Atrial Fibrillation: Pharmacological Therapy

Transcription

1 Atrial Fibrillation: Pharmacological Therapy Chinmay Patel, MD, Mohammed Salahuddin, MD, Andria Jones, DO, Aashay Patel, MBBS, Gan-Xin Yan, PhD, and Peter R. Kowey, MD, FAHA Abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. Although once considered a nuisance arrhythmia, recent clinical trial evidence suggests that the presence of AF is an important independent predictor of mortality and morbidity. The primary goals of AF treatment are relief of symptoms and prevention of stroke. The value of anticoagulation with warfarin has been proven unequivocally. Control of ventricular rate with atrioventricular nodal blocking agents the so-called rate control strategy is least cumbersome and sometimes the best approach. By contrast, efforts to restore and maintain sinus rhythm using antiarrhythmic drugs the rhythm control approach although tedious, may be ideal in patients who are young or highly symptomatic and in those with new-onset AF. The relative merits of both treatment strategies are discussed in this article, emphasizing the excellent clinical trial data that support each. (Curr Probl Cardiol 2011;36: ) Problem Statement T he epidemic of atrial fibrillation (AF) affects approximately 1% of the adult population of the United States. It is projected that by the year 2050, there will be almost 15 million patients with AF. 1-3 It is a very common cardiac arrhythmia in clinical practice. Thirty years of follow-up data from the Framingham Study cohort have suggested that Competing Interests. None. Curr Probl Cardiol 2011;36: /$ see front matter doi: /j.cpcardiol Curr Probl Cardiol, March

2 the lifetime risk of developing AF is 1 in 4 for men and women older than 40 years with a higher predisposition for men and white Americans. 4,5 Although AF is uncommon before the age of 60 years, its prevalence increases markedly thereafter, affecting about 10% of the population by 80 years of age. 2 Additionally, the presence of AF is associated with higher long-term risk of stroke, heart failure, and all-cause mortality. 6,7 With the aging population, this disease burden contributes enormously to morbidity and mortality. 8 The total direct costs of treating patients with AF in the year 2005 were estimated at more than $6bn. 9 Thus, AF is a costly public health problem. Current Therapy of Atrial Fibrillation Today, therapy for AF is multidimensional with treatment options spanning from pharmacologic therapy to invasive electrophysiological intervention. 10 The principle goals of these treatments are relief of symptoms and prevention of stroke. Pharmacologic therapy principally includes anticoagulation with warfarin, control of heart rate or rhythm, and supportive nonarrhythmic drug therapy. There is a consensus regarding the indications and benefits of anticoagulation in AF; however, debate continues regarding whether to pursue the strategy of control of the ventricular rate (rate control) or the strategy of maintenance of sinus rhythm (SR) (rhythm control), to prevent and even reverse atrial remodeling. 11,12 Catheter-based radiofrequency ablation is a promising approach that can be used as an alternative or as an adjunct to antiarrhythmic drugs. 13 This article discusses the strategy of rate vs rhythm control, currently available antiarrhythmic drugs, and the role of adjuvant pharmacotherapy of prevention of AF. Radiofrequency ablation and anticoagulation in AF are beyond the scope of this article and are discussed elsewhere. 10 Classification of Atrial Fibrillation According to the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) Task Force on Clinical Guidelines for the management of AF, AF can be classified into 4 types: first detected episode, paroxysmal, persistent, and permanent. 10 Paroxysmal AF terminates spontaneously, with episodes typically lasting less than 24 hours and up to 7 days. Persistent AF requires cardioversion (pharmacologic or electrical) to terminate and the episodes last more than 7 days. Permanent AF describes continuous AF that has failed cardioversion or where cardioversion has never been attempted. Recurrent AF describes 2 or more episodes of paroxysmal or 88 Curr Probl Cardiol, March 2011

3 persistent AF. The term lone AF defines young patients who develop AF in the absence of readily identifiable cardiopulmonary or systemic disease that can lead to AF. These patients in general tend to have a better prognosis. Irrespective of AF type, symptoms due to AF are quite variable. Upwards of 45% of patients were diagnosed with AF incidentally during an electrocardiogram for unrelated reasons in 2 major population studies. 14,15 However, many patients have subtle symptoms, such as nonspecific fatigue, listlessness, and anxiety, that potentially remain undetected unless specifically probed by a physician. Many such patients feel more energetic after restoration of SR. By contrast, some patients are clearly symptomatic with palpitation, lightheadedness, fatigue, and reduced exercise tolerance. Patients with hypertension, left ventricular hypertrophy, and restrictive cardiomyopathy are particularly sensitive to the loss of atrioventricular (AV) synchrony and decreased diastolic filling. Determining how symptomatic the patient is because of AF remains a principle problem because patients who are not having many symptoms may be appropriate for simple rate control strategy and patients who have functional decline may benefit from rhythm control. Rhythm vs Rate Control The initial therapy for AF is often directed toward restoration of SR by means of cardioversion and maintenance of SR by antiarrhythmic drugs. The proposed advantages of the rhythm control strategy are symptomatic improvement, improved exercise tolerance, reduced risk of stroke, and possibly discontinuation of anticoagulation. The alternative approach is simply control of the ventricular rate using AV nodal blocking therapy or rate control. This decision is empiric. The strategy of rhythm control was presumed superior to rate control because of its proposed benefits of preservation of ventricular function, improved quality of life (QoL), and possible mortality advantage. However, contradictory results were obtained from a series of randomized prospective clinical trials summarized in Table The largest of these 5 trials, Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) 20 and Rate Control vs Electrical Cardioversion for Persistent Atrial Fibrillation (RACE), 19 failed to show any mortality benefit of maintaining SR in AF patients. Instead, a tread toward greater mortality was seen with the rhythm control strategy overtime. AFFIRM enrolled more than 4000 patients aged 65 years or more with paroxysmal and persistent AF and randomized them to receive rate control or antiarrhythmic drug therapy. In the rhythm control group, antiarrhythmic drugs and cardioversion were necessary to Curr Probl Cardiol, March

4 TABLE 1. Major clinical trials comparing rate control vs rhythm control strategy in AF Study Type of AF No./Mean follow-up AFFIRM Paroxysmal persistent n 4060 followed for 3.5 y RACE Persistent recurrent ( 24 h-1 yr) n 522 followed for 2.3 y PIAF Persistent (7 d to 1 yr) n 252 followed for 1 y HOT CAFÉ Persistent (7 d to 2 yr) n 205 followed for 1.7 y STAF Persistent ( 4 wk-1 yr) n 200 followed for 19.6 mo AF-CHF Paroxysmal or persistent ( 1 yr) LVEF 35% HF (NYHA Class 2 to 4) n 1276 followed for 36 mo Abbreviations: AF, atrial fibrillation; Pt, patients; HR, hazard ratio; HF, heart failure; QoL, quality of life; CVA, cerebrovascular accident; CV, cardiovascular; HF, congestive heart failure. maintain SR. In the rate control group, -blockers, calcium-channel blockers, digoxin, or combinations of these drugs were used to control the ventricular rate to 80 bpm at rest and 110 bpm after a 6-minute walk. The rate control group received continuous anticoagulation during the period of the study. In the rhythm control group, continuous anticoagulation was encouraged but could be stopped at the physician s discretion if SR was maintained for at least 12 weeks. At an average follow-up of 3.5 years, a trend toward a lower all-cause mortality was observed in the rate control group (21%) compared with the rhythm control patients (24%). 20 A higher risk for ischemic stroke was 90 Curr Probl Cardiol, March 2011

5 TABLE 1. Continued Outcomes Patients in SR (%) rhythm vs rate control Primary rhythm vs rate control 62.6% vs 34.6% All-cause mortality: No difference (HR: 1.15) 39% vs 10% Composite of CV death, HF hospitalization, bleeding thromboembolic complications, pacemaker, severe adverse effects: 22.6% vs 17.2% (no difference) 56% vs 10% Symptomatic improvement: no difference 63.5% Composite of all-cause mortality, thromboembolic events, major bleeding: No difference 40% vs 12% at 1 y; 26% vs 11% at 2 y; 23% vs 0% at 3 y Composite of death, CVA, cardiopulmonary resuscitation: No difference Secondary rhythm vs rate control Composite of death, CVA, major bleeding, and cardiac arrest: Not different. Rhythm control: more hospitalization trend toward higher mortality. Rhythm control: improve exercise tolerance but more hospitalization and side effects. QoL not changed. Rhythm control: improve exercise tolerance but more hospitalizations Rhythm control: trend toward improved QoL but increased hospitalizations. Roughly 73% vs 30% CV death: No difference All-cause mortality, CVA,CHF, QoL: No difference Rhythm control: frequent hospitalization. seen in the rhythm control group primarily due to inadequate anticoagulation. At 5 years of follow-up, only 62% of patients were in SR in the rhythm control group and the actuarial rate of crossover from rhythm control to rate control group was almost 37%. Inability to maintain SR and drug intolerance were the principle reasons for crossover. The results of AFFIRM underscored nonsuperiority of either strategy for treatment of AF and limited efficacy and significant adverse effects of current antiarrhythmic drugs and need for therapeutic anticoagulation. Similarly, RACE enrolled 522 patients with persistent AF and randomized them to rate control or rhythm control. At a mean follow-up of 2.3 years, no difference was found between the 2 groups in the composite endpoint. 19 Similar but smaller scale trials like Pharmacological Intervention in Atrial Fibrillation (PIAF), 17 The Strategies of Treatment of Curr Probl Cardiol, March

6 Atrial Fibrillation (STAF), 16 and How to Treat Chronic Atrial Fibrillation (HOT CAFE) 18 failed to prove superiority of rhythm control over rate control or vice versa with respect to their primary clinical endpoints that included mortality (Table 1). Three meta-analyses that combined the results of these 5 studies showed nonsuperiority of either strategy with regard to all-cause mortality, but a trend favoring better outcome with rate control over rhythm control Additionally, patients in the rate control strategy had a reduced risk of the combined endpoint of all-cause death and thromboembolic stroke (odd ratio 0.84, 95% CI , P 0.02) 23 and reduced rates of hospitalization. 22 Moreover, the recently published Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial failed to show any benefit of rhythm control strategy even in patients with a left ventricular ejection fraction of 35% and symptoms of CHF in whom there is a theoretical benefit of rhythm control. In light of the above, the strategy of maintaining SR in AF has fallen out of favor and many primary care physicians have resorted to the passive and less complex approach of rate control for management of AF. Melvin M. Scheinman: The primacy of appropriate anticoagulant therapy was apparent in the AFFIRM trial for both the rhythm and the rate control groups in terms of stroke prevention. The current practice of warfarin therapy has important limitations in terms of need for frequent checks of INR, drug-drug interactions, dietary restrictions, and genetic variations in warfarin metabolism. These problems have led to interest in the use of alternative anticoagulant therapy. A recently published trial (RE-LY Randomized Evaluation of Long-Term Anticoagulation Therapy) 1 compared a direct thrombin inhibitor (Dabigatran) in 2 doses vs (110 mg and 150 mg) with warfarin therapy. There was noninferiority in terms of risk of stroke between either dose of Dabigatran compared with warfarin and the higher dose proved superior to warfarin therapy. Major bleeding was less for those treated with the lower dose. The direct thrombin inhibitors do not require blood monitoring, have no significant drug-drug interactions, and thus promise to revolutionize anticoagulant therapy (Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: ). Is There a Role of Rhythm Control in Pharmacologic Management of Atrial Fibrillation? Although trial evidence clearly supports the strategy of rate control over rhythm control for management of AF, a prudent quest for optimal rhythm control pharmacotherapy continues. 24,25 Before abandoning rhythm control, 92 Curr Probl Cardiol, March 2011

7 several important questions need to be addressed. The arguments supporting rhythm control can be outlined as follows: 1. It should be noted that the results from the AFFIRM and RACE trial bear more relevance to an elderly population (mean ages of patients were 70 and 68, respectively) with nonrheumatic AF and few or no symptoms (episodes of AF that occurred less than once per month). 26 For young, symptomatic patients with rheumatic AF, rhythm control strategy has been shown to reduce mortality and to improve QoL Antiarrhythmic drugs are frequently perceived as highly proarrhythmic, perhaps more proarrhythmic than they really are. Although increased mortality with rhythm control is frequently ascribed to proarrhythmic drug effects, a post-hoc analysis of cause-specific mortality and mode-ofdeath of AFFIRM data showed that the trend toward increased mortality in the rhythm control arm was in fact due to noncardiovascular death, specifically, pulmonary disorders and cancer. Mortality related to cardiovascular causes was the same in both groups. 28 Complementing these data, a post-hoc analysis of the AFFIRM population showed that the presence of SR was an important determinant or a marker for survival. 29 However, in this analysis, antiarrhythmic drug therapy was not associated with improved survival. 29 This mismatch suggests that benefits of antiarrhythmic drugs may have been offset by potential adverse effects. The rhythm control strategy might provide better outcomes if safer antiarrhythmic drugs become available. By contrast, in the rate control arm of AFFIRM, achieving resting or exercising heart rate targets failed to predict any of the clinical outcomes, including survival, QoL, and functional status In addition to cardiac and extracardiac side effects, limited efficacy of current antiarrhythmic drugs may also account for lack of benefit of maintaining SR. In the clinical trials comparing the efficacy of the rate vs rhythm control strategy in patients with AF, at the end of the trial period only % patients randomized to the rhythm control strategy were found to be in SR. In AFFIRM only 62.5% patients dosed with antiarrhythmic drugs were in SR at the end of the 5-year study period It can be argued that if effective antiarrhythmic drugs become available for maintenance of SR, it could swing the pendulum in favor of the rhythm control strategy. 4. Additionally, it can be argued that although these trials demonstrated equivalency of rate and rhythm control strategy in terms of mortality, they lack precision in determining what constitutes optimal rate or rhythm control. 31 Curr Probl Cardiol, March

8 5. It is clear that patients with AF have poor QoL 32 and impaired functional status, and several lines of evidence suggest that restoration of SR can improve vitality Evidence supporting the role of current antiarrhythmic drugs in improving QoL and functional status in patient with AF is inconsistent, but may favor their use. 17,18,37-39 In the absence of any mortality difference, patients who are symptomatic from AF may benefit from an attempt to restore SR. Rate Control Agents The rate control strategy in AF is fairly straightforward. It constitutes using drugs that slow conduction through the AV node, thus avoiding excessively rapid ventricular rates. A persistently high ventricular rate in AF may not only make the patient more symptomatic, but also can lead to tachycardia-induced cardiomyopathy. Conduction through the AV node is in turn influenced by the presence or absence of intrinsic conduction system disease and sympathetic and parasympathetic tone. The AV node characteristically displays the property of decremental conduction. That is, as more impulses arrive at the AV node per unit of time, conduction progressively becomes slower. An intrinsically higher atrial rate may be one of the reasons rate control is easier during AF compared with atrial flutter. The choice of agent for rate control strategy depends on the patient s hemodynamic status, presence of contraindications, and indications for a particular drug and drug tolerance. It may also be simply a matter of physician preference. Intravenous formulations of drugs have faster onset of action than oral administration and are therefore valuable in acute settings. What is considered adequate rate control is controversial. 31 As mentioned earlier, the degree of heart rate control achieved has failed to predict survival, QoL, or functional status. 30 A recent trial, RACE II, compared Lenient vs Strict rate control in management of AF and compared their effects on cardiovascular morbidity and mortality. 40 A total of 614 patients with permanent AF were randomly assigned to either a lenient (resting heart rate 110 bpm) or a strict (resting heart rate 80 bpm and heart rate 110 bpm with moderate exercises) rate control strategy. At 3-year follow-up, lenient rate control was noninferior to strict rate control in the prevention of major cardiovascular events and mortality rate. Contrary to the commonplace belief, lenient rate control was not associated with worsening of heart failure or frequent hospitalizations. 40 Both groups had similar improvement in their symptoms and lenient rate control was easier to achieve. The result of RACE II may lead 94 Curr Probl Cardiol, March 2011

9 to a revision of the current ACC/AHA guidelines that recommend the ventricular rates of bpm during rest and bpm during exercises when rate control strategy is employed for AF management. 10 Choices for rate control are limited. Candidates include -blockers (class II), calcium channel blockers (class IV), and digoxin. Some of these agents have additional antihypertensive properties and their selection may serve multiple purposes. All -blockers are effective in rate control for AF, particularly in AF associated with adrenergic drive. They prevent shortening of refractoriness at all levels in the heart. They block adrenergic activation of calcium channels and thereby prolong the refractoriness of the AV node as conduction through the AV node is calcium dependent. The effectiveness of -blockers as first-line drugs for rate control was demonstrated in the AFFIRM substudy. 41 Overall rate control was achieved in 70% of patients given -blockers as the first drug (with or without digoxin), 54% with calcium channel blockers (with or without digoxin), and 58% with digoxin. In the acute setting, intravenous esmolol, metoprolol, propanolol, or atenolol has a rapid onset and can be given in a postoperative or acute setting. Esmolol may be given as a continuous infusion and has a short half-life, which is beneficial in critically ill patients. The choice and route of administration should be based on the patient s hemodynamics and other comorbidities. -Blockers should be used with caution in patients who are hypotensive or have heart failure. Nondihyrdopyridine calcium channel blockers, verapamil and diltiazem, are commonly used for rate control in AF. These agents are valuable in patients who are intolerant or have contraindications to -blockers, such as severe obstructive lung disease. These agents affect calcium-dependent slow action potential upstroke in the sinus and AV node, resulting in slowing of conduction. As they have no effect on fast sodium-dependent conduction, they have no effect of QRS duration. Calcium channel blockers can also be given intravenously when rapid onset of action is needed. Non-dihydropyridine calcium channel antagonists should be avoided in patients with heart failure and in the presence of acute left ventricular systolic dysfunction. Once a first-line agent for AF, digoxin is primarily useful in controlling heart rates at rest or in combination with other AV nodal blocking drugs. Digoxin enhances vagal activity and thus reduces sinus node automaticity and prolongs AV nodal conduction and refractoriness. Digoxin is usually tolerated in patients with heart failure or hypotension but is less effective in high sympathetic states. Intravenous digoxin requires 60 minutes to take effect and its peak effect can be delayed up to 6 hours. Digoxin Curr Probl Cardiol, March

10 should be administered carefully in elderly people, in patients with renal insufficiency, and with medications that may potentiate its toxic effects. One interesting study by Farshi et al evaluated 5 different drug regimens digoxin, atenolol, diltiazem, digoxin atenolol, and digoxin diltiazem for rate control in patients with permanent AF. 42 The same 12 patients were assigned to receive all 5 treatments for a 2-week interval. The combination of atenolol, 50 mg with digoxin, 0.25 mg d 1, was the most effective regimen in controlling the ventricular response during daily activity; however, exercise duration in all groups was similar. 42 Rhythm Control The rhythm control strategy includes restoration of SR and maintenance thereafter. Upwards of 70% patients with new-onset AF of 72 hours convert to SR spontaneously with most spontaneous cardioversion occurring within first 24 hours. 43 Electrical remodeling of the atria starts as early as at the onset of AF. 44 Therefore, timely restoration of SR should be accomplished using electric or pharmacologic cardioversion in patients who do not cardiovert spontaneously. Management of patients with new-onset AF deserves special mention here. New-onset AF, but not persistent AF, has been shown to be associated with substantially higher mortality within the first 4 months and has been found to be an independent predictor of mortality. 45,46 Although the exact reasons for these findings are not clear, restoration of SR by cardioversion should be strongly considered in patients with new-onset AF. Many of these patients may remain in SR especially if precipitating causes are corrected. Guidelines for therapeutic anticoagulation before and after cardioversion are outlined in the ACC/AHA consensus statement. 10 Cardioversion: Electrical and Pharmacologic DC cardioversion is an effective and frequently preferred method for restoration of SR in AF. In an appropriate setting, DC cardioversion is almost 95% effective, safe, and well tolerated, with the major risk being thromboembolic stroke that can be minimized with appropriate anticoagulation. Patients need to be fasting for at least 6-8 hours and require pain control and analgesia. Digitalis toxicity should be ruled out before considering DC cardioversion for atrial arrhythmia. Pretreatment with an appropriate antiarrhythmic drug may improve the success rate of DC cardioversion and prevent recurrence. 10 Melvin M. Scheinman: The authors well emphasize the efficacy of directcurrent cardioversions for treatment of atrial fibrillation for patients who 96 Curr Probl Cardiol, March 2011

11 cannot be converted to sinus despite maximal energy and correct chest paddle position. The clinician should consider use of adjuvant drug therapy. For example, it has been shown that the use of ibutilide may decrease the defibrillator threshold and has been shown to be effective in increasing efficacy of direct shock therapy (Oral H, Souza JJ, Michaud GF, et al. Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment. N Engl J Med 1999:340: ). Although DC cardioversion is more effective in restoring SR, pharmacologic cardioversion may be useful if electrical cardioversion cannot be performed. It is particularly effective if AF is paroxysmal or recent in onset. Although multiple agents have been used for pharmacologic cardioversion historically, current ACC/AHA guidelines recommend flecainide, ibutilide, amiodarone, and dofetilide for pharmacologic cardioversion of AF of less than 7 days duration. Intermittent oral administration of a single high dose of flecainide, mg, or propafenone, mg, may be effective as a Pill-in-Pocket approach for reliable patients with structurally normal hearts and paroxysmal AF. 47 Ibutilide is a class III antiarrhythmic agent that blocks the rapidly activating delayed rectifier potassium (I Kr ) current and prolongs refractoriness of atrial and ventricular cells. Ibutilide is approved for rapid cardioversion of AF of short duration and it is given in a single dose of 1 mg over 10 minutes. Termination of AF is usually seen within minutes, and if not, 1 more dose can be given. The efficacy of intravenous ibutilide for rapid conversion of atrial flutter is in the range of 50-70%, whereas its efficacy for conversion of AF is 30-50%. Approximately 80% of atrial tachyarrhythmias that terminate do so within 30 minutes after the initiation of the intravenous infusion. Ibutilide infusion leads to QT interval prolongation and torsade de pointes (TdP) may develop in up to 2% of the patients. Electrolyte disturbances, such as hypokalemia and hypomagnesemia, must be corrected before ibutilide administration. After infusion, irrespective of cardioversion, patients need to be monitored for 4 hours and QT interval must be normal before discharge. Vernakalant is a novel intravenous antiarrhythmic agent that blocks a use-dependent sodium current and early activating potassium current and is relatively atrially selective. 48 The US Food and Drug Administration has not yet approved the drug for use in the United States, but it has been given preliminary approval in Europe. Initial studies have demonstrated vernakalant to be effective in terminating acute episodes of AF. In a phase 2 clinical trial, infusion of 2 mg/kg vernakalant in patients with AF led to cardioversion of up to 61% within first 30 minutes without any proar- Curr Probl Cardiol, March

12 rhythmic effects. 49 Atrial Arrhythmia Conversion Trial I randomized AF patients to receive vernakalant or placebo and stratified them according to duration of AF 7 days or 8-45 days. 50 Vernakalant was more effective in short-duration AF with a cardioversion rate of 51%. Similar efficacy and safety of vernakalant was recently reported in patients with postoperative AF who were evaluated in Atrial Arrhythmia Conversion Trial II. 51 Rhythm Control Agents Most cardiologists do not start antiarrhythmic drug therapy after cardioversion of the first episode of AF. However, antiarrhythmic drugs are required to maintain SR in patients with recurrent paroxysmal or persistent AF. Without antiarrhythmic drug therapy, recurrence of AF is almost 71-84% at 1 year and it can be reduced to 44-67% by appropriately selected antiarrhythmic drug therapy. 52 The choice of antiarrhythmic drug must be individualized and should balance the benefits of maintaining SR against side effects. The major clinical trials demonstrating efficacy of various antiarrhythmic drugs in the maintenance of SR are listed in Table 2 and their principle mechanism of action and side effects are listed in Table 3. Amiodarone. The cardiac safety and efficacy of amiodarone have been demonstrated in multiple randomized and nonrandomized trials. For example, the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) was a double-blind, placebo-controlled trial that assigned 665 patients with persistent AF on anticoagulants to receive amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients) and followed them for years. 39 The primary endpoint was the time to first recurrence of AF beginning on day 28. Patients who failed pharmacologic cardioversion by the 28th day received DC cardioversion. In total, 27.1% of the amiodarone group, 24.2% of the sotalol group, and 0.8% of the placebo group spontaneously cardioverted. During long-term follow-up, the median times to recurrence of AF were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat analysis. Amiodarone was 6 times as effective as sotalol in preventing first AF recurrence. Interestingly, in a subgroup of patients with ischemic heart disease, amiodarone and sotalol were equally effective in preventing the first recurrence of AF (median time to recurrence of AF was 569 days with amiodarone therapy and 428 days with sotalol therapy, P 0.53). The rate of maintenance of SR was significantly higher at 1 year with amiodarone than sotalol or 98 Curr Probl Cardiol, March 2011

13 placebo (52 vs 32% and 13% on intention to treat analysis). Restoration and maintenance of SR significantly improved QoL and exercise capacity without significant adverse effects across all the groups. 39 Similar results were found in the Canadian Trial of Atrial Fibrillation (CTAF) that randomized 403 patients who had at least 1 episode of symptomatic AF in the preceding 6 months to receive either amiodarone, sotalol, or propafenone. 53 During a mean follow-up of 16 months, only 35% of patients on amiodarone treatment had recurrence of AF compared with 63% patients on sotalol or propafenone, and there was a longer median time to recurrence with amiodarone, 468 vs 98 days. Similar finding were reported in a substudy of AFFIRM comparing the efficacy of amiodarone, sotalol, and a class I drug. 54 At 1-year follow up, the likelihood of achieving the primary endpoint that included maintaining SR was significantly higher in the amiodarone group (60-62%) compared with sotalol (38%), or class I drug. 54 However, 18% patients treated with amiodarone discontinued the drug due to adverse events. A recent systemic review assessing safety and efficacy of current antiarrhythmic drugs that included 44 trials enrolling about 11,322 patients with AF showed that at 6-month follow-up, amiodarone (odds ratio (OR), 0.19) reduced recurrences of AF significantly more than combined class I drugs (OR, 0.31) and more than sotalol (OR, 0.43). 52 SAFE-T and CTAF excluded patients with AF who had New York Heart Association (NYHA) class III or IV heart failure. This group was addressed in post-hoc analysis of Veterans Affairs Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy Trial. 55 Treatment with amiodarone in patients with reduced ejection fraction in this trial decreased the incidence of AF and provided better rate control in those patients who developed AF. About 31% of patients who were in AF at the beginning of enrollment spontaneously converted to SR. These patients also had a mortality benefit compared with those who did not cardiovert. However, the recently reported AF-CHF trial failed to substantiate this beneficial effect of amiodarone in patients with CHF. 56 The rhythm control strategy primarily with amiodarone had a neutral effect on mortality. The efficacy and cardiac safety of amiodarone may be explained by its multireceptor affinity. 57 Traditional, pure class III agents like dofetilide, predominantly block IK r, the rapidly activating delayed rectifier potassium current, a major current implicated in drug-induced arrhythmia. This leads to prolongation of action potential duration of cardiac myocytes with preferential prolongation of action potential of midmyocardial M cells leading to an increase in dispersion of repolarization, thus creating Curr Probl Cardiol, March

14 TABLE 2. Major clinical trials investigating role of antiarrhythmic drugs in AF management Study Inclusion criteria Specific exclusion criteria Treatment follow-up SAFE-T Persistent AF 72 h and AF at randomization on therapeutic anticoagulation Paroxysmal AF A flutter NYHA class 3/4 CHF Placebo vs amiodarone vs sotalol. followed for y CTAF Paroxysmal AF with at least 1 episode of AF in last 6 mo Persistent AF 6 mo NYHA class 3/4 HF Amiodarone vs sotalol vs propafenone followed for 16 mo RAFT Symptomatic AF within last 12 mo who were in SR at randomization Permanent AF NYHA class 3/4 HF Recent myocardial infarction Placebo vs propafenone SR (425, 325, 225 bid) followed for 39 wk SAFIRE-D ATHENA AF or A-flutter from 2 to 26 wk Paroxysmal/persistent AF/A-flutter with at least 1 risk factor: HTN, DM, stroke, TIA, LA 50 mm or LVEF 40% Uncompensated HF Permanent AF NYHA class 4 HF Placebo vs dofetilide 125, 250, 500 g bid followed for 1 y Placebo vs dronedarone, 400 mg twice daily for 12 mo DIAMOND-AF AF at time of enrollment in patients with LVEF 35% and past history of NYHA class 3/4 HF or MI Creatinine clearance 20 baseline QTc 460 Placebo vs dofetilide, 250 g bid ANDROMEDA NYHA class 3/4 HF plus LVEF 35% Recent acute MI Acute pulmonary edema Placebo vs dronedarone, 400 mg twice daily for 12 mo AF-CHF Episode of AF in last 6 mo plus LVEF 35% plus NYHA class 2-4 HF AF 12 mo Placebo vs amiodarone in most of the patients Abbreviations: AF, atrial fibrillation; SR, sinus rhythm; CAD, coronary artery disease; CV, cardiovascular; QoL, quality of life; HF, congestive heart failure; HTN, hypertension; DM, diabetes; TIA, transient ischemic attack; LVEF, left ventricular ejection fraction; RR, relative risk; MI, myocardial infarction. a Significant P value. 100 Curr Probl Cardiol, March 2011

15 TABLE 2. Continued Results Primary end points Secondary end points Time to AF recurrence: placebo:6 Spontaneous conversion to SR: Placebo 0.8%, amiodarone: 487 sotalol: 74 d a Amiodarone, 27%, Sotalol, 25% a Time to AF recurrence patient with CAD: Amiodarone: 569 d Sotalol: 428 d SR at 1 y: Placebo 13%, Amiodarone, 52%, Sotalol, 32% Rhythm control: improved QoL and exercise tolerance. Adverse events not significantly different. Time to AF recurrence: Amiodarone: Recurrent AF during follow-up: Amiodarone, 35% 468 sotalol/propafenone, 98 d a Sotalol/propafenone, 65% a Adverse effect requiring drug discontinuation: Amiodarone, 18% Sotalol/propafenone, 11% Time to AF recurrence: Placebo: 41 d Propafenone SR 425, 325, 225 mg: 300, 291, and 112 d, respectively a Conversion to SR: dofetilide 125, 250, 500 g bid: 6.1%, 9.8%, and 29.9%, respectively placebo: 1.2% a Probability of maintaining SR at 1 y: Dofetilide 125, 250, 500 g bid: 0.40, 0.37, 0.58 placebo: 0.25 a Death from all-cause or first occurrence of cardiovascular hospitalization: 24.2% RR reduction favoring dronedarone a Adverse effects requiring drug discontinuation: Propafenone SR 425 mg: 25% placebo: 13% a Adverse effect: 0.8% on dofetilide developed TdP with 1 sudden cardiac death Death from any cause: 16% fewer deaths with dronedarone Cardiovascular deaths: 29% RR reduction a Cardiovascular hospitalization: 26% RR reduction a Incidence of stroke 34% RR reduction a Length of hospitalization: Reduced by 1.26 d/patient/ year a Conversion to SR: Dofetilide: 44% HF hospitalization: Dofetilide vs placebo was (RR, 0.69) a Placebo: 14 a All-cause hospitalization: Dofetilide vs placebo (RR, 0.70) a Probability of maintaining SR at 1 y: SR was associated with significant reduction in mortality Dofetilide: 79% (RR, 0.44) a Placebo: 42% a Death from any cause or HF hospitalization: Dronedarone: 17% Placebo: 12% CV death: 27% in rhythm control (mostly amiodarone) vs 25% in rate control. Not different. All-cause mortality: Dronedarone: 8.1% Placebo: 3.8% a Cardiovascular hospitalization: Dronedarone: 2.9% Placebo: 15.7% a All-cause mortality, HF worsening, hospitalization, QoL, cost of care, and composite of death due to stroke, HFor CV causes: No difference Curr Probl Cardiol, March

16 TABLE 3. Commonly used antiarrhythmic drugs Drug Class Ia Procainamide Quinidine Disopyramide Primary mechanism of action Use-dependent I Na blockade Use-dependent I Na blockade Use-dependent I Na blockade Class Ic Flecainide Propafenone Class III Sotalol Amiodarone Use-dependent I Na blockade Use-dependent I Na blockade Reverse use-dependent blockade of I Kr in addition to -blockade Blockade of I Kr,I Ks,I Na, antiadrenergic property Dronedarone Dofetilide Ibutilide Blockade of I Kr,I Ks,I Na, antiadrenergic property Blockade of I Kr Blockade of I Kr Abbreviations: iv, intravenous; TdP, torsade de pointes; CHF, congestive heart failure; VT, ventricular tachycardia. a milieu for arrhythmia. They also exhibit reverse use-dependence; that is, increased block of these ion channels at slower heart rates predisposes to pause-dependent TdP Conversely, pure class I sodium channel blocking agents exhibit positive use-dependence and slow conduction velocity and increase QRS width at higher heart rates. In contrast, amiodarone is predominantly a blocker of IK s the slowly activating delayed rectifier potassium current, which confers less reverse use-dependence than IK r blockers. 61 Additionally, amiodarone exhibits class I use-dependence when dosed chronically. 62 Amiodarone also blocks L-type calcium channels and has - and -antiadrenergic activity. 62,63 Thus, amiodarone displays activity corresponding to all 4 Vaughan Williams classes, which may explain higher efficacy of drug in maintaining SR. ACC/AHA/ESC guidelines for antiarrhythmic drug therapy to maintain SR in patients with AF describe a role for amiodarone in patients with 102 Curr Probl Cardiol, March 2011

17 TABLE 3. Continued Recommended dose Cardioversion Rhythm control Side effects mg iv over min mg/d Hypotension with (iv) dose. Druginduced lupus Not recommended mg/d Diarrhea, nausea, TdP, hypotension, QT prolongation, vagolytic effect Not recommended mg/d Anticholinergic (urinary retention, dry mouth), negative iontropic, TdP, CHF mg orally mg/d QRS prolongation, CNS side effects mg orally mg/d Gastrointestinal upset, modest negative iontropic Not recommended mg/d Bradycardia, QT prolongation, bronchospasm 150 mg iv over 30 min followed by mg/min mg for 7 d followed by mg/d Thyroid, pulmonary, skin, liver, ocular, dyspepsia, QT prolongation. Not recommended 400 mg twice daily Gastrointestinal-nausea, diarrhea Not recommended g twice daily QT prolongation and TdP. 1 mg iv over 10 min, may be repeated once Not recommended QT prolongation, TdP, monomorphic VT, nausea, headache, hypotension, bundle branch block, AV nodal block structurally normal hearts, in the presence of low ejection fraction, in the presence of coronary artery disease, and with hypertension. 10 Although amiodarone is considered one of the most efficacious drugs among currently available antiarrhythmic drugs, the potential for serious extracardiac side effects is a significant limiting factor. A meta-analysis of 4 clinical trial enrolling 1465 patients showed that 1 year of treatment with even low-dose amiodarone was associated with higher odds of experiencing thyroid (OR, 4.2), neurologic (OR, 2.0), skin (OR, 2.5), ocular (OR, 3.4), cardiac (OR, 2.2), or pulmonary toxicity (OR, 2.0). 64 The odds for discontinuing amiodarone due to side adverse events was almost 1.5 times the control group. 64 Amiodarone is an iodinated benzofuran derivative with a structural formula that closely resembles that of thyroid hormone. It contains about 37% iodine by weight, from which 10% is deiodinated to yield free iodide. With a daily maintenance dose of amiodarone between 100 and Curr Probl Cardiol, March

18 600 mg, about mg of iodide is released into the systemic circulation that is equivalent to 35- to 140-fold excess of daily intake. 65 This leads to critically high intrathyroidal iodine levels that may cause suppression of thyroid hormone biosynthesis leading to hypothyroidism. Hyperthyroidism may occur in the presence of an autonomous thyroid nodule (type 1) or due to thyroiditis related to direct toxic effect of excessive iodine (type 2). 66 Iodine also increases the lipophilicity of the drug, resulting in significant accumulation of drug and its metabolite (desethyl-amiodarone) in adipose tissue and highly perfused organs, such as liver, lung, and skin, leading to end-organ toxicity. Dronedarone. Despite its efficacy, a high propensity for extracardiac side effects and difficult kinetics is limiting factors in the clinical use of amiodarone. This led to the development of an analogue drug, dronedarone, recently US Food and Drug Administration approved for AF. 67 Dronedarone is a benzofuran derivative that has a methane sulfonyl group instead of an iodine group. This reduces dronedarone s potential of noncardiac toxicity while reducing its half-life. Dronedarone displays similar electrophysiological properties to amiodarone and has effects on multiple cardiac ion channels. Like amiodarone, it displays characteristics that span the Vaughn Williams classification scheme (I to IV). Based on early preclinical and clinical studies, 400 mg bid was determined to be the optimal dose for dronedarone taken with food. At this dose, dronedarone is well tolerated except for mild and occasional gastrointestinal upset and is devoid of significant thyroid, pulmonary, ocular, hepatic, or proarrhythmic toxicities. 68 The European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of SR (EURIDIS) and the American- Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of SR (ADONIS) trials 69 assessed the efficacy of dronedarone (400 mg bid) for the maintenance of normal SR after electrical, pharmacologic, or spontaneous conversion of AF or Atrial flutter (AFL). A majority of patients received concomitant antithrombotic medication and -blockers. Dronedarone significantly delayed the time to recurrence of AF to 116 days compared with 53 days in the placebo group. At 12 months, the rate of recurrence was 64.1% in the dronedarone group and 75.2% in the placebo group (hazard ratio, 0.75; 95% confidence interval, ; P 0.001). The Efficacy and Safety of Dronedarone for the Control of Ventricular Rate During Atrial Fibrillation (ERATO) study 70 showed that dronedarone was well tolerated when added to standard rate control therapy 104 Curr Probl Cardiol, March 2011

19 ( -blockers, digitalis, or calcium channel antagonists) in patients with permanent AF and reduced the ventricular response during rest and exercise. The ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe CHF Evaluating Morbidity Decrease) was a mortality trial that investigated the effects of dronedarone in patients with AF and severe CHF. 71 After enrollment of 627 patients, ANDROMEDA was stopped prematurely after a median follow-up of 2 months due to a higher mortality with dronedarone, 8% compared with placebo (3.8%). The reasons for increased mortality in the ANDROMEDA trial remain unclear but may be related to the negative inotropic effect of the drug. ATHENA (Assess the Efficacy of Dronedarone for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter) enrolled 4628 patients with stable AF who had at least 1 cardiovascular risk factor. 72 Treatment with dronedarone in ATHENA was associated with a significant reduction in the primary endpoint of all-cause mortality and cardiovascular hospitalizations. This was principally driven by reduced cardiovascular hospitalizations. There was a trend toward a lower overall mortality with dronedarone treatment and importantly there was a statistically significant reduction in death because of cardiac arrhythmia (hazard ratio, 0.55, P 0.01). The reduction in cardiovascular hospitalizations was accounted for mostly by fewer admissions for AF. A post-hoc analysis demonstrated that dronedarone was associated with a significant reduction in the adjusted risk of stroke compared with placebo, a benefit that was preserved in patients who were already receiving antithrombotic therapy. 73 Although dronedarone has shown excellent safety and tolerability in its clinical trials, it was shown to be less effective than amiodarone in preventing AF recurrence in Efficacy and Safety of Dronedarone vs Amiodarone for the Maintenance of SR in Patients with AF trial. 74 However, dronedarone was better tolerated with fewer discontinuations for side effects. In light of the above data, dronedarone is an important addition to the antiarrhythmic armamentarium for AF with a few caveats. Gastrointestinal discomfort and diarrhea are the principle side effects of the drug. Dronedarone causes partial inhibition of tubular transport of creatinine and may cause an increase in serum creatinine concentration that is not related to glomerular filtration. Dronedarone also increases plasma digoxin and simvastatin levels that may necessitate dose reduction. 67 In Curr Probl Cardiol, March

20 light of the ANDROMEDA trial, dronedarone should not be used in a patient with acute decompensated heart failure and in the presence of a very low ejection fraction. 67 Class Ic Drugs: Flecainide and Propafenone. Class Ic drugs agents, propafenone and flecainide, are useful agents for maintaining SR in patients with structurally normal hearts or minimal heart diseases. These drugs cause use-dependent block of the peak inward sodium current, and they significantly slow conduction velocity, leading to an increase in wavelength of the reentrant waveform and also an increase in the post-repolarization refractory periods. Propafenone has -blocking activity as well. In the RAFT trial [Efficacy and Safety of Sustained-Release Propafenone (propafenone SR) for Patients with Atrial Fibrillation], 523 patients with a history of symptomatic AF who were in SR were randomly assigned to receive placebo or propafenone SR 425, 325, or 225 mg twice daily. Recurrent symptomatic arrhythmias were documented using transtelephonic electrocardiographic monitoring. 75 Propafenone SR significantly prolonged the time to first symptomatic atrial arrhythmia recurrence at all 3 doses compared with placebo. The median time to recurrence was 41 days in the placebo, 300 days in the propafenone SR 425-mg group, 291 days in the 325-mg group, and 112 days in the 225-mg group. Similar results were seen in ERAFT (the European Rythmol Atrial Fibrillation Trial). 76 Flecainide was shown to be effective in preventing recurrences of AF in the Flecainide Multicenter Atrial Fibrillation Study, with an excellent tolerability profile. 77 In addition to preventing the recurrence of AF, both of these drugs have been shown to be effective in terminating paroxysmal AF using single oral loading doses. Class Ic agents also slow conduction over accessory pathways and thus may be useful for treatment of arrhythmias associated with Wolff Parkinson White syndrome. 78 Both drugs are well tolerated with the principle side effect of propafenone being nausea and gastrointestinal discomfort and flecainide with mild neurologic side effects. Both of these agents have been associated with hypotension and bradycardia after conversion to SR. Class Ic agents also may convert AF into slow atrial flutter conducts 1:1, leading to wide complex tachycardia that may mimic ventricular tachycardia. To prevent rapid ventricular rates, class Ic agents should be prescribed with AV nodal blocking agents like -blockers or calcium channel blockers. Class Ic agents are contraindicated in patients with ischemic heart disease and congestive heart failure. 79 Class III Drugs: Sotalol and Dofetilide. Sotalol is a useful agent for management of AF. Sotalol blocks the I Kr in addition to its -adrenergic 106 Curr Probl Cardiol, March 2011

21 blocking effects. Thus, sotalol prolongs atrial and ventricular effective refractory periods and slows conduction in the AV node. It displays reverse use dependency with more pronounced I Kr blockade at a slower heart rate that may lead to significant QT prolongation and risk of TdP during bradycardia. Sotalol is a modestly effective drug in the prevention of AF as seen in the SAFE-T and CTAF studies above. It should be avoided in patients with significant left ventricular hypertrophy, heart failure, and severe asthma, and in patients with the congenital or acquired long QT syndrome. Dofetilide is a pure class III antiarrhythmic drug that blocks the I Kr and is devoid of -adrenergic blocking effects. Thus, dofetilide causes dose-dependent prolongation of the QT interval without any effects on PR interval or QRS duration and prolongs the atrial and ventricular effective refractory periods. The SAFIRE-D (Symptomatic Atrial Fibrillation Investigative Research on Dofetilide) study investigated the safety and efficacy of dofetilide in patients with chronic AF for conversion to maintenance of SR. 80 SAFIRE-D randomized 325 patients with AF or atrial flutter to receive 125, 250, or 500 g of dofetilide twice daily based on QTc response and calculated creatinine clearance. Dofetilide was effective in pharmacologic cardioversion at higher doses (30% at 250 g twice daily doses vs 1.2% for placebo) with most cardioversions occurring within the first 36 hours of treatment initiation. At 1-year follow-up, 58% patients on 500 g bid dofetilide maintained SR. Two cases of TdP occurred (0.8%). Because dofetilide does not have negative inotropic effects like sotalol and class Ic agents, it seemed a very attractive agent for treatment of AF in patients with CHF. This was studied formally in by the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) study group in 2 large randomized control trials, DIAMOND-CHF and DIAMOND-AF. 81,82 The DIAMOND-AF trial randomized 506 patients of AF or atrial flutter with low ejection fraction and congestive heart failure or recent acute myocardial infarction to receive either adjusted dose dofetilide or placebo in addition to traditional treatment. 81 Over the course of the study, 59% of patients cardioverted to SR on dofetilide. In those patients who converted to SR, the probability of maintaining SR at 1 year was 79% with dofetilide vs 42% with placebo (P 0.001). Although dofetilide had no effect on all-cause mortality, restoration and maintenance of SR was associated with a significant reduction in mortality (risk ratio, 0.44; 95% CI, ; P ). In addition, dofetilide therapy was associated with a 30% reduction in all-cause or congestive heart failure hospitalizations. TdP occurred in 4 (1.6%) Curr Probl Cardiol, March