Atrial Fibrillation Pharmacological Therapy by fdh56iuoui


									   Atrial Fibrillation: Pharmacological
 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 pres-
         ence 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 ventricu-
         lar 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;36:87-120.)

Problem Statement
        he epidemic of atrial fibrillation (AF) affects approximately 1% of
 T      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;36:87-120.
0146-2806/$ – see front matter

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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 regard-
ing 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 remod-
eling.11,12 Catheter-based radiofrequency ablation is a promising ap-
proach 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 phar-
macotherapy of prevention of AF. Radiofrequency ablation and antico-
agulation in AF are beyond the scope of this article and are discussed
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
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
  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 stud-
ies.14,15 However, many patients have subtle symptoms, such as nonspe-
cific 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 hypertro-
phy, and restrictive cardiomyopathy are particularly sensitive to the loss
of atrioventricular (AV) synchrony and decreased diastolic filling. Deter-
mining 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 ob-
tained from a series of randomized prospective clinical trials summarized
in Table 1.16-20 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

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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              n     1276 followed for 36 mo
                    35% HF (NYHA Class 2 to 4)

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 anticoagu-
lation 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
TABLE 1. Continued

   Patients in SR (%)                                        Secondary rhythm vs rate
 rhythm vs rate control   Primary rhythm vs rate control             control
62.6% vs 34.6%            All-cause mortality:              Composite of death, CVA,
                             No difference                    major bleeding, and
                             (HR: 1.15)                       cardiac arrest: Not
                                                              different. Rhythm control:
                                                              more hospitalization trend
                                                              toward higher mortality.
39% vs 10%                Composite of CV death, HF
                            hospitalization, bleeding
                            complications, pacemaker,
                            severe adverse effects: 22.6%
                            vs 17.2% (no difference)
56% vs 10%                Symptomatic improvement: no       Rhythm control: improve
                            difference                         exercise tolerance but
                                                               more hospitalization and
                                                               side effects. QoL not
63.5%                   Composite of all-cause mortality,   Rhythm control: improve
                          thromboembolic events, major         exercise tolerance but
                          bleeding: No difference              more hospitalizations
40% vs 12% at 1 y; 26% Composite of death, CVA,             Rhythm control: trend toward
  vs 11% at 2 y; 23% vs   cardiopulmonary resuscitation:       improved QoL but
  0% at 3 y               No difference                        increased hospitalizations.
Roughly 73% vs 30%      CV death: No difference             All-cause mortality, CVA,CHF,
                                                               QoL: No difference
                                                            Rhythm control: frequent

seen in the rhythm control group primarily due to inadequate anticoagu-
lation. 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 random-
ized 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 Inter-
vention in Atrial Fibrillation (PIAF),17 The Strategies of Treatment of

Curr Probl Cardiol, March 2011                                                          91
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.21-23
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 0.73-0.98, 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 maintain-
ing 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 Evalu-
ation 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 monitor-
ing, have no significant drug-drug interactions, and thus promise to revolu-
tionize anticoagulant therapy (Connolly SJ, Ezekowitz MD, Yusuf S, et al.
Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med

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
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.27
2. 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-of-
   death 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 cardio-
   vascular 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.30
3. 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 39-63.5% 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.16-20 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

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5. It is clear that patients with AF have poor QoL32 and impaired
   functional status, and several lines of evidence suggest that restoration
   of SR can improve vitality.33-36 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
  What is considered adequate rate control is controversial.31 As men-
tioned 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 hospital-
izations.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
to a revision of the current ACC/AHA guidelines that recommend the
ventricular rates of 60-80 bpm during rest and 90-115 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. -Block-
ers should be used with caution in patients who are hypotensive or have
heart failure.
  Nondihyrdopyridine calcium channel blockers, verapamil and dilti-
azem, 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 antago-
nists 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 2011                                            95
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 occur-
ring 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 anticoag-
ulation. 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 direct-
current cardioversions for treatment of atrial fibrillation for patients who

96                                                Curr Probl Cardiol, March 2011
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 pre-
treatment. N Engl J Med 1999:340:1849-54).

  Although DC cardioversion is more effective in restoring SR, pharma-
cologic 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 car-
dioversion of AF of less than 7 days’ duration.
  Intermittent oral administration of a single high dose of flecainide,
200-300 mg, or propafenone, 450-600 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 (IKr) current and prolongs refrac-
toriness 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 40-60
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-

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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 postop-
erative 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 1-4.5 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. Interest-
ingly, 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
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
  The efficacy and cardiac safety of amiodarone may be explained by its
multireceptor affinity.57 Traditional, pure class III agents like dofetilide,
predominantly block IKr, the rapidly activating delayed rectifier potas-
sium 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 2011                                           99
TABLE 2. Major clinical trials investigating role of antiarrhythmic drugs in AF management

                                                  Specific exclusion
   Study             Inclusion criteria                criteria              Treatment follow-up
SAFE-T          Persistent AF 72 h and         Paroxysmal AF A flutter      Placebo vs amiodarone
                  AF at randomization          NYHA class 3/4 CHF            vs sotalol. followed
                  on therapeutic                                             for 1-4.5 y

CTAF            Paroxysmal AF with at          Persistent AF 6 mo          Amiodarone vs sotalol
                  least 1 episode of AF        NYHA class 3/4 HF             vs propafenone
                  in last 6 mo                                               followed for 16 mo

RAFT            Symptomatic AF within          Permanent AF                Placebo vs
                  last 12 mo who were          NYHA class 3/4 HF             propafenone SR
                  in SR at randomization       Recent myocardial             (425, 325, 225 bid)
                                                 infarction                  followed for 39 wk

SAFIRE-D        AF or A-flutter from 2 to       Uncompensated HF            Placebo vs dofetilide
                  26 wk                                                      125, 250, 500 g
                                                                             bid followed for 1 y
ATHENA          Paroxysmal/persistent          Permanent AF                Placebo vs
                  AF/A-flutter with at          NYHA class 4 HF               dronedarone, 400
                  least 1 risk factor:                                       mg twice daily for 12
                  HTN, DM, stroke, TIA,                                      mo
                  LA 50 mm or LVEF

DIAMOND-AF      AF at time of enrollment       Creatinine clearance        Placebo vs dofetilide,
                  in patients with LVEF            20 baseline QTc           250 g bid
                    35% and past                   460
                  history of NYHA class
                  3/4 HF or MI

ANDROMEDA NYHA class 3/4 HF plus               Recent acute MI             Placebo vs
            LVEF 35%                           Acute pulmonary               dronedarone, 400
                                                 edema                       mg twice daily for
                                                                             12 mo

AF-CHF          Episode of AF in last 6        AF    12 mo                 Placebo vs amiodarone
                  mo plus LVEF 35%                                           in most of the
                  plus NYHA class 2-4 HF                                     patients
Abbreviations: AF, atrial fibrillation; SR, sinus rhythm; CAD, coronary artery disease; CV, cardio-
vascular; 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
  Significant P value.

100                                                                Curr Probl Cardiol, March 2011
TABLE 2. Continued

         Primary end points                              Secondary end points
Time to AF recurrence: placebo:6       Spontaneous conversion to SR: Placebo 0.8%,
  amiodarone: 487 sotalol: 74 da          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 da Sotalol/propafenone, 65%a
                                       Adverse effect requiring drug discontinuation:
                                          Amiodarone, 18% Sotalol/propafenone, 11%
Time to AF recurrence: Placebo:        Adverse effects requiring drug discontinuation:
  41 d                                    Propafenone SR 425 mg: 25% placebo: 13%a
Propafenone SR 425, 325, 225
  mg: 300, 291, and 112 d,
Conversion to SR: dofetilide 125, 250, Adverse effect: 0.8% on dofetilide developed TdP with
  500 g bid: 6.1%, 9.8%, and              1 sudden cardiac death
  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: 0.25a
Death from all-cause or first           Death from any cause: 16% fewer deaths with
  occurrence of cardiovascular            dronedarone
  hospitalization: 24.2% RR            Cardiovascular deaths: 29% RR reductiona
  reduction favoring dronedaronea      Cardiovascular hospitalization: 26% RR reductiona
                                       Incidence of stroke 34% RR reductiona
                                       Length of hospitalization: Reduced by 1.26 d/patient/
Conversion to SR: Dofetilide: 44%      HF hospitalization: Dofetilide vs placebo was (RR, 0.69)a
  Placebo: 14a                         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%
Death from any cause or HF             All-cause mortality:
  hospitalization:                        Dronedarone: 8.1%
Dronedarone: 17% Placebo: 12%             Placebo: 3.8%a
                                          Cardiovascular hospitalization: Dronedarone: 2.9%
                                          Placebo: 15.7%a
CV death: 27% in rhythm control        All-cause mortality, HF worsening, hospitalization,
  (mostly amiodarone) vs 25% in           QoL, cost of care, and composite of death due to
  rate control. Not different.            stroke, HFor CV causes: No difference

Curr Probl Cardiol, March 2011                                                                101
TABLE 3. Commonly used antiarrhythmic drugs

      Drug                                   Primary mechanism of action
Class Ia
  Procainamide             Use-dependent INa blockade

  Quinidine                Use-dependent INa blockade

  Disopyramide             Use-dependent INa blockade

Class Ic
  Flecainide               Use-dependent INa blockade
  Propafenone              Use-dependent INa blockade

Class III
  Sotalol                  Reverse use-dependent blockade of IKr in addition to -blockade

  Amiodarone               Blockade of IKr, IKs, INa, antiadrenergic property

  Dronedarone              Blockade of IKr, IKs, INa, antiadrenergic property
  Dofetilide               Blockade of IKr
  Ibutilide                Blockade of IKr

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.58-60 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 IKs—the slowly
activating delayed rectifier potassium current, which confers less reverse
use-dependence than IKr blockers.61 Additionally, amiodarone exhibits
class I use-dependence when dosed chronically.62 Amiodarone also
blocks L-type calcium channels and has - and -antiadrenergic activ-
ity.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
TABLE 3. Continued
              Recommended dose

   Cardioversion             Rhythm control                   Side effects

500-1200 mg iv over      2000-4000 mg/d          Hypotension with (iv) dose. Drug-
  30-60 min                                        induced lupus
Not recommended          600-1200 mg/d           Diarrhea, nausea, TdP, hypotension,
                                                   QT prolongation, vagolytic effect
Not recommended          450-600 mg/d            Anticholinergic (urinary retention, dry
                                                   mouth), negative iontropic, TdP,

200-400 mg orally        150-300 mg/d            QRS prolongation, CNS side effects
450-600 mg orally        400-600 mg/d            Gastrointestinal upset, modest
                                                   negative iontropic

Not recommended          80-320 mg/d             Bradycardia, QT prolongation,
150 mg iv over 30        400-1200 mg for 7 d     Thyroid, pulmonary, skin, liver,
  min followed by          followed by 100-300     ocular, dyspepsia, QT
  0.5-1 mg/min             mg/d                    prolongation.
Not recommended          400 mg twice daily      Gastrointestinal-nausea, diarrhea
Not recommended          125-500 g twice daily   QT prolongation and TdP.
1 mg iv over 10 min,     Not recommended         QT prolongation, TdP, monomorphic
  may be repeated                                  VT, nausea, headache,
  once                                             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 extra-
cardiac 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 experi-
encing 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 2011                                                     103
600 mg, about 3.5-31 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, droneda-
rone, 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) trials69 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% confi-
dence interval, 0.65-0.87; P 0.001).
  The Efficacy and Safety of Dronedarone for the Control of Ventricular
Rate During Atrial Fibrillation (ERATO) study70 showed that dronedar-
one was well tolerated when added to standard rate control therapy

104                                               Curr Probl Cardiol, March 2011
( -blockers, digitalis, or calcium channel antagonists) in patients with
permanent AF and reduced the ventricular response during rest and
  The ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Mod-
erate-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 droneda-
rone in ATHENA was associated with a significant reduction in the
primary endpoint of all-cause mortality and cardiovascular hospitaliza-
tions. This was principally driven by reduced cardiovascular hospitaliza-
tions. There was a trend toward a lower overall mortality with droneda-
rone 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
  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. Gastrointesti-
nal 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 2011                                        105
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 activ-
ity 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 tachy-
cardia. 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 IKr in addition to its -adrenergic

106                                              Curr Probl Cardiol, March 2011
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 IKr 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 IKr 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, 0.30-0.64; P 0.0001). 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 2011                                          107
FIG 1. Choice of antiarrhythmic drugs for maintenance of sinus rhythm in patients with atrial

dofetilide-treated patients who responded to discontinuation of drug.81
Incidence of TdP was 3.3% in the DIAMOND-CHF trial.82
  Thus, due to its QT prolonging effect, dofetilide carries a small but
lethal risk of TdP. The risk can be minimized by carefully adjusting the
dose of dofetilide based on renal function, instituting a 72-hour in-
hospital monitoring period after initiation of dofetilide, and correcting
electrolyte disturbances like hypokalemia and hypomagnesemia. Drugs
like erythromycin, ketoconazole, and verapamil may increase plasma
dofetilide levels by inhibiting its metabolism and hence should not be
administered concomitantly.

Selection of an Antiarrhythmic Drug
  Current ACC/AHA/ESC suggestions for selection of appropriate anti-
arrhythmic drug therapy for maintenance of SR are shown in Fig 1.
Because ventricular proarrhythmia is more common in patients with
structural heart disease or congestive heart failure, choice of antiarrhyth-
mic drug therapy is based on the presence or absence of structural heart
disease or CHF. Class Ic drugs are preferred for patients with structurally
normal hearts due to their long-term safety and tolerability profile. Sotalol
can be used as an alternative in this group of patients. Class Ic drugs have
been shown to increase mortality in patients with ischemic heart disease
and CHF,79 based on the finding that class Ic drugs should not be used for
AF management in this group of patients. In patients with coronary artery
disease, sotalol can be used as a first-line agent due to its -blocking

108                                                          Curr Probl Cardiol, March 2011
effects in addition to antiarrhythmic efficacy and neutral effects on
mortality.83 In patients with hypertension and significant left ventricular
hypertrophy (LVH), amiodarone is the only recommended drug for
rhythm control; however, in the absence of “significant” left ventricular
hypertrophy, recommendations resemble those for patients with structur-
ally normal hearts. Amiodarone and dofetilide can be used alternatively in
post myocardial infarction patients if sotalol fails or is not well tolerated.
  In patients with CHF, amiodarone and dofetilide are the only drugs that
can be safely used for management of AF based on DIAMOND-AF,
AF-CHF, and Veterans Affairs Congestive Heart Failure: Survival Trial
of Antiarrhythmic Therapy trials.55,56,81 Dronedarone is likely to find its
place in management of AF in all categories of patients except those with
NYHA class III-IV CHF. Additionally, patients who have vagally
mediated AF may benefit from flecainide or disopyramide. Patients with
adrenergically mediated AF may benefit from sotalol or -blockers.
  Except for dofetilide and sotalol, almost any antiarrhythmic drug can be
initiated in the outpatient setting. Before starting any antiarrhythmic drug
with class III effects, it is important to check the baseline electrocardio-
gram, electrolytes, and renal and hepatic function. Sotalol can be initiated
as an outpatient unless there is baseline prolonged QT interval 450 ms
or there are predisposing risk factors for TdP. Class Ic drugs like
flecainide, propafenone, and amiodarone and its analogue dronedarone
have been shown to be safe when started in the outpatient setting. Patients
on amiodarone require semiannual monitoring of thyroid, liver, and
pulmonary function tests and yearly ocular examinations.

Melvin M. Scheinman: Patients with atrial fibrillation also frequently have
concomitant atrial flutter and, as pointed out by the authors, atrial flutter may
be associated with worsening of symptoms. The clinician should be mindful
of agents used for therapy of atrial fibrillation that may promote atrial flutter.
The latter is particularly true for the 1c agents (propafenone and flecainide). In
contrast, the class III agents (particularly dofetilide but also sotalol) are more
effective for the prevention of atrial flutter.

Adjuvant Therapy
  This section briefly reviews the evidence supporting adjuvant non-
antiarrhythmic drugs for the prevention of AF. These drugs work
primarily by preventing atrial remodeling, as shown in Fig 2. Adjuvant
therapy for AF has been extensively reviewed in the current literature.84

Curr Probl Cardiol, March 2011                                                109
FIG 2. Atrial remodeling in atrial fibrillation and the role of adjuvant agents.

Angiotensin Converting Enzyme Inhibitors
(ACE-I)/Angiotensin II Receptor Blocker (ARB)
  The Renin-Angiotensin-Aldosterone system (RAAS) has been shown to be
extensively involved in the initiation and perpetuation of AF; hence, the
blockade of RAAS with either ACE-I or ARB may have a role in the
prevention of AF.85 This has been demonstrated in several clinical trials. For
example, the TRACE (TRAndolapril Cardiac Evaluation) study showed
that treatment with trandolapril led to a 50% reduction in the risk of
developing AF in patients with left ventricular dysfunction due to acute
myocardial infarction at 3-year follow-up.86 Similarly in SOLVD (Study
of Left Ventricular Dysfunction), enalapril markedly reduced the risk for
developing AF in patients with heart failure.87
  Similar to ACE-I, treatment with valsartan in patients with heart failure
reduced the risk of developing AF by 37% in Valsartan Heart Failure
Trial (Val-HeFT).88 Conversely, the irbesartan in patients with heart
failure and preserved ejection fraction (I-PRESERVE) trial showed that
treatment with irbesartan did not affect the incidence of atrial arrhythmias
in patients with heart failure with preserved ejection fraction at 4-year
  Finally, a meta-analysis of 11 randomized control trials, including more
than 50,000 patients, showed that both ACE-I and ARBs were effective
in prevention of AF and reduced the risk of developing AF by 28%. This
protective effect was more pronounced in patients with reduced ejection

110                                                            Curr Probl Cardiol, March 2011
fraction but not in patients with only high blood pressure.90 Contrary to
the above, in Losartan Intervention For End-point reduction in hyperten-
sion (LIFE) study, losartan significantly reduced the incidence of new-
onset AF in hypertensive patients compared with atenolol.91
  Additionally, 2 small studies showed that the patients with AF who
were electrically cardioverted were more likely to stay in SR during a 4-
to 8-week follow-up when concomitant ARB or ACE-I was administered
along with amiodarone compared with amiodarone alone.92,93 However,
in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
Miocardico–Atrial Fibrillation (GISSI-AF) trial, valsartan was used alone
without any antiarrhythmic drug therapy. It failed to reduce recurrence of
AF at 1-year follow-up.94 Based on these data, we believe that RAAS
modulators should be used preferentially for the treatment of hyperten-
sion and congestive heart failure patients considered at risk for AF, but we
cannot recommend their use for AF suppression alone.
Anti-Inflammatory Agents
  Inflammation appears to be involved in the early phase of electrical
remodeling that promotes AF. High-sensitivity C-reactive protein, a
biomarker of inflammation, is elevated in patients with AF compared with
those in SR; hence, it has been assumed that anti-inflammatory agents
might have a role in the prevention of AF.
  Statins. Several studies have suggested therapeutic benefit of statins for
prevention of AF.84 In a retrospective study involving patients with suspected
acute coronary syndrome, new-onset AF was significantly less likely to occur
if they were on a statin at the time of presentation.95 Adabag et al
demonstrated that AF was less common among statin-treated patients with
heart failure.96 A prospective study by Tsai et al showed that in patients with
permanent pacemakers, atrial high-rate episodes were significantly lower in
statin-treated patients compared with a nonstatin group at 1-year follow-up.97
Similarly, in a prospective study of patients receiving an implanted cardio-
verter-defibrillator, statin therapy was associated with a significant reduction
in the development of AF or atrial flutter compared with the nonstatin
group.98 In the Atorvastatin for Reduction of Myocardial Dysrhythmia After
Cardiac Surgery (ARMYDA-3) study, atorvastatin was shown to signifi-
cantly reduce postcardiac surgery AF vs placebo.99 Similar result were found
in 2 meta-analyses.100,101
  Corticosteroids. Because of their anti-inflammatory effects, corticoste-
roids may prevent AF. A recently published trial of patients undergoing
coronary bypass graft surgery with or without aortic valve replacement
found that perioperative use of corticosteroids decreased the incidence of

Curr Probl Cardiol, March 2011                                             111
postoperative AF.102 The trial corroborated findings from smaller stud-
ies.103,104 However, the risk of long-term side effects may outweigh their
potential benefit in AF management and is a major limitation. Well-
designed prospective randomized controlled trials are needed to define the
role of steroids for AF prevention.
  Fish Oils ( -3 PUFA). -3 PUFA may inhibit the potassium currents
[transient outward potassium current (Ito) and ultrarapid delayed rectifier
potassium current (IKur)] and the voltage-gated sodium current (INa) in
human atrial myocytes, which may contribute to their antifibrillatory
effect in the atrium. In a prospective randomized trial of fish oil vs
placebo, started in patients 5 days before undergoing coronary artery
bypass grafting and continued throughout their hospital stay, the inci-
dence of postoperative AF was significantly lower in the fish oil group.105
However, the Rotterdam study prospectively examined the relationship
between dietary fish intake, long-chain omega-3 fatty acid supplementa-
tion, and the incidence of AF. After a mean follow-up of 6.4 years, neither
omega-3 fatty acid nor dietary fish intake was linked to a lower incidence
of AF.106 Role of -3 PUFA in the prevention of AF remains an area of
active research, and we anticipate the results of large randomized trials
that should provide conclusive information.107,108
Calcium Channel Blocker (CCB) and the Other Agents
  Theoretically, reducing calcium influx into atrial myocytes should
prevent episodes of AF. De Simone et al demonstrated that administering
verapamil, 3 days before cardioversion, improved the maintenance of SR
when combined with propafenone or amiodarone.109 Other studies that
used verapamil alone for the prevention of recurrent AF did not show a
sustained improvement over 1 to 3 months of follow-up.110 CCB may
have a role if used in conjunction with other antiarrhythmic agents and/or
electrical cardioversion, but their value in maintaining SR is unclear.
  Based on the current data, it is probably premature to recommend any
particular adjuvant agent solely for the prevention or treatment of AF. The
clinical use of these agents should be limited to their primary indications
pending conclusive evidence from prospective randomized clinical trials
of benefit and safety, specifically in AF patients.

  As outlined above, there are multiple treatment options available for
management of AF. An ideal approach to AF management should start
with prevention of AF in the population at highest risk using adjuvant
therapy outlined above. When AF develops, it is reasonable either to

112                                              Curr Probl Cardiol, March 2011
pursue the strategy of simple rate control or to cardiovert the patient and
maintain SR using antiarrhythmic drugs. The rhythm control strategy is
favored in patients with intolerable symptoms and those who are young
with structurally normal hearts. Available antiarrhythmic drugs are at
most 60% effective in maintaining SR at 1 year. There are multiple novel
agents in development with new targets and include prevention of
structural and electrical remodeling. Availability of such agents will
improve our ability to prevent and treat AF.

Melvin M. Scheinman: The authors have presented a truly masterful and
complete exposition covering modern pharmacologic management of patients
with atrial fibrillation. This is not only a worthy practical compendium useful for
the day-to-day management of these patients but also covers new potentially
important breakthroughs in terms of newer antiarrhythmics on the horizon, as
well as the important potential role for “upstream” therapy including anti-
inflammatory and rennin-angiotensin inhibitors. The authors well explain the
pathophysiologic issues involved in the genesis of atrial fibrillation and the
rationale for drug use in terms of effects on ion channel function. The tables and
figures provide ready access to appropriate drug therapy as well as dosage and
major side effects. This splendid essay is required reading for the clinician tasked
with care of the patient with atrial fibrillation.

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