Atrial Fibrillation: Antiarrhythmic Therapy

Atrial Fibrillation: Antiarrhythmic Therapy Mitchell A. Psotka, MD, PhD, and Byron K. Lee, MD Abstract: Atrial fibrillation is the most common cardiac arrhythmia and is associated with significant morbidity, mortality, and economic cost. Although the benefit of anticoagulation has been well described, control of the underlying rhythm disturbance can be achieved in various ways. Numerous therapeutic options exist and continue to be developed; however, the single best strategy has not been elucidated, and rate or rhythm controlling strategies may both be undertaken. The selection of particular agents to successfully achieve these strategies takes into account patient preference and comorbidity, as well as the efficacy and side effect profiles of the possible medications. This review discusses the evidence behind the various agents typically used to treat atrial fibrillation as well as provides a framework on which to make clinical decisions while initiating and continuing therapy. (Curr Probl Cardiol 2014;39:351–391.)

Introduction he burden of atrial fibrillation (AF) is between 3 and 6 million patients in the United States, approximately 1% of the total population, and the prevalence continues to increase with aging of society.1,2 It is the most common cardiac arrhythmia; causes substantial morbidity and mortality; and complicates patients with heart failure, ischemic coronary disease, cerebrovascular disease, sepsis, and those in the perioperative period. Based on data from the past decade, it is estimated that the incremental annual cost of AF for the United States is

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Disclosures: Dr Psotka has no relevant conflicts of interest to disclose. Dr Lee has received honoraria from Boston Scientific, Biotronik, and St. Jude. He is a consultant for CardioNet and receives research support from Zoll. Curr Probl Cardiol 2014;39:351–391. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2014.07.004

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approximately $26 billion.3 This expense is largely owing to hospital admissions, which can be prevented by appropriate control of this arrhythmia.4 Dr. Joseph S. Alpert: AF is also the most common arrhythmia reimbursed by Medicare for inpatient care, thus further emphasizing how common this entity is in the US hospital population.

The overall purpose of AF therapy is to prevent patient adverse outcomes. These outcomes may be symptoms that impair quality of life or hard end points such as stroke, hospitalization, or death. Unfortunately, AF may cause a diverse array of specific as well as vague symptoms, including palpitations, dyspnea, lightheadedness, syncope, weakness, or angina. Symptoms can be inconsistent and both symptomatic and asymptomatic AF may occur in the same patient.5,6 The choice of therapeutic strategy depends on patient characteristics and the clinical setting. Characterizing AF by whether it is symptomatic, how long episodes last, and whether it is an intrinsic arrhythmia or due to an extrinsic stimulus helps steer therapeutic choices. Whether AF is recurrent and perseveres in a given patient affects the choice of medical therapy. Because of this, national and international guidelines define at least 3 categories of recurrent AF: paroxysmal, persistent, and permanent.7 Paroxysmal AF lasts less than 7 days and terminates spontaneously. Persistent AF lasts for greater than 7 days, necessitates pharmacologic or electrical cardioversion for termination, and can progress to permanent AF. Permanent AF is either unresponsive to chemical or electrical cardioversion or is long-standing AF for which cardioversion has not been attempted, though it does not have a precise duration. An individual patient may demonstrate both paroxysmal and persistent AF, and during the initial encounter it may be impossible to distinguish which type of AF is present. It is also relevant to distinguish AF instigated by reversible insults from AF due to underlying cardiac electrical dysfunction.7 AF without a reversible insult is termed primary AF, wherein management focuses on the arrhythmia itself, whereas secondary AF often improves with resolution of the underlying insult. Causes of secondary AF include myocardial infarction, cardiac and thoracic surgery, cardiac and thoracic inflammatory states, toxin ingestion such as ethanol, hyperthyroidism and states of metabolic derangement, acute pulmonary embolism, and infection. The management of 352

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secondary AF should focus on treatment or removal of the underlying etiology in addition to therapy for the arrhythmia itself. When secondary AF persists despite management of potential contributing mechanisms, it may require treatment as primary AF. AF that occurs without any other identifiable cardiopulmonary disease, termed “lone AF,” typically is associated with a favorable prognosis compared with other AF categories. Dr. Joseph S. Alpert: AF in younger patients is often the lone AF entity.

This review focuses on the uses of antiarrhythmic medications to control AF; however, therapeutic management of AF can involve multiple treatment modalities. Catheter ablation and surgical procedures are not discussed in this work. These interventions should be viewed as complementary to the pharmacologic therapy described here. Additionally, although the management of AF focuses on controlling the arrhythmia and preventing its thromboembolic complications, anticoagulant therapy is also untouched in this review as the increasing collection of novel antithrombotic agents deserves its own elaboration. This article details the choice of therapy for rate and rhythm control strategies in the urgent, chronic, and perioperative settings. The primary goals of these therapies are to reduce symptoms and decrease the risk of adverse outcomes, including hospitalization, stroke, myocardial infarction, heart failure, and death. Dr. Joseph S. Alpert: However, stroke prevention is an essential therapeutic element in patients with AF.

Rate vs Rhythm Control Theoretical advantages to maintaining sinus rhythm (SR), a rhythm control strategy, compared with a heart rate (HR) control strategy mediated by atrioventricular (AV) nodal blocking agents, include improved symptom control, improved cardiac circulatory function, decreased cardiac remodeling, and decreased stroke risk. Although current evidence from multiple randomized controlled trials does not convey a mortality benefit for the maintenance of SR, meta-analyses suggest that rhythm control may provide an advantage to young subgroups.8,9 Compared with evenly spaced ventricular activation, Curr Probl Cardiol, October 2014

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AF-mediated irregular ventricular activation at the same rate decreases cardiac output by 15%, and persistently elevated ventricular rates can produce a tachycardia-induced cardiomyopathy.10-12 Mechanistically, cardioversion and maintenance of SR causes reverse remodeling of atrial enlargement induced by AF and may provide some advantage to a rhythm control strategy.13 Dr. Joseph S. Alpert: Stroke risk is reduced if patients are persistently in SR. Unfortunately, silent episodes of AF, not noted by the patient or the physician, are often present in patients who are asymptomatic and who request discontinuation of anticoagulant therapy. In this setting, patients must be advised that stroke risk persists, and hence anticoagulation therapy should not be discontinued.

Multiple randomized controlled trials have failed to demonstrate a distinction in outcomes between rate and rhythm control strategies. 14-20 The largest trial, atrial fibrillation follow-up investigation of rhythm management (AFFIRM), studied 4060 patients older than 65 years with paroxysmal or persistent AF for 5 years.17,18 Patients were randomized to rhythm vs rate control. Antiarrhythmic choice was made by the treating physician and 62.8% of patients used amiodarone, 41.4% sotalol, 14.5% propafenone, 8.3% flecainide, and 0.6% dofetilide during the trial. HR control was targeted to less than 80 beats per minute (BPM) at rest or less than 110 with exertion, and the researchers used digoxin, nondihydropyridine calcium channel blockers, and β-adrenergic antagonists. All patients in the rate control population received anticoagulation, whereas it could be stopped in the antiarrhythmic group once SR was maintained for 4 weeks. There was a statistically significant decrease in hospitalization with rate control, and there were statistically more cerebrovascular ischemic events in the antiarrhythmic arm apparently because of discontinued anticoagulation. Although there was a nonsignificant decrease in all-cause mortality in the rate control arm, post hoc analyses have demonstrated that this was primarily owing to noncardiovascular death.21 Specifically, the rates of cardiovascular and arrhythmic death were not statistically different between the rate control and rhythm control groups. The deaths responsible for the differences between the treatment arms were adjudicated to be caused by pulmonary processes and cancer. There was significant crossover, with 14.9% of the rate control group initiating antiarrhythmic medication and 37.5% of the rhythm control 354

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group switching to rate control, likely because at 5 years follow-up only 62.6% of the rhythm control arm were in SR. There was no difference in quality of life between the groups. Dr. Joseph S. Alpert: As noted earlier, many of these patients were undoubtedly still at risk for stroke when their anticoagulant therapy was discontinued.

Smaller trials of persistent AF support the results of AFFIRM. The second largest, the rate control versus electrical cardioversion for persistent atrial fibrillation (RACE) trial enrolled 522 patients with persistent AF lasting less than 1 year.17 The average age of the patients was 68 years, but subjects younger than 60 years were included, and follow-up was for mean 2.3 years. Patients previously on amiodarone were excluded. The rhythm control protocol required initial cardioversion followed by sotalol as the first-line agent. Further antiarrhythmic therapy then included flecainide, propafenone, and finally amiodarone in that order. The rate control arm targeted a resting HR less than 100 BPM, and if symptoms or intolerance to AV nodal agents arose, those randomized to the rate control arm underwent AV nodal ablation with pacemaker placement instead of allowing antiarrhythmic crossover. In the rhythm control group, anticoagulation could be discontinued after 4 weeks of documented SR, similar to AFFIRM. RACE demonstrated no significant difference between the groups with respect to cardiovascular death, thromboembolism, heart failure, or adverse medication effects. The conundrum was addressed in patients with heart failure in the atrial fibrillation and congestive heart failure (AF-CHF) trial and found to be consistent with other studies. In AF-CHF, 1376 patients with left ventricular ejection fraction (LVEF) r35% and paroxysmal or persistent AF of less than 1 year were treated with either rate or rhythm control and followed up for 3.1 years.19 Amiodarone was the medication of choice with 82% of the rhythm control arm on amiodarone at 12 months; however, sotalol and dofetilide could be used if needed. Rate control therapy included only β-blockers and digoxin, and targeted a resting HR less than 80 BPM or less than 110 with exertion. Patients unable to be controlled with AV nodal agents were recommended for AV nodal ablation and pacemaker placement to reduce study arm crossover; however, 21% crossed over to the rate control group anyway. More than 80% of the rhythm control group was in SR at 2 years follow-up. There Curr Probl Cardiol, October 2014

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was no statistically significant difference in cardiovascular death, allcause mortality, stroke, or worsening heart failure between the study arms. The Japanese rhythm management trial for atrial fibrillation (J-RHYTHM) studied only patients with paroxysmal AF and found similar results but suggests that healthier patients may benefit from rhythm control.20 In J-RHYTHM, 823 patients who were followed up for a mean of 1.6 years were randomized to rate vs rhythm control and the choice of agent was unblinded according to the Japanese AF guidelines. The average age was 65 years, and they were relatively healthy as 78.1% had a CHADS2 score r1.22 Anticoagulation was continued in all patients, even in SR, because of the increased ischemic events in the AFFIRM rhythm control arm. Patients primarily received Class I agents, including pilsicainide in 32.5%, cibenzoline in 20.8%, propafenone in 11.7%, and flecainide in 8.1%, and amiodarone only in 0.5%. In the rhythm therapy arm, 84.3% of patients were in SR after 2 years. In the rate control group, 51.5% were treated with β-blockers, 26.5% with calcium channel blockers, and 19.1% with digoxin. There was no significant difference between the study arms with regard to mortality, which overall at trial end was only 0.9%, compared with 8% at 2 years in AFFIRM.18 However, the composite of total mortality, thromboembolism, worsening heart failure, and physical or psychological disability was significantly improved in the rhythm control arm of this population because of improved quality of life. Unfortunately, these results do not apply universally given the lack of blinding and the fairly healthy population studied. Meta-analyses on this topic confirm the conclusion that rhythm control does not appear advantageous over rate control in most patients with paroxysmal or persistent AF, but that there may be a healthier group of patients in whom rhythm control may be preferred. Two groups each analyzed 10 trials that directly compared both the strategies.8,9 Correspondingly, 7867 patients and 7876 patients were analyzed. Most of the data were from AFFIRM, RACE, J-RHYTHM, and AF-CHF, but these analyses also included smaller 150-250 patient trials that studied young patients with rheumatic AF. All-cause mortality was not different between both the treatment groups in the meta-analyses.8,9 There were also no significant differences in rates of cerebrovascular or systemic thromboembolism, worsening heart failure, or bleeding. Rehospitalization was significantly lower with rate control therapy, with a relative risk of 0.67 (CI: 0.50-0.90, P = 0.007). However, when the analysis was limited to patients younger than 65 years, rate control had an increased relative risk of all-cause mortality of 3.03 (CI: 1.59-5.75, P = 0.0007) and an increased 356

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risk of the composite outcome of mortality, worsening heart failure, thromboembolism, and bleeding with an odds ratio of 1.89 (CI: 1.28-2.86, P = 0.002), mainly driven by an increased risk of heart failure.8,9 Dr. Joseph S. Alpert: As noted throughout this article, the decision for rate control vs rhythm control should be individualized from patient to patient. Patients should be completely informed concerning the risks and benefits of anticoagulant therapy and the final decision concerning its use is then negotiated.

There remain possible advantages to rhythm control that have not been resolved by prospective randomized controlled trials. As described, antiarrhythmic therapy may be beneficial in young symptomatic patients with few comorbidities.23 This may be because atrial size increases over time in patients with persistent AF even in those patients starting with normally sized atria.24 Evidence from animal models also demonstrates that compared with a regular rhythm, irregular ventricular response directly reduces cardiac output by 9%.25 Tachycardia particularly due to AF worsens ventricular function and control of that tachycardia resolves that dysfunction.12 In AFFIRM, post hoc analyses have associated maintained SR with survival, even though antiarrhythmic therapy does not.26 SR may also be an attractive goal that is not attainable with current therapeutic means. The relatively poor ability of the current agents to protect against regression to AF underlies the lack of benefit for a rhythm control strategy. As discussed earlier, only 62.6% of the patients in the rhythm control arm of AFFIRM were in SR by the end of the trial.18 The incomplete positive effects combined with the known adverse effects of the studied antiarrhythmic therapeutic agents may outweigh their benefits in maintaining SR. Improved medications may overcome these drawbacks. For instance, patients that converted to SR with dofetilide had decreased mortality and hospitalization, but this agent was not routinely used in the trials comparing rhythm and rate control.27 Dr. Joseph S. Alpert: Patients with ischemic heart disease may develop clinically important ischemia secondary to the marked increase in HR; patients with preexisting heart failure may decompensate secondary to the increase in myocardial oxygen demand that accompanies the AF tachycardia.

By contrast, some purported benefits of a rhythm control strategy have been disproven. Although a rhythm control strategy may be conceived as a way to avoid anticoagulation therapy in patients with AF, it appears that a Curr Probl Cardiol, October 2014

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rhythm control strategy does not lower the stroke rate in patients with AF.18 This conclusion is supported by data from AFFIRM and RACE where the control strategy did not alter stroke rates, and warfarin decreased the incidence of ischemic stroke in both groups.17,28 Rate control can benefit the patient with uncontrolled AF without conversion to SR. In patients with a tachycardia-induced cardiomyopathy, rate control alone can improve ejection fraction; median ejection fraction increased from 25% to 52% with rate control in one small study.12 Finally, although the indication for a rhythm control strategy is symptomatic AF despite HR control, or inability to control HR because of medication intolerance or comorbidity, this is only supported by limited data for improved quality of life and functional status.15 Practically, the decision to initiate a rate control or rhythm control strategy takes into account the type and duration of AF, the severity and quality of the symptoms, patient comorbidities, age, and overall treatment goals. Based on the data described earlier, it is reasonable to apply an initial rate control strategy to an asymptomatic elderly patient with cardiovascular comorbidities. In cases of resistant symptoms, a rhythm control strategy can be undertaken. In younger patients, it may be more reasonable to attempt rhythm control, particularly if the patient is symptomatic, as the anatomical and electrical changes that occur during persistent AF become refractory to cardioversion as the patient ages. The aforementioned data should not affect decision making within the advanced cardiovascular life support algorithm, as the trials described all refer to stable patients without hypotension. Finally, it is always critical to follow the appropriate guidelines for anticoagulation when considering a rhythm control strategy and cardioversion.7 Dr. Joseph S. Alpert: I agree with the authors concerning this very important point.

Medications for Rate Control Controlling the ventricular rate in a patient with AF without conversion to SR typically involves modulating the AV node. Conduction through the AV node is dependent on calcium channels that can be modulated by various stimuli, including autonomic and vagal tone as well as by the inherent properties and disease of the AV node, such as refractoriness, scar, and the presence of multiple electrical pathways. Conduction through the AV node has distinct properties that are relevant to the control of AF. The 358

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AV node demonstrates decremental conduction, meaning that stimulation by greater numbers of action potentials causes AV nodal conduction to slow. In this way, the faster the repetitive atrial stimulus the more of these signals are likely to be blocked and not conduct to the ventricle. However, when considering a rate control strategy, it is essential to determine that no bypass tract between the atria and ventricles exists. When conduction through the AV node is decreased, an antegrade conducting bypass tract can capture the ventricular tissue and lead to paradoxically more rapid ventricular rates that can degenerate into ventricular fibrillation and death.29 Antegrade conducting bypass tracts are usually unaffected by changes in autonomic tone or vagal stimulus, associated with sudden cardiac death, and a contraindication to AV nodal blockade. The appropriate target HR during a rate control strategy has been prospectively evaluated. The rate control efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control II (RACE II) randomized, open-label trial compared maintenance of a target resting HR lower than 80 BPM in the strict group vs lower than 110 BPM in the lenient group in 614 patients with permanent AF.30 HR measurement was made in the supine position after 2-3 minutes of rest. The strict population was also targeted to a HR lesser than 110 with exertion. The medications used were primarily β-blockers, calcium channel antagonists, and digoxin, alone or in combination. The population was relatively healthy, with 61% having a CHADS2 score of 0-1, and the mean was 1.4. RACE II followed up patients for 2-3 years after randomization and found no significant difference between both the groups in terms of cardiovascular death, heart failure hospitalization, stroke, embolism, bleeding, or life-threatening arrhythmias. Post hoc analysis of only the patients with heart failure in RACE II demonstrated similar results.31 However, only 67% of the total strict rate control group achieved their target resting HR compared with 98% of the lenient control group, despite requiring more than 9 times the number of cumulative visits to adjust medications. The mean resting HR after 1 year of trial participation was 86 ⫾ 16 BPM in the lenient group and 75 ⫾ 12 BPM in the strict group, which likely minimized any potential treatment effect. Nevertheless, the current practice guidelines recommend titration of AV nodal agents to a lenient resting HR o 110 BPM in patients with asymptomatic AF and with an LVEF 4 40%.7 Successful rate control should be evaluated by ambulatory HR monitoring including periods of exercise and rest. There are only a few classes of agents used for HR control in AF. Factors, such as patient hemodynamic stability, comorbidity, including the presence of heart failure, and physician as well as patient preference, Curr Probl Cardiol, October 2014

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determine the choice between them. The rapidity with which the HR must be controlled in rapid AF constitutes a branch point. Multiple intravenous rate control agents exist for expeditious control as compared with oral agents, though these medications can also be used if the oral route of administration is unavailable. Intravenous agents include the β-blockers esmolol, metoprolol, and propranolol; the nondihydropyridine calcium channel blockers verapamil and diltiazem; and digoxin. AV nodal action occurs with β-blockers within 5 minutes and for nondihydropyridines within 7 minutes, whereas digoxin takes at least 60 minutes.7 Rate control medications may also lower blood pressure, which can be either advantageous or detrimental. In patients with systolic heart failure, the effect of β-blockers and amiodarone should be tested cautiously, the nondihydropyridines should be avoided, and digoxin can be used freely though monitored closely. Multiple AV nodal blocking medications can be combined to provide appropriate HR control in AF with the main adverse effect to monitoring being bradycardia and high-degree AV nodal block. Numerous β-adrenergic receptor-blocking agents can be used for HR control in AF, and these agents do have the potential to cause cardioversion. βBlockers inhibit the effect of adrenergic stimuli and increase the electrical refractory period throughout cardiac tissue. Through this mechanism, they inhibit adrenergic stimulation of calcium channels and increase AV nodal refractoriness. A secondary study of AFFIRM queried the efficacy of these as rate control agents.32 In AFFIRM, 24% of patients in the rate control arm were treated with β-blockers alone, 17% with calcium channel blockers alone, and 16% with digoxin alone. However, the HR of 70% of patients who were given β-blockers were appropriately rate controlled, whereas with calcium channel blockers and digoxin the success rates were 54% and 58%, respectively. A small trial comparing β-blockers and calcium channel agents with and without digoxin found β-antagonists to be a superior monotherapy, with further improvement when combined with digoxin.33 Oral β-blockers that may provide long-term therapy include metoprolol, carvedilol, atenolol, and propranolol. Sotalol, which also has type III antiarrhythmic action, provides rate control by way of its β-blocking activity when it fails to maintain SR. Dr. Joseph S. Alpert: Patients who are NPO can be treated with a continuous infusion of esmolol or repeated timed intravenous injections of other β-blockers, for example, metoprolol.

The nondihydropyridine calcium channel blockers can be used for rate control and are useful for patients unable to tolerate β-blockers. 360

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Functionally, these directly inhibit AV nodal action potentials, though notably they also have this action on the sinus node for patients not in permanent AF. These agents do not prolong the QRS on electrocardiography because there is no change in sodium conductance. They should be avoided in heart failure with decreased LVEF. Both diltiazem and verapamil are effective for rate control in AF and can be used in patients with bronchospasm, in contrast to β-blockers. A small trial comparing the effect of the nondihydropyridines in AF demonstrated improved HR control with both, as well as improved exercise tolerance, without significant difference between both.34 Additionally, comparison between diltiazem, amiodarone, and digoxin for rate control demonstrated diltiazem to be superior in terms of rate control and symptom improvement in patients with acute hospitalized AF.35 Dr. Joseph S. Alpert: Verapamil can cause troublesome constipation, particularly in elderly patients.

The niche for digoxin as a rate control agent in AF continues to diminish because of comparatively poor efficacy, toxicity, and narrow therapeutic window. It is currently primarily useful only to control the HR at rest in patients with limited activity or in combination rate control therapy with additional agents, and is only recommended by the guidelines in patients with heart failure and AF.7,36 Digoxin functions by increasing vagal tone, which decreases sinus node automaticity, decreases AV nodal conduction, and increases AV nodal refractoriness. Unfortunately, elevated sympathetic tone from sources such as fever or hyperthyroidism can overcome the vagally mediated effects of digoxin. Digoxin lowered the resting HR in patients with AF but not the exercise HR in multiple trials, as compared with calcium channel and β-blocking agents, which decreased HR in both the settings.37 However, digoxin is the agent most demonstrated to be effective in combination with βadrenergic or calcium channel antagonists and may synergize with them.33 Nonetheless, despite altering the autonomic milieu of the heart, in small trials, digoxin was no more effective than placebo in cardioversion.38,39 The most common adverse effects are ventricular arrhythmias, AV block, and sinus pauses. Serum concentration is determined by renal function, as well as by numerous interactions with other agents, and the ideal concentration is 0.5-1.0 ng/mL when measured at least 8 hours after the previous digoxin dose.36 Furthermore, even when given Curr Probl Cardiol, October 2014

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intravenously the initial effect is delayed for 1 hour, the maximum effect further delayed up to 6 hours, and a half-life of 2 days can prolong up to 7 days with renal dysfunction. Dr. Joseph S. Alpert: Dosing digoxin to these blood levels has been shown to be beneficial in heart failure patients. Higher blood levels are usually required for HR control in patients with AF.

Although amiodarone can be used as a rate control agent during AF according to the major guidelines, except with permanent AF, this carries the risk of pharmacologic cardioversion and is an off-label use in the United States.7 Therefore, amiodarone is typically not used in patients that are not appropriately anticoagulated and is used in patients in whom other rate control agents have failed. Amiodarone has multiple modes of AV nodal action, including β-adrenergic and calcium channel antagonism, in addition to its antiarrhythmic activity inhibiting sodium and potassium fluxes. Although amiodarone as a rate control agent has not demonstrated resultant improvements in exercise tolerance or quality of life because of its antiarrhythmic activity, it can be used in patients with an accessory pathway for HR control.40 Unfortunately, much of the effect of amiodarone on AF HR is delayed for days after intravenous administration, weeks after oral administration, and long-term use is associated with numerous well-described side effects of the medication, including pulmonary, dermatologic, thyroid, and corneal dysfunction. Finally, amiodarone can exacerbate heart failure and hypotension due to its adrenergic blockade. Less than 1-g loading dose demonstrates increased left ventricular filling pressures and decreased cardiac index concomitant with reduced HR.41 Dr. Joseph S. Alpert: Nevertheless, it is remarkable how well intravenous amiodarone is usually tolerated without exacerbating CHF in patients with markedly reduced left ventricular function.

Medications for Conversion to SR Rhythm control requires initial cardioversion, by spontaneous, electrical, or chemical means. Patients with new acute-onset AF lasting less than 72 hours will spontaneously convert to SR 68% of the time, with 66% of those converting within 24 hours.42 However, for patients who do not spontaneously convert to sinus rhythm, cardioversion may be facilitated. Cardioversion is recommended in patients with hemodynamic 362

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instability and stable patients with intolerable AF symptoms.7 Electrical direct current cardioversion is typically highly effective and safe, but pharmacologic therapy can improve the success rate in patients' refractory despite high energy and appropriate electrode placement. Pharmacologic therapy can also be employed without electrical cardioversion; however, it is less effective particularly for AF duration of greater than 1 week.43 Agents recommended to be used for pharmacologic cardioversion include flecainide, propafenone, ibutilide, amiodarone, and dofetilide, with the latter 3 being most useful in AF lasting more than 1 week.7 The need for anticoagulation and prevention of thromboembolism in patients undergoing cardioversion, although outside the scope of this work, deserves close attention.7 Antiarrhythmic medications are categorized by the Vaughan-Williams classification based on their mechanism of action.44 Class I medications directly block sodium channels, Class II cause β-adrenergic receptor blockade, Class III prolong repolarization by interfering with potassium channels, and Class IV, the nondihydropyridine calcium channel blockers, inhibit L-type calcium channels. Class I agents are further subdivided based on their effects on conduction and repolarization into Class IA, which have additional anticholinergic effects (disopyramide, procainamide, and quinidine); Class IB (lidocaine and mexilitine); and Class IC, which inhibit the peak inward sodium current and increase the effective refractory period (flecainide and propafenone). Class III agents include amiodarone, dronedarone, dofetilide, ibutilide, and sotalol, which lengthen the atrial and ventricular effective refractory periods. Antiarrhythmic agents can have activity from multiple classes. The appropriate doses, mechanisms, and adverse effects of the commonly used antiarrhythmic agents are summarized in the Table. Electrical cardioversion success for persistent AF can be enhanced by a variety of pharmacologic agents. Pharmacologic pretreatment can be used for patients who fail initial electrical cardioversion, or those with AF recurrence. AF reinitiation after cardioversion can occur within minutes or be delayed for weeks, and the overall effectiveness of cardioversion for persistent AF is at least 70%.45,46 However in 1 trial, maintenance of SR at 4 weeks occurred in only 37% of those who cardioverted.46 Amiodarone, flecainide, ibutilide, propafenone, and sotalol increase cardioversion rates as well as reduce AF recurrence. There is mild evidence for β-blockade in this situation, specifically for carvedilol, and contradictory evidence for calcium channel blockers. Diltiazem and verapamil have been demonstrated to both decrease and increase AF recurrence following cardioversion.47-50 There is poor evidence for dofetilide, procainamide, and Curr Probl Cardiol, October 2014

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Table. Medications used for cardioversion and rhythm control in patients with AF Medication

Mechanism

Route

Cardioversion dose

Rhythm control dose

5-7 mg/kg over 30-60 min then – 1-2 g daily until 10 g total, then 200-400 mg daily maintenance Orally 1-2 g daily (600-800 mg daily 600-1000 mg daily until 10 g outpatient) until 10 g total, total, then 100-400 mg daily then 100-400 mg daily maintenance maintenance 400-750 mg daily Disopyramide Use-dependent Orally Not indicated INa and cholinergic blockade Orally GFR 4 60 mL/min: 500 μg twice 125-500 μg twice daily adjusted Dofetilide IKr blockade daily for renal function and QT prolongation during inpatient GFR = 40-60 mL/min: 250 μg initiation twice daily GFR = 20-40 mL/min: 125 μg twice daily GFR o 20 mL/min: contraindicated 400 mg twice daily Dronedarone IKr, IKs, INa, and Orally Not indicated β-adrenergic blockade Amiodarone

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Flecainide

IKr, IKs, INa, and IV β-adrenergic blockade

1.5-3.0 mg/kg over 10-20 min Use-dependent IV INa blockade Orally 200-300 mg

– 50-150 mg twice daily

Adverse effects Hypotension, bradycardia, QT prolongation, torsades de pointes, GI upset, constipation, phlebitis (IV form only), photosensitivity, pulmonary toxicity, polyneuropathy, hepatic toxicity, thyroid dysfunction, ocular toxicity, and warfarin interaction

Torsades de pointes, heart failure, glaucoma, urinary retention, and dry mouth

QT prolongation and torsades de pointes.

Nausea, diarrhea, increased serum creatinine (unchanged GFR), bradycardia, hepatic toxicity, heart failure, warfarin interaction, and digoxin interaction Hypotension, atrial flutter with rapid ventricular conduction, ventricular tachycardia, heart failure, and QRS prolongation

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Table. Continued Medication Ibutilide

Mechanism IKr blockade

Procainamide Use-dependent INa and cholinergic blockade Propafenone Use-dependent INa blockade Quinidine

Sotalol

Route IV

Cardioversion dose 1 mg over 10 min, may repeat once

Rhythm control dose Not indicated

IV 500-1200 mg over 30-60 min Orally Not indicated

– 2000-4000 mg daily

IV 1.5-2.0 mg/kg over 10-20 min Orally 600 mg

– 225-450 mg twice daily

Use-dependent Orally 0.75-1.5 g divided over 6-12 h, INa and with an AV nodal agent cholinergic blockade Orally Not indicated Reverse usedependent IKr and β-adrenergic blockade

GFR, glomerular filtration rate; IV, intravenous; GI, gastrointestinal.

600-1200 mg daily, in 2-3 divided doses

80-320 mg daily

Adverse effects QT prolongation, torsades de pointes, monomorphic ventricular tachycardia, headache, hypotension, bundle branch block, and AV nodal block Drug-induced lupus and hypotension (with IV formulation)

Hypotension, atrial flutter with rapid ventricular conduction, ventricular tachycardia, heart failure, and GI upset Diarrhea, nausea, torsades de pointes, hypotension, QT prolongation, and vagolysis

Torsades de pointes, QT prolongation, heart failure, bradycardia, and bronchospasm

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disopyramide. Quinidine loaded 24-48 hours may effectively augment cardioversion for persistent AF; however, it is not routinely used due to its adverse effects.51,52 Specific agents are further discussed later. Amiodarone can facilitate electrical cardioversion and decrease AF recurrence. Treatment of persistent AF for 6 weeks before electrical cardioversion and for 6 weeks afterward increased the conversion rate from 83%-100%.47 In this setting, it was superior to diltiazem.49 In a later trial, with 4 weeks of pretreatment and an approximate 8-g oral load, amiodarone and carvedilol both raised the cardioversion rate from 73% to 93%.47,53 However, a month after conversion 39% of patients in the placebo group, 28% of patients treated with carvedilol, and 17% of patients on amiodarone reverted to AF.53 Amiodarone pretreatment also reduced the total energy needed for successful cardioversion. In another study, a loading dose of 6-g amiodarone caused spontaneous cardioversion in patients who previously failed electrical cardioversion. Cardioversion during the oral load occurred in 18%, and it facilitated successful repeat cardioversion in 59% of the patients, all of whom had failed initial electrical cardioversion.54 Of those who did convert to SR with amiodarone, 52% continued to be in SR 1 year afterward. Ibutilide, another Class III agent, can also potentiate electrical cardioversion and prevent AF recurrence. Ibutilide pretreatment with 1 mg before transthoracic cardioversion increased the restoration of SR from 72%-100%.55 Ibutilide allowed cardioversion in 92%-100% of patients who failed electrical cardioversion and reduced the mean energy required.55,56 Ibutilide at this dose also demonstrated decreased AF recurrence compared with verapamil, and similar efficacy as amiodarone following pulmonary vein isolation.57,58 The Vaughan-Williams Class IC agents decrease recurrence and cause pharmacologic cardioversion, but do not potentiate electrical cardioversion. Intravenous flecainide pretreatment 30 minutes before cardioversion in persistent AF neither improved efficacy nor decreased energy usage.59 Patients with persistent AF who were administered 750 mg of oral propafenone for 2 days had neither a significant improvement in restoration of SR with electrical cardioversion nor a decrease in shock energy.60 Nevertheless, some of these patients did convert to sinus rhythm with propafenone alone, some converted to atrial flutter, which allowed cardioversion to SR with lower energy, and 74% vs 53% with placebo maintained SR 2 days after cardioversion.60 Multiple agents can be employed for pharmacologic cardioversion. Pharmacologic cardioversion has a main advantage over electrical cardioversion in that it does not require sedation; the anticoagulation guidelines are identical for both the methods. Pharmacologic cardioversion is most effective if performed within 24 hours of AF onset and loses efficacy after 1 week.43,61 366

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Flecainide and propafenone can be used both inpatient and outpatient, but additional agents only to be used in the hospital setting include quinidine, procainamide, disopyramide, amiodarone, ibutilide, and dofetilide. Sotalol is contraindicated for cardioversion owing to possible harm. Pure β-blockers may have a modest cardioversion effect, but the other rate control agents, digoxin and nondihydropyridine calcium channel antagonists, do not. Those medications with the greatest proven efficacy for AF of less than 1 week are flecainide, dofetilide, ibutilide, amiodarone, and propafenone, with dofetilide, amiodarone, and ibutilide being most useful in AF that is present for more than a week. Dofetilide is only an oral agent and ibutilide only intravenous, but flecainide, amiodarone, and propafenone can be administered orally or intravenously. For patients with myocardial dysfunction, the Class III agents amiodarone and dofetilide are the safest and most effective, but often take more than 24 hours to achieve cardioversion. The Class IC agents flecainide and propafenone are effective for pharmacologic cardioversion of AF. Controlled trials of a single oral or intravenous dose of flecainide converted up to 68% of recent-onset AF in 2 hours and 91% in 8 hours.62 Propafenone has similar efficacy either orally or intravenously.62 For single-dose propafenone, the rate of conversion to SR ranges from 56%-83%.63 For hemodynamically stable paroxysmal AF in patients with normal hearts responsive to flecainide or propafenone, an outpatient pill-in-pocket approach can be used. Patients are given 200-300 mg of flecainide or 450-600 mg of propafenone to take when they enter AF to stimulate cardioversion.64-66 Contraindications include AV or sinus node dysfunction, conduction system disease, QT prolongation, or Brugada syndrome. Oral flecainide and propafenone have a 94% cardioversion success rate within 6 hours in select patients in the outpatient setting. Propafenone was more rapid but demonstrated similar conversion frequency as amiodarone.67 Patients are instructed to take the chosen medication 5 minutes after the onset of palpitations and not to take more than 1 dose in 24 hours. This approach decreases emergency room visits and hospitalizations.64 Unfortunately, only 12% of patients with AF meet the criteria described, and only 80% of those are responsive to flecainide or propafenone. Dr. Joseph S. Alpert: Careful clinical and ECG assessment is required when one employs type III agents, as they can precipitate episodes of torsades de pointes.

The Class IA agents quinidine and procainamide are infrequently used but are superior to placebo. Quinidine has been avoided primarily because of Curr Probl Cardiol, October 2014

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perceived weak efficacy compared with other antiarrhythmics, as well as a poor side effect profile that includes interactions with multiple cardiac agents.68 Procainamide may sometimes be used as an alternative to amiodarone for conversion of recent-onset AF in the presence of an AV bypass tract, but has not been well explored for use in persistent AF.69 Procainamide is not used for long-term therapy because of its association with the development of antinuclear antibodies as well as agranulocytosis. Neither oral quinidine nor procainamide are currently readily available in the United States. Dr. Joseph S. Alpert: Short-term (1-2 day) intravenous infusions of procainide are often successful in terminating new-onset AF, particularly in postoperative patients who develop AF.

Amiodarone has been heavily studied for cardioversion of recent-onset AF, with positive results limited by the underlying high spontaneous rate of SR conversion. In a meta-analysis of 18 trials of AF lasting less than 7 days, intravenous amiodarone led to cardioversion within 24 hours in 76% of patients. This was compared with 60% for placebo and 72% for all other antiarrhythmic medications administered, mainly propafenone and flecainide.70 However, 17% of the patients given amiodarone had adverse events attributed to the medication, including infusion phlebitis, bradycardia, and hypotension.70 A smaller meta-analysis of trials demonstrated similar efficacy in cardioversion of recent-onset AF by amiodarone compared with Class IC agents, but only after 24 hours.71 The conversion rates to SR were 15% and 32% at 2 hours, 42% and 63% at 8 hours, and 66% and 71% at 24 hours in the amiodarone and Class IC agent groups, respectively. When compared with placebo, the conversion rates to SR were 17% and 11% at 2 hours, 56% and 43% at 8 hours, and 82% and 56% at 24 hours in the amiodarone and placebo groups, respectively.71 Amiodarone demonstrates stronger activity when compared with placebo in patients with persistent AF. Although the relative risk for cardioversion with amiodarone for AF lasting less than 48 hours was only 1.43 (CI: 1.25-1.57) in a meta-analysis, the relative risk for AF lasting greater than 48 hours was 4.33 (CI: 2.76-6.77).72 Thus, heterogeneity of AF duration likely accounts for at least some of the weak overall effect seen in other meta-analyses, as AF of short duration is likely to convert to SR spontaneously. Randomized trials demonstrate the same. In a trial, amiodarone converted 27% of persistent AF to SR at 1 month vs 1% for placebo, whereas in another it converted 80% vs 40% with placebo.73 368

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Intravenous ibutilide has efficacy similar to amiodarone for cardioversion of both recent-onset and persistent AF, but it is not routinely used owing to its side effects. Ibutilide is a Class III agent. Given intravenously, it cardioverts 30%-50% of AF within 1 hour, though is more effective with atrial flutter, with a 50%-80% conversion rate.74 Dofetilide can be used for cardioversion in persistent AF, as demonstrated in the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) trial. In SAFIRE-D, 325 patients with persistent AF or atrial flutter were randomized to dofetilide or placebo, with dosing based on renal function and QT prolongation.75 Compared with 1.2% of patients who converted to SR with placebo, 30% converted to SR with the 250 mg twice daily dosing, and 91% of those converted within the first 36 hours. Dofetilide can be used in patients with reduced LVEF. In the Danish investigations of arrhythmia and mortality on dofetilide (DIAMOND) trial subset of patients with decreased LVEF, dofetilide caused cardioversion in 59% of patients with baseline AF compared with 34% in the placebo group.27 Dr. Joseph S. Alpert: As noted earlier, this agent can precipitate torsades de pointes and patients receiving this agent should be closely monitored.

Medications for Maintenance of SR After initiating a rhythm control strategy, frequently with cardioversion, SR must then be maintained. Without therapy, the rate of AF recurrence at 1 year is at least 70%-84%, which can be reduced to 43%-67% with treatment. Numerous antiarrhythmic medications can be used to maintain SR but have varying efficacies and adverse effects, and the risk of AF recurrence must be balanced with the potential adverse effects. The appropriate doses, mechanisms, and adverse effects of the commonly used antiarrhythmic agents are summarized in the Table. The choice of antiarrhythmic agent depends on patient comorbidities, preference for certain adverse effects, and efficacy. A recent Cochrane review of 56 randomized controlled trials and more than 20,000 patients with paroxysmal, persistent, or permanent AF identified increased mortality with quinidine, disopyramide, and sotalol when used for maintenance of SR.52 They all reduced AF recurrence, the main end point studied. The number needed to harm to cause 1 death over 1 year for the combined Class IA agents was 106, with 166 for sotalol. By contrast, flecainide, propafenone, amiodarone, dronedarone, dofetilide, and metoprolol reduced Curr Probl Cardiol, October 2014

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AF recurrence without increasing mortality, though they had their own adverse effects.52 No antiarrhythmic agent decreased mortality. The number needed to treat for 1 year to avoid recurrent AF was between 3 and 10 for these medications, with amiodarone being the most effective. Amiodarone is the only agent widely compared directly with other antiarrhythmics and has demonstrated superior efficacy. Compared with flecainide, propafenone, dronedarone, and sotalol, the odds ratio of AF recurrence with amiodarone therapy is 0.36-0.45.52 The cardiac safety of amiodarone has been repeatedly demonstrated. The sotalol amiodarone atrial fibrillation efficacy trial (SAFE-T) randomized 665 patients with persistent AF to amiodarone, sotalol or placebo for 1-4.5 years.73 Those patients not in SR after 1 month were electrically cardioverted. Pharmacologic cardioversion occurred in 27.1%, 24.2%, and 0.8%, and electrical cardioversion was successful in 27.7%, 26.5%, and 32.1% in the amiodarone, sotalol and placebo groups, respectively. Intention-totreat analysis demonstrated significantly different median times to AF recurrence of 487, 74, and 6 days in the amiodarone, sotalol, and placebo groups, respectively. Exercise capacity and validated quality-of-life scores were significantly improved in those patients maintained in SR. The Canadian trial of atrial fibrillation (CTAF) demonstrated similar efficacy for amiodarone in paroxysmal or persistent AF.76 In this openlabel trial, 403 patients were randomized to amiodarone, sotalol, or propafenone for 16 months. AF recurred in 35% of patients taking amiodarone compared with 63% of patients taking sotalol or propafenone. Two trials have demonstrated the relative safety of amiodarone with reduced LVEF. In the rate vs rhythm control trial AF-CHF performed in patients with LVEF r 35%, 82% of the rhythm control arm was on amiodarone at 12 months, and there was no significant difference in mortality, worsening heart failure, or stroke from the rate control arm.19 In the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy, 103 patients with persistent or permanent AF at randomization and LVEF r 40% were randomized to amiodarone or placebo for 1 year.77 Amiodarone lowered the ventricular response rate at all time points for those patients with AF, and 31% vs 8% of those patients converted to SR with amiodarone or placebo, respectively. There was no significant difference in survival between the treatment groups. Amiodarone is thus guideline-based for patients not only with structurally normal hearts, but also those with reduced systolic function, hypertension, and in the presence of coronary artery disease.7 Amiodarone is indicated for use with AF in the setting of myocardial infarction along with β-adrenergic antagonists and digoxin. 370

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Dronedarone was developed as an improved analogue of amiodarone with methane sulfonyl instead of iodine groups to try to limit extracardiac toxicity; however, it demonstrates only mild efficacy. Replacement of the iodine decreased lipophilicity and its half-life; however dronedarone maintained Vaughan-Williams Classes I-IV activity.78 In the European trial in atrial fibrillation or flutter patients receiving dronedarone for the maintenance of SR (EURIDIS) and American-Australian-African trial with dronedarone in atrial fibrillation or flutter patients for the maintenance of SR (ADONIS), 1237 patients with known AF who had converted by spontaneous, electrical, or pharmacologic means were randomized to dronedarone or placebo for maintenance of SR.79 Most patients received concomitant β-adrenergic antagonists. Dronedarone decreased AF recurrence at 12 months to 64.1% from 75.2% for placebo as well as decreased symptomatic recurrences. In the assess the efficacy of dronedarone for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter trial, 4628 patients with paroxysmal or persistent AF and at least 1 additional cardiovascular risk factor were randomized to dronedarone or placebo.80 Of these patients, 42% were older than 75 years, 86% had hypertension, 30% had coronary artery disease, only 12% had an LVEF less than 45%, and 16% had valvular disease. At median follow-up of 22 months, dronedarone decreased the combined end point of all-cause mortality or cardiovascular hospitalization from 39.4% to 31.9%, primarily driven by decreased cardiovascular mortality and hospitalizations, particularly for AF. Dronedarone for rate control during AF was studied twice and is not approved for this use. In the efficacy and safety of dronedarone for the control of ventricular rate during atrial fibrillation study, patients with permanent AF and resting HR more than 80 BPM were randomized to dronedarone or placebo for 6 months. 81 Dronedarone significantly decreased ventricular rates at rest and with exertion and retrospectively for those patients who had recurrence of AF in EURIDIS and ADONIS, there was similar improvement in HR. 79 Unfortunately, when used in the dronedarone in high risk permanent atrial fibrillation (PALLAS) trial, patients with permanent AF with risk factors, including ischemic coronary disease, heart failure with reduced LVEF, or history of stroke, who were randomized to dronedarone had increased mortality, stroke, arrhythmia, and hospitalization for heart failure compared with those in the placebo group.82 The trial was stopped early for these reasons. Dronedarone in patients with heart failure worsens mortality. In the antiarrhythmic trial with dronedarone in moderate-to-severe congestive heart failure evaluating morbidity decrease (ANDROMEDA), 627 Curr Probl Cardiol, October 2014

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patients with LVEF r 35% and new or worsening heart failure symptoms without recent myocardial infarction were randomized to dronedarone or placebo.83 ANDROMEDA was stopped prematurely after 7 months because of increase in mortality to 8.1% with dronedarone vs 3.8% with placebo. There were also increased hospitalizations. Retrospectively, close to 70% of patients in PALLAS had heart failure, but only 20% of those had reduced systolic function, suggesting that dronedarone might be avoided in patients with heart failure and preserved LVEF as well.82 Dronedarone was compared directly with amiodarone in the efficacy and safety of dronedarone versus amiodarone for the maintenance of SR in patients with atrial fibrillation trial.84 Excluding heart failure and thyroid disease, 504 patients with persistent AF were randomized to dronedarone or amiodarone for a median of 7 months. Dronedarone was inferior to amiodarone for the combined efficacy and safety end point of time to AF recurrence or drug discontinuation for adverse effects, 75.1% for dronedarone vs 58.8% with amiodarone, which was driven by increased AF recurrence with dronedarone. There was no significant distinction in the overall safety profile, as 39.3% vs 44.5% of patients reported adverse effects with dronedarone and amiodarone, respectively; however, dronedarone caused mainly gastrointestinal events and was less frequently discontinued because of adverse effects. The Class IC agents flecainide and propafenone are effective for maintaining SR in patients with structurally normal hearts. In the efficacy and safety of sustained release propafenone for patients in atrial fibrillation trial, 523 patients with paroxysmal AF in SR at enrollment were randomized to propafenone or placebo.85 Heart rhythm was remotely monitored. Propafenone dose dependently increased the median time to AF recurrence to more than 300 days with the highest dose and 112 days with the lowest dose, compared with that of placebo of 41 days. In the highest dose group, 425 mg twice daily, 25% of patients withdrew because of adverse effects compared with that of 13.5% for placebo, primarily consisting of dizziness, dyspnea, gastrointestinal effects, and fatigue. These results are supported by the smaller European rythmol atrial fibrillation trial, also in patients with paroxysmal AF.86 The flecainide multicenter AF study randomized 239 patients to open-label flecainide or quinidine. Over 1 year, approximately 90% of patients maintained SR; however, 18% discontinued treatment because of adverse flecainide effects.87 The Class IA agent quinidine was equally effective, but 30% of subjects discontinued because of adverse effects. Class IC agents are contraindicated in patients with heart failure or ischemic coronary disease 372

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based on their increased mortality in the cardiac arrhythmia suppression trial.88 Dr. Joseph S. Alpert: Propafenone has mild β-blocking properties. Patients with contradictions to β-blockers may develop adverse events related to the intrinsic β-blocking effect of propafenone.

Class II agents, β-blockers do appear to maintain SR in patients with AF. After successful electric cardioversion, 394 patients with persistent AF were randomized to metoprolol succinate or placebo and followed up for 3 months.89 Over the study period, only 49% of those treated with metoprolol relapsed into AF compared with 60% of those in the placebo group. Additionally, those patients that relapsed into AF with metoprolol had significantly slower HR. Open-label studies have compared pure β-blockers such as atenolol with antiarrhythmic agents such as sotalol and demonstrated similar efficacy.90 Nevertheless, these agents do not have success rates similar to the more effective Class III agents. It should be noted that part of the beneficial effect of β-blockade may stem from creating AF recurrences that are less symptomatic and thus undetected. Sotalol is a Class III agent with β-adrenergic antagonism that both prolongs the atrial and ventricular refractory periods and slows conduction in the AV node. It is moderately effective in preventing AF recurrence compared with placebo but was inferior to amiodarone in SAFE-T and CTAF.73,76 Although only 13% of placebo-treated patients maintained SR at 1 year, 32% and 52% of the sotalol- and amiodarone-treated patients remained in SR, respectively. However, in a post hoc analysis of SAFE-T, there was no significant difference in maintenance of SR in the subgroup of patients with ischemic coronary disease compared with amiodarone.73 Dofetilide is a Class III agent without additional β-adrenergic activity. In the SAFIRE-D trial, 325 patients with persistent AF or atrial flutter were randomized to dofetilide or placebo with dosing based on renal function and QT prolongation.75 At 1-year follow-up, 25% of patients in the placebo group were still in SR compared with 58% of the 500 μg twice daily dofetilide group. Overall, there was a small but significant increase in arrhythmia in the dofetilide-treated patients, with 2 cases of torsades de pointes and 1 sudden cardiac death. Dofetilide lacks the negative inotropy of sotalol and can be used in patients with reduced LVEF. In the DIAMOND trial, 1518 patients with heart failure due to systolic dysfunction were randomized to dofetilide or placebo without any significant change in mortality over 18 months follow-up.91 Dofetilide Curr Probl Cardiol, October 2014

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did reduce hospitalization for worsening heart failure in this cohort, primarily in patients with known AF. In the subgroup of 506 patients with known AF or atrial flutter at baseline, it caused significant cardioversion to SR over placebo (59% vs 34%). Of those patients who converted 79% remained in SR during 18 months follow-up compared with 42% who were on placebo.27 Additionally, those patients who had restoration of SR had significantly reduced mortality with an odds ratio of 0.44, as well as reduced rehospitalization compared with placebo. Although not directly effective on the cardiac electrical machinery, some nonantiarrhythmic medications may decrease the incidence and recurrence of AF. These medications appear to function by inhibiting pathologic atrial remodeling and inflammation and indirectly act on ion channel operation. Medications investigated in this class include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), aldosterone antagonists, and statins. Although these agents are effective in preventing new-onset AF, their ability to improve recurrence rates is inconsistent, and they are only recommended for primary prevention in patients at risk.7,92,93 Other adjuvant agents for which there are little supportive data in secondary prevention of AF include polyunsaturated fatty acids and corticosteroids.92 Inhibition of the angiotensin II signaling system with ACE inhibitors or ARBs has been extensively studied with regard to recurrent AF. Although many open-label trials without placebo and meta-analyses including them have demonstrated reduced recurrent AF, and these medications decrease atrial fibrosis, pressure, and premature contractions, double-blind placebo controlled trials have not produced significant results.92 In the candesartan in the prevention of relapsing atrial fibrillation double-blind trial, 171 patients with persistent AF were randomized to candesartan or placebo 3 weeks before electrical cardioversion.94 In the candesartan and placebo groups, 79% and 81% of the patients, respectively, were cardioverted successfully and followed up for 6 months. There was no significant difference in the recurrence of AF between the treatment groups. In the larger Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiac Atrial Fibrillation trial, 1442 patients with paroxysmal AF currently in SR were randomized to valsartan or placebo.95 There was no significant difference in the recurrence of AF at 1 year, 51.4% vs 52.1% for the treatment and placebo arms, respectively. There was also no difference in recurrence in any of the prespecified subgroups including subjects also treated with antiarrhythmic medications or with heart failure. These findings are supported by a secondary outcome from the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular 374

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events—irbesartan.96 In total, 9016 patients with paroxysmal, persistent, or permanent AF were randomized to irbesartan or placebo. The average CHADS2 score was 2.0 ⫾ 1.1 and 65% had permanent, 20% paroxysmal, and 15% persistent AF. There was no significant difference in recurrence of AF or on hospitalization for AF between the treatment groups at a mean of 4.1 years. There was an increase in hypotension and renal dysfunction in the irbesartan arm. Thus, from the majority of data it appears that ACE inhibitors and ARB therapies are only effective in primary prevention of AF.93 It may be that these medications cannot reverse the pathologic remodeling of AF but may only prevent it from occurring initially. Aldosterone antagonists have been poorly studied for AF recurrence; however, they have been shown to alter ion currents, atrial fibrosis, inflammation, and remodeling. Patients with higher aldosterone levels also appear to progress more often from paroxysmal to persistent AF.92 A secondary analysis of the eplerenone in mild patients hospitalization and survival study in heart failure trial investigated the role of aldosterone antagonism on AF. Patients with an LVEF o 35% were randomized to eplerenone or placebo and followed up for median 21 months.97 In this analysis, eplerenone decreased the incidence of new-onset AF, though AF recurrence was not interrogated. In a small retrospective observational study of 161 patients undergoing catheter ablation for persistent or permanent AF, those patients treated with eplerenone had a greater freedom from AF at 2 years follow-up.98 A small open-label trial of 164 patients with paroxysmal AF on a β-blocker randomized to spironolactone or placebo with or without enalapril did show merit.99 There was a significant reduction in recurrent AF over the 12-month trial period and decreased progression to permanent AF. Overall, the evidence for aldosterone antagonism to prevent AF recurrence is still building. Statins have been intermittently demonstrated to benefit patients attempting to maintain SR but the effect is not robust. The mechanism seems likely related to their anti-inflammatory effect but they are also known to be pleiotropic in action and alter membrane ion channels.92 Although retrospective, observational and open-label trials have shown decreased AF recurrence with statin therapy after cardioversion, randomized controlled investigations have not. A multicenter, prospective, doubleblind trial of atorvastatin in 234 patients with persistent AF for 2 weeks before cardioversion and 4 weeks afterward demonstrated only a nonsignificant improvement in AF recurrence.100 In the statin therapy for the prevention of atrial fibrillation trial, 64 patients were randomized to atorvastatin or placebo starting 1 week before cardioversion, then continued for 12 months.101 There was no significant reduction in AF Curr Probl Cardiol, October 2014

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recurrence between the groups. A meta-analysis of 4 trials including the ones described earlier, analyzing 424 patients, demonstrated no benefit for statins in preventing AF recurrence.102 Furthermore, a larger meta-analysis including more heterogeneous statin trials of 139,169 patients for secondary prevention of AF also was unable to demonstrate significant benefit.103 It is thus unclear if there is a beneficial effect of statin therapy on prevention of AF recurrence.

Medications for Maintenance of SR During Procedures AF may occur after both noncardiac and cardiac surgery. The incidence after cardiac surgery approaches 50%-60% and is highest in those patients who undergo bypass grafting as well as valve surgery. Postoperative AF increases hospital stay length, increases the incidence of stroke, and is associated with increased hospital mortality. The perioperative state includes multiple risk factors for AF development and recurrence, including inflammation associated with surgical trauma, particularly with mediastinal interventions, as well as hemodynamic stress, catecholamine surges, electrolyte abnormalities, and perioperative medication use.104 The incidence of postoperative AF peaks 2-3 days after surgery, with approximately 40% of patients with AF having multiple episodes.104 Nevertheless, in patients without a history of AF, there is spontaneous conversion to SR within 24 hours in 80% of patients, with overall 90% conversion to SR by 8 weeks. Postoperative AF can be treated similarly to AF occurring in other situations; however, there are evidence-based therapies for prophylaxis. A Cochrane review of 118 studies including more than 17,000 participants found multiple treatments that decreased postoperative AF following cardiac surgery.105 Although interventions did not improve mortality or significantly decrease stroke, they did decrease hospital length of stay. Medications that decrease the incidence of AF include β-blockade (odds ratio ¼ 0.33, CI: 0.26-0.43), sotalol (odds ratio ¼ 0.34, CI: 0.26-0.43), magnesium administration (odds ratio ¼ 0.55, CI: 0.41-0.73), and amiodarone (odds ratio ¼ 0.43, CI: 0.34-0.54). AF incidence in the treatment groups together was 18%, whereas it was 32% for the control groups. Similar percentages were observed for the individual interventions.105 Magnesium was typically given as 1.5-g intravenously daily for 4 days after surgery with or without a preoperative dose. Medications ineffective for prevention of AF include digoxin and calcium channel antagonists. Amiodarone has been evaluated in multiple prospective trials and deserves particular attention. In the amiodarone reduction in coronary heart trial, 300 patients were randomized to 1-g intravenous amiodarone or 376

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placebo for 2 days after cardiac surgery.106 Although AF occurred in 47% of the placebo group, amiodarone significantly reduced the incidence to 35%. Only 50% of patients were taking β-blockers in this trial. In the prophylactic oral amiodarone for the prevention of arrhythmias that begin early after revascularization, valve replacement, or repair trial, 601 patients were randomized to 6 days of 10-mg/kg intravenous amiodarone before surgery, with another 6 days of therapy afterward.107 Amiodarone decreased the incidence of atrial tachyarrhythmias that included AF from 29.5% in the placebo group to 16.1%. In the atrial fibrillation suppression trial II, 160 patients were randomized to amiodarone or placebo following cardiac surgery, with approximately 1 g of amiodarone given intravenously for the first 24 hours then 600 mg twice daily orally for 4 days.108 Overall, 80% of patients took concomitant β-blockers and the postoperative incidence of AF was reduced from 39% to 22% by amiodarone, with a reduction in symptomatic AF from 21% to 7%. Because β-blockers have a superior safety profile at the time of surgery and as long-term therapy compared with amiodarone, the guidelines favor their use in patients undergoing surgery to prevent postoperative AF.7 In those patients not initiated preoperatively, they are also useful for rate control for AF that develops after surgery. In patients at high risk of AF postoperatively, additional administration of prophylactic amiodarone is recommended. Amiodarone can be used for cardioversion as well as the other antiarrhythmic medications discussed previously.

Precautions and Adverse Effects With Antiarrhythmic Medications The choice of antiarrhythmic agent for AF requires a clear understanding of the adverse event profiles of these medications in addition to their relative efficacy and whether they can be used with structural heart disease. As discussed earlier, there does not appear to be a clear overall benefit to maintenance of SR in most patients with AF, and in elderly patients there is a trend toward harm. Thus the choice of antiarrhythmic agent depends on patient comorbidities and known side effect profiles as summarized in the Table. Many effective agents can only be used in patients without structural heart disease (flecainide and propafenone) or without heart failure (dronedarone) such that in patients with myocardial dysfunction, the Class III agents amiodarone or dofetilide are the safest. The considerations for antiarrhythmic agent choice are summarized in Figures 2 and 3, which have been modified from the current international guidelines.7,109 Curr Probl Cardiol, October 2014

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The Class IC agents cannot be used with structural heart disease (including wall thickness Z1.5 cm) or reduced systolic function because of their negative inotropic effects and have additional side effects related to their sodium channel blockade.7 Propafenone causes mild diverse gastrointestinal effects, whereas flecainide causes mild neurologic effects including dizziness and vision changes.85,87 Both agents can cause bradycardia after conversion of AF to SR, sometimes associated with hypotension. More significantly, these medications can convert AF to slow atrial flutter as well as increase AV nodal conduction leading to 1:1 conduction and rapid supraventricular rates. Owing to this propafenone and flecainide should be administered with AV nodal inhibiting agents such as β-blockers or calcium channel blockers. The Class IA medications should not be continued if the corrected QT interval prolongs for more than 520 ms. The Class III agents have QT prolonging activity mediated by their potassium channel blockade. In patients with LVEF o 20% treated with ibutilide before electrical cardioversion for persistent AF, 3% of patients had polymorphic ventricular tachycardia.55 The risk with ibutilide is increased in the presence of hypokalemia or hypomagnesemia, though may be lower with concomitant Class IC agent use. Nevertheless, an additional 5% of ibutilide-treated patients develop monomorphic ventricular tachycardia. Dofetilide increases the risk of torsades de pointes dose dependently and dosing requires adjustment for renal function. In SAFIRE-D, patients were monitored on telemetry for a minimum of 3 days during dofetilide initiation, and there were 10 withdrawals from the protocol owing to QT prolongation, as well as 2 cases of torsades de pointes and 1 sudden cardiac death.75 In DIAMOND trial, 3.3% of patients treated with dofetilide developed torsades de pointes.27,91 Sotalol has specific reverse use dependency such that the potassium channel blockade increases at lower HR, which causes more pronounced QT prolongation during bradycardia, with resultant further increased risk of torsades de pointes. Sotalol should be avoided in patients with already long QT intervals (uncorrected QT over 460 ms), as well as in those with left ventricular hypertrophy, heart failure, or severe bronchospasm. Due to the QT prolonging effects of the Class III agents and the associated risk of torsades de pointes, initiation of these medications should be performed in the inpatient setting with telemetry monitoring. Dofetilide specifically should be dose adjusted based on renal function (Table) and monitoring should continue for 72 hours after initiation, whereas potassium and magnesium levels are maintained within normal limits. Dosing should be reduced if the QT interval prolongs more than 378

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20% over baseline or more than 550 ms as was performed in the major trials of this agent.91 Dofetilide plasma levels can be increased by concomitant administration of erythromycin, ketoconazole, and verapamil, so these should be avoided. Patients must be closely monitored after ibutilide administration, and the QT reduced to baseline before discharge, which typically takes more than 4 hours, and sometimes 24-48 hours. Although repeatedly the most effective agent for cardioversion and maintenance of SR in patients with AF, amiodarone is not the first-line rhythm control agent because of its multiple toxicities. A meta-analysis of 4 trials of amiodarone for suppression of ventricular ectopy in patients with heart failure or after myocardial infarction demonstrated that less than 400 mg daily was associated with odds ratios of 2-4 for thyroid, neurologic, skin, ocular, cardiac, and pulmonary toxicity after 1 year.110 Specifically, both hyperthyroidism and hypothyroidism, tremor, ataxia, peripheral neuropathy, rash with and without photosensitivity, blue skin discoloration, blurred vision, corneal deposits, bradycardia, and respiratory symptoms with x-ray changes were associated. Amiodarone also inhibits degradation of warfarin, likely leading to the increased minor bleeding in SAFE-T.73 In the CTAF trial, 18% of patients had to discontinue amiodarone because of adverse effects, specifically including pulmonary toxicity, hypothyroidism, and hyperthyroidism.76 Although amiodarone is typically used at a lower maintenance dose than in these studies, at 200 mg daily, toxicities persist. The mechanism of the diffuse amiodarone toxicity is multifactorial. Amiodarone chemical structure resembles thyroid hormone and contains significant free iodide such that with daily maintenance therapy greater than 35 times the daily intake of iodide is released into the systemic circulation.111 High intrathyroid iodide levels can suppress thyroid hormone synthesis causing hypothyroidism. Alternatively, excess iodide can allow increased thyroid hormone production by an autonomous thyroid nodule or the iodide can cause direct toxicity and thyroiditis, which can cause hyperthyroidism.112 In nonthyroid organs, amiodarone is highly lipophilic, also owing to the iodine, which allows accumulation of it as well as its metabolites in well-perfused organs. Owing to these effects, patients on amiodarone require yearly monitoring of thyroid and hepatic function, pulmonary function testing, and ocular examinations. By removal of the iodine groups, dronedarone was designed to lack the systemic toxicities of amiodarone, specifically the thyroid, Curr Probl Cardiol, October 2014

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pulmonary, ocular, hepatic, or arrhythmic adverse effects.78 What remained was mild gastrointestinal upset with abdominal pain or diarrhea, as well as partial inhibition of renal tubular creatinine transport that raises serum creatinine; however, this is not related to altered glomerular filtration.79,80 Nonetheless, patients discontinue dronedarone significantly more than placebo because of adverse events. In EURIDISADONIS, 18% vs 15% discontinued use, and 13% vs 8% in the assess the efficacy of dronedarone for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter trial (ATHENA).79,80 Furthermore, ANDROMEDA and PALLAS demonstrated that dronedarone should not be used in patients with decreased LVEF because of increased mortality and other adverse events.82,83 This detrimental effect may stem from the negative inotropic action of the agent. When compared with amiodarone in efficacy and safety of dronedarone versus amiodarone for the maintenance of SR in patients with atrial fibrillation trial (DIONYSOS), the overall rate of adverse events with dronedarone was similar, even though they less frequently caused discontinuation of the medication.84 Furthermore dronedarone still interacts with common medications such as warfarin, still has hepatic toxicity, and increases the levels of digoxin and simvastatin.113 Finally, because of the adverse effect on mortality as well as other cardiovascular end points, dronedarone should not be used in permanent AF.82 Patients on dronedarone should be screened using electrocardiography every 3 months to ensure conversion from AF, or the medication should be discontinued. This requirement makes dronedarone somewhat cumbersome to use.

Selection of Rate Control and Antiarrhythmic Therapy With recurrent paroxysmal or persistent AF that is hemodynamically stable either a rate or rhythm control strategy appears to be appropriate. Choice of rate control agent is determined primarily by patient comorbidities (Fig 1). In patients without other cardiac disease, β-blockers, calcium channel blockers, or digoxin can all be used, and these agents can be combined if needed. Digoxin alone may be appropriate in sedentary patients without significant sympathetic tone. Amiodarone but not dronedarone can serve as a rate control agent if cardioversion is not being avoided (patients on long-term anticoagulation) or is unlikely (cases of permanent AF). In patients with heart failure, digoxin can be used, β-blockers and amiodarone should be used with caution, and calcium channel blockers are contraindicated. Patients with obstructive 380

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Fig 1. Pharmacologic rate control management strategy in patients with AF.

pulmonary disease or asthma with bronchospasm should ideally avoid βblockers but these can likely be used except with severe bronchospastic disease. Dr. Joseph S. Alpert: But, patients with COPD without bronchospasm can often tolerate β-blockade.

Indications for initiation of a rhythm control strategy include ongoing symptoms in spite of well-controlled HR or inability to control HR with available rate control agents. A rhythm control strategy often requires cardioversion followed by maintenance therapy, and thromboembolic risk should be appropriately controlled before embarking on rhythm control. In patients who do not spontaneously convert to SR, electrical and pharmacologic cardioversion are viable options (Fig 2). AF less than 1-week duration in patients without structural heart disease is more amenable to cardioversion by Class IC agents but can be treated by dofetilide, ibutilide, dronedarone, or amiodarone, which have efficacy after 1 week as well. In patients who do not cardiovert with pharmacologic therapy alone, these agents increase the rate of successful electrical cardioversion. In a small subset of patients without structural heart disease a pill-in-pocket strategy may be undertaken once a Class IC agent has been demonstrated to be effective during an inpatient visit. Curr Probl Cardiol, October 2014

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Fig 2. Pharmacologic cardioversion strategy in patients with AF. (Adapted from the American College of Cardiology-American Heart Association-Heart Rhythm Society and the European Society of Cardiology Guidelines.7,109)

Once the decision has been made to pursue a rhythm control maintenance strategy, the primary branch points involved in selection of antiarrhythmic therapy are whether the patient has structural heart disease (Fig 3). In the absence of any structural abnormalities, Class IC agents can be employed given their overall low incidence of adverse effects and efficacy. If desired sotalol is also guideline based in these patients; however, there appears to be an association between its use and increased mortality in a modern Cochrane review.52 If Class IC agents and sotalol are ineffective or not tolerated, amiodarone, dofetilide, or dronedarone can be used. Sotalol and dofetilide require inpatient initiation of therapy. Unlike the Class IC agents that can promote atrial flutter and rapid conduction, Class III agents demonstrate enhanced prevention of atrial flutter should it arise. In patients with structurally abnormal hearts, the degree of dysfunction determines the appropriate agents. Hypertension without left ventricular hypertrophy is treated as an essentially normal heart, and Class IC agents can be used as mentioned earlier. In the presence of left ventricular hypertrophy, the only recommended agents are amiodarone or dronedarone as other possibilities have not been well studied. Class IC agents should be avoided in patients with ischemic coronary disease or reduced systolic function, as they are associated with increased mortality. 382

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Fig 3. Pharmacologic rhythm control strategy in patients with AF. (Adapted from the American College of Cardiology-American Heart Association-Heart Rhythm Society and the European Society of Cardiology Guidelines.7,109)

Sotalol can be used in those with ischemic coronary disease and can be considered first line along with dofetilide in this setting. Amiodarone but not dronedarone is the second-line agent for patients with ischemic coronary disease, though for dronedarone this is a matter of debate. In patients with heart failure or reduced LVEF, the available agents are limited to only amiodarone and dofetilide. Although not included in this review, failure of pharmacologic therapy for rhythm control should prompt consideration of catheter ablation.

Conclusions This article details the multiple pharmacologic treatment options for AF rate and rhythm control. When primary prevention fails, either a rate control or a rhythm control strategy appears viable given the current pharmacologic possibilities. Rate control is possible using a limited catalog of agents, whereas rhythm control may require electrical or pharmacologic cardioversion and frequently necessitates antiarrhythmic therapy to maintain SR. Rhythm control is currently favored in patients with intractable symptoms in spite of appropriate rate control, and in young patients with structurally normal hearts, but the evidence for this approach is not robust. Even when employed, currently available antiarrhythmic agents are at best modestly effective in maintaining SR, with approximately two-thirds of Curr Probl Cardiol, October 2014

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patients successfully controlled in SR at 1 year. Adjuvant agents for secondary prevention continue to be investigated; however, progress is still needed to treat this common arrhythmia. Dr. Joseph S. Alpert: The authors are to be congratulated on this detailed and excellent review of a very common clinical entity requiring careful evaluation, thought, and judicious therapy. They cite the new American College of Cardiology-American Heart Association Guidelines. This article will be the last word on the subject for many readers.

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