strategy is reasonable ^r4r10
  • Most patients with AF should undergo at least 1 attempt to achieve rhythm control ^r7
  • Patients in whom symptoms are well controlled with rate control alone and with limited life expectancy or advanced age may opt to not receive rhythm control therapy ^r7
• Rhythm control (restoration and maintenance of sinus rhythm)
  • Pharmacologic cardioversion, electrical cardioversion, or an ablative procedure can restore sinus rhythm
  • There is a growing body of evidence suggesting early initiation of a rhythm control strategy is superior to rate control in patients with recent onset of AF (within 1 year) ^r73
    • Early rhythm control was associated with significantly lower risks of all-cause mortality and stroke in a large global registry ^r73
    • Associated with a lower risk of adverse cardiovascular outcomes compared with rate control treatment for patients at high risk for cardiovascular complications and may be preferred for this group ^r74r75
    • May be preferable for younger patients, as AF may become less reversible, and eventually irreversible, over time ^r4
  • Rhythm control may be beneficial in reducing hospitalizations for heart failure, mortality, development of dementia, and worsening of cardiac structural abnormalities ^r4
  • Rhythm control may be beneficial in patients with reduced LV function and persistent AF, as high burden of AF may be contributing to the reduced LV function
  • Rhythm control with maintenance of sinus rhythm confers improvements in symptoms and quality of life, above those achieved with rate control alone, for some patients
  • Patients diagnosed with AF within the previous 12 months with AF-induced induced cardiomyopathy; heart failure with reduced, preserved, or mid-range ejection fraction; or a CHA₂DS₂-VASc score of at least 2 are candidates for early rhythm control ^r7
  • Considerations when choosing this strategy ^r4
    • Pericardioversion anticoagulation or precardioversion left atrial imaging is required for patients in whom electrical or pharmacologic cardioversion is planned who are not on already on anticoagulation therapy; see anticoagulation above section
    • Antiarrhythmic agents have a variety of significant precautions and contraindications; consult cardiologist for selection of safe and effective drug based on individual factors
  • Choice of rhythm control method depends on a variety of factors, including urgency of the need to restore sinus rhythm, duration of AF, success with previous efforts at rhythm control, and individual preference
    • Emergent electrical cardioversion is indicated when there is hemodynamic instability and in the setting of acute coronary syndrome with worsening ischemia that does not immediately respond to IV atrioventricular-nodal blocking drugs ^r4
      • Hemodynamic instability is uncommonly a direct result of AF and mandates a rapid search for underlying reversible conditions (eg, sepsis, gastrointestinal bleeding) that are contributing to the instability
    • For new-onset AF in a stable patient presenting to an emergency department
      • Consider nonemergent (but during initial encounter) cardioversion with appropriate anticoagulation precautions
        • Cardioversion is safe for any of the following individuals: ^r45
          • Patients who have had adequate anticoagulation for at least 3 weeks
          • Patients with onset of AF within 12 hours and no history of stroke, transient ischemic attack, or valvular heart disease
          • Patients with onset of AF within 12 to 48 hours and no history of stroke, transient ischemic attack, or valvular heart disease and negative finding for thrombus on transesophageal echocardiography or fewer than 2 of the following CHADS-65 criteria:
            • Age 65 years or older
            • Diabetes
            • Hypertension
            • Heart failure
        • Electrical cardioversion is increasingly attempted on initial emergency department visit, often with discharge home versus stay in observation bed or overnight monitored admission
          • Consider especially for younger patients, as opposed to an initial trial of only rate control strategy ^r11
          • After successful cardioversion, can withhold the start of long-term antiarrhythmic drug treatment until warranted by recurrence of AF ^r2r76
          • 75% of patients will have a recurrence within 1 year ^r76
        • Pharmacologic cardioversion is rarely attempted in emergency departments in the United States ^r11
          • Pharmacologic cardioversion is most effective when initiated within 7 days of onset of an episode
          • Can use oral flecainide or propafenone if absence of structural heart disease has been confirmed; however, length of time for drug effect (at least 4-6 hours) means that emergency department use is impractical ^r11
    • For patients with infrequent paroxysmal AF
      • Consider outpatient, pill-in-the-pocket pharmacologic cardioversion on an as-needed basis to restore sinus rhythm
        • This strategy involves self-administering propafenone or flecainide and a dose of β-blocker or nondihydropyridine calcium channel blocker ^r4
          • Patient takes β-blocker or calcium channel blocker 30 minutes before taking the antiarrhythmic agent to prevent a rapid ventricular response in case conversion to atrial flutter could occur
          • Patient then takes a single dose of flecainide (200-300 mg) or propafenone (450-600 mg)
        • Monitor patient during initial self-administration to establish safety, then monitor (telemetry for at least 6 hours, blood pressure checks, and 12-lead ECG monitoring) before discharge. Patients can be discharged with prescriptions to use on an as-needed basis at home ^r77
        • Good choice for younger patients and those with a low burden of disease; appropriate for athletes with infrequent symptomatic paroxysmal AF^r39
    • For patients with frequent paroxysmal AF or persistent AF
      • Can attempt either electrical or pharmacologic cardioversion to restore sinus rhythm; ablation procedures are an option when antiarrhythmic drugs are ineffective or not tolerated
      • Electrical cardioversion
        • Safe and effective option for restoring sinus rhythm in patients with paroxysmal or persistent AF ^r78
        • Electrocardioversion of AF and subsequent maintenance of sinus rhythm are more likely to be successful when AF duration is less than 6 months ^r13
          • Reasonable to perform repeated electrocardioversion in patients with persistent AF, provided that sinus rhythm can be maintained for a clinically meaningful period between procedures ^r2
        • May be preferred approach in patients with risk of heart failure as some agents used for pharmacologic cardioversion have been associated with heart failure in patients undergoing pharmacologic cardioversion ^r78
      • Pharmacologic cardioversion ^r4
        • Reasonable to attempt pharmacologic cardioversion if no contraindications are present
        • A variety of antiarrhythmic drugs are effective at restoring sinus rhythm, including fast‐acting agents (IV vernakalant, flecainide, ibutilide) and slower‐acting and/or oral agents (eg, propafenone, amiodarone, sotalol) ^r78
        • Most likely to be effective when initiated within 7 days after the onset of an episode ^r2
        • Malignant arrhythmias have been observed with use of dofetilide, ibutilide, sotalol, quinidine, and vernakalant for pharmacologic cardioversion: caution and close monitoring are required ^r78
        • Antiarrhythmic drug options
          • Amiodarone ^r79
            • May cause pulmonary toxicity; obtain baseline chest radiograph and pulmonary function testing before initiation
            • Time to conversion to sinus rhythm may be longer than with other agents ^r4
          • Flecainide ^r80
            • Contraindicated for patients with preexisting second- or third-degree AV block or right bundle branch block associated with left hemiblock
            • Requires adjustment for renal dysfunction
          • Dofetilide ^r81
            • Begin use of telemetry for monitoring patient and ensure serum potassium is within reference range before initiating therapy. Potassium should be maintained in reference range throughout dofetilide therapy
            • Calculate estimated creatinine clearance using the Cockcroft-Gault equation and determine dose based on creatinine clearance

              • Initial dofetilide dosing based on creatinine clearance (calculated via Cockcroft-Gault equation).

                Data from Tikosyn--Dofetilide Capsules. Prescribing information. Pfizer. National Library of Medicine Daily Med website. Updated October 9, 2020. Accessed March 29, 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=02438044-d6a3-49e9-a1ac-3aad21ef2c8c.

                Creatinine clearance (mL/minute)	Dose
                More than 60	500 mcg twice daily
                40 to 60	250 mcg twice daily
                20 to 40	125 mcg twice daily
                Less than 20	Usage contraindicated

            • Obtain baseline QTc (for heart rate 60 beats per minute or higher) or QT (for heart rate less than 60 beats per minute). If QTc/QT is higher than 440 milliseconds, do not use dofetilide. Note: no data on use when heart rate is less than 50 beats per minute
            • Check QTc/QT 2 to 3 hours after first dose and adjust dose if necessary based on change in QTc/QT; if QTc/QT increase is 15% of baseline or less, continue current dose; if more than 15% of baseline or more than 500 milliseconds, decrease dose
            • If QTc/QT increase is more than 15% of baseline or more than 500 milliseconds, decrease dose according to table below

              • Dofetilide dose adjustment after first dose.

                Data from Tikosyn--Dofetilide Capsules. Prescribing information. Pfizer. National Library of Medicine Daily Med website. Updated October 9, 2020. Accessed March 29, 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=02438044-d6a3-49e9-a1ac-3aad21ef2c8c.

                If the starting dose based on creatinine clearance is:	Then the adjusted dose (for QTc or QT prolongation) is:
                500 mcg twice daily	250 mcg twice daily
                250 mcg twice daily	125 mcg twice daily
                125 mcg twice daily	125 mcg once daily

            • If at any time after the second dose of dofetilide the QTc/QT increases to higher than 500 milliseconds, discontinue dofetilide
          • Ibutilide ^r82
            • Reasonable option for pharmacological cardioversion for patients without reduced LV function ^r4
            • Can lead to torsades de pointes; must be administered during ECG monitoring until QTc interval is back to baseline (at least 4 hours)
            • Discontinue if marked prolongation of QT or QTc develops
            • If any arrhythmic activity is noted, longer monitoring is required; patients with abnormal liver function should be monitored for longer than 4 hours
          • Propafenone ^r83
            • Considered proarrhythmic for patients with structural heart disease; use with caution
          • IV procainamide may be considered if other agents are contraindicated ^r4
          • IV vernakalant is another option (available in Canada and Europe but not in the United States)
      • Maintenance of sinus rhythm following cardioversion
        • Following successful cardioversion, initiate appropriate oral antiarrhythmic drug therapy to decrease likelihood of AF recurrence
        • Overall, efficacy of antiarrhythmic drugs is only modest, with a recurrence rate of 43% to 67%, based on a 2019 Cochrane review ^r1r84
        • Consider presence or absence of structural heart disease, coronary artery disease, and potential to prolong the QT interval when choosing the specific antiarrhythmic drug; consultation with a cardiologist is recommended
        • Sotalol, dofetilide, amiodarone, and dronedarone cause drug-induced QT-interval prolongation, and sotalol has been specifically linked to increased risk of death compared with placebo, based on data from 5 randomized controlled trials (relative risk, 2.23; 95% confidence interval, 1.03-4.81) ^r84
        • Amiodarone is not only the most effective drug for maintaining sinus rhythm but also the drug associated with the highest toxicity and treatment withdrawal; do not use as first line treatment except for patients with heart failure ^r2
        • First line antiarrhythmic drug for patients with heart failure is dofetilide or amiodarone ^r2r76
        • First line drug for patients with coronary artery disease is dofetilide, dronedarone, or sotalol.^r76 Flecainide (and propafenone, by inference) increases mortality in this population ^r2
        • Without structural heart disease, first line antiarrhythmic drugs include dofetilide, sotalol, dronedarone, flecainide, and propafenone ^r76
        • Specific precautions
          • Sotalol ^r76
            • Initiate or re-initiate oral sotalol in a facility that can provide continuous ECG monitoring and cardiac resuscitation by personnel who are trained in the management of serious ventricular arrhythmias. Hospitalize patients for whom sotalol has been initiated or re-initiated for at least 3 days or until steady-state concentrations are achieved. Normalize serum potassium and magnesium concentrations before initiating. Monitor the QTc interval every 2 to 4 hours after each dose
            • Contraindicated for patients with systolic heart failure or significant left ventricular hypertrophy, sinus bradycardia (less than 50 beats per minute), sick sinus syndrome, second- or third-degree atrioventricular block without pacemaker, congenital or acquired long QT syndrome, cardiogenic shock, serum potassium less than 4 mEq/L, or baseline QT interval greater than 450 milliseconds
            • Renal dose adjustments are required for creatinine clearance less than 60 mL/minute, and use is contraindicated for patients with creatinine clearance less than 40 mL/minute
          • Dronedarone
            • Do not use for maintenance of sinus rhythm in patients with New York Heart Association class III and IV heart failure or patients who have had an episode of decompensated heart failure in the past 4 weeks, due to the risk of increased early mortality due to heart failure ^r4
            • Contraindicated for patients with permanent AF in whom normal sinus rhythm will not or cannot be restored; dronedarone doubles the risk of death and heart failure events for patients with permanent AF
      • Ablation of AF
        • Catheter ablation
          • Catheter-delivered radiofrequency or cryoablation is used to isolate arrhythmogenic impulses originating from the area of the pulmonary vein ostia (known as pulmonary vein isolation or pulmonary vein antrum isolation)
          • Candidates for catheter ablation (according to an international expert consensus statement) include: ^r19
            • Patients who remain symptomatic despite antiarrhythmic drugs
            • Patients intolerant of antiarrhythmic drugs
            • Patients with either symptomatic paroxysmal AF or symptomatic persistent AF (reasonable as first line therapy before trial of an antiarrhythmic drug)
            • Patients with AF-mediated tachycardia-induced cardiomyopathy ^r38
            • Patients with paroxysmal AF who have symptomatic pauses, so-called brady-tachy syndrome (reasonable as first line therapy to avoid pacemaker implantation)
            • Patients with heart failure with reduced ejection fraction (reasonable option) ^r19r85
          • Considered first line therapy for patients with concomitant AF and heart failure with reduced ejection fraction ^r86
          • Recommended as first line therapy or alternative if antiarrhythmic drugs are contraindicated or poorly tolerated in athletes with symptomatic paroxysmal or persistent AF ^r39r87
            • Intolerance to medical therapy is likely greater in the athletic population owing to impact on performance ^r39
        • Outcomes of catheter ablation versus medical therapy
          • CABANA trial showed that for a broad population of patients with symptoms, catheter ablation, compared with medical therapy, led to clinically important and significant improvements in quality of life at 12 months ^r88
            • No significant reductions in specific end points of death, disabling stroke, serious bleeding, or cardiac arrest; however, treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers ^r89
          • In a randomized controlled trial comparing several common techniques for ablation, about 75% of patients, overall, were asymptomatic 1 year after catheter ablation when monitored using an implanted loop recorder ^r90
            • Although at least 1 documented recurrence of an atrial tachyarrhythmia within 12 months occurred in 53% of patients, the burden of AF (percentage of time in AF) was reduced by about 99%
          • Randomized controlled trial results published in 2021 reported the following:
            • Cryoballoon ablation as initial therapy was superior to drug therapy for prevention of atrial arrhythmia recurrence in patients with paroxysmal AF ^r91
            • In patients receiving initial treatment for symptomatic paroxysmal AF, there was a significantly lower rate of AF recurrence with catheter cryoballoon ablation than with antiarrhythmic drug therapy ^r92
          • Evidence suggests that catheter ablation as first line therapy for symptomatic paroxysmal AF results in lower rate of tachyarrhythmia recurrence compared with conventional antiarrhythmic drug therapy, with a similar adverse event profile ^r93r94
          • Mixed data on whether catheter ablation versus medical therapy impacts cognitive outcomes for patients with AF ^r95
          • Catheter ablation (but not optimized medical therapy) was associated with improvement in psychological symptoms of anxiety and depression in patients with symptomatic AF ^r96
        • Surgical ablation
          • Surgical ablation of AF is a recommended option for patients undergoing any first-time nonemergency cardiac surgery ^r19r72r97r98
            • Left atrial appendage obliteration to reduce thromboembolic complications is also recommended for all first-time nonemergent cardiac surgery procedures ^r72
            • Surgical ablation plus left atrial appendage obliteration was associated with significant reduction in 3-year mortality and readmission for stroke in patients with AF who underwent coronary artery bypass grafting or valve repair or replacement ^r99
          • May be performed via conventional thorascopic surgery, via minimally invasive techniques, or a hybrid approach consisting of a combined surgical-percutaneous catheter ablation
          • Standalone surgical or hybrid ablation is reasonable for patients with previously unsuccessful catheter ablation ^r19
        • Cautions with ablative therapy
          • Ablative procedures do not eliminate need for anticoagulation
            • All patients should continue oral anticoagulation for at least 3 months after catheter ablation with longer term anticoagulation determined by individual stroke risk ^r4
            • Catheter ablation to restore sinus rhythm should not be performed with the sole intent of eliminating the need for long-term anticoagulation ^r39
          • Antiarrhythmic drug treatment for 3 months after ablation can reduce risk of recurrent AF and associated hospitalizations ^r97r100
            • Benefit does not appear to continue beyond 6 months
• Rate control ^r4
  • Rate control is as effective as rhythm control for preventing cardiovascular morbidity and mortality in large randomized controlled trials ^r8r9
    • May be preferable for patients without symptoms who have a structurally and functionally normal heart and when risks of restoring sinus rhythm outweigh benefits ^r76
    • Can be the initial strategy for patients with new-onset AF with a plan for cardioversion to sinus rhythm after 3 weeks of anticoagulation, if atrioventricular-nodal blocking drugs are ineffective or not tolerated ^r11
  • Use an atrioventricular-nodal blocking drug as initial therapy ^r4
    • NOTE: Do not use atrioventricular-nodal blocking drugs for patients with known or suspected Wolff-Parkinson-White syndrome; preferential ventricular excitation through accessory pathway and extremely rapid ventricular rates can occur, resulting in hemodynamic collapse
      • For these patients, aim to revert to sinus rhythm with an antiarrhythmic drug, specifically procainamide or ibutilide, if hemodynamics are stable; or use electrocardioversion
    • Options include:
      • Nondihydropyridine calcium channel blockers
        • Both verapamil and diltiazem are effective ^r4
        • Standard of care in the acute setting where rapid control of ventricular rate is desired; either can be given intravenously ^r4
        • Rate control was achieved in 54% of patients treated with oral calcium channel blockers as first drug in AFFIRM^r101 trial
        • Use with caution for patients with heart failure or sinus node dysfunction: should not be given to patients with left ventricular ejection fraction less than 40% ^r4
      • β-Blockers
        • In the acute setting where rapid control of ventricular rate is desired, metoprolol, propranolol, or esmolol can be given intravenously ^r2
        • Oral atenolol, metoprolol, nadolol, and propranolol are effective for ongoing ventricular rate control and have the most data to support their use ^r4
          • Rate control was achieved in 70% of patients given a β-blocker as first drug in the AFFIRM trial
        • Use with caution for patients with decompensated heart failure
      • Cardiac glycosides (ie, digoxin)
        • In the acute setting, not optimal for rapid control of ventricular response due to slow onset of action and delayed peak plasma concentration
        • For long-term rate control, not typically used as a first line drug; ineffective at controlling the ventricular response during exercise ^r76
        • May be useful in the following situations:
          • Setting of heart failure (no negative inotropic effects); however, may increase risk of death^r102 in this population ^r2
          • In combination with a β-blocker and/or a nondihydropyridine calcium channel blocker when ventricular rate control is insufficient ^r4
          • For sedentary or bedbound patients for whom lack of rate control during exercise is not an important factor
      • Amiodarone
        • IV amiodarone may be considered for acute rate control in patients with rapid ventricular response rate who are critically ill and/or in decompensated heart failure if beta blockers and nondihydropyridine calcium channel blockers are ineffective or contraindicated ^r4
          • Although primarily used as an antiarrhythmic (rather than a rate control agent), amiodarone exerts sympatholytic and calcium-antagonistic properties that can depress atrioventricular-nodal conduction
        • Toxicities and drug interactions limit long-term use of amiodarone for control of ventricular rate

      • Rapid ventricular rate control using IV medications.

        Drug	Dose
        β-Blockers
        Metoprolol	2.5 to 5 mg IV every 5 minutes up to 3 doses
        Esmolol	50 mcg/kg/minute continuous IV infusion, initially Titrate by 50 mcg/kg/minute every 4 minutes until goal heart rate is attained Usual dose: 25 to 200 mcg/kg/minute Max: 300 mcg/kg/minute May give 500 mcg/kg IV over 1 minute at initiation and before each infusion rate increase up to 3 doses
        Propranolol	1 mg IV every 2 minutes as needed for up to 3 doses
        Nondihydropyridine calcium channel blockers
        Verapamil	0.075 to 0.15 mg/kg (Usual dose: 5 to 10 mg) IV bolus May administer an additional 0.15 mg/kg (usual dose: 10 mg) IV bolus 30 minutes after initial bolus if no response, followed by 0.005 mg/kg/minute continuous IV infusion
        Diltiazem	0.25 mg/kg (usual dose: 15-20 mg) IV bolus, followed by 5 to 10 mg/hour continuous IV infusion, initially Titrate by 5 mg/hour as needed. Max: 15 mg/hour May administer an additional 0.35 mg/kg (usual dose: 20-25 mg) IV bolus 15 minutes after initial bolus if needed
        Other agents
        Digoxin	Not recommended for rapid ventricular rate control; onset of action is more than 1 hour with peak effect delayed 6 hoursr2

    • Goal heart rate is guided by symptoms, generally less than 100 to 110 beats per minute at rest for most patients ^r4r103
      • Lenient rate control (less than 110 beats per minute) is effective as strict rate control (less than 80 beats per minute at rest) in preventing cardiovascular events, including heart failure hospitalizations, stroke, arrhythmias, and cardiovascular death, according to results found in RACE II trial ^r103
      • More strict rate control is important when an elevated ventricular rate is contributing to ventricular dysfunction (known as tachycardia-mediated cardiomyopathy)
  • Nonpharmacologic rate control with atrioventricular node ablation and permanent pacemaker implantation can be an option for some patients ^r38
    • Reasonable when pharmacologic management is inadequate and rhythm control is not achievable. Most appropriate for the following: ^r2
      • Older adult patients (because the procedure mandates lifelong pacemaker dependency)
      • Patients with tachycardia-mediated cardiomyopathy with ventricular rate refractory to medical therapy
      • Patients who remain symptomatic with uncontrolled rapid ventricular response despite pharmacologic rate control therapy
    • Long-term data on outcomes are limited

Monitoring

• Reevaluate thromboembolic event risk and need for anticoagulation annually using a validated clinical risk score, such as CHA₂DS₂-VASc ^r4
• Monitoring anticoagulation
  • Patients taking warfarin: measure INR at least weekly during initial therapy and at least monthly once anticoagulation is stable. Goal INR is 2 to 3 for most patients^r4
  • Patients taking direct oral anticoagulants do not usually require monitoring of coagulation ^r10r146
    • Routine coagulation tests (prothrombin time and activated partial thromboplastin time) do not provide an accurate assessment of anticoagulant effects
    • Commercial assays to measure direct oral anticoagulant serum concentration are available, but results are not well correlated with outcomes. Use these assays only for specific indications, including: ^r4
      • Measurement of drug concentrations in patients undergoing urgent surgical procedures
      • Detection of potentially toxic drug concentrations in patients with chronic kidney disease or those undergoing dialysis
      • Detection of potential drug-drug interactions to guide dose adjustment
      • Evaluation of drug absorption in patients after bariatric surgery
      • Assessment of patient adherence
  • Patients who are at high risk for bleeding (ie, high HAS-BLED score) require closer follow-up
• Monitoring rate and rhythm
  • Ambulatory rhythm monitoring (eg, Holter monitor, event recorders) and exercise testing can be useful to judge the adequacy of rate control ^r4
  • Monitor for adverse effects of antiarrhythmic drugs with periodic measurement of QT interval and electrolyte levels
  • Many agents require modification for decreased renal function; monitor at baseline and periodically

Complications

• Thromboembolism ^c107
  • Embolic stroke ^c108
    • 5-fold increased risk of stroke with nonvalvular AF ^r27r147
    • 20-fold increased risk of stroke with AF associated with mitral stenosis ^r147
    • Stroke associated with AF is associated with greater disability and higher mortality than stroke not associated with AF, and recurrence is more likely ^r148
    • Anticoagulation, if eligible by CHA₂DS₂-VASc score, and control of other stroke risk factors (eg, hypertension, dyslipidemia) can greatly reduce stroke risk ^r2
  • Peripheral thromboembolism risk is a rare complication, but most events are subclinical ^c109
    • Managed with surgical embolectomy
• Heart failure ^c110d6
  • Heart failure and AF have a bidirectional association, share many of the same risk factors, and frequently complicate each other
  • AF can lead to or exacerbate both heart failure with reduced ejection fraction (ie, tachycardia-mediated ventricular dysfunction) and heart failure with preserved ejection fraction
• Cognitive impairment and dementia (vascular dementia or Alzheimer disease) ^{r149c111c112d7}
  • AF is a risk factor for cognitive dementia, independent of clinical stroke. Strongest association was for younger participants with the longest duration of AF in prospective, population-based study ^r150
  • Mechanism is likely multifactorial, including nonapparent strokes, cerebral microinfarcts, and reduced cerebral blood flow
  • Indirect evidence that effective anticoagulation in AF reduces the risk of cognitive impairment and dementia ^r151
  • Observational study of effect of catheter ablation (versus no ablation) on a variety of outcomes showed a significantly lower risk of dementia (both Alzheimer and non-Alzheimer types) among patients who underwent ablation ^r152

Prognosis

• AF is a chronic disease characterized by exacerbations and remissions ^r19
  • Tends to progress from paroxysmal to persistent over time and may eventually become irreversible
• In general, outcomes for specific therapies are better for paroxysmal AF than for persistent AF ^r2
• Prognosis is affected by any underlying structural heart disease
• AF has many associated adverse outcomes, including stroke, heart failure, cognitive impairment, Alzheimer disease, and 2-fold increased mortality risk. The extent to which these outcomes can be mitigated by restoring sinus rhythm is uncertain ^r89r149r153
• There is higher relative risk of cardiovascular and all-cause mortality, stroke, and heart failure in females than males ^r139

Screening

Prevention

• Manage or treat known AF risk factors
  • Identify and treat hypertension, prediabetes, and diabetes ^c119c120c121
    • Metformin or SLGT2 inhibitors are preferred for patients requiring pharmacologic treatment for diabetes ^r38
  • Recommend normal weight maintenance and weight loss if patient has obesity or overweight ^{r38c122c123c124}
    • For patients with obesity, bariatric surgery has been associated with reduced risk of new AF compared with medical management of obesity ^r158
  • Advise smoking cessation ^c125d5
  • Advise patients to limit alcohol consumption and avoid binge drinking ^r38c126
  • For patients with hyperthyroidism, restore and maintain euthyroid state ^c127c128
• May consider ACE inhibitor or angiotensin receptor blocker for primary prevention of new-onset AF in patients with heart failure with reduced left ventricular ejection fraction or in those with hypertension ^r2
• Statin therapy may be reasonable for primary prevention of new-onset AF after coronary artery surgery ^r2