Atrial Fibrillation and Flutter

Atrial Fibrillation (AF) is the most common sustained arrhythmia.

Biggest risk factors are age, hypertension, cardiac diseases, diabetes, and obesity.

Untreated AF increases mortality, predisposes to stroke and other thromboembolic complications, impairs quality of life, and may lead to heart failure (tachycardia-induced cardiomyopathy).

The most critical factor for prognosis is anticoagulation therapy.

As an arrhythmia, AF is rarely life-threatening. 

Definition and Classification

AF is a supraventricular arrhythmia characterized by rapid, disorganized atrial electrical and mechanical activity.

Classification is based on recurrence tendency and duration:

• Paroxysmal AF: Sinus rhythm returns spontaneously or via cardioversion (electrical/pharmacological) within 7 days.

• Persistent AF: Sinus rhythm does not return within 7 days, or returns with intervention after >7 days.

• Long-standing persistent AF: Rhythm control chosen despite AF persisting over a year.

• Permanent AF: Rhythm control is no longer pursued; AF is accepted.
   

Silent (subclinical) AF: Symptoms suggestive of AF are present, but diagnosis hasn't been confirmed by ECG, or short (<30s) asymptomatic episodes are found via devices (e.g., pacemaker memory).

Lone AF: AF in otherwise healthy individuals <60 years old. Ceases to be “lone” if comorbidities develop.

AF burden: Proportion of monitored time the patient is in AF.

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Acute AF: Recently onset symptomatic episode. Duration assessment (<12 h, 12–24 h, 24–48 h) is critical for cardioversion timing.

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Natural history of atrial fibrillation involves increasing frequency and duration of paroxysms, slowly progressing to permanent AF.

Prevalence and Incidence

Prevalence in adults: 2–4%
Rare under age 60 (0.4%), but >20% in those over 75. Average age of AF patients is around 75 years

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Annual incidence: 0.1% in under 40s; nearly 2% in those over 80One in three >55 years old will experience AF during their lifetime

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Very common in heart failure, especially severe (NYHA IV): ~50% prevalence

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Pathophysiology

Focal AF: begins as frequent premature atrial contractions (PACs) lead to creation of multiple micro-reentry circuits in the atrial tissue. Atrial fibrillation is frequently launched by a PAC. These PACs usually originate near the pulmonary vein ostia,  which is the target of catheter ablation.

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Structural remodeling (atrial dilation, fibrosis) and autonomic tone also contribute to atrial fibrillation

Vagal AF: Occurs at rest/night, often postprandially, as the heart rate slows.

Sympathetic AF: Triggered by physical/mental stress, as the heart rate increases.

AF perpetuates itself – structural/electrical remodeling caused by persistent atrial fibrillation episodes reinforces the arrhythmia. AF gradually becomes more prolonged, recurs more frequently, and restoring sinus rhythm becomes more difficult.

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Risk Factors

Over 70% of AF patients have structural heart disease or systemic disease predisposing to atrial fibrillation

The most significant single factor predisposing to atrial fibrillation is age.

Major cardiovascular risk factors:

• Hypertension

• Heart failure

• Valvular disease

• Coronary artery disease
   

Other risk factors:

• Diabetes

• Obesity

• Sleep apnea

• Thyroid disorders

• Renal impairment

• Chronic pulmonary diseases

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AF can be preceded by or triggered by other SVTs (e.g., atrial flutter, AVNRT). On the other hand, atrial fibrillation often precedes atrial flutter.

Regular exceptionally intense endurance training (>1,500 cumulative hours) increases AF risk, but overall, physical activity is protective. The beneficial effects of exercise are so great that it is not reasonable to stop exercising to prevent atrial fibrillation.

Acute triggers: Alcohol excess, MI, pericarditis, myocarditis, PE. Treating the underlying condition often restores sinus rhythm without cardioversion.

Cardioversion should not most often be performed until the acute triggering factor has passed.

AF can be familial; ion channel mutations identified, but genetic testing not routinely needed.

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Thromboembolic Complications

AF is the leading cause of cardiogenic thromboembolism:

• 20–30% of stroke patients have AF

• Explains ~10% of cryptogenic strokes
   

Major stroke risk factors in AF:

• Prior stroke/TIA

• Age ≥75

• Moderate/severe mitral stenosis (stroke risk up to 17× in rheumatic valve disease)

• Mechanical prosthetic valve

• Hypertrophic cardiomyopathy
   

Other significant risk factors:

• Heart failure

• Hypertension

• Diabetes

• Age 65–74

• Atherosclerosis (CAD, carotid plaque, PAD)

• CKD

• Dyslipidemia

• smoking
   

AF-related thromboembolism risk is somewhat lower in paroxysmal than persistent/permanent AF.

In HCM, moderate/severe mitral stenosis, or amyloidosis, lifelong anticoagulation is required regardless of CHA₂DS₂-VA score.

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Hemodynamics

AF reduces cardiac output by ~15–30% due to loss of atrial contraction and AV dyssynchrony. A too rapid/irregular ventricular response also decreases cardiac output, especially in diastolic heart failure.

If LV systolic function is normal, impact is minor, but in systolic heart failure, AF may cause sudden deterioration in hemodynamics.

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Symptoms and Clinical Findings

AF may be asymptomatic or symptoms may be very mild (~50%).

Typical symptoms:

• Palpitations

• Fatigue, reduced exercise capacity

• Dizziness

• Chest pain

• Dyspnea

• Polyuria

  • atrial distention leads to reduced secretion of antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP)

Symptom severity is assessed using EHRA classification.

Syncope is rare; raises suspicion of aortic stenosis or pre-excitation syndromes (e.g., WPW).

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ECG Findings

Due to rapid, disorganized atrial activity (450–600 bpm), no normal P waves are visible; baseline appears irregular. Ventricular response is irregular due to variable AV conduction.

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QRS complex is usually narrow, but can be wide in aberrant conduction, bundle branch block, or WPW (delta wave).

Very fast (>200 bpm), wide-complex AF is rare and suggests an accessory pathway (WPW).

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ECG Recordings from Rhythm Management Devices and Implantable Monitors

In prolonged monitoring (e.g., Holter monitoring, inpatient telemetry, or pacemaker memory), diagnosing atrial fibrillation (AF) requires at least a 30-second episode of atrial fibrillation.

• Atrial fibrillation episodes shorter than 30 seconds are referred to as atrial high rate episodes (AHREs).
   

The clinical significance of these atrial arrhythmias recorded in device memory and their duration regarding the need for anticoagulation therapy in continuous monitoring remains unclear.

Findings from recent research suggest that in patients with brief atrial fibrillation episodes (>6 minutes but ≤24 hours) detected via pacemaker memory, routine anticoagulation therapy may even be harmful.

When considering anticoagulation, in addition to arrhythmia burden, thromboembolic risk factors must be taken into account. The more thromboembolic risk factors a patient has, the shorter the AF episodes are thought to become clinically relevant.

Different Diagnostic Criteria Based on Patient Monitoring Context

The diagnostic criteria for atrial fibrillation differ between continuously monitored patients and symptomatic patients undergoing standard ECG.

For Continuously Monitored Patients

(e.g., pacemaker, prolonged inpatient telemetry):

• Diagnosis requires an AF episode lasting at least 30 seconds.

• There are no strict criteria for initiating anticoagulation; this is instead guided by stroke risk assessment (e.g., CHA₂DS₂-VA) and AF burden.

• Anticoagulation is usually not initiated for episodes <6 minutes.

• Episodes between 6 minutes and 24 hours fall into a gray area (anticoagulation may be harmful).

• Episodes >24 hours often justify starting anticoagulation.
   

For Patients with Symptoms or Randomly Detected AF on ECG:

• If a random/routine ECG shows AF throughout the entire recording, the diagnostic criteria for AF are met despite of symptoms.

• If an outpatient has symptoms suggestive of AF and a Holter or other ambulatory ECG monitoring is performed, a 30-second AF episode in such monitoring is sufficient for diagnosis and usually indicates initiation of anticoagulation

• The above approach is based on the understanding that not all AF episodes are symptomatic, and symptomatic patients—or those incidentally found to be in AF—are likely to have a high AF burden.

Echocardiography

A transthoracic echocardiogram is routinely performed once in all patients diagnosed with atrial fibrillation (AF) to assess for possible structural heart disease.

• The purpose is to identify heart failure and structural abnormalities (e.g., left ventricular hypertrophy, valvular disease).

• It also supports the identification and management of AF risk factors.
   

In older individuals without clinical signs or symptoms suggesting heart disease (e.g., heart failure, valvular disease, coronary artery disease), echocardiography may be omitted if:

• Rate control is the selected treatment strategy, and

• Ventricular rate is adequately controlled (“economical rate”).

Diagnostic Investigations

In patients with first-time AF, unexpected recurrence, or when initiating preventive medication, the following should be checked:

• Basic blood count

• Electrolytes: sodium, potassium

• Creatinine

• Thyroid-stimulating hormone (TSH)

• Glucose

• Lipid profile

• Urine screening test
   

Additional Tests:

• Specific safety tests may be required depending on the chosen therapy (e.g., amiodarone, dronedarone, anticoagulants).

• Echocardiography recommended.

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Choosing Between Rate Control and Rhythm Control

First-Time Symptomatic AF Episode:

• Attempting to restore sinus rhythm is almost always recommended.

• Spontaneous cardioversion occurs within 1–2 days in 50–70% of cases.
   

Elderly Patients (>65 years) with No or Mild Symptoms (EHRA 1–2):

• Rate control and rhythm control offer comparable prognosis and quality of life.

• Therefore, rhythm control may be omitted, focusing instead on:

  • Treating AF risk factors

  • Starting anticoagulation if indicated

Younger Patients (<65 years):

• A single rhythm conversion is typically performed, even if asymptomatic.

Factors Supporting Rate Control

• Symptoms are manageable with AV nodal blockers.

• AF recurs quickly (<2 months) after cardioversion and long-term antiarrhythmic therapy is not feasible.

• Large left atrium: successful rhythm restoration and maintenance are unlikely if left atrial diameter > 5 cm.

  • Recurrence risk increases with moderate (42–48 ml/m²) to severe (>48 ml/m²) atrial enlargement.

• AF has persisted for >6–12 months.

• Low physical activity.
   

Factors Supporting Rhythm Control

• Good response to antiarrhythmic medication.

• Normal left atrial size.

• Arrhythmia duration <6 months.

• Patient is physically active.
   

Rhythm control is the primary option regardless of comorbidities if:

• Severe symptoms (EHRA 3–4)

• Hemodynamic instability, despite AV nodal blockers

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Management of Acute AF Episodes and Cardioversion

Hemodynamically Unstable AF

• Immediate electrical cardioversion is indicated regardless of anticoagulation status.
   

Stable AF Caused by Acute Illness

Treat the underlying cause first; restore sinus rhythm after stabilization.

Common triggers include:

• Myocardial infarction

• Acute decompensation of heart failure

• Myocarditis

• Hyperthyroidism

• Electrolyte imbalance
   

Spontaneous conversion to sinus rhythm occurs in ~70% of cases within 1–2 days. Therefore, immediate cardioversion is often unnecessary,  especially in minimally symptomatic patients. A patient with previously diagnosed AF and stable condition may wait 1–2 days at home before seeking cardioversion.

In an unanticoagulated patient who is at low or moderate risk of thrombosis (CHA2DS2VA ≤ 1), spontaneous return to sinus rhythm should not be waited for more than 48 hours to avoid postponing cardioversion as AF of more than 48hours requires 3 weeks of anticoagulation therapy prior to cardioversion.

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In an unanticoagulated patient who is at high risk of thrombosis (CHA2DS2VA ≤ 2), spontaneous return to sinus rhythm should not be waited for more than 24 hours to avoid postponing cardioversion.

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Conditions for Safe Elective Cardioversion (AF ≥48h or Unknown Duration)

If AF Duration is >48 Hours or unknown, without adequate anticoagulation, the risk of thromboembolism associated with cardioversion is 5–7% within 30 days. >80% of events occur within the first 7 days of which ~70% within the first 2 days.

If AF Duration Is Unclear, start anticoagulation and plan elective cardioversion if indicated.

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Cardioversion can proceed if any one of the following is fulfilled:

1. A direct oral anticoagulant (DOAC) has been taken regularly for at least 3 weeks.

2. Warfarin therapy with INR > 2 has been therapeutic for ≥3 weeks.

3. A transesophageal echocardiogram (TEE) or cardiac CT shows no intracardiac thrombus.
    

Even Low Stroke Risk (CHA₂DS₂-VA ≤1) doesn't completely eliminate stroke Risk. After elective cardioversion for low stroke risk patients (who have been anticoaculated for at leat 3 weeks prior) anticoagulation is resumed for minimum of 4 weeks. Stroke risk after cardioversion remains due to atrial stunning, which promotes thrombus formation post-cardioversion.

Early Cardioversion in Non-Anticoagulated Patients

If anticoagulation is required before early cardioversion:

• Start either:

  • A DOAC with a small amount of water, or

  • LMWH followed by DOAC from next dose

  • Low molecular weight heparin (LMWH) + warfarin

    • If using warfarin, continue LMWH until INR reaches therapeutic levels.​

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Cardioversion without prior anticoagulation is acceptable only if:

• CHA₂DS₂-VA ≤ 1 and

• AF duration <12 hours

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Post-Elective Cardioversion Anticoagulation:

CHA2DS2VA ≥ 2: Continue anticoagulation indefinitely, even if sinus rhythm is restored

CHA2DS2VA ≤1: Continue for ≥1 month, and if CHA2DS2VA=1 consider indefinite treatment if additional risk factors exist (e.g., smoking, dyslipidemia, renal impairment)

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Management of atrial flutter cardioversion follows the same anticoagulation protocols as AF.

Kuva 8. Antikoagulaatiohoito akuutissa (alle 48 tuntia kestäneessä) eteisvärinässä. Akuutissa eteisvärinässä varhaisen rytminsiirron mahdollisuus arvioidaan tukosvaaratekijöiden ja rytmihäiriön keston perusteella. Pienen ja keskisuuren riskin potilailla eteisvärinän kardioversioon liittyvä tulosvaara on niin pieni, että antikoagulaatiohoitoa ei tarvita ennen eikä jälkeen rytminsiirron, jos rytmihäiriön kesto on alle 12 tuntia. Jos rytmihäiriön kesto on 12–48 tuntia myös heille annetaan ensimmäinen annos suoraa antikoagulantti (tai pieni molekyylistä hepariinia ja varfariina) jo ennen rytminsiirtoa, kuten suuren riskin potilaille ja rytminsiirron jälkeen AK-hoitoa jatketaan riskitekijöiden mukaan vähintään 1 kuukauden ajan tai pysyvästi (ks. tarkemmin teksti).

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Transesophageal Echocardiography (TEE)–Guided Cardioversion

Cardioversion can be safely performed even after >48 hours of AF if TEE confirms the absence of left atrial thrombus.

Start DOAC, or LMWH + warfarin prior to TEE

Relative Contraindications for cardioversion on TEE:

• Spontaneous echo contrast (“smoke effect”)

• Reduced flow velocity in the left atrial appendage
   

consider TEE guided cardioversion if patient is highly symptomatic (EHRA 3–4) and other criteria for safe cardioversion aren’t met.

Rate Control in Acute Atrial Fibrillation

Goal is resting heart rate <110 bpm. Resting heart rate of <110bpm does not increase the risk of tachycardia-induced cardiomyopathy compared to stricter rate control (vs 80 bpm)

Iintravenously given drugs have rapid onset of action. 

Drug Onset Times (IV):

• Metoprolol: When given as a bolus the onset of action is 2 to 3 minutes, with a peak effect within 20 minutes. Onset ~20 min, when infused over 10 min.

• Digoxin: Onset 5–30 min, peak effect in 1–5 hours
   

Medication Options for Rate Control

1. Beta Blockers (e.g., Metoprolol)

• Inhibit the sympathetic system; effectively lower ventricular rate

• Generally very safe

• Use cautiously if EF <20% or history of severe heart failure. Prefer digoxin/amiodarone in these cases. Beta blockers have negative inotropic effect which may in worst case even cause cardiogenic shock.
   

2. Calcium Channel Blockers (Verapamil, Diltiazem)

• Direct action on the AV node

• Well tolerated in patients without structural heart disease

• Contraindicated in heart failure due to negative inotropic effects
   

3. Digoxin

• Slower onset and less effective than beta-blockers or calcium channel blockers

• Preferred in acute heart failure (e.g., pulmonary edema). Does not have negative inotropic effect.

• Can be administered via:

  • Slow oral digitalization: start directly with maintenance dose (0.0625–0.25 mg daily)

    • Steady state in ~7–10 days

  • IV loading: initial 0.25–0.5 mg over several minutes, followed by 0.25 mg q6h up to 0.75–1.5 mg as needed (10 to 12 mcg/kg lean body weight).

  • Oral loading: 0.5 mg initial, then 0.25 mg q6h up to total loading dose of 0.75 to 1.5 mg

• For most patients, the maintenance dose of digoxin will be between 0.125 mg and 0.25 mg daily
   

Contraindications: Pre-excitation Syndromes (WPW)

• Beta-blockers, calcium channel blockers, and digoxin may increase conduction via accessory pathways.

• Avoid these in patients with delta waves or known WPW.
   

4. Amiodarone

• Slows AV conduction by blocking both the sympathetic system and slow calcium channels

• Not a first-line drug for acute rate control (except hemodynamically unstable AF)

• Extracardiac side effects and proarrhythmia are rare in short-term use.

• Can be used:

  • In postoperative, critically ill, or hemodynamically unstable patients

  • Has minimal negative inotropic effects

  • Also slows conduction through accessory pathways, thus may be cautiously used in WPW
     

Beta-blocker + calcium channel blocker combination should be avoided, except in special cases, due to additive negative inotropy

Digoxin may be combined with a beta-blocker or a calcium channel blocker

Electrical Cardioversion

In acute AF (<48 hours), electrical cardioversion restores sinus rhythm in >90% of cases. Efficacy decreases as AF duration increases—delay should be avoided in elective procedures.

Use maximum defibrillation energy from the start for better efficacy as it works better than low energy and step by step escalated energy.

Schmidt et al compared 360-360-360 J shocks with 125-150-200 J escalating shocks. Sinus rhythm was (1min after cardioversion) restored in 88% in the max energy group and 66% in the low energy - escalation group

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It is common practice to give total of three shocks before determining that cardioversion has failed. If Cardioversion Fails despite of maximal energy:

-Administer ibutilide (1 mg IV over 10 min) and retry cardioversion during same sedation
-Alternatively: initiate oral antiarrhythmic therapy and reattempt cardioversion after drug stabilization

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Hypotension following electrical and pharmacological cardioversion or spontaneous return to sinus rhythm is relatively common. It might be caused by relative hypovolemia due to increased diuresis caused by atrial fibrillation. Also return to sinus rhythm decreases sympathetic tone which might lead do vasodilatation and lower blood pressure. It is therefore recommended to be prepared for intravenous fluid treatment before cardioversion.

Contraindications for Electrical Cardioversion:

• Reversible cause of AF (e.g., electrolyte imbalance, severe hyperthyroidism)

• Severe sinus or AV node dysfunction without a pacemaker

  • Clues: bradycardia or regular and slow ventricular rate which might indicate nodal rhythm

• Rhythm fluctuates spontaneously between AF and sinus

  • Antiarrhythmic drugs preferred in these cases

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Pharmacological Cardioversion

Pharmacological cardioversion is effective in acute AF, though generally less effective than electrical cardioversion

Not recommended for elective cardioversion due to reduced efficacy with prolonged AF

Flecainide

More effective than placebo in acute AF

Ventricular proarrhytmias are rare, but use with an AV nodal blocker (e.g., beta-blocker) to prevent paradoxical ventricular acceleration

Might be used in WPW syndrome, as it slows accessory pathway conduction

Contraindications:

• Acute MI or decompensated heart failure

• History of MI or existing heart failure

• Sinus node dysfunction, AV block (2nd or 3rd degree), bundle branch block without pacemaker

• Atrial flutter (increases risk of 1:1 AV conduction)
   

Common Side Effects:

• Dizziness, visual disturbances

• Transient hypotension

• Paradoxical rapid ventricular response

• Bradycardia following sinus rhythm restoration
   

Clinical Trials:

1. Donovan et al. (IV flecainide 2 mg/kg, max 150 mg in 30 min):

   • 1h sinus rhythm: 57% vs. 14% (placebo)

   • 6h sinus rhythm: 67% vs. 35% (placebo)
      

2. IV Flecainide vs. amiodarone vs. placebo:

   • Sinus rhythm restored in 59% (flecainide), 34% (amiodarone), 22% (placebo). Flecainide was significantly more effective than placebo, no difference compared to amiodarone after 2h.
      

3. Capucci et al. Oral flecainide (300 mg):

   • 3h: 68% vs. 28% (placebo)

   • 8h: 91% vs. 48% (placebo)
      

Intravenous flecainide acts faster, but efficacy is similar to oral administration.

Flecainide appears to be as effective ad ibutilide and quinidine and is at least as effective or more effective as amiodarone. 

Flecainide does not appear to improve success rate of electrical cardioversion as ibutilide does.

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Vernakalant

IV vernakalant is more effective than placebo in acute AF <48h. After 72 hours effectiveness of vernakalant decreases significantly.

Does not effect ventricular rate

Targets ultra fast potassium and sodium channels mainly in the atria and does not have a significant effect QT interval

Sinus rhythm is restored in 11 minutes on average

Common Side Effects:

• Altered taste, tingling, nausea, sneezing

• Serious AEs are rare, but hypotension may occur
   

Contraindications:

• Severe heart failure (NYHA IV)

• Aortic stenosis

• QT >440ms

• hypotonia

Clinical Trials:

1. Two-dose escalation study:

   • 0,5 mg/kg in 10 minutes + 30 minutes after 1 mg/kg vs 3 mg/kg and 2 mg/kg vs placebo

   • 61% conversion with high-dose vernakalant vs. 5% with placebo after 30 minutes from the second infusion

   • median time to rhythm conversion was 14 minutes in the high dose group
      

2. IV vs placebo:

   • 3mg/kg in 10 minutes + 2mg/kg 15min after first infusion if needed vs placebo

   • AF of 3 hours to 7 days was converted to sinus rhythm in 62% in the active treatment group vs. 5% placebo

   • AF of 8 days to 45 days was converted to sinus rhythm in 24% in the active treatment group vs. 0% placebo

Vernakalant is more effective than placebo, but is not superior to amiodarone or ibutilide

Amiodarone

More effective than placebo but significantly slower-acting than other agents

Best option for post-op, critically ill, or hemodynamically unstable patients

In a study conducted by Khan et al., the effectiveness of intravenous bolus and infusion administration of amiodarone in cardioversion was investigated. They concluded that amiodarone is superior to placebo in converting recent-onset atrial fibrillation to sinus rhythm only if used in higher doses (>1500 mg/day). Conversion rates of recent-onset atrial fibrillation with the use of amiodarone range from 34% to 95%, depending on the dose of amiodarone used, the duration of atrial fibrillation, the size of the left atrium, and the duration of follow-up after administration. 

Adverse effects associated with long-term amiodarone therapy are rare during treatment in acute setting.

Amiodarone also slows conduction in accessory pathways, and therefore it can be used with caution in patients with Wolff-Parkinson-White (WPW) syndrome.

Rarely causes proarrhythmia; minimal negative inotropy. Amiodarone can prolong QT interval but rarely causes torsades de pointes.

Clinical Trials:

• Short-term efficacy: minimal difference from placebo at 2–3h

• Long-term efficacy (20–24h): 80–90% conversion rate vs. 40–60% (placebo)

• Randomized controlled trials of oral cardioversion medications have found similar 24-hour conversion rates between amiodarone versus flecainide and propafenone. In a study published a few years ago, 72 patients with acute atrial fibrillation were randomized to receive either oral amiodarone (30 mg/kg) or placebo. After eight hours, 50% of the patients who received amiodarone and 20% of those in the placebo group had converted to sinus rhythm. At 24 hours, the respective rates were 87% in the amiodarone group versus 35% in the placebo group. The average time to conversion to sinus rhythm was 8.7 hours in the amiodarone group and 7.9 hours in the placebo group.

Ibutilide

Effective in converting atrial flutter and AF

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Significant proarrhythmic risk, especially torsades de pointes. Ibutilide induces torsades de pointes ventricular tachycardia in approximately 4–8% of patients, suitable for use only in specialized care settings.

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ibutilide does not affect ventricular rate

Compared to most other antiarrhythmic drugs, ibutilide has the advantage of a rapid onset of action and high efficacy in treating atrial flutter.

Contraindications:

• Sick sinus syndrome

• AV block (2nd/3rd degree)

• Polymorphic VT

• Hypokalemia

• QTc > 440 ms

• HR < 50 bpm
   

Studies:

In comparative studies, ibutilide has been shown to be significantly more effective than procainamide and sotalol, and equally effective as amiodarone and flecainide.
Stambler et al.:  (1,0 mg + 0,5 mg or 1,0 mg + 1,0 mg 10 min infusion), 47% vs. 2%, better in flutter (63%) than AF (31%). Median time to conversion 27 minutes.

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Beta blockers

There is no evidence supporting the effectiveness of beta-blockers in the cardioversion of acute atrial fibrillation.

Rhythm Control / Prevention of Recurrence

Without antiarrhythmic treatment, 80–90% of patients experience AF recurrence within a year after cardioversion.

Paroxysmal AF has a higher recurrence risk than persistent AF.

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Antiarrhythmic medication is considered when patients tolerate AF poorly.

Early initiation of antiarrhythmic medication improves efficacy.

Antiarrhythmic Drugs

The choice depends primarily on comorbid cardiac conditions.

Beta-blockers are simple and safe; can be initiated in primary care.

Sotalol should be initiated in hospital with telemetry due to proarrhythmia risk.

Flecainide, dronedarone, amiodarone can usually be started in an outpatient clinic

Objective drug effectiveness can be assessed using ECG monitoring.

Before changing the dose or discontinuing the medication due to lack of efficacy, it is essential to ensure that the drug’s effect has had sufficient time to stabilize.

Plasma levels do not correlate well with clinical response but may help in toxicity/interactions.

Goal of antiarrhytmic treatment is symptom relief and reduced AF episode frequency— total arrhythmia elimination is rare.

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Among the cardiac adverse effects, the most problematic are proarrhythmia and worsening of heart failure due to the drug’s negative inotropic effect.

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Class II Agents – Beta-blockers

Beta blockers seem to prevent symptomatic AF episode recurrence by slowing AF ventricular rate.

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Beta blockers cannot generally be considered to be atrial stabilizing agents as the commonly used agents such as flecainide, sotalol and amiodarone. Beta-blockers have not been considered to be atrial stabilizing agents except in two well-defined situations. First, a small population of patients experience recurrent AF in association with stress or anxiety; these patients with adrenergically mediated AF may respond well to beta-blockade (as opposed to the opposite syndrome of vagally mediated AF, in which beta-blockers may exacerbate AF). Second, and more common, is the use of beta-blockers for prevention of AF in patients following cardiothoracic surgery.

Beta blockers enhance effects and reduce proarrhythmia of other antiarrhythmics

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May reduce AF symptoms by slowing ventricular rate

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The efficacy of conventional beta-blockers appears to be comparable to that of sotalol (80 mg twice daily)³. A study by Plewan et al demonstrates that sotalol (160 mg x day and bisoprolol 5 mg x day) are equally effective in maintaining sinus rhythm.

Clinical Studies:

• German RCT (n=394): Metoprolol reduced recurrence post cardioversion to 48.7% vs. 59.9% (placebo). Patients had persistent AF. 62% received 100 mg/day, 18.3% received 50 mg/day, and 16.8% received 200 mg/day of metoprolol. Electrocardiograms (ECGs) were recorded at one week, and at 1, 3, and 6 months, or earlier if the patients felt that atrial fibrillation had recurred. In the metoprolol group, atrial fibrillation recurred in 96 patients (48.7%), compared to 118 patients (59.9%) in the placebo group. Among those with recurrent atrial fibrillation, the heart rate was significantly lower in the metoprolol group (98 ± 23 bpm) than in the placebo group (107 ± 27 bpm).

Class IC Agents – Flecainide

Flecainide is superior to placebo and class IA drugs (eg quinidine) for recurrence prevention

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In individuals with structurally normal hearts, flecainide does not affect mortality, and serious adverse effects are rare

Combine with AV nodal blocker to reduce proarrhythmia

Before initiating class IC antiarrhythmic medication, cardiac structure and function must be assessed by echocardiography. A clinical exercise test or coronary imaging should be performed unless coronary artery disease can be reliably excluded by other means

Contraindications:

• Prior myocardial infarction

  • In patients with history of MI, flecainide increases mortality by ~2.5x.

• Heart failure

• Structural heart disease

• Allowed in hypertension if no LV hypertrophy >14 mm

• Can be used cautiously in WPW syndrome

Clinical Studies:

• Cochrane meta-analysis (n = 12 559): flecainide vs placebo in paroxysmal or persistent AF prevention. Risk ratio for AF recurrence 0.31

• Multicenter RCT (n = 64): flecainide (200-400mg/day) vs placebo. The interval between atrial fibrillation episodes increased from 6.2 days to 27 days. During the four-month follow-up period, atrial fibrillation was completely prevented in 31% of patients receiving flecainide, compared to 9% in the placebo group.

• Nordic RCT: Flecainide (150mg x2) vs placebo. 7% vs. 50% recurrence over 3 months

Class III Agents – Amiodarone, Dronedarone, Sotalol

Amiodarone

Amiodarone is significantly more effective compared to placebo in preventing recurrence of atrial fibrillation. It appears to be the most effective drug for atrial fibrillation prevention.

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In randomized double-blind studies, amiodarone has been shown to be more effective than dronedarone, sotalol, propafenone, and quinidine. According to a meta-analysis, amiodarone also appears to be more effective than flecainide.

The use of amiodarone requires numerous precautions and careful monitoring.

Due to numerous non-cardiac adverse effects amiodarone is not considered uitable as first-line long-term therapy for AF prevention

Several drug interactions, especially with warfarin and DOACs

However, amiodarone causes very little proarrhythmia and is safe in heart failure and post-MI patients.

Use the lowest effective dose (100–200 mg/day) after loading (e.g., 600 mg/day × 2 weeks) to minimize risk for adverse effects

Studies:

• Channer et al.: Patients had persistent AF. They were randomized to receive either placebo or amiodarone (400 mg/day for two weeks followed by 200 mg/day) starting two weeks before cardioversion and continuing for either 8 weeks or 52 weeks afterward. After eight weeks, 51% of the patients receiving amiodarone were in sinus rhythm, compared to only 16% in the placebo group (relative risk 35%). At one-year follow-up , long-term amiodarone therapy was significantly more effective in preventing recurrence of atrial fibrillation compared to short-term amiodarone therapy combined with placebo (49% vs. 33%).

• Cochrane meta-analysis (n = 12 559): Compared amiodarone to placebo in the prevention of paroxysmal or persistent atrial fibrillation. Amiodarone was significantly more effective than placebo in preventing recurrence of atrial fibrillation, with a relative risk of 0.19

Dronedarone

Dronedarone (400 mg twice daily) is more effective than placebo in preventing the recurrence of atrial fibrillation

In the DIONYSOS study and a related meta-analysis, dronedarone was found to be significantly less effective than amiodarone. However, dronedarone is associated with substantially fewer adverse effects compared to amiodarone.

Dronedarone, like amiodarone, exhibits pharmacological effects corresponding to all classes of the Vaughan–Williams classification.

Contraindications:

• Heart failure, increases mortality

• Permanent AF, increases mortality

• Prior amiodarone-induced toxicity

• Concurrent dabigatran use

Dronedarone therapy requires regular monitoring.

The medication should be discontinued if atrial fibrillation becomes chronic or if other contraindications arise.

Dronedarone has minimal impact on renal function, but serum creatinine levels may increase because the drug competes with creatinine for renal excretion.

Clinical Studies:

• EURIDIS: dronedarone 400mg x2 vs placebo. Time to recurrence: 96 vs. 41 days.

• ADONIS: dronedarone 400mg x2 vs placebo. Time to recurrence: 158 vs. 59 days

• DAFNE: Participants randomized to dronedarone at daily doses of 800 mg (400 mg BID), 1200 mg, or 1600 mg, or placebo, and followed for 6 months.

  • At the 800 mg/day dose (400 mg BID): Median time to first AF recurrence: ~60 days, versus ~5.3 days with placebo. That corresponds to a ~55% relative risk reduction. Higher doses (1200 mg and 1600 mg) did not provide additional benefit.

Sotalol

More effective than placebo. Similar in efficacy to quinidine, propafenone, bisoprolol. Less effective than amiodarone.

The class III effect becomes apparent only at high doses (over 160 mg/day). At lower doses, the drug acts like a conventional beta-blocker.

Significant risk of QT prolongation. Usually used under cardiologist supervision.

Sotalol reduces ventricular rate but it is not to be used solely for this purpose due to risk of QT prolongation and torsades de pointes

Clinical Studies:

Cochrane meta-analysis: sotalol vs placebo in maintaining sinus rhythm after pharmacological or electrical cardioversion in patients with paroxysmal or persistent atrial fibrillation. The follow-up period was one year. Patients had either lone atrial fibrillation or mild structural heart disease, but not severe heart failure. A normal QT interval was required. The daily sotalol doses ranged from 80 to 320 mg. Sotalol reduced the incidence of atrial fibrillation by approximately half, with a relative risk of 0.53.

Class V agents - Digoxin

Not effective for AF recurrence prevention

May even increase and prolong vagal AF episodes

Useful in heart failure patients who can't tolerate other rate control drugs

Digoxin alone is often insufficient to provide rate control during exertion in physically active patients

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ACE Inhibitors and ARBs

May reduce AF incidence in heart failure and hypertension. They are thought to reduce atrial stretch and prevent structural remodeling

In a meta-analysis of seven randomized studies, ACE inhibitors and ARB blockers reduced the incidence of atrial fibrillation by 43% in patients with heart failure and hypertension.

Catheter Ablation for AF Prevention

Goal is to Improve symptoms and quality of life

Generally catheter ablation does not improve prognosis. May improve outcomes in select patients with severe heart failure

In catheter ablation therapy, arrhythmogenic foci located in the antral region of the pulmonary veins are electrically isolated from the surrounding atrial tissue (pulmonary vein isolation).

The primary indication for catheter ablation is (severely) symptomatic, drug-refractory paroxysmal or persistent atrial fibrillation. As a first-line treatment, ablation may also be considered for patients with lone paroxysmal atrial fibrillation.

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Best candidates:

• Paroxysmal AF

• No significant heart disease

• Left atrial diameter <5 cm

• Frequent P-on-T atrial extrasystoles

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Rapid atrial fibrillation associated with Wolff–Parkinson–White (WPW) syndrome is life-threatening. Patients with this condition should always be evaluated for catheter ablation of the accessory pathway

Efficacy:

• more effective than medication in preventing the recurrence of both paroxysmal and persistent atrial fibrillation.

• 60–85% success rate in lone paroxysmal AF refractory to drugs

• Poorer outcomes in long-standing AF, obesity, structural heart disease. Weight loss is advised in obese patients before ablation.

Complications are rare but potentially serious:

• Cardiac tamponade (1–2%)

• Pulmonary vein stenosis (<1%)

• Thromboembolism (<1%)

• Phrenic nerve palsy (1–2%)

• Esophageal perforation (<0.1%)

Ablation does not eliminate the need for anticoagulation.

To prevent thromboembolic complications related to the procedure, it is recommended that even low-risk patients begin direct oral anticoagulation at least 3 weeks prior to the intervention.

After the procedure, anticoagulation therapy should be continued for 2–3 months in low-risk patients, while those at high risk of thrombosis (CHA₂DS₂-VA score ≥ 2) are advised to remain on lifelong anticoagulation.

If atrial fibrillation is triggered by another arrhythmia (e.g., AV nodal reentrant tachycardia, AV reentrant tachycardia, atrial tachycardia, or atrial flutter), catheter ablation of the triggering arrhythmia may also prevent the occurrence of atrial fibrillation. Catheter ablation of atrial flutter reduces the incidence of atrial fibrillation.

Surgical treatment for AF

A concomitant procedure (maze procedure) aimed at eliminating atrial fibrillation during cardiac surgery effectively prevents recurrence of atrial fibrillation.

Surgical treatment may be considered if a patient with atrial fibrillation is undergoing cardiac surgery for another indication. Otherwise, surgical treatment for atrial fibrillation is rarely justified.

Rate Control in Permanent AF

In mildly symptomatic patients (EHRA 1–2), prognosis with rate control is equivalent to rhythm control.

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The goal is for the patient to be symptom-free and for the ventricular rate to be <110 bpm at rest.

​​Symptomatic patients benefit from stricter rate control, with a target ventricular rate of 60–80 beats per minute at rest and 90–115 beats per minute during light exertion, such as walking.

Persistent mean rates >110 bpm risk tachycardia-induced cardiomyopathy.

Pharmacologic treatment

Prefer beta-blockers which have documented efficacy in other cardiac conditions (bisoprolol, carvedilol, metoprolol)

Calcium channel blockers (verapamil, diltiazem) are effective in rate control. Can especially be used in physically active patients without heart failure.

Digoxin is more effective at rest than during exertion and is thus best suited for less active patients or those with heart failure.

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Amiodarone slows the ventricular rate in atrial fibrillation. Long-term use of amiodarone for ventricular rate control is rarely appropriate.

In general, amiodarone should be discontinued if the patient remains in permanent atrial fibrillation, unless there is another indication for its use, such as prevention of ventricular tachycardia.

However, it can be used, for example, as a bridging therapy while awaiting AV nodal ablation.

Combination Therapy

If a single agent is insufficient following combinations can be used:

• Beta-blocker + digoxin

• Calcium channel blocker + digoxin

• In select cases: beta-blocker + calcium channel blocker (± digoxin), amiodarone

  • beta-blocker and calcium channel blockers have additive negative inotropic effect

In refractory cases: consider permanent pacemaker + AV node ablation

Dronedarone is contraindicated in permanent atrial fibrillation, even though it effectively slows the ventricular rate. It increases mortality, stroke risk, cardiovascular events, and the need for hospitalization in patients with permanent atrial fibrillation and additional risk factors.

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Atrioventricular (AV) Node Ablation

Atrioventricular (AV) nodal ablation improves quality of life and reduces the need for hospitalization but does not affect mortality.

First a permanent pacemaker is implanted, and usually 2–3 weeks later, complete AV block is induced by catheter ablation.

In some patients with paroxysmal AF and tachy-brady syndrome, the dosage of rate-slowing medication can be increased after pacemaker implantation so that AV nodal ablation is not necessary.

AV nodal ablation does not eliminate atrial fibrillation or the need for anticoagulation therapy.

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Indications

• Resting HR >110 bpm despite maximal tolerated medical therapy (and rhythm control not desirable or possible)

• Severe symptoms from rapid AF

• Drug side effects are intolerable

• Biventricular pacing (CRT) compromised by high ventricular rate (<90% pacing time)

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Anticoagulation in Atrial Fibrillation

The need for anticoagulation therapy is assessed using the CHA₂DS₂-VA score.
For high-risk patients (CHA₂DS₂-VA ≥ 2), anticoagulation therapy is generally indicated, even if the risk of bleeding is increased.
For intermediate-risk patients (CHA₂DS₂-VA = 1), the decision on anticoagulation therapy should be made individually, taking into account:

• the results of manageable risk factors (e.g., the significance of elevated blood pressure is minimal if it is well controlled)

• minor thromboembolic risk factors (e.g., smoking, dyslipidemia, and renal impairment) which increase the risk of thrombosis

• bleeding risk (anticoagulation should be avoided if the bleeding risk is high).
   

For low-risk patients (CHA₂DS₂-VA = 0), anticoagulation therapy is not given because the potential benefit is smaller than the risks.

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Factors that increase the risk of bleeding include:

• Age over 65 years

• Previous serious bleeding event

• Hypertension (systolic blood pressure > 160 mmHg)

• Severe renal failure

• Severe liver failure

• Cancer and other diseases or conditions predisposing to bleeding (e.g., anemia, thrombocytopenia, platelet dysfunction, diabetes)

• Other anticoagulant or antiplatelet medications (e.g., ASA, NSAIDs) and fish oil supplements

• Heavy alcohol consumption

• Genetic factors

• Dementia

• Occupations or hobbies with a high risk of injury

• Poor treatment adherence (e.g., fluctuating INR values or irregular use of a direct oral anticoagulant)

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The risk of bleeding can be assessed using the HAS-BLED score.

For patients at high risk of thromboembolism, anticoagulation therapy is generally indicated even if the bleeding risk is elevated.

The appropriateness of anticoagulation therapy should be evaluated with particular care if the HAS-BLED score > CHA₂DS₂-VA score.

If the risk of serious bleeding is greater than the thromboembolic risk, anticoagulation therapy should not be initiated; however, left atrial appendage closure may be considered.

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Specific reversal agents are available for all direct oral anticoagulants.

Idarucizumab reverses the effect of dabigatran

Andexanet alfa reverses the effect of factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban).
Prothrombin complex concentrate (PCC) can reverse the effect of factor Xa inhibitors, but not dabigatran.

Direct oral anticoagulants are contraindicated in patients with moderate or severe mitral stenosis and in those with a mechanical heart valve.

In patients with a bioprosthetic valve that does not require warfarin therapy, direct oral anticoagulants may be used as in other patients with atrial fibrillation.

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Direct Oral Anticoagulants (DOACs)

Dabigatran (direct thrombin inhibitor)

• Dose: 150 mg twice daily

• Reduce to 110 mg twice daily if:

  • Age >80

  • On verapamil

  • eGFR 30–50 ml/min
     

• Contraindicated if:

  • Mechanical heart valve

  • Mitral stenosis

  • eGFR <30 ml/min

  • ALT > 2x ULN

  • significant liver disease

  • Concurrent use of potent P-glycoprotein inhibitors or dronedarone.
     

• Antidote: Idarucizumab

Apixaban (factor Xa inhibitor)

• Dose: 5 mg twice daily

• Reduce to 2.5 mg twice daily if ≥2 of:

  • Age ≥80

  • Weight ≤60 kg

  • Creatinine ≥130 µmol/L
     

• Contraindications:

  • Mechanical valve

  • mitral stenosis

  • Severe hepatic impairment

  • Use of potent CYP3A4 and P-glycoprotein inhibitors.
     

• Antidote: Andexanet alfa or PCC

Edoxaban (factor Xa inhibitor)

• Dose: 60 mg once daily

• Reduce to 30 mg if:

  • eGFR 15–49 ml/min

  • Weight <60 kg
     

• Contraindications:

  • Mechanical valve

  • mitral stenosis

  • eGFR < 15 ml/min

  • Use of potent CYP3A4 and P-glycoprotein inhibitors.
     

• Antidote: Andexanet alfa or PCC

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Rivaroxaban (factor Xa inhibitor)

• Dose: 20 mg once daily

• Reduce to 15 mg if eGFR 30–49 ml/min

• Contraindications:

  • Mechanical valve

  • mitral stenosis

  • eGFR < 15 ml/min

  • Use of potent CYP3A4 and P-glycoprotein inhibitors.

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​Antidote: Andexanet alfa or PCC

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Warfarin

Warfarin prevents strokes significantly more effectively than placebo and ASA.

Depending on the level of risk, between 15 and 238 patients must be treated with warfarin for one year to prevent a single stroke.

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The dose of warfarin is adjusted based on INR measurements.

For the prevention of stroke and to minimize bleeding complications, an INR of 2–3 is the ideal therapeutic range. The target range may vary if the patient has, for example, a mechanical heart valve.
The “time in therapeutic range” (TTR) value expresses the percentage of time during which the therapy has remained within the therapeutic INR range.
The efficacy and safety of warfarin therapy are optimal when TTR exceeds 80%.

Exceptionally high or low individual INR values increase the risk of thromboembolic and bleeding complications regardless of the TTR.

In patients with atrial fibrillation and coronary artery disease, warfarin monotherapy is usually sufficient to prevent events related to both atrial fibrillation and atherosclerotic disease. Exceptions include patients with a mechanical mitral valve (requiring permanent combination therapy) or those with a history of percutaneous coronary intervention (requiring temporary combination therapy).

In emergencies, the effect of warfarin can be reversed with PCC or vitamin K.

Left atrial appendage closure

Percutaneous closure of the left atrial appendage with an occlusion device appears to prevent thromboembolic strokes as effectively as warfarin therapy.

Despite the risk of complications, the procedure should be considered for high-risk patients with an exceptionally high bleeding risk or in whom oral anticoagulation therapy is contraindicated.

It may also be considered if a high-risk patient experiences a serious bleeding complication during therapeutic anticoagulation.

The procedure can also be performed during cardiac surgery.