Antiarrhythmic Therapy in Atrial Fibrillation

Antiarrhythmic agents work by blocking the sodium channel, the potassium channel, the calcium channel, or the adrenergic receptors. Sodium channel blockade reduces the rate of rise of phase 0, which prolongs the QRS complex. Potassium channel blockade, on the other hand, lengthens the repolarization (phase 4) and therefore prolongs the QT interval.¹

Vaughan Williams Classification of Antiarrhythmic Drugs. In the Vaughan Williams classification system, class I agents are sodium channel blockers, class II are β-blockers, class III are potassium channel blockers, and class IV are calcium channel blockers.²

Class I Antiarrhythmic Agents

The class I agents are grouped into class IA (which depress phase 0), class IB (which have little effect on phase 0 in normal tissue), and class IC (which markedly depress phase 0).³ Class I drugs block sodium influx into the cells and therefore slow the atrial as well as ventricular conduction velocity and, it is hoped, terminate the arrhythmia.⁴ Class I agents are proarrhythmic and their use should be limited to patients who have no structural heart disease (that is, they are free of ischemia, infarction, valvular disease, hypertrophy, and conduction system disease).⁵ Class IC agents have more clinical application in patients with atrial fibrillation (AF), and these include drugs such as flecainide, propafenone, and moricizine.

Use Dependence and Reverse-Use Dependence

Drugs with high use (frequency) dependence bind more avidly to the ion channels during faster heart rates and therefore exert more sodium channel blockade during tachycardia.⁶ In contrast, drugs with “reverse” use (frequency) dependence bind more avidly to ion channels during slower heart rates.⁷ The clinical implication of this concept is that a drug with use dependence is effective in terminating an arrhythmia, while a drug with reverse-use dependence is effective in preventing an arrhythmia. In other words, a drug with reverse-use dependence is not helpful in acute management of a tachyarrhythmia.

Flecainide

Flecainide is an extremely potent sodium channel blocker and is very effective in treating AF and premature ventricular contractions that have been triggered in patients with structurally normal hearts.⁸ Sodium channel blockers increase the pacing but increase the defibrillation threshold as well—sometimes dramatically, so they should be avoided in patients with pacemakers or implantable cardioverter-defibrillators. The Cardiac Arrhythmia Suppression Trial (CAST) tested the hypothesis that suppression of ventricular ectopy after myocardial infarction reduces the incidence of sudden death. The study was discontinued early when results showed that sodium channel blockers were associated with higher mortality rates.⁹ This adds to the evidence that sodium channel blockers should not be used in patients with structural heart disease.

Flecainide is generally administered at doses of 50 to 150 mg, twice daily. It can be increased to 200 mg twice daily, but serum levels should be carefully monitored at these higher doses. The absorption of the drug can be adversely altered by foods, especially milk.¹⁰ An increase in the QRS duration by 15% to 20% is expected and is a sign that the drug is working effectively. Flecainide can be taken as a single oral loading dose of 300 mg to convert AF.¹¹ Because flecainide is a drug with use-dependence effect, the chance of proarrhythmic toxicity increases with exertion when the heart rate is faster. Therefore, exercise testing is recommended before dismissing patients who have begun a regimen of flecainide. Flecainide is associated with minimal risk of proarrhythmia in patients with structurally normal hearts.¹²

Propafenone

Propafenone has significant β-blocker activity and should be used with caution in patients with atrioventricular or ventricular conduction disease. The pharmacologic effects are similar to those of flecainide, although sodium blockade might be slightly less potent.¹³ Propafenone (like flecainide) causes QRS prolongation; therefore, patients should be monitored carefully for increased pacing, as well for defibrillation thresholds. Propafenone is absorbed best with food. Gastrointestinal side effects are frequent but usually transient. Its β-blockade effect may lead to asthmatic exacerbation, blurred vision, and paresthesias.¹⁴

The usual dosage is 150, 225, or 300 mg, 2 or 3 times a day. A sustained-release formulation of 225, 325, or 425 mg is also available and should be taken twice a day. A single dose of 600 mg has been used for pharmacologic conversion of AF.¹⁵ Propafenone is the ideal drug for the “pill-in-the-pocket” conversion of AF—although propafenone is less effective than flecainide, its intrinsic β-blockade activity prevents the paradoxical increase in the ventricular response that is seen with other class I antiarrhythmic agents.¹³

Class III Antiarrhythmic Agents

Class III antiarrhythmic drugs act primarily by blocking the potassium channels and therefore can lead to prolongation of the action potential and the QT interval. This can lead to ventricular arrhythmia (torsades de pointes). Amiodarone, dronedarone, sotalol, and dofetilide are examples of class III drugs.

Amiodarone

Amiodarone is the most potent antiarrhythmic drug. The intravenous formulation is a strong β-blocker, whereas the oral formulation has more potent class III activity.¹⁶ The full oral loading dose is 10 g. Gastrointestinal intolerance is most common during the initial loading and can best be prevented if the drug is loaded gradually (400 mg/d for 1 mo). Amiodarone commonly leads to prolongation of the QT interval, but because of its homogeneous blockade of the potassium channels, the risk of torsades de pointes is relatively minor (<1%).¹⁷

The iodine moiety leads to diffuse tissue penetration and toxicities of multiple organ systems, most of which are reversible. Major toxicities of amiodarone include hyper- and hypothyroidism, retinal deposits and idiosyncratic optic neuritis (irreversible and unpredictable), and congestive and inflammatory hepatopathy.

The pulmonary inflammatory presentation is characterized by cough, dyspnea, fever, elevated sedimentation rate, and eosinophilia. Development of ophthalmic or pulmonary side effects warrants discontinuation of the drug. Most side effects occur when doses of 400 mg/d or greater are used. Recommended screening tests include pulmonary function tests, thyroid function tests, liver function tests, and chest radiographs. The thyroid function tests, liver function tests, and chest radiographs should be repeated at 3, 6, and 12 months, and annually thereafter. Eye examinations are not required at baseline but should be performed annually thereafter.

Dronedarone

Dronedarone, a modified analogue of amiodarone, has the pharmacologic ability to block multiple ion channels, including the L-type calcium current, the inward sodium current, and multiple potassium currents. When dronedarone is used in patients with lone AF, the risk of cardiovascular hospitalizations is reduced.¹⁸ Dronedarone has sympatholytic effects, prolongs the time to recurrence of AF, and slows the ventricular rate in AF by an average of 11 to 13 beats/min. Dronedarone has a half-life of 1 to 2 days and is generally less efficacious than amiodarone, but has no risk of thyroid or pulmonary toxicity.

There have been a number of reports of hepatic toxicity related to dronedarone administration, including rare but severe cases of liver damage. Dronedarone is contraindicated in patients with decompensated heart failure, in whom its use is shown to increase adverse cardiovascular events and mortality rates.¹⁹

Sotalol

Sotalol is less potent than amiodarone as a potassium channel blocker and more potent as a β-blocker. Its effects on defibrillation thresholds are not very well known; some believe that it can increase the defibrillation threshold, while others believe that it decreases the threshold. Sotalol is ineffective in terminating AF because it is reverse-use dependent, but it can be effective in preventing arrhythmia.²⁰ It has a half-life of 6 to 12 hours, and can be used in doses of 80 to 160 mg twice daily. Sotalol should be avoided in patients who have creatinine clearance rates of less than 40 mL/min.

Dofetilide

Dofetilide is a pure potassium channel blocker. It is very effective in cardioverting patients with AF and safe to use in patients with structural heart disease.²⁰ The risk of torsades de pointes is substantial (4%); therefore, dofetilide must be initiated in the hospital. Its use should be avoided in patients who have advanced renal failure (creatinine clearance rate, <20 mL/min).

Antiarrhythmic Therapy in Atrial Fibrillation 533

Pharmacologic Management of Patients with Newly Discovered Atrial Fibrillation. For pharmacologic management, patients who have newly discovered AF are categorized into those with paroxysmal AF and those with persistent AF. In patients with newly discovered paroxysmal AF, no antiarrhythmic therapy is indicated unless the patient is significantly symptomatic (for example, hypotension, heart failure, or angina pectoris).²¹ Anticoagulation might be warranted, depending on the patient's risk of stroke.

For asymptomatic patients who have persistent AF (defined as AF that does not spontaneously convert), anticoagulation and rate control should be provided as needed, but there is no need for antiarrhythmic treatment. In patients with persistent AF who are symptomatic despite rate control, antiarrhythmic therapy can be considered, and it should be provided before any attempt at cardioversion. This is to increase the chance of cardioversion and to maintain the sinus rhythm afterward.²¹

Maintenance of Sinus Rhythm on the Basis of Concomitant Heart Disease. In patients with no or minimal structural heart disease, the first-line antiarrhythmic therapy is flecainide, propafenone, dronedarone, or sotalol— any one of these drugs, because they have fewer extracardiac side effects. If these are ineffective, amiodarone or dofetilide can be tried, or the patient can be considered for catheter ablation.^16,21

In patients with heart failure, amiodarone and dofetilide are the only antiarrhythmic drugs that are proved to be safe, and they should be tried first. If ineffective, catheter ablation should be considered. In patients with left ventricular septal thickness greater than 1.3 cm, amiodarone is the only drug of choice. If there is no septal hypertrophy, any of the class IC or class III drugs (that is, flecainide, propafenone, dronedarone, or sotalol) can be safely administered. Finally, in patients with coronary artery disease, sotalol or dofetilide can be used safely as the first-line antiarrhythmic treatment. Amiodarone is the second-line treatment and should be provided to those who fail to respond to the above-mentioned drugs; catheter ablation should be reserved for those in whom pharmacologic therapy is ineffective.²¹