US Pharm. 2013;38(2):20-23.
ABSTRACT: Antiarrhythmic therapy for atrial fibrillation comprises
a broad range of medications that are used to prevent conversion from
normal sinus rhythm to atrial fibrillation, as well as to control
symptoms. These medications, although effective, require extensive
monitoring and patient education. The antiarrhythmics most commonly used
to maintain normal sinus rhythm in atrial fibrillation patients are the
class IC agents flecainide and propafenone and the class III agents
amiodarone, dronedarone, sotalol, and dofetilide. Recommended monitoring
parameters include renal and hepatic function, drug interactions, QT
prolongation, and exacerbation of heart failure. Patient education
should include drug interactions, adverse effects, and recommendations
for laboratory monitoring. Community pharmacists are in a unique
position to provide guidance on these medications to patients and
Atrial fibrillation affects more than 2 million people in the United States, making it the most common atrial arrhythmia.1
It also accounts for one-third of hospitalizations for cardiac
arrhythmias. This high prevalence is likely due to a combination of
factors, including the increased incidence of chronic heart disease and
the aging of the population. The median age of patients with atrial
fibrillation is 75 years, with 70% of patients aged between 65 and 85
years.1 Common heart conditions that can lead to or
exacerbate atrial fibrillation include heart failure (HF), coronary
artery disease (CAD), cardiac surgery, and valvular disease.
Atrial fibrillation is caused by ectopic foci that arise in the
atria, commonly after structural heart damage. These foci cause the
atria to beat irregularly and out of coordination with the ventricles.
Chronic atrial fibrillation can adversely affect a patient’s quality of
life; most patients experience some degree of palpitation, dizziness,
and dyspnea. More severe symptoms can occur when abnormal signals
transmit to the ventricles, causing a rapid ventricular response that
can result in hypotension, tachycardia, syncope, and chest pain. Another
serious complication of atrial fibrillation is the higher risk of
stroke or transient ischemic attack (TIA) due to a cardioembolic
Treatment Goals and Strategies
The treatment goals for a patient with atrial fibrillation are to
control the ventricular response and prevent thromboembolic
complications.2 The need for long-term anticoagulation to
reduce the risk of stroke and TIA is based on the patient’s risk level
as measured by the CHADS2 (Cardiac failure, Hypertension, Age, Diabetes, Stroke Doubled) scoring system. Risk factors included in CHADS2 are HF, hypertension, age greater than 75 years, diabetes, and previous history of stroke or TIA. Patients with no CHADS2 risk
factors are considered to be at low risk for thromboembolic events and
should not receive anticoagulant therapy or aspirin monotherapy.
Patients with a CHADS2 score of 1 or higher have a
moderate-to-high risk of thromboembolism, and treatment with warfarin or
one of the new anticoagulants, such as dabigatran, rivaroxaban, or
apixaban, is recommended.2
Strategies to control the ventricular response include rhythm control
and rate control. The rate-control method allows the atria to continue
to fibrillate, and pharmacotherapy (commonly, beta-blockers,
nondihydropyridine calcium channel blockers, and digoxin) is used to
control the ventricular rate.1 The rhythm-control strategy
utilizes a pharmacologic or nonpharmacologic modality to restore the
atria to normal sinus rhythm, after which pharmacologic therapy is used
to maintain normal sinus rhythm.
While rhythm control offers the advantage of increased cardiac output
due to preservation of synchronized atrial contraction, no studies have
demonstrated a benefit in clinical outcomes versus rate control. The
Atrial Fibrillation Follow-up Investigation of Rhythm Management
(AFFIRM) was a landmark randomized, multicenter trial of rate control
versus rhythm control in 4,060 patients at high risk for stroke or
death. AFFIRM found no significant difference between rhythm control and
rate control in mortality incidence over 5 years (hazard ratio 1.15;
95% CI 0.99-1.34), but higher rates of hospitalization and adverse
effects were seen in the rhythm-control group.3
Although rhythm control with antiarrhythmic therapy does not confer a
mortality benefit over rate control, it is a mainstay of therapy for
atrial fibrillation patients, especially those who remain symptomatic
despite adequate rate control.4 Antiarrhythmic agents are
categorized according to the Vaughan Williams classification: class I,
sodium channel blockers; class II, beta-blockers; class III, potassium
channel blockers; and class IV, calcium channel blockers.5
This review will focus on the use of class IC and III agents for
maintenance of normal sinus rhythm in patients with atrial fibrillation.
Class IC Agents
The class I antiarrhythmic agents are sodium channel antagonists,
with the class IC agents having a slow ion-channel dissociation and
classes IA and IB having intermediate and fast dissociation kinetics,
respectively.1 Class IC antiarrhythmic medications are
proarrhythmic, and their use should be limited to patients without
structural heart disease. The Cardiac Arrhythmia Suppression Trial
(CAST) was designed to determine whether the class IC agents encainide,
flecainide, and moracizine reduced the incidence of ventricular ectopy
and sudden cardiac death after myocardial infarction (MI) in 1,498
patients.6 However, CAST was discontinued prematurely because
of an increased incidence of mortality from arrhythmias, acute MI with
shock, or congestive HF in the encainide and flecainide groups.6 Therefore, the use of class IC agents, including flecainide and propafenone (TABLE 1), should be limited to patients without left ventricular hypertrophy, CAD, and HF.1
These agents are generally less efficacious than other antiarrhythmics;
approximately 23% of patients maintain normal sinus rhythm at 1 year.1
Flecainide (Tambocor): Flecainide is a potent sodium channel blocker that may be used in atrial fibrillation patients without structural heart disease.1,7
For atrial fibrillation maintenance, flecainide is generally dosed at
50 to 150 mg orally twice daily, with a dose decrease of 50% if the
glomerular filtration rate is 50 mL/min or less; plasma levels are
monitored closely. It also may be taken as a single oral loading dose of
200 to 300 mg for atrial fibrillation conversion. Plasma levels of
flecainide may be monitored in the inpatient setting, with a goal trough
level between 0.2 and 1.0 mcg/mL. Common adverse effects include
dizziness, tremor, and HF exacerbation. If flecainide is used
concomitantly with digoxin, the digoxin dose should be reduced by
Propafenone (Rythmol): In addition to its sodium
channel–blocking activity, propafenone has significant beta-blocking
activity that may be beneficial in the management of atrial
fibrillation.1,8 Typical dosing for the immediate-release
formulation ranges from 150 to 300 mg orally two to three times daily.
The extended-release formulation is dosed at 225 to 425 mg orally twice
daily. The dose should be reduced in patients with hepatic or renal
dysfunction, which will affect propafenone’s metabolism and excretion,
respectively. Propafenone also may be taken as an oral loading dose of
600 mg for atrial fibrillation conversion. Adverse effects include
unusual taste, asthma exacerbation, and dizziness. Digoxin and warfarin
doses should be decreased with the use of propafenone.
Class III Agents
Class III agents are potassium channel blockers that exert their
effects by prolonging the action potential. This leads to prolongation
of the QT interval, which increases the risk of torsades de pointes
(TDP), a potentially lethal ventricular arrhythmia. Common class III
agents used for maintenance of normal sinus rhythm include amiodarone,
dronedarone, sotalol, and dofetilide (TABLE 1).
Amiodarone (Cordarone, Pacerone): Amiodarone is a
potent antiarrhythmic that has properties of all four Vaughan Williams
classes (sodium channel blocker, potassium channel blocker, calcium
channel blocker, beta-blocker).1,9 Amiodarone and dofetilide
are the only two antiarrhythmic agents that do not increase mortality in
HF patients. Amiodarone is safe for patients with structural heart
damage and generally is considered more efficacious for maintaining
normal sinus rhythm than other antiarrhythmics; rates of 62% to 69% at 1
year have been reported.1,3 The IV formulation has strong
beta-blocking activity, whereas the oral formulation has more potassium
channel–blocking activity. Because of its large volume of distribution
(Vd) (approximately 60 L/kg), amiodarone requires a 10-g
loading dose (oral or IV) before the dose is decreased to the lowest
effective dose. Amiodarone inhibits numerous CYP enzymes, including 3A4,
2D6, 2C9, 2C19, and P-glycoprotein. Therefore, drug interactions and
dose adjustments should be monitored closely when amiodarone is
initiated or discontinued. Medications affected include digoxin,
warfarin, and hydroxymethyl glutaryl coenzyme A reductase inhibitors
Because of amiodarone’s iodine moiety and affinity for adipose
tissue, use of the drug will lead to numerous organ-system toxicities,
including hypothyroidism, hyperthyroidism, retinal deposits,
inflammatory hepatopathy, and pulmonary fibrosis.1,9 Most of
these adverse effects occur with doses exceeding 400 mg per day, which
is the basis for the recommendation to reduce amiodarone to the lowest
effective dose (commonly 200 mg daily for atrial fibrillation).
Pulmonary-function tests, thyroid-function tests, liver-function tests,
and chest radiographs are recommended at baseline, at 3, 6, and 12
months, and then annually thereafter to monitor for toxicity. An eye
examination should be performed annually. Because of amiodarone’s large Vd
and slow rate of elimination (mean half-life of 58 days; range 15-142
days), antiarrhythmic effects will persist for weeks or months after the
drug is discontinued.
Dronedarone (Multaq): Dronedarone is a modified analogue of amiodarone that possesses similar properties of all four Vaughan Williams classes.1,10 Dronedarone is generally less efficacious than amiodarone, but has a lower incidence of organ toxicities.11
It is administered orally strictly at 400 mg twice daily.
Contraindications to therapy include New York Heart Association
functional class IV HF or recent HF exacerbation, severe hepatic
impairment, second- or third-degree heart block, or heart rate under 50
beats per minute. Dronedarone also is not recommended for patients who
are in permanent atrial fibrillation with no cardioversion planned.12
Dronedarone is not associated with the multitude of toxicities
occurring with amiodarone, but adverse effects include abdominal pain,
nausea, diarrhea, QT prolongation, and HF exacerbation. There have been
recent reports of hepatic toxicity, including severe liver damage.
Because dronedarone is a CYP3A4 substrate, it should be avoided with
concurrent CYP3A4 inhibitors, such as ketoconazole, voriconazole,
cyclosporine, and clarithromycin. Dronedarone will increase serum
concentrations of digoxin and statins.
Sotalol (Betapace): Although sotalol has effects on the potassium channel, its beta-blocking activity is more potent.1,13
It is ineffective for conversion of atrial fibrillation and should be
used only to maintain normal sinus rhythm. Sotalol is a modestly
effective antiarrhythmic; approximately 37% of patients maintain normal
sinus rhythm at 1 year, similar to the efficacy of class IC agents.1
Sotalol is dosed at 80 to 160 mg orally twice daily, and it is
recommended to reduce the frequency to once daily if creatinine
clearance (CrCl) is between 40 and 60 mL/min. Sotalol is contraindicated
for atrial fibrillation when CrCl is less than 40 mL/min. Many of
sotalol’s adverse effects are due to the drug’s beta-blocking activity,
including HF exacerbation, bradycardia, atrioventricular block, and
bronchospasm. Sotalol should be initiated in the hospital setting in
order to monitor for QT-interval prolongation, because there is a risk
of TDP within the first few days of initiation.
Dofetilide (Tikosyn): Dofetilide, a pure class
III potassium channel blocker, is effective for both atrial fibrillation
cardioversion and maintenance of normal sinus rhythm.1,14 It
is the only other medication, besides amiodarone, that does not
increase mortality in patients with HF. The risks of QT prolongation and
TDP upon initiation are high (4%), however, so dofetilide must be
initiated in the hospital setting. It is generally efficacious, with
approximately 58% of patients maintaining normal sinus rhythm at 1 year.1
The dose of dofetilide ranges from 125 to 500 mcg orally twice daily
based on CrCl. Use is contraindicated if CrCl is less than 20 mL/min.
The first five doses must be given in the hospital, with ECGs performed 2
to 3 hours after each dose to monitor for QT prolongation. Subsequent
dose adjustments are based on these QT measurements. In order to
prescribe and dispense dofetilide, the physician, hospital, and pharmacy
must be registered with the manufacturer. Drug interactions that affect
dofetilide concentrations include CYP3A4 inhibitors and medications
that inhibit active tubular secretion in the kidneys.
The Pharmacist’s Role
Pharmacists in the community setting are ideally situated to
participate in the management of antiarrhythmic therapy in patients with
atrial fibrillation. As evidenced by the multitude of interactions,
adverse effects, and monitoring parameters listed above, there are many
opportunities for pharmacists to provide patient education and to advise
prescribers. The initiation or discontinuation of medications that
affect concentrations of antiarrhythmic therapy is common, and
potentially serious effects could ensue without involvement by the
pharmacist. In addition to medication education, the pharmacist also can
discuss with patients the indication and purpose of antiarrhythmic
medications in the prevention of atrial fibrillation events. In this
manner, pharmacists can be involved in the overall management of
patients with atrial fibrillation.
1. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused
updates incorporated into the ACC/AHA/ESC 2006 guidelines for the
management of patients with atrial fibrillation: a report of the
American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines developed in partnership with the
European Society of Cardiology and in collaboration with the European
Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57:e101-e198.
2. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for
atrial fibrillation: antithrombotic therapy and prevention of
thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest. 2012;141(suppl 2):531S-575S.
3. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833.
4. Zimetbaum P. Antiarrhythmic drug therapy for atrial fibrillation. Circulation. 2012;125:381-389.
5. Vaughan Williams EM. Classification of antidysrhythmic drugs. Pharmacol Ther B. 1975;1:115-138.
6. Preliminary report: effect of encainide and flecainide on
mortality in a randomized trial of arrhythmia suppression after
myocardial infarction. N Engl J Med. 1989;321:406-412.
7. Tambocor (flecainide) product information. Northridge, CA: 3M Pharmaceuticals; June 1998.
8. Rythmol (propafenone) product information. Research Triangle Park, NC: GlaxoSmithKline; June 2011.
9. Cordarone (amiodarone) product information. Philadelphia, PA: Wyeth Pharmaceuticals Inc; October 2011.
10. Multaq (dronedarone) product information. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; September 2012.
11. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term,
randomized, double-blind, parallel-group study to evaluate the efficacy
and safety of dronedarone versus amiodarone in patients with persistent
atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21:597-605.
12. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365:2268-2276.
13. Betapace (sotalol) product information. Wayne, NJ: Bayer Healthcare Pharmaceuticals; October 2010.
14. Tikosyn (dofetilide) product information. New York, NY: Pfizer Inc; February 2011.
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