Atrial Fibrillation: Pharmacologic Treatment Options

Lindsay A. Helms, PharmD, BCPS*
Clinical Specialist, Surgical Critical Care
The Johns Hopkins Hospital
Baltimore, Maryland, USA

Atrial fibrillation (AF) is associated with increased long-term risk of stroke, heart failure and mortality.(1) The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial focused on rate versus rhythm control and showed no difference in stroke rate or mortality between these two therapeutic options. The trial did show increased adverse effects and a trend toward increased mortality in the rhythm control group.(2) Each patient with AF is unique, should be assessed individually and treated based on symptomatology and risk factors. Non-pharmacologic therapies, such as direct current cardioversion and ablation, can lead to rhythm control but are not without risk. Additionally, many pharmacologic options for rate and rhythm control are available. This review will address pharmacologic options, adverse effects and clinical pearls related to drug therapy.

Antiarrhythmics can be divided into four classes using the Vaughan-Williams classification. The classes that can be used primarily for the rhythm control or pharmacologic cardioversion of AF are class I and III antiarrhythmics (Table 1). Procainamide does not appear to be as effective as ibutilide or flecainide in converting AF to normal sinus rhythm (NSR), but it did perform better than propafenone and placebo for this indication.(3) It is administered as a loading dose followed by a continuous infusion.(3) Adverse effects include hypotension and ventricular arrhythmias.(3,4) Oral procainamide is no longer manufactured in sustained or extended-release formulations, making it an inconvenient long-term alternative for the management of AF; however, it is still considered a therapeutic option for pharmacologic conversion of AF in the American Heart Association (AHA) practice guidelines.(1)

Single-dose flecainide has been studied in patients with mild structural heart disease, and its effectiveness was compared to that of amiodarone, propafenone and placebo. Oral flecainide performed better than placebo, propafenone and intravenous (IV) amiodarone for the conversion of new onset AF.(3) Flecainide is a first-line agent for the conversion of AF.(1) It can cause cardiac dysrhythmia, blurred vision, corneal deposits, headache, dizziness and nausea. Additionally, flecainide is contraindicated in structural heart disease because of the risk of  heart failure exacerbation and increased mortality.(4)

In single-dose and repetitive-dose studies, propafenone was successful in the conversion of AF; hence, the AHA recommends it as a first-line agent if conversion is deemed necessary.(1) At least 11 placebo-controlled trials have evaluated propafenone in patients with AF for no more than two weeks; the drug was found to be more effective than flecainide and quinidine and resulted in more rapid conversion than IV amiodarone.(3) Side effects associated with propafenone include altered taste sensation, gastrointestinal upset, cardiac dysrhythmias and neurologic changes.(4) Pharmacokinetic considerations include the large number of drug-drug interactions secondary to the multi-pathway metabolism via CYP 450 isoenzymes.(4)

Ibutilide is structurally similar to sotalol, though it lacks beta-adrenergic properties and primarily affects the flow of sodium into cells; it also may reduce potassium flow.(4) The efficacy of this agent in converting AF to NSR has been studied extensively with positive results. It is recommended for the treatment of propafenoneresistant AF and recurrent AF after treatment with propafenone and flecainide.(1) When administering ibutilide, the risk of ventricular tachycardia is high (>3%), so a patient should be monitored continuously; the infusion should be stopped as soon as the patient converts to NSR, even if the entire dose has not been given.

Dofetilide is a treatment option for the conversion of AF and atrial flutter.(1) Prescribing requirements are strict because of serious adverse effects associated with therapy. Patients must have continuous cardiac monitoring for a minimum of three days upon initiation of dofetilide therapy.(5) Before prescribing this agent, the provider must participate in the manufacturer’s educational certification program. In addition, pharmacies must verify that a prescriber is certified, and the pharmacy must be enrolled in the Tikosyn in Pharmacy SystemTM (T.I.P.S.) program before dispensing the drug.(5) Dofetilide is renally adjusted, and many drug-drug interactions can affect its metabolism and excretion.

Sotalol acts as an inhibitor of potassium channels and also has non-selective beta-blocking properties, which makes it an effective option for the prevention of recurrent AF. It is not effective when given for pharmacologic cardioversion, but has performed as well as propafenone and is superior to quinidine and placebo for the maintenance of NSR.(1) Sotalol has not been studied extensively in patients with heart failure or atrioventricular node conduction disturbances. It must be doseadjusted for renal insufficiency and has a high prevalence of QTc prolongation. Patients should be monitored continuously in a cardiac setting at initiation. Sotalol can cause neurologic changes, dyspnea and bradycardia.(4)

Amiodarone, one of the most frequently used and well-studied antiarrhythmics, has the properties of all of the antiarrhythmic classes. It has been shown to be effective and safe in acute and chronic AF. It can be used successfully in postsurgical patients as well as in patients with severe heart failure with less risk of exacerbation. Amiodarone is not a benign drug; it has numerous long-term side effects including thyroid toxicity, hepatotoxicity and pulmonary fibrosis. Compared to the other class III agents, amiodarone has a low incidence of arrhythmia.(4) It has a very long halflife (up to 90 days) and is highly lipophilic, leading to potential skin discoloration and corneal deposits over time. Additionally, amiodarone must be loaded to achieve therapeutic concentrations in the blood, which may take several days to accomplish. Numerous drug-drug interactions are possible because amiodarone is an inhibitor of CYP 450 3A4, 1A2, 2C9 and 2D6 isoenzymes.

Dronedarone recently was approved by the U.S. Food and Drug Administration for the treatment of AF. This drug is structurally similar to amiodarone but lacks iodine and has slightly altered end chains, which decrease its toxicity profile, lipophilic properties, and half-life. Compared to amiodarone, dronedarone has a much shorter half-life (24 hours). The drug significantly decreases heart rate and increases QT and QTc intervals compared to placebo; however, the adverse effects did not differ between the groups. Hepatotoxicity has not been documented with dronedarone, potentially because adverse effects associated with long-term use have not yet been established. In a trial designed to evaluate long-term use in patients with left ventricular dysfunction, enrollment was stopped early because of an increased incidence in death in the treatment group.(6) A black box warning is included in the dronedarone labeling regarding its use in patients with New York Heart Association class III and IV heart failure.

Pharmacologic agents used for rate control in AF are Vaughan-Williams class II and IV antiarrhythmics (Table 2). These agents are the mainstay of current AF therapy. Studies investigating ventricular rate control in patients with AF found that this therapeutic outcome was not detrimental to left ventricular function.(1) The AHA recommends beta-blockers or non-dihydropyridine calcium channel blockers for patients with persistent or permanent AF. The decision to use a class II or IV agent is based on patient-specific needs and underlying medical problems, in addition to the drug’s pharmacokinetics. No data clearly indicate that one of these agents is more effective than another for the management of AF. Bradycardia, heart block and hypotension are the most frequently experienced adverse effects of these medications.(1,4) Additionally, all rate control agents should be used with extreme caution in patients with preexisting left ventricular dysfunction because of the risk for hemodynamic compromise.

Digoxin, a cardiac glycoside not included in the Vaughan-Williams classification, has been extensively studied for in the treatment of AF. It is recommended for patients with AF and heart failure and can be considered in patients who lead an inactive lifestyle, as the effects of digoxin are lost during strenuous activity.(1)

Other “upstream” agents for the treatment of AF which do not directly act on a conduction pathway within myocardial cells include 3-hydroxy-3-methylglutaryl- Coenzyme A reductase inhibitors (HMG CoA-reductase inhibitors or “statins”). These have been discussed with enthusiasm recently and are showing great promise. Some of the benefits of statins go well beyond the lipid-lowering effects originally studied. Primarily, the pleiotropic effects are suspected to decrease the risk of acute AF and potentially increase the chance of conversion back to NSR. Several review articles evaluate the available literature, work primarily done in cardiac and thoracic surgery patients.

Because of the effect that statins have on C-reactive protein, tumor necrosis factor-alpha and interleukins, they may be effective adjunct therapy to the agents previously discussed for the treatment of AF. Caution must be exercised when considering these data, as they are taken primarily from case reports and case series, along with post-hoc analysis. Only the review by Liakopoulos et al conducted a funnel plot analysis to assess for publication bias; the authors found that there is indeed bias regarding the beneficial properties of statins for the treatment of perioperative AF.(7) More randomized controlled trials are needed to determine the role of statins in the prevention and treatment of AF.

Several pharmacologic agents are available for the treatment of AF. Almost all are antiarrhythmics, but there is emerging information regarding statins and their anti-inflammatory, upstream effects. Strong data suggest that patients can be safely and effectively managed through rate control instead of rhythm control; however, all medications have a risk-benefit profile and each patient is different. Therefore, treatment must be individualized based on underlying risk factors and medical conditions.

Special thanks to Jessica Crow, PharmD, BCPS, CNSC, and John Lindsley, PharmD, BCPS.

References:

1. Fuster V, et al. ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.|

2. Wyse DG, et al. A comparison of rate and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833.

3. Slavik RS, et al. Pharmacologic conversion of atrial fibrillation: a systemic review of available evidence. Prog Cardiovasc Dis. 2001;44:121-152.

4. Tikosyn FAQs. Pfizer Web site. http://www.tikosyn.com/Tikosyn_Dofetilide_FAQs.html#presc10. Accessed December 11, 2009.

5. Ehrlich JR, et al. Novel approaches for pharmacological management of atrial fibrillation. Drugs. 2009;69:757-774.

6. DRUGDEXâ System Drug Evaluation. In: Klasco RK, ed. DrugKnowledgeâ System (electronic version). http://www.micromedex.com/products/drugdex/. Accessed December 11, 2009.

7. Liakopoulos OJ, et al. Statins for the prevention of atrial fibrillation after cardiac surgery: a systematic literature review. J Thorac Cardiovasc Surg. 2009;138:678-686.