Antiarrhythmic Drug Therapy for Rhythm Control in Atrial Fibrillation

Quinidine

Quinidine, an alkaloid derived from the bark of the cinchona plant (and a diastereomer of the antimalarial drug quinine ²⁹ ), was first discovered in the 19th century ³⁰ and is one of the oldest cardiac medications still in use today. Quinidine blocks sodium and potassium channels, with variable electrophysiologic properties depending on drug concentration. At low concentrations, it primarily blocks sodium current (I _Na) and the rapid component of the delayed rectifier potassium current (I _Kr). At high concentrations, however, it also blocks multiple other potassium currents (including I _Ks, I _KATP, and I _to) and l-type calcium channels (I _CaL). ²⁹ Quinidine’s sodium channel blocking effect exhibits “use dependence,” whereby it is more pronounced at fast heart rates and high concentrations, while its potassium channel blocking effect exhibits “reverse use dependence,” whereby it is most pronounced at slow heart rates and lower drug concentrations. In addition to its effect on potassium, sodium, and calcium channels, quinidine has additional vagolytic, α-blocking, and β-blocking properties. ²⁹ The majority of quinidine is metabolized in the liver via cytochrome P (CYP) 3A4, although some drug is renally eliminated. Quinidine is a potent inhibitor of CYP2D6 and P-glycoprotein (P-gP) and as a result reduces digoxin clearance. ²⁹

Quinidine is currently available in 2 formulations, quinidine gluconate and quinidine sulfate, both of which are taken 3 times per day. Both formulations are well absorbed with a half-life of approximately 8 hours. One beneficial and often overlooked feature of quinidine is that it can be used safely in patients with structural heart disease and renal dysfunction. Despite its efficacy in suppressing AF, however, use of quinidine has fallen out of favor due to concerns about side effects and safety and the availability of newer AADs. Current use of quinidine in the treatment of AF is therefore rare, and patients often experience difficulty obtaining the drug due to high costs and lack of availability. ³¹

Side effects are common, with diarrhea and other gastrointestinal symptoms being most frequent. Less common noncardiac side effects include thrombocytopenia, rash, and cinchonism (headache and tinnitus). Adverse cardiac side effects include severe QRS widening at high doses, and QT prolongation and torsades de pointes (TdP) independent of drug concentration. ²⁹

Concern about quinidine originated from a meta-analysis of 6 small trials that revealed increased mortality associated with quinidine use (mortality rate 2.9% vs 0.8% for quinidine and control, respectively). ³² A recent Cochrane review incorporating larger and more recent studies demonstrated that quinidine use was associated with a nonstatistically significant trend toward an increase in mortality (pooled odds ratio 2.26, 95% confidence interval [0.93-5.45], P = .07). ³³ Many of the older studies of quinidine were conducted before the important adverse interaction between quinidine and digoxin was appreciated, and this might account for some of the excess mortality observed early on. ³² More recent studies that evaluated the combination of quinidine and verapamil (which may suppress early after depolarizations that can trigger TdP ³⁴ ) demonstrated low rates of all-cause mortality. ^35,36 If tolerated, quinidine remains an effective option to treat AF, especially when other AADs have failed or are contraindicated due to patient comorbidities. ³⁷

Disopyramide

Disopyramide, which was first evaluated in the 1960s, ³⁸ shares many electrophysiological properties with quinidine, despite being chemically distinct. Disopyramide blocks both I _Na and I _Kr and prolongs both action potential duration and refractory period. ³⁹ As a result, similar to quinidine, it causes QT prolongation and QRS widening (at higher doses). Disopyramide is available in an immediate-release formulation, which is dosed 4 times per day, and a sustained-release formulation, which is taken twice daily. It has high oral bioavailability and a half-life of approximately 6 to 8 hours in patients with normal renal function. Drug is metabolized primarily by the kidneys although some drug is also metabolized by the liver via CYP3A4, ²⁹ and dose adjustment is necessary in patients with renal dysfunction and hepatic dysfunction. ³⁹

One of the main limitations of disopyramide is that it has strong anticholinergic effects, and due to the frequency with which it can induce urinary retention, its use is limited in men, especially those with prostatic hypertrophy. Other anticholinergic effects such as constipation, dry mouth, visual disturbances, and glaucoma can also occur. ²⁹ Additionally, due to strong negative inotropic effects, use of disopyramide is contraindicated in patients with heart failure and reduced LV systolic function. ⁴⁰ Hemodynamic effects in patients with structurally normal hearts, however, are minimal. Due to its negative inotropic properties, disopyramide may be a reasonable AAD to use in patients with AF who also have hypertrophic cardiomyopathy and outflow tract obstruction, ⁴¹ although strong data supporting its use in this situation are lacking. Like quinidine, use of disopyramide has been associated with increased mortality, ³³ although study of disopyramide for suppression of AF in a clinical trial settings is lacking in comparison to other AADs. Overall, use of disopyramide in the treatment of AF is exceedingly rare.

Sotalol

Sotalol, a nonselective β-blocker that exerts its antiarrhythmic effects through inhibition of the delayed rectifier potassium current I _Kr, was developed in the 1960s. ⁴² It is administered as an equal combination of l- and d-enantiomers, and although both enantiomers have equivalent potassium channel blocking properties, the l-enantiomer is a much stronger β-antagonist. ⁴² d-Sotalol, a pure I _Kr blocker associated with increased mortality in patients with prior myocardial infarction (MI) and LV dysfunction potentially due to lack of β-blockade and proarrhythmia, is not clinically available. ⁴³

Sotalol is easily absorbed, has a very high bioavailability, and is not protein bound. It is administered twice daily and has a half-life of approximately 8 hours. It is excreted unchanged in the urine, with dose adjustments required in patients with impaired renal function, and does not undergo any hepatic metabolism. ⁴⁴ Sotalol causes dose-dependent prolongation of action potential duration, atrial and atrioventricular (AV) nodal refractory periods, and the QT interval in a reverse use-dependent manner. In general, despite its β-blocking properties, sotalol is not a negative inotrope due to a concomitant increase in contractility due to action potential duration prolongation; however, in some cases, it can exacerbate heart failure. ⁴⁴ As sotalol has β-blocking properties, in some patients, it can exacerbate reactive airway disease. Overall, however, it has few other side effects. Drug interactions are predominantly related to potentially dangerous interactions with other QT-prolonging medications that can precipitate TdP. The risk of adverse events such as TdP is dose-/QT interval dependent and may be increased due to the bradycardic effects of the drug. When used properly and at usual doses, the risk of TdP is <1%. ⁴⁵

Drug therapy is usually initiated at a dose of 80 mg twice daily. In patients with a creatinine clearance between 40 and 60 mL/min, the dose is reduced to once daily. Use is not recommended for patients with creatinine clearance <40 mL/min. After allowing 3 days for the drug to reach steady state, an electrocardiogram (ECG) is obtained, and if the QT interval (<500 ms) and heart rate allow, the dose can be uptitrated as needed (increasing by 40 mg increments) until reaching a maximum dose which is usually 160 mg twice daily. The drug manufacturer recommends that sotalol be initiated in the hospital, ⁴⁵ but data have suggested that outpatient drug initiation can be safely performed in select patients in SR (see subsequent sections).

In general, sotalol is a modestly effective AAD. In the Canadian Trial of Atrial Fibrillation (CTAF) amiodarone was superior to sotalol or propofanone (at a mean of 16 months, 65% of patients treated with amiodarone and 37% of patients treated with sotalol or propofanone remained free of AF recurrence). ⁴⁶ Similarly, in the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) comparing amiodarone, sotalol, and placebo in patients with persistent AF, sotalol was superior to placebo but inferior to amiodarone in maintaining SR (median time to recurrence 487 days, 74 days, and 6 days for amiodarone, sotalol, and placebo, respectively, P < .001). In the subgroup of patients with ischemic heart disease, however, amiodarone and sotalol were equally efficacious in preventing AF recurrence (median time to recurrence 569 days and 428 days for amiodarone and sotalol, respectively, P = .53). ⁴⁷ In meta-analyses, efficacy of sotalol is similar to efficacy of most AADs other than amiodarone. ³³

Flecainide

Flecainide was developed in the 1970s. ⁴⁸ It is administered twice daily (at doses between 50 and 200 mg), has a bioavailability of approximately 90%, and its half-life ranges from 7 to 23 hours. ⁴⁹ Metabolism takes place primarily in the liver via CYP2D6 and CYP1A2 with further renal excretion of metabolites, and dose adjustment is therefore necessary in patients with advanced renal failure. Flecainide exerts its electrophysiologic effects primarily by blocking the rapid sodium current responsible for phase 0 of the cardiac action potential (I _Na). Flecainide kinetics are strongly influenced by heart rate; because it has very slow dissociation from ion channels at fast heart rates, drug binding to sodium channels during tachycardia is enhanced and drug effect is therefore magnified. Compared to other sodium channel blocking, drugs with intermediate dissociation kinetics, such as quinidine and disopyramide, flecainide’s very slow dissociation kinetics, can produce significant QRS widening at normal heart rates. If this is observed, it should prompt drug discontinuation. ⁴⁸

The Cardiac Arrhythmia Suppression Trial (CAST) demonstrated an increase in mortality associated with flecainide use in patients with MI and premature ventricular beats. ⁵⁰ Flecainide also has negative inotropic effects likely related to both its sodium channel–blocking properties and the fact that drug clearance is significantly reduced in patients with heart failure. ⁴⁸ Flecainide is therefore not appropriate for use in patients with structural heart disease and prior MI. Whether flecainide can be safely used in patients with mild/stable coronary artery disease without MI is unclear, but such use is not currently recommended. ²⁴

The major cardiovascular toxicity of flecainide when used in the treatment of AF is conversion of AF to atrial flutter with rapid ventricular rates due to 1:1 AV conduction. This can occur due to slowing and organization of atrial arrhythmias to the point that the AV node is able to conduct 1:1 rather than at intervals of 2:1 or higher. Thus, flecainide use may result in atrial flutter with very rapid ventricular rates > 200 bpm which can cause syncope, or even induce ventricular tachycardia or ventricular fibrillation. Therefore, flecainide should always be used with another drug which slows AV nodal conduction (such as a β-blocker or calcium channel blocker), unless AV nodal conduction is already significantly impaired. ²⁴ A hybrid strategy of using flecainide after ablation of atrial flutter may also be helpful in patients who have AF and flecainide-induced atrial flutter. ^51,52 In select patients who wish to avoid taking medication daily, a “pill-in-the-pocket” strategy, where a high dose of flecainide (200-300 mg) is taken at the onset of an episode of AF, has also been validated, ⁵³ but this should only be used if the patient has demonstrated in a monitored setting that he or she can take such high doses of flecainide without significant adverse effects. ²⁴ Other common side effects of flecainide include dizziness, visual disturbances, nausea, dyspnea, and other neurologic symptoms.

Propafenone

Propafenone was initially approved in Europe in 1977 and in the United States in 1989 for treatment of ventricular arrhythmias. It is primarily a sodium channel–blocking drug and shares many properties with flecainide. In addition to its sodium channel–blocking properties, propafenone also blocks potassium channels (including I _Kr, I _to, and inward rectifying potassium channels), calcium channels, and β-adrenergic receptors. Dissociation kinetics are slightly faster than flecaninde ⁵⁴ but are still slower than quinidine or disopyramide.

Standard dosing of propofanone is every 8 hours, although an extended-release preparation can be administered twice daily. Propofanone is well absorbed, although via extensive first-pass hepatic metabolism bioavailability may be as low as ∼10%. The drug is highly protein bound. Metabolism is primarily by hepatic oxidation via CYP2D6, and dose reduction is required in patients with hepatic dysfunction. ⁵⁴ Genetic variations in metabolism are responsible for variations in drug effect and systemic side effects. ^55,56

Like flecainide, propofanone should not be used in patients with structural heart disease and/or coronary artery disease/prior MI, and 1:1 atrial flutter can result from administration during AF. Although propofanone has some intrinsic β-blocking properties, given the risk of rapid atrial flutter, it should usually be used with an additional AV nodal-blocking agent.

Amiodarone

Amiodarone, an iodainated benzofuran derivate, is the most common AAD prescribed for AF, ⁵⁷ despite the fact that it has never been approved for this indication. It was developed in the 1960s and was initially used as an antianginal agent until the 1970s when its antiarrhythmic properties were discovered. ^58,59 Amiodarone exerts a multitude of electrophysiological effects on cardiac tissue. It blocks I _Na, I _Kr, I _Ks, I _Kur, I _CaL, acetylcholine sensitive potassium channels (I _KAch), I _to, α-receptors, and β-receptors ⁶⁰ and therefore has a wide range of electrophysiological effects on all types of cardiac tissues. Amiodarone has an oral bioavailability of approximately 30% to 50% and is highly lipophilic with a very large volume of distribution and an extremely long and highly variable elimination half-life on the order of weeks to months. ^29,61 The electrophysiological effects of oral amiodarone therefore are usually delayed for days (with full effects not expected for weeks) after initiation, although effects can be seen faster with intravenous administration. ⁶¹ Drug levels do not correlate with clinical efficacy. ⁶¹ Amiodarone is hepatically metabolized by CYP3A4 to desethyl-amiodarone which shares similar antiarrhythmic properties with amiodarone. ⁶⁰ Dosage should be adjusted in patients with severe hepatic dysfunction, but dose reduction is not required in patients with renal dysfunction or patients on dialysis.

Due to its prolonged half-life, amiodarone is usually initiated at a total daily dose of 600 to 800 mg (divided into 2-3 doses) to achieve a loading dose of 10 g over a period of 7 to 10 days. The dose is then reduced to maintenance of 200 mg daily, although a dose of 400 mg daily may be used for a few weeks after initial loading in select patients. ²⁴ Of note, this dose is lower than what would typically be used for treatment of ventricular arrhythmias. Slower loading may minimize adverse effects such as gastrointestinal distress and suppression of sinus node and AV nodal conduction. ⁶² Administration with food also increases bioavailability ⁶³ and reduces gastrointestinal side effects. Although some patients may convert from AF to SR during loading, many patients do not, and this has no effect on long-term drug efficacy once appropriate drug levels have been achieved and SR is restored. ⁶⁴

In studies comparing the relative efficacy of AADs in suppressing AF, amiodarone is consistently the most effective AAD available ^46,47,65 although a multitude of side effects limit its widespread use. Amiodarone contains a significant amount of iodine, is structurally similar to the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄), and inhibits both peripheral conversion of T₄ to T₃ and entry of T₃ and T₄ into cells. ⁶⁶ Most patients develop some perturbation in thyroid function tests including an elevation in T₄ and thyroid-stimulating hormone and a reduction in T₃ which are not indicative of hyperthyroidism and do not require treatment. ⁶⁶ Amiodarone can, however, induce both hypo- and hyperthyroidism, and up to one-quarter of patients may develop clinically relevant thyroid dysfunction while on the drug. ⁶⁶ Hypothyroidism is more common in areas with high dietary iodine intake, while hyperthyroidism predominates in areas with iodine deficiency. ⁶⁶ Treatment of hyperthyroidism with amiodarone discontinuation, methimazole, propylthiouracil, steroids, or thyroidectomy in severe cases where continued use of amiodarone is necessary may be required. ⁶⁶ Recurrence of AF while on amiodarone may be a sign of hyperthyroidism even if there are no other clinical signs pointing to thyroid derangement. Drug discontinuation and/or thyroid replacement are the main treatments for amiodarone-induced hypothyroidism. ⁶⁶

Nonspecific gastroenterological symptoms such as nausea are common and may resolve with dose reduction. ⁶¹ Severe hepatotoxicity is rare (<3%), ⁶¹ but patients will frequently have minor abnormalities in transaminases, which can mimic nonalcoholic fatty liver disease. ⁶⁷ This low-level inflammation can, in rare cases, result in cirrhosis if unrecognized and the drug is continued. ⁶¹ Acute amiodarone-induced hepatitis, often after parenteral administration, has also been described. ⁶⁸ Treatment of amiodarone-induced hepatitis is supportive, with discontinuation of the drug.

Pulmonary toxicity occurs in approximately 2% of patients treated with amiodarone. ⁶¹ Patient age and duration of therapy are significant risk factors. ⁶⁹ Preexisting pulmonary disease increases the risk of amiodarone-induced pulmonary toxicity but does not increase total mortality or pulmonary mortality associated with use of amiodarone, and the drug can be used cautiously in patients with mild lung disease. ⁷⁰ Pulmonary toxicity may present at any time point during amiodarone therapy and usually presents with cough with later development of dyspnea and fever. ⁷¹ Chest X-ray reveals diffuse infiltrates, consolidations, and pleural thickening. ⁷² Pulmonary function testing usually reveals evidence of restrictive physiology and impaired diffusing capacity, and computed tomography of the chest can reveal evidence of fibrosis and ground glass opacities. ^71,72 Findings on bronchoscopy are nonspecific for amiodarone toxicity but reveal an increase in inflammatory cells with structurally abnormal “foamy” macrophages. ⁷² Lung biopsy is usually avoided due to a high incidence of postprocedure acute respiratory distress syndrome and high mortality. ⁷² Treatment of amiodarone-induced pulmonary toxicity includes drug discontinuation and treatment with steroids. ⁷¹

Cardiac side effects include bradycardia, which is often dose related. ⁷³ Prolongation of the QT interval occurs in almost all patients, although, despite this, rates of TdP (<0.5%) are significantly lower than for other drugs that prolong the QT interval such as sotalol and dofetilide, likely due to amiodarone’s simultaneous effects on other ion channels. Amiodarone can also cause photosensitivity and rarely causes blue skin discoloration or alopecia. ⁶² Neurologic side effects including neuropathy, tremor, and cognitive impairment are rare. ⁷⁴ Almost all patients develop corneal deposits, which have no clinical significance, but optic neuropathy can rarely develop. ⁷⁵

Amiodarone has multiple clinically significant drug interactions. Amiodarone inhibits CYP3A4, CYP2C9, and P-gP and can increase the drug effect of coadministered warfarin, digoxin, statins (especially simvastatin), and multiple other drugs.

Dofetilide

Dofetilide, one of the newest AADs available for treatment of AF, was approved for use in the United States in the year 2000. It is not approved or available in Europe. Dofetilide blocks the rapid component of the delayed rectifier potassium current (I _Kr) and unlike most other AADs has minimal effects on other ion channels. It therefore prolongs the QT interval, and its main adverse event is TdP. Dofetilide exhibits reverse use dependence, whereby the effect of I _Kr blockade is diminished as the heart rate increases, and the risk of drug toxicity is amplified at low heart rates. ⁷⁶ Drug potency is also affected by extracellular potassium concentration, and hypokalemia and hyperkalemia can increase or decrease drug potency, respectively. ⁷⁷

Dofetilide has high oral bioavailability of >90%. It is taken twice daily, and the starting dose (between 125 and 500 µg) is carefully selected based on renal function to avoid significant QT prolongation and Tdp. During the initial drug loading period, the dose of dofetilide dose may be further adjusted based on the change in QT interval after each dose during required inpatient monitoring (see subsequently). Dofetilide’s half-life is 6 to 10 hours, and approximately 80% of the drug is excreted unchanged in the urine via cationic secretion, while the remainder is metabolized in the liver by CYP3A4 prior to renal excretion. ^76,78 Dofetilide does not inhibit or induce any CYP450 enzymes, ⁷⁸ although there are still many important interactions with common drugs. Coadministration of other drugs that can prolong the QT interval should be avoided. ⁷⁹ Verapmil, cimetidine, ketoconazole, trimethoprim, and hydrochlorothiazide can also significantly increase dofetilide levels and cannot be coadministered. ^78,80

Although dofetilide has demonstrated efficacy and safety when used in patients with reduced LV systolic function and/or coronary artery disease, ^81,82 it remains relatively underutilized, primarily due to the requirement that drug initiation take place during a 3-day inpatient hospitalization. This was mandated because most adverse proarrhythmic events occurred in the first 3 days after drug initiation. Additionally, physicians and pharmacies have to be specially certified to prescribe and dispense the drug, respectively.

In the Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) study, dofetilide was effective at converting AF to SR with a dose-dependent response of 6% to 30%, and 91% of patients converted to SR within 36 hours. Between 40% and 60% of patients on dofetilide remained in SR at 1 year which was significantly better than placebo (25% at 1 year, P = .001). ⁸³ The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) Study ⁸² randomized 1518 patients with LV dysfunction and symptomatic heart failure to dofetilide or placebo and found no difference in total mortality at 18 months (41% vs 42% in dofetilide and placebo groups, respectively). Dofetilide has also demonstrated safety when used in patients with MI within 1 week and reduced LV function. ⁸¹ Overall, dofetilide has not been associated with an increased mortality risk. ³³ Rates of TdP ranged from ∼1% in the SAPHIRE-D to ∼3% in the DIAMOND trials. Women, patients with severe heart failure, recent MI, and prolonged baseline QT are at increased risk of TdP. Dofetilide has only been studied and approved for use in patients with persistent AF, and efficacy in patients with paroxysmal AF is less clear.

Dronedarone

Although amiodarone is highly effective in maintaining SR, as noted earlier, its myriad toxicities frequently limit its use. Dronedarone, a noniodinated benzofuran derivative with a structure similar to amiodarone (with the addition of a methyl–sulfonyl group and without the iodine moieties), was developed to overcome these limiting toxicities by reducing its interaction with thyroid physiology, decreasing lipophilicity, ⁸⁴ and shortening plasma half-life (∼13-19 hours). ⁸⁵ Similar to amiodarone, dronedarone blocks a wide array of cardiac ion channels, including I _Kr, I _Ks, I _K1, I _KAch, I _Na, I _CaL, α-receptors, and β-receptors. ^84,86 Dronedarone is administered at a fixed dose of 400 mg twice daily and is well absorbed, but extensive first-pass metabolism limits bioavailability. Administration with food can increase bioavailabilty up to 4-fold. ⁸⁴ Dronedarone pharmacokinetics are not significantly influenced by age, gender, weight, or renal function. Serum creatinine usually increases due to inhibition of creatinine secretion and does not reflect impaired renal function. ⁸⁴ Dose adjustments are only recommended in patients with severe hepatic dysfunction. ⁸⁴

Dronedarone is metabolized by and inhibits CYP3A4 and P-gp and therefore is associated with many significant drug–drug interactions. Coadministration of other strong inhibitors of CYP3A4 such as azole antifungals, grapefruit juice, and cyclosporine is contraindicated. ⁸⁴ Dronedarone can also significantly increase levels of statin medications and digoxin, resulting in increased toxicity. Unlike amiodarone, dronedarone has no interactions with warfarin ⁸⁴ and has no significant effect on thyroid function.

In the A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in patiENts with Atrial Fibrillation/Atrial Flutter (ATHENA) trial, compared to placebo, dronedarone was associated with a reduction in the composite outcome of hospitalization due to cardiovascular events or death (hazard ratio (HR) 0.76, P < .001). ⁸⁷ The Randomized, Double-Blind TrIal to Eval-uate the Efficacy and Safety of DrOnedarone [400 mg bid] Versus AmiodaroNe [600 mg qd for 28 daYS, then 200 mg qd Thereafter] for at Least 6 mOnths for the Maintenance of Sinus Rhythm in Patients with AF (DYONYSOS) study compared amiodarone to dronedarone in 504 patients with persistent AF and found that amiodarone was significantly more effective than dronedarone at preventing recurrence of AF (HR 1.59, P < .0001) but was associated with significantly more adverse thyroid, neurological, ocular, and dermatological side effects at 1 year. ⁸⁸

Despite these favorable initial results, the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, which randomized 3236 patients with persistent AF and cardiovascular risk factors to placebo or dronedarone used as a rate-controlling agent, was stopped prematurely due to safety concerns: The composite end point of stroke, systemic embolism, MI, or cardiovascular death was significantly more frequent in dronedarone-treated patients (HR 2.3, P = .002). Compared to placebo, the individual outcomes of cardiovascular death (HR 2.1, P = .046), arrhythmic death (HR 3.3, P = .03), stroke (HR 2.3, P = .02), and heart failure hospitalizations (HR 1.8, P = .02) were also significantly increased in the dronedarone group. ⁸⁹

The divergent results from the PALLAS and ATHENA studies could be related to the fact that ATHENA allowed enrollment of patients with paroxysmal AF and higher rates of concomitant digoxin use in PALLAS. However, another study (Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease [ANDROMEDA]) which randomized patients with LV systolic dysfunction (LV ejection fraction ≤ 35%) and New York Heart Association (NYHA) class III or IV symptoms within the prior month to dronedarone or placebo found a similar increase in mortality in dronedarone-treated patients (HR 2.1, P = .03) which was frequently due to worsening heart failure. ⁹⁰ Although approximately 20% of patients in ATHENA had NYHA class II-III heart failure, and subgroup analysis did not suggest an increase in mortality or adverse events in this subgroup of patients, the severity of heart failure in ATHENA was lower than in ANDROMEDA, and this may explain the disparate results. ⁸⁷ Nonetheless, based on increased mortality, dronedarone should be avoided in patients with congestive heart failure, and it should not be used as a rate-control agent in patients with long-standing persistent or permanent AF.

Ranolazine

Ranolazine blocks sodium, potassium, and calcium currents and is approved as an antianginal agent, although evidence has emerged regarding its antiarrhythmic properties for both atrial and ventricular arrhythmias. Ranolazine inhibits peak and late I _Na, the rapidly and slowly delayed rectifier potassium currents (I _Kr and I _Ks, respectively), and is a relatively weak inhibitor of l-type calcium channels (I _CaL). ⁹¹ Ranolazine is administered twice daily, has a half-life of 7 hours, and is predominantly hepatically metabolized by CYP3A4 prior to renal excretion. Dose adjustment is therefore reasonable in both renal and hepatic failure, although the drug manufacturer does not require such adjustment. ⁹²

Data supporting use of ranolazine as an AAD for AF are limited. In a substudy of patients with non-ST-segment elevation acute coronary syndrome in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial, compared to placebo, treatment with ranolazine resulted in a reduction in AF events over 1-year follow-up (2.9% vs 4.1%, P = .01), and patients with baseline paroxysmal AF had an overall lower burden of AF (4.4% vs 16.1% for ranolazine and placebo, respectively, P = .015). ⁹³ The PHase 2, Proof of Concept, Randomized, Placebo-Controlled, PArallel Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in CoMbination On Atrial FibrillatioN Burden in Subjects with ParoxYsmal Atrial Fibrillation (HARMONY) study, which compared placebo, ranolazine, dronedarone, and the combination of ranolazine and dronedarone, found that ranolazine alone had no effect on pacemaker detected AF burden over 12 weeks of follow-up, but the combination of ranolazine and dronedarone was superior to placebo in reducing AF burden. ⁹⁴ In the Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion (RAFFAELLO) study, administration of ranolazine after cardioversion from AF to SR was ineffective at prolonging time to AF recurrence, although there was a trend toward reduced AF recurrences in patients treated with high-dose ranolazine. ⁹⁵ Based on this limited evidence, ranolazine should not be used as a primary rhythm control agent in AF, and current guidelines do not recommend its use as an AAD for AF. Given the synergistic effects of ranolazine with dronedarone ⁹⁶ or amiodarone ⁹⁷ in suppressing AF, ranolazine may have a role as a second AAD in select patients.

Ranolazine prolongs the QT interval in a dose-dependent manner predominantly via its effect on I _Kr, but its inhibition of the late sodium current is protective against TdP. ^98,99 Although a significant increase in TdP has not been observed, caution should still be exercised when using ranolazine in patients with significant QT prolongation or in patients who are taking other QT-prolonging drugs. ⁹² The most common side effects include headache, dizziness, nausea, and constipation.

Ibutilide

Ibutilide, a methanesulfonamide derivative with similar structure to sotalol, is an intravenous I _Kr blocker that is used only for acute termination of AF. ¹⁰⁰ In addition to its potassium channel–blocking effects, ibutilide activates late inward sodium current and, unlike sotalol, does not exhibit significant reverse use dependence. ¹⁰⁰ It has minimal hemodynamic effects and can be used safely in patients with structural heart disease and prior MI. Despite its efficacy in terminating both AF and atrial flutter, due to its blockade of I _Kr and facilitation of late inward sodium current, ibutilide prolongs action potential duration and the QT interval and use has been associated with an increased risk of TdP (overall rate ∼4%). ¹⁰¹ Patients must therefore be monitored closely for at least 4 hours after the infusion has ended and QTc has returned to baseline. ^{102 -104} Noncardiac side effects other than nausea are rare. ¹⁰¹

Ibutilide is usually administered as a 1-mg infusion over 10 minutes, with a repeat 1-mg infusion 10 minutes after the first infusion completes if necessary. Patients weighing <60 kg should receive a dose of 0.01 mg/kg. Potassium and magnesium should be replete prior to administration, and the drug should be avoided in patients with baseline QT prolongation or use of other drugs that can prolong the QT. ¹⁰⁰ Ibutilide has a large volume of distribution and an average half-life of 6 hours. It undergoes hepatic metabolism via CYP3A4 and renal excretion, and although dose reductions are not required in either hepatic or renal dysfunction, patients with liver disease may metabolize ibutilide more slowly and require a prolonged period of postinfusion monitoring. ¹⁰⁰

Vernakalent

Vernakalent is a new AAD that blocks multiple ion channels but has the unique benefit of only affecting atrial tissue. Its major antiarrhythmic effect in AF is inhibition of the ultra-rapid delayed rectifying potassium channel (I _Kur) which is highly selective for atrial tissue. It also has weak effects on I _to and rate-dependent effects on I _Na. ¹⁰⁵ Vernakalent is available only as an intravenous infusion, and it is metabolized by CYP2D6 ¹⁰⁵ with an elimination half-life of approximately 2 hours. Multiple studies have demonstrated that intravenous administration of vernakalent is able to rapidly terminate AF episodes of less than 7 days duration in about 50% of patients without significant proarrhythmia. ^{106 -108} Common side effects include hypotension, bradycardia, dysgeusia, sneezing, and cough. ¹⁰⁶ Vernakalent has been approved for use only in Europe for the acute termination of AF. Prior to approval in the United State, the Federal Drug Administration requested that an additional phase III study be performed, and during this study a patient died during drug infusion. The study was canceled, and for this reason, the drug has not been approved in the United States. ¹⁰⁹ Development of a sustained-release oral formulation has also been discontinued.

Vanoxerine

Vanoxerine is a dopamine transporter antagonist that was initially developed for treatment of depression and Parkinson disease. In addition to its effects on dopamine receptors, it blocks I _Kr, I _Na, and I _CaL in a use-dependent manner. It has no effect on dispersion of repolarization and therefore is thought to have a reduced risk of proarrhythmia. ¹¹⁰ Early animal studies demonstrated efficacy in terminating AF and atrial flutter. ^111,112 There are limited data on use in humans, although in a small placebo-controlled randomized trial of 104 patients with AF lasting <7 days duration, administration of oral vanoxerine was associated with conversion to SR in a dose-dependent manner. Side effects were generally mild and included QT prolongation, bradycardia, gastrointestinal symptoms (nausea and vomiting), and neurologic symptoms (headache and dizziness). ¹¹³ A larger study evaluating use of vanoxerine for conversion of AF and atrial flutter to SR is currently underway (clinicaltrials.gov NCT02454283).

Other Novel AADs Under Development

Many novel AADs have failed to reach market, and multiple novel AADs for the treatment of AF are currently under development. Great effort has been put forth to find drugs that act only or predominantly on atrial tissue to reduce side effects (including the risk of ventricular arrhythmias). Multiple drugs that target I _Kur or acetylcholine-sensitive potassium channels are currently in the early stages of development. ¹¹⁴ Other novel drugs that stabilize ryanodine receptors (K201 ^{115 -117} ) or gap junctions (rotigaptide ^118,119 ) are also under development, but data in humans remain limited at this point in time. It is likely that other novel drug targets will be discovered in the future as well.