Artigo

1. Review Article
Management Strategies in Atrial Fibrillation in Patients With
Heart Failure
Amir Y. Shaikh, MD,* Abhishek Maan, MD,* E. Kevin Heist, MD, PhD,† Dennis A. Tighe, MD,‡
Gerard P. Aurigemma, MD,‡ and David D. McManus, MD, FACC, FHRS‡
Abstract: Atrial fibrillation (AF) and heart failure (HF) frequently occur
current evidence-based pharmacologic and invasive therapeutic
together, and their coexistence is associated with a poor prognosis. AF and
options for managing AF in patients with coexistent HF.
HF share risk factors, but their relationship involves complex hemodynamic,
neurohormonal, inflammatory, ultrastructural, and electrophysiologic pro- EPIDEMIOLOGY AND RISK FACTORS: ATRIAL
cesses that extend beyond epidemiological associations. The shared mecha- FIBRILLATION AND HEART FAILURE
nisms underlying AF and HF have important implications for the treatment of HF and AF share several common risk factors such as coro-
AF in patients with HF. This article focuses on reviewing contemporary data nary artery disease, valvular heart disease, diabetes mellitus, hyper-
as it pertains to AF management in patients with HF and provides insight into tension, obesity, and obstructive sleep apnea. AF and HF have
investigational therapies currently under development. inextricably linked complex ultrastructural, electrophysiologic, and
Key Words: atrial fibrillation, heart failure, rate control, rhythm control, neurohormonal processes that promote their coexistence.6 AF is thus
catheter ablation, antiarrhythmic drugs exceedingly common in HF, affecting 30% of all individuals with
(Cardiology in Review 2012;20: 288–296) HF.7 Men and women with AF have a threefold and 11-fold increased
risk, respectively, of the combined end point of HF and all-cause
mortality when compared with those in sinus rhythm.1,8 Conversely,
the development of HF is associated with a 4.5- to 5.9-fold increased
risk of future AF.7,8 There is a direct relationship between the preva-
A trial fibrillation (AF) is the most common sustained arrhythmia
in industrialized nations, with a lifetime risk of approximately
25% for individuals over 40 years of age. The incidence of AF and
lence of AF and worsening HF class (Fig. 2). Although data on this
topic are limited, patients with HF and preserved systolic function
are also vulnerable to AF at alarmingly high rates. As in patients with
heart failure (HF) increases markedly with advancing age. The HF and reduced systolic function, development of AF among those
prevalence of both these disorders has increased over the last few with normal left ventricular (LV) systolic function may represent a
decades related in part to increasing survival of patients with other precipitant and/or consequence of diastolic HF.12–15
forms of cardiovascular disease. The growing burden of AF has pro-
found impact on public health because it is associated with increased
morbidity, mortality, and health-care expenditure.1,2 The prevalence TREATMENT OF ATRIAL FIBRILLATION AND HEART
of AF is highest in those with clinical cardiovascular disease and FAILURE
occurs most commonly in older age groups.1,3 Like AF, chronic HF Rate vs Rhythm Control of Atrial Fibrillation
is highly prevalent, predominantly affecting the elderly, and exerts a
A rhythm control strategy for asymptomatic patients with AF
profoundly negative influence on the public health.1,4–8
and HF has long been presumed to be advantageous based on the
The adverse hemodynamic consequences of AF, including
known deleterious effects of AF with respect to cardiovascular hemo-
elevated cardiac filling pressures, chronically increased heart rates,
dynamics, thromboembolic risk, and quality of life. Investigators
irregular ventricular intervals, lack of effective atrial contraction,
have also hypothesized that restoration of sinus rhythm may reverse
and loss of atrioventricular (AV) synchrony, can impair ventricular
the progression of HF.16 However, since 2000, 5 studies have com-
function and contribute to HF.9 Similarly, ventricular dysfunction
pared rhythm to rate control strategies, yet no study to date has dem-
can create a substrate predisposed to AF through its effect on atrial
onstrated superiority of a rhythm control in patients with AF with
size, conduction properties, and fibrosis (Fig. 1).10 Patients with HF
respect to major clinical end points. Several of these studies included
therefore may have atrial structural, mechanical, and electrical char-
patients with AF and HF (Table 1).17–21
acteristics distinct from those without HF. The pathophysiological
Not surprisingly, in light of the relatively small number of
mechanisms underlying AF likely differ between patients with AF
patients with AF and HF included in many of the landmark rhythm
and HF when compared with AF alone.11 In this article, we discuss
vs rate control trials, there remains controversy with respect to the
optimal treatment strategy for the patient with AF and HF.18,19 A sub-
group analysis involving Atrial Fibrillation Follow-up Investigation
of Rhythm Management participants suggested that patients with HF
From the *Department of Medicine, University of Massachusetts Medical School, and AF had an increased risk of death when assigned to rhythm as
Worcester, MA; †Cardiac Arrhythmia Service, Massachusetts General Hospi- compared with rate control, whereas the findings of the Rate Con-
tal and Harvard Medical School, Boston, MA; and ‡Division of Cardiology, trol Efficacy in Permanent Atrial Fibrillation study suggested that
University of Massachusetts Medical School, Worcester, MA.
Disclosure: The authors have no conflicts of interest to report. patients with AF and HF had improved survival if sinus rhythm was
Correspondence: David D. McManus, MD, Department of Medicine, Cardiology maintained.18,22 In the Congestive Heart Failure: Survival Trial of
Division, Electrophysiology Section, University of Massachusetts Medical Antiarrhythmic Therapy (CHF-STAT)23 and Danish Investigations
Center, 55 Lake Avenue North, Worcester, MA 01655. E-mail: mcmanusd@ of Arrhythmia and Mortality on Dofetilide (DIAMOND)24 stud-
ummhc.org.
Copyright © 2012 by Lippincott Williams & Wilkins
ies, participants with HF and AF who achieved conversion to sinus
ISSN: 1061-5377/12/288-296 rhythm had improved survival when compared with HF patients who
DOI: 10.1097/CRD.0b013e31825dcf9b remained in AF.
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2. Cardiology in Review • Volume 20, Number 6, November/December 2012 AF in HF Patients
Risk factors
Electrical atrial remodeling Structural atrial remodeling
Atrial electrical and mechanical dysfunction
AF
- RVR
Neurohormonal Dysregulation of Increased
- Irregular rate Decreased Fibrosis
activation intra-cellular filling pressure
- Loss of atrial kick cardiac output
calcium
- Increased MR, TR
HF
Tachycardia LV dilatation and hypertrophy
mediated
cardiomyopathy
MI LVH
Risk factors
Figure 1. Pathophysiological interactions of AF and HF. AF indicates atrial fibrillation; HF, heart failure; LV, left ventricle;
LVH, left ventricular hypertrophy; MI, myocardial infarction; MR, mitral regurgitation; RVR, rapid ventricular rate; TR, tricuspid
regurgitation.
major study end points, the study authors concluded that rhythm con-
trol should not be routinely recommended for asymptomatic patients
with AF and HF.21 One of the major and notable limitations of rhythm
control among patients with AF and HF included in the aforemen-
tioned studies was the limited long-term efficacy of antiarrhythmic
drug (AAD) therapy in these patients (only 44% of participants
remaining in sinus rhythm in DIAMOND, 51% in CHF-STAT, and
58% in Atrial Fibrillation in Congestive Heart Failure).21,23,24 These
findings suggest that although conversion to sinus rhythm is a posi-
tive prognostic sign in patients with HF and AF, the limited efficacy
and toxicities of contemporary AADs in such patients limits the over-
all impact of the rhythm control strategy.
The adequacy of ventricular rate control in patients with AF
and HF has not been studied extensively,25 but the Rate Control Effi-
Figure 2. Prevalence of AF in several major HF trials. Adapt- cacy in Permanent Atrial Fibrillation II trial26 evaluated the potential
ed from Eur Heart J.10 AF indicates atrial fibrillation; HF, heart benefits of strict (resting heart rate <80 bpm, heart rate <100 bpm
failure; NYHA, New York Heart Association. during a 6-minute walk) vs lenient (resting heart rate <110 bpm)
rate control in patients with permanent AF. Lenient rate control was
found to be noninferior to strict rate control in terms of 3-year esti-
The issue of rate vs rhythm control in patients with AF and HF mated cumulative incidence of death from cardiovascular causes,
was further addressed in the landmark Atrial Fibrillation in Conges- hospitalization for HF, thromboembolic events, bleeding, and life-
tive Heart Failure trial,21 which is the largest study to-date designed threatening arrhythmias. However, in this study, the mean ejection
specifically to investigate whether rhythm control pharmacologic fraction (EF) was 52%, while the patients who had EF <40% were
strategies impact mortality over rate control therapy in patients with only 15% of the total subjects. Thus, no conclusions can be drawn
HF. On the basis of their observation that patients with AF and HF regarding lenient or strict rate control in HF patients with permanent
randomized to rhythm control were at equivalent risk for all of the AF. In addition, the long-term effects of a rapid heart rate response
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3. Shaikh et al Cardiology in Review • Volume 20, Number 6, November/December 2012
TABLE 1. Clinical Trials Comparing Rate vs Rhythm Control Strategy in AF and HF
Mortality, Ischemic Stroke,
History of Rate Control Rhythm Control Rate/Rhythm Rate/Rhythm Hospitalization, Rate/
Trials Patients FU (yr) CHF (%) (SR, %) (SR, %) Control (%) Control (%) Rhythm Control (%)
STAF17 200 1.6 55.5 BB, NCCB, Class I or III AADs 8/4 1/5 26/54, P = 0.001
DIG, or (23)
AVNA (0)
RACE18 522 2.3 50 BB, NCCB, Class I or III AADs 7/6.8*, NS 5.5/7.9†, NS 5.4/3.8
DIG (26) (39)
AFFIRM19 4060 3.5 23.1 BB, NCCB, Class I or III AADs 25.9/26.7, 5.5/7.1, P = 0.79 73/80.1, P < 0.001
DIG (34.6) (62.6) P = 0.08
HOT-CAFE20 205 1.7 62 BB, NCCB, Sotalol or Class I 1/3, NS 0/3, NS 5/100, P = 0.001
DIG (N.A.) AADs (63.5)
AF-CHF21 1376 3.1 100 BB, Digoxin, Amiodarone, 25/27, NS 2/1, NS 59/64, P = 0.06
NCCB Sotalol (58%)
(30%)
AFFIRM indicates Atrial Fibrillation Follow-up Investigation of Rhythm Management; AF-CHF, Atrial Fibrillation in Congestive Heart Failure; FU, follow-up; AADs,
antiarrhythmic drugs; AVNA, atrioventricular nodal ablation or modification; BB, β-blockers; DIG, digoxin; HOT-CAFÉ, How to Treat Chronic Atrial Fibrillation; NA, no data
available; NCCB, nondihydropyridine calcium channel antagonists; NS, not statistically significant or P values not available; RACE, Rate Control Efficacy in Permanent Atrial
Fibrillation; SR, patients in sinus rhythm at study end or latest follow-up; STAF, Strategies of Treatment of Atrial Fibrillation.
*Cardiovascular mortality.
†Thromboembolic complications.
to AF on ventricular function were not studied and the study was Pharmacologic Agents for Rhythm Control in Atrial
inadequately powered to provide conclusive data on all clinically rel- Fibrillation and Heart Failure
evant differences in clinical outcomes between the 2 groups.26 The Amiodarone is a class III AAD having functional overlap
most recent American College of Cardiology Foundation/American with class I AADs, β-blockers, and calcium channel blocker drugs.
Heart Association/Heart Rhythm Society guidelines state that strict Despite the fact that it is not Food and Drug Administration approved
rate control is not more beneficial than lenient rate control in patients for the conversion of AF or maintenance of sinus rhythm in patients
with persistent AF and stable LV function, although uncontrolled with AF, amiodarone is one of the most widely used rhythm con-
tachycardia may over time be associated with a reversible decline in trol agents. Amiodarone is an effective agent for acute cardioversion,
ventricular performance.25 although the time from drug administration to conversion of AF may
be slower with amiodarone than class Ic agents. Amiodarone appears
Pharmacologic Agents for Rate Control in Atrial to be the most effective agent for long-term maintenance of normal
Fibrillation and Heart Failure sinus rhythm in patients with AF with or without HF.37–42 In a sub-
β-blockers are first-line agents for achieving rate control in AF study of the CHF-STAT trial, the long-term effects of amiodarone on
and for reducing long-term morbidity and mortality in HF, especially morbidity and mortality in patients with HF and AF were evaluated
among patients with severely reduced systolic function.27 Carvedilol during a 4-year period.43 It showed that in patients with HF, amioda-
therapy significantly improved the LVEF and showed a trend toward rone has a significant potential to spontaneously convert patients in
a reduction in the combined end point of death or HF hospitalization AF to sinus rhythm, with patients who convert having a lower mortal-
in patients with concomitant AF and HF in a retrospective analy- ity rate than those who do not. Amiodarone also prevented the devel-
sis of “US Carvedilol Heart Failure Trial.”28 However, carvedilol is opment of new-onset AF and significantly reduced the ventricular
not a β1-selective blocker and might not result in optimal rate con- rate in those with persistent AF.43 On the basis of these and other
trol. Bisoprolol and metoprolol succinate have also been shown to findings, amiodarone remains a first-line agent for the acute conver-
improve mortality among patients with HF,29 and labetalol has also sion and maintenance of sinus rhythm in patients with AF and HF.
demonstrated effectiveness for ventricular rate control in patients However, the benefit of amiodarone must be weighed against its well-
with AF.30 Nebivolol, a highly β1-selective blocker has been shown as documented potential long-term adverse effects.44
an effective and well-tolerated treatment for HF in elderly patients.31 Dronedarone is a multiclass AAD that has a superior safety
Nondihydropyridine calcium channel blockers (verapamil profile and shorter half-life than amiodarone. Dronedarone has been
and diltiazem) are effective rate controlling agents in AF, but their shown to reduce the rate of hospitalization and death in patients with
negative inotropic properties can worsen systolic HF.10 Some stud- AF.45 However, the Antiarrhythmic Trial with Dronedarone in Mod-
ies suggest that the short-term use of intravenous diltiazem in AF erate to Severe CHF Evaluating Morbidity Decrease (ANDROM-
and moderate-to-severe HF may be safe and effective; however, EDA) study demonstrated increased cardiovascular mortality among
their safety in chronic heart rate control in patients with coexisting patients with advanced and recently decompensated HF.46 In contrast,
HF remains to be proven, and these agents are generally avoided in a post hoc analysis of ATHENA (A Placebo-Controlled, Double-
patients with severe HF.32,33 Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400
Digoxin as monotherapy for AF rate control is ineffective and not mg bid for the Prevention of Cardiovascular Hospitalization or Death
recommended.34,35 A small study in patients with AF and HF suggested from any Cause in Patients with Atrial Fibrillation/Atrial Flutter)
that the combination of digoxin and a β-blocker (carvedilol), however, study patients with AF and stable HF demonstrated that dronedar-
reduces symptoms, improves ventricular function, and leads to a bet- one did not increase mortality and showed a reduction of cardiovas-
ter rate control than either agent alone.36 It remains unclear whether cular hospitalization or death similar to the overall population.47,48
digoxin affects mortality in patients with AF and HF.10 In addition, Dronedarone is therefore contraindicated in patients with New York
digoxin is not effective for heart rate reduction during exercise. Thus, Heart Association (NYHA) class IV or unstable NYHA classes II
digoxin is often a helpful adjunctive agent for patients with AF and HF and III HF.48 The most recently published PALLAS (Permanent Atrial
in whom rate control is not adequately achieved with β-blockers alone. Fibrillation Outcome Study Using Dronedarone on Top of Standard
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4. Cardiology in Review • Volume 20, Number 6, November/December 2012 AF in HF Patients
Therapy)69 study, which was prematurely terminated, demonstrated mechanisms that promote atrial structural or electrophysiological
that dronedarone increased the rates of HF, stroke, and death from remodeling. None of these agents have specific approval for AF pre-
cardiovascular causes in patients with permanent AF who were at vention, but they are available for clinical use and their present indi-
risk for major vascular events, thus raising serious concerns about cations (hypertension, coronary artery disease, and heart failure) are
dronedarone’s clinical utility in the future.49 some of the most frequent associations of AF.63
Dofetilide, a class III AAD, has substantial evidence support- Several epidemiological and experimental studies suggest
ing its use in patients with AF and HF.24,50–52 A substudy of the DIA- that n-3 polyunsaturated fatty acids (PUFA) may exert antiar-
MOND trial showed that although all-cause mortality was unaffected rhythmogenic or antifibrillatory effects.64 The Gruppo Italiano per
by dofetilide treatment, use of this AAD led to a significant reduction lo Studio della Sopravvivenzanell’Infarto Miocardico-Heart Fail-
of hospitalization for HF.24 Torsades de pointes is a known complica- ure trial demonstrated a small benefit of n-3 PUFA administration
tion of dofetilide use and this life-threatening arrhythmia developed with respect to reducing cardiovascular mortality in patients with
in <1% of patients in the dofetilide treatment arm of the DIAMOND HF (of whom 20% had concomitant AF).64 However, a recent meta-
study. However, there was no significant difference in the total analysis of 10 randomized controlled trials evaluating the role of
arrhythmic mortality between the dofetilide and placebo groups in n-3 PUFA for AF demonstrated that there were no significant ben-
patients with AF and severe LV dysfunction.51 When patients are efits of n-3 PUFA supplementation for AF prevention.65 Due to their
dosed appropriately and monitored for QTc prolongation, patients anti-inflammatory effects, statin drugs are also theorized to be of
with AF and HF can be treated with dofetilide without any detectable benefit with respect to the primary prevention of AF. However, a
increase in mortality risk.51 recent meta-analysis evaluating 22 trials of statin agents showed no
Ibutilide is an intravenous class III AAD shown to have mod- significant reduction in the rates of AF among individuals random-
est-to-high conversion rates with AF, particularly when administered ized to receive statin agents.66
within a few weeks of AF onset.53–55 However, ibutilide infusion car- Several large randomized studies have suggested that renin-
ries a 2–4% risk of precipitating polymorphic ventricular tachycar- angiotensin-aldosterone system blockade with angiotensin- convert-
dia. Given the propensity for ventricular arrhythmias among patients ing enzyme inhibitors or angiotensin I receptor blockers may reduce
with LV dysfunction, ibutilide should be used cautiously among the incidence or recurrence of AF.67,68 However, the recently pub-
patients with AF and HF with decreased systolic function.56 lished Atrial Fibrillation Clopidogrel Trial with Irbesartan for Pre-
Sotalol is a class III AAD with strong β-blocking effects. The vention of Vascular Events (ACTIVE I) study, which evaluated the
Survival With Oral d-Sotalol trial, which involved prophylactic admin- effect of irbesartan on cardiovascular outcomes in 9016 patients with
istration of d-sotalol (an investigational agent which contains class III AF, demonstrated that the irbesartan treatment among patients with
but not β-blocking properties) to patients with severe LV dysfunction intermittent AF who were in sinus rhythm at enrollment had no effect
after myocardial infarction, was prematurely terminated as it dem- on rates of AF recurrence.69 Similarly, the Gruppo Italiano per lo Stu-
onstrated an increased cardiovascular mortality among those treated dio della Sopravvivenzanell’Infarto Miocardico-Heart Failure study
with sotalol.57 In a retrospective analysis derived from 22 clinical trials did not demonstrate a significant reduction in the occurrence of new-
involving 3135 adult patients who received oral d,l-sotalol for AF, a onset or recurrent AF events in patients with HF or LV hypertrophy
history of HF was one of the factors most predictive of torsades de randomized to receive valsartan.70
pointes ventricular tachyarrhythmia.58 The Sotalol Amiodarone Atrial The ACTIVE I trial did show a significant reduction in HF hos-
Fibrillation Efficacy Trial demonstrated that as compared to amioda- pitalization rate with the addition of irbesartan in patients with AF.69
rone, sotalol has similar efficacy in converting persistent AF to sinus These findings are consistent with the results of a trial of angiotensin
rhythm.37 Amiodarone was superior to sotalol, however, with respect to receptor blockers in patients with a low EF71 and with the results of
maintenance of sinus rhythm, although this difference was not signifi- the Candesartan in Heart Failure: Assessment of Reduction in Mor-
cant among the subgroup of patients with ischemic heart disease. How- tality and Morbidity Preserved trial (NCT00634712),72 involving
ever, Sotalol Amiodarone Atrial Fibrillation Efficacy Trial excluded patients with a normal EF and HF. However, ACTIVE I results differ
patients with NYHA class III or IV HF. On the basis of available from those of the Telmisartan Randomized Assessment Study in ACE
data suggesting that HF patients treated with sotalol are vulnerable to Intolerant Subjects with Cardiovascular Disease (NCT00153101)73;
increased rates of potentially life-threatening ventricular arrhythmias, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes
sotalol is generally avoided in patients with AF and severe HF.59 Research (NCT00097786)74; and Irbesartan in Heart Failure with
Flecainide and Propafenone are type Ic AADs, which have a Preserved Ejection Fraction (NCT00095238) study75; all of which
class I recommendation for the acute cardioversion of AF. These drugs showed no benefit of additional angiotensin receptor blockers with
also are effective in the long-term maintenance of sinus rhythm, often respect to HF.
used as a “pill-in-the-pocket” approach.60,61 The Cardiac Arrhythmia
Suppression Trial, which involved administration of encainide or Device-Based and Ablative Therapies for Atrial
flecainide for the suppression of ventricular ectopy after myocardial Fibrillation and Heart Failure
infarction, showed an increased rate of death from arrhythmia and An implantable cardiac defibrillator (ICD) is indicated for the
shock in patients treated with encainide or flecainide.62 Therefore, prevention of sudden death from ventricular tachycardia and ven-
type Ic AADs are generally avoided in patients with ischemic cardio- tricular fibrillation in high-risk populations.11 Cardiac resynchroniza-
myopathy, coronary heart disease, and HF. These agents should also tion therapy (CRT), or biventricular pacing, is another device-based
be avoided in patients with nonischemic cardiomyopathy because of therapy known to improve symptoms and reduce mortality in patients
their negative inotropic action. with HF and left bundle branch block.76–82 CRT, through its saluta-
tory benefits on hemodynamic function and cardiac remodeling, has
also been theorized to reduce the incidence of AF. However, in the
PHARMACOLOGIC AGENTS FOR THE PREVENTION Cardiac Resynchronization in Heart Failure trial, randomization to
OF ATRIAL FIBRILLATION AND HEART FAILURE CRT did not result in any reduction in the incidence rates of AF at
It has been hypothesized that drugs such as renin-angiotensin- 30 months of follow-up.76,83 Of note, however, approximately 10%
aldosterone system inhibitors, 3-hydroxy-3-methyl-glutaryl-CoA of patients enrolled in Cardiac Resynchronization in Heart Failure
reductase inhibitors (statins), and omega-3 fatty acids can prevent Study who had been characterized as having “permanent” AF con-
the incidence of new or recurrent AF by targeting pathophysiological verted to sinus rhythm after implantation with CRT.84
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5. Shaikh et al Cardiology in Review • Volume 20, Number 6, November/December 2012
Patients with AF and HF who undergo biventricular pacemaker the 2011 American College of Cardiology Foundation/American Heart
or ICD implantation remain less likely to respond to CRT, perhaps due to Association/Heart Rhythm Society guidelines now recommend con-
low rates of biventricular pacing.85 A recent meta-analysis of 23 observa- sidering catheter-based AF ablation for the treatment of symptomatic,
tional studies demonstrated that AF was associated with an increased risk paroxysmal AF in patients with significant left atrial dilatation or with
of nonresponse to CRT (Relative Risk = 1.32; P = 0.001) and all-cause significant LV dysfunction.25
mortality (Relative Risk = 1.50; P = 0.015). The presence of AF was The Cox-maze surgical procedure involves placing multiple
also associated with less improvement in quality of life, 6-minute walk incisions within the left and right atrial myocardium, with the inten-
distance, and LV end-systolic volume, but not LVEF. The hypothesis that tion of interrupting potential reentry and isolating AF triggers. The
poor CRT response among patients with AF and HF is explained by low Cox-maze procedure has excellent long-term efficacy, with nearly
rates of biventricular pacing is supported by a recent analysis, showing 90% of treated patients remaining in sinus rhythm at 10 years.
that AF patients who underwent AV node ablation and CRT implanta- Although it is usually avoided in patients with HF, the Cox-maze
tion had significantly improved EFs, exercise tolerance, and decreased operation has been shown to be safe and effective for rhythm con-
hospitalizations as compared to patients with AF and HF who underwent trol of AF.105,106 Although the full “cut and sew” Cox-maze procedure
biventricular ICD implantation alone.86–89 In addition, there is a possible (with lesions created by surgical incision) is now rarely performed
risk of increased inappropriate ICD shocks due to rapid conduction of due to its complexity, variants of this procedure are in widespread
AF to the ventricles in patients who undergo ICD implantation without use, typically using either cryo- or radiofrequency energy to create
AV nodal ablation. ablative lesions. These procedures are most commonly performed
Catheter-based AF ablation has been shown to be safe and effec- via thorascopic access as a stand-alone procedure for AF or via ster-
tive for rhythm control among patients with symptomatic AF, includ- notomy or thoracotomy when combined with other cardiac surgical
ing those with HF (Fig. 3).90–93 Five studies have specifically focused procedures requiring more complete surgical access.
on the benefit of catheter-based AF ablation among patients with AF
and HF. These studies have shown that Catheter-based AF ablation
significantly improved the cardiac function, symptom burden, exercise FUTURE DIRECTIONS IN THE MANAGEMENT OF
capacity, and quality of life of patients with AF and HF.94–98 The Pulmo- ATRIAL FIBRILLATION AND HEART FAILURE
nary Vein Antral Isolation vs AV Node Ablation with Biventricular Pac- Because ventricular proarrhythmia is one of the most com-
ing for the Treatment of AF in Patients with CHF trial99 demonstrated mon and life-threatening complications of the available AADs used
that pulmonary vein isolation resulted in significant improvement in in AF, much attention has been focused on developing atrial-selective
EF and 6-minute walk distance as compared to AV nodal ablation and AADs for AF. Atrial selectivity could be achieved by targeting ion
biventricular pacemaker implantation. Catheter ablation for AF was channels that are selectively expressed in the atria or by achievement
also shown to be superior to AAD therapy for maintaining normal of atrial-selective Na+ channel blockade via state-selective block-
sinus rhythm at a 1-year follow-up.100–104 On the basis of these data, ing properties that produce more block for atrial than for ventricular
Figure 3. Catheter-based radiofrequency AF ablation. View of the posterior left atrium. It shows antral pulmonary vein isola-
tion (a.) and isolation of the posterior left atrium (b.). The multispline mapping catheter (c.) is positioned over the posterior left
atrium showing lack of potentials after isolation (shaded arrow); whereas the potentials are still present (empty arrow) on the
coronary sinus catheter (d.). AF indicates atrial fibrillation; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein;
RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein.
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6. Cardiology in Review • Volume 20, Number 6, November/December 2012 AF in HF Patients
Maintenance of sinus rhythm in AF with co-existent HF
Avoid: Flecaninide, Propafenone, lbutilide
NYHA Class I – II HF HTN with significant LVH NYHA Class III – IV HF
Avoid:
Dronedarone
Dofetilide Amiodarone Sotalol
Inpatient initiation, monitor Monitor for effects on thyroid,
creatinine clearance and QTc lungs and liver
Dofetilide
Inpatient initiation, monitor
creatinine clearance and QTc
Amiodarone Radiofrequency catheter
Monitor for effects on thyroid, ablation/Pulmonary vein
lungs and liver isolation
Amiodarone
Monitor for effects on thyroid,
lungs and liver
May consider Dronedarone or
Sotalol if HF is mild and
clinically stable
Cox – Maze surgical ablation if concurrent valvular/cardiac surgery
Figure 4. An algorithmic approach to maintenance of sinus rhythm in patients with AF and coexistent stable HF. AF indicates
atrial fibrillation; HF, heart failure; NYHA, New York Heart Association.
action potentials, or that are highly selective for rapid rhythms like Ranolazine, an antianginal drug, has atrial-selective antiar-
AF.63 Nowhere is the importance of atrial selectivity more important rhythmic properties. Two recent nonrandomized studies showed
than in the patient with AF and HF because such patients are espe- that ranolazine safely converts new-onset or paroxysmal AF and
cially susceptible to serious ventricular arrhythmias such as ventricu- promotes maintenance of sinus rhythm.115,116 Large prospective stud-
lar tachycardia and fibrillation. ies of ranolazine in suppression of AF are currently ongoing.117 A
Vernakalant is an atrial-selective AAD that affects cardiac recently published, nonrandomized, single-center study of patients
Na+ and several K+ channels, including the atrial-selective currents undergoing bypass surgery demonstrated that ranolazine signifi-
IKur and IKACh.107 Vernakalant has been studied primarily in the cantly reduced rates of AF as compared to amiodarone, with no dif-
setting of acute conversion of recent-onset AF, but a longer-acting ference in the incidence of adverse events.118 Animal studies suggest
oral preparation is in development.108 Randomized, double-blind, pla- that ranolazine may be particularly effective for the treatment of AF
cebo-controlled studies demonstrated an efficacy of approximately when combined with dronedarone,119 but there are no conclusive data
50% for the acute conversion of AF to sinus rhythm, with very few regarding the use of this drug combination in humans.
side effects.109–111 ATI-2042 (budiodarone) is a chemical analog of amiodarone
The recently published A Phase III Superiority Study of Ver- with a half-life of 7 hours. Electrophysiology similar to amiodarone,
nakalant vs Amiodarone in Subjects With Recent Onset AF (AVRO) the drug may have fewer side effects, drug-drug interactions, and
trial112 concluded that vernakalant demonstrated superior efficacy toxicity. A recent small phase II study showed that it reduces AF bur-
when compared with amiodarone for acute conversion of recent- den.120 SSR149744C (celivarone) is another amiodarone analog in
onset AF, resulted in rapid conversion (median time of 11 minutes development for the treatment of AF.121
in responders), and was associated with a higher rate of symptom
relief compared with amiodarone. However, a major limitation of this
study was the short follow-up period (90 minutes) and short infusion CONCLUSIONS
period (24 hours) for amiodarone. Preliminary results from a double- Patients with AF and HF are unique with respect to their under-
blind, placebo-controlled, randomized dose-ranging phase 2 study lying pathophysiology, treatment response, and long-term outcome.
showed that high-dose oral vernakalant prevented recurrence of AF Although patients with AF and HF are at high risk for increased mor-
without detectable proarrhythmia.113 However, patients with decom- bidity and mortality, a variety of therapies, including drugs, devices,
pensated HF, EF <35% and NYHA class III–IV HF were excluded, and ablation procedures, are available to aid in the management of
and thus the generalizability of this study’s findings to those with AF symptomatic and asymptomatic patients with both AF and HF. We
and severe HF is unknown. A recently published phase III random- recommend a sequential approach for maintenance of sinus rhythm
ized controlled trial of vernakalant demonstrated that at a dose of 500 in patients with AF and coexistent HF (Fig. 4). Based on the available
mg twice daily, oral vernakalant appears to be reasonably effective therapies outlined above, we believe that an individualized approach
and safe for the prevention of AF recurrence after cardioversion.114 can improve symptoms and prognosis for patients with AF and HF.
© 2012 Lippincott Williams & Wilkins www.cardiologyinreview.com | 293
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7. Shaikh et al Cardiology in Review • Volume 20, Number 6, November/December 2012
‍REFERENCES The Department of Veterans Affairs CHF-STAT Investigators. Circulation.
1998;98:2574–2579.
1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial
fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042–1046. 2
4. Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment
of atrial fibrillation-flutter in patients with reduced left ventricular function:
2. Kannel WB, Abbott RD, Savage DD, et al. Epidemiologic features of chronic a Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIA-
atrial fibrillation: the Framingham study. N Engl J Med. 1982;306:1018–1022. MOND) substudy. Circulation. 2001;104:292–296.
3. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrilla- 2
5. Wann LS, Curtis AB, January CT, et al.; 2011 Writing Group Members;
tion in adults: national implications for rhythm management and stroke pre- 2006 Writing Committee Members; ACCF/AHA Task Force Members. 2011
vention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) ACCF/AHA/HRS focused update on the management of patients with atrial
Study. JAMA. 2001;285:2370–2375. fibrillation (updating the 2006 guideline): a report of the American College of
4. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–2018. Cardiology Foundation/American Heart Association Task Force on Practice
5. Cha YM, Redfield MM, Shen WK, et al. Atrial fibrillation and ven- Guidelines. Circulation. 2011;123:104–123.
tricular dysfunction: a vicious electromechanical cycle. Circulation. 2
6. Van Gelder IC, Groenveld HF, Crijns HJ, et al.; RACE II Investigators. Lenient
2004;109:2839–2843. versus strict rate control in patients with atrial fibrillation. N Engl J Med.
6. McManus DD, Shaikh AY, Abhishek F, et al. Atrial fibrillation and heart fail- 2010;362:1363–1373.
ure parallels: lessons for atrial fibrillation prevention. Crit Pathw Cardiol. 2
7. Deedwania PC, Lardizabal JA. Atrial fibrillation in heart failure: a compre-
2011;10:46–51. hensive review. Am J Med. 2010;123:198–204.
7. Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improving survival for 2
8. Joglar JA, Acusta AP, Shusterman NH, et al. Effect of carvedilol on survival
patients with atrial fibrillation and advanced heart failure. J Am Coll Cardiol. and hemodynamics in patients with atrial fibrillation and left ventricular dys-
1996;28:1458–1463. function: retrospective analysis of the US Carvedilol Heart Failure Trials Pro-
8. Lloyd-Jones DM, Larson MG, Leip EP, et al.; Framingham Heart Study. gram. Am Heart J. 2001;142:498–501.
Lifetime risk for developing congestive heart failure: the Framingham Heart 2
9. Fonarow GC. A review of evidence-based beta blockers in special populations
Study. Circulation. 2002;106:3068–3072. with heart failure. Rev Cardiovasc Med. 2008;9:84–95.
9. Pozzoli M, Cioffi G, Traversi E, et al. Predictors of primary atrial fibrillation 3
0. Wong CK, Lau CP, Leung WH, et al. Usefulness of labetalol in chronic atrial
and concomitant clinical and hemodynamic changes in patients with chronic fibrillation. Am J Cardiol. 1990;66:1212–1215.
heart failure: a prospective study in 344 patients with baseline sinus rhythm. J
3
1. Flather MD, Shibata MC, Coats AJ, et al.; SENIORS Investigators. Random-
Am Coll Cardiol. 1998;32:197–204.
ized trial to determine the effect of nebivolol on mortality and cardiovascu-
1
0. Neuberger HR, Mewis C, van Veldhuisen DJ, et al. Management of atrial lar hospital admission in elderly patients with heart failure (SENIORS). Eur
fibrillation in patients with heart failure. Eur Heart J. 2007;28:2568–2577. Heart J. 2005;26:215–225.
1
1. Heist EK, Ruskin JN. Atrial fibrillation and congestive heart failure: risk fac- 3
2. Goldenberg IF, Lewis WR, Dias VC, et al. Intravenous diltiazem for the treat-
tors, mechanisms, and treatment. Prog Cardiovasc Dis. 2006;48:256–269. ment of patients with atrial fibrillation or flutter and moderate to severe con-
1
2. Castillo JC, Anguita MP, Jiménez M; BADAPIC Group. Outcome of heart gestive heart failure. Am J Cardiol. 1994;74:884–889.
failure with preserved ejection fraction: a multicentre Spanish registry. Curr 3
3. Heywood JT. Calcium channel blockers for heart rate control in atrial fibrilla-
Cardiol Rev. 2009;5:334–342. tion complicated by congestive heart failure. Can J Cardiol. 1995;11:823–826.
1
3. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejec- 3
4. Khan IA, Nair CK, Singh N, et al. Acute ventricular rate control in atrial fibril-
tion fraction in a population-based study. N Engl J Med. 2006;355:260–269. lation and atrial flutter. Int J Cardiol. 2004;97:7–13.
1
4. Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al. Differences between 3
5. Farshi R, Kistner D, Sarma JS, et al. Ventricular rate control in chronic atrial
patients with a preserved and a depressed left ventricular function: a report fibrillation during daily activity and programmed exercise: a crossover open-
from the EuroHeart Failure Survey. Eur Heart J. 2004;25:1214–1220. label study of five drug regimens. J Am Coll Cardiol. 1999;33:304–310.
1
5. Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk fac- 3
6. Khand AU, Rankin AC, Martin W, et al. Carvedilol alone or in combination
tors to heart failure with preserved or reduced ejection fraction: insights from with digoxin for the management of atrial fibrillation in patients with heart
the framingham heart study of the national heart, lung, and blood institute. failure? J Am Coll Cardiol. 2003;42:1944–1951.
Circulation. 2009;119:3070–3077.
3
7. Singh BN, Singh SN, Reda DJ, et al.; Sotalol Amiodarone Atrial Fibrillation
1
6. Grogan M, Smith HC, Gersh BJ, et al. Left ventricular dysfunction due to Efficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial
atrial fibrillation in patients initially believed to have idiopathic dilated car- fibrillation. N Engl J Med. 2005;352:1861–1872.
diomyopathy. Am J Cardiol. 1992;69:1570–1573.
3
8. Hilleman DE, Spinler SA. Conversion of recent-onset atrial fibrillation with
1
7. Carlsson J, Miketic S, Windeler J, et al.; STAF Investigators. Randomized intravenous amiodarone: a meta-analysis of randomized controlled trials.
trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Pharmacotherapy. 2002;22:66–74.
Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol.
2003;41:1690–1696. 3
9. Chevalier P, Durand-Dubief A, Burri H, et al. Amiodarone versus placebo and
class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-anal-
1
8. Van Gelder IC, Hagens VE, Bosker HA, et al.; Rate Control versus Electri- ysis. J Am Coll Cardiol. 2003;41:255–262.
cal Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison
of rate control and rhythm control in patients with recurrent persistent atrial 4
0. Letelier LM, Udol K, Ena J, et al. Effectiveness of amiodarone for conver-
fibrillation. N Engl J Med. 2002;347:1834–1840. sion of atrial fibrillation to sinus rhythm: a meta-analysis. Arch Intern Med.
2003;163:777–785.
1
9. Wyse DG, Waldo AL, DiMarco JP, et al.; Atrial Fibrillation Follow-up Investi-
gation of Rhythm Management (AFFIRM) Investigators. A comparison of rate 4
1. Doyle JF, Ho KM. Benefits and risks of long-term amiodarone therapy for per-
control and rhythm control in patients with atrial fibrillation. N Engl J Med. sistent atrial fibrillation: a meta-analysis. Mayo Clin Proc. 2009;84:234–242.
2002;347:1825–1833. 4
2. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial
2
0. Opolski G, Torbicki A, Kosior DA, et al.; Investigators of the Polish How fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med.
to Treat Chronic Atrial Fibrillation Study. Rate control vs rhythm control in 2000;342:913–920.
patients with nonvalvular persistent atrial fibrillation: the results of the Pol- 4
3. Deedwania PC, Singh BN, Ellenbogen K, et al. Spontaneous conversion and
ish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest. maintenance of sinus rhythm by amiodarone in patients with heart failure and
2004;126:476–486. atrial fibrillation: observations from the veterans affairs congestive heart fail-
1. Roy D, Talajic M, Nattel S, et al.; Atrial Fibrillation and Congestive Heart
2 ure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of
Failure Investigators. Rhythm control versus rate control for atrial fibrillation Veterans Affairs CHF-STAT Investigators. Circulation. 1998;98:2574–2579.
and heart failure. N Engl J Med. 2008;358:2667–2677. 4
4. Hilleman D, Miller MA, Parker R, et al. Optimal management of amio-
2
2. Curtis AB, Gersh BJ, Corley SD, et al.; AFFIRM Investigators. Clinical factors darone therapy: efficacy and side effects. Pharmacotherapy. 1998;18(6 pt
that influence response to treatment strategies in atrial fibrillation: the Atrial 2):138S–145S.
Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) 4
5. Hohnloser SH, Crijns HJ, van Eickels M, et al.; ATHENA Investigators. Effect
study. Am Heart J. 2005;149:645–649. of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med.
2
3. Deedwania PC, Singh BN, Ellenbogen K, et al. Spontaneous conversion 2009;360:668–678.
and maintenance of sinus rhythm by amiodarone in patients with heart 4
6. Køber L, Torp-Pedersen C, McMurray JJ, et al.; Dronedarone Study Group.
failure and atrial fibrillation: observations from the veterans affairs con- Increased mortality after dronedarone therapy for severe heart failure. N Engl
gestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). J Med. 2008;358:2678–2687.
294 | www.cardiologyinreview.com © 2012 Lippincott Williams & Wilkins
CRD_v20n6.indb 294 10/1/2012 10:38:52 AM

8. Cardiology in Review • Volume 20, Number 6, November/December 2012 AF in HF Patients
47. Hohnloser SH, Connolly SJ, Crijns HJ, et al. Rationale and design of ATHENA: 6
9. ACTIVE I Investigators, Yusuf S, Healey JS, Pogue J, et al. Irbesartan in
A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy patients with atrial fibrillation. N Engl J Med. 2011;364:928–938.
of dronedarone 400 mg bid for the prevention of cardiovascular Hospitaliza- 7
0. GISSI-AF Investigators, Disertori M, Latini R, Barlera S, et al. Valsartan for
tion or death from any cause in patiENts with Atrial fibrillation/atrial flutter. prevention of recurrent atrial fibrillation. N Engl J Med. 2009;360:1606-17.
J Cardiovasc Electrophysiol. 2008;19:69–73. Erratum in: N Engl J Med. 2009;360:2379.
48. Hohnloser SH, Crijns HJ, van Eickels M, et al.; ATHENA Investigators. Drone- 7
1. McMurray JJ, Ostergren J, Swedberg K, et al.; CHARM Investigators and
darone in patients with congestive heart failure: insights from ATHENA. Eur Committees. Effects of candesartan in patients with chronic heart failure
Heart J. 2010;31:1717–1721. and reduced left-ventricular systolic function taking angiotensin-converting-
49. Connolly SJ, Camm AJ, Halperin JL, et al.; PALLAS Investigators.
enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767–771.
Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 7
2. Yusuf S, Pfeffer MA, Swedberg K, et al.; CHARM Investigators and Com-
2011;365:2268–2276. mittees. Effects of candesartan in patients with chronic heart failure and pre-
5
0. Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients served left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet.
with congestive heart failure and left ventricular dysfunction. Danish Inves- 2003;362:777–781.
tigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl 7
3. The TRANSCEND Investigators. Effects of the angiotensin-receptor blocker
J Med. 1999;341:857–865. telmisartan on cardiovascular events in high-risk patients intolerant to angio-
5
1. Køber L, Bloch Thomsen PE, Møller M, et al.; Danish Investigations of tensin- converting enzyme inhibitors: a randomized controlled trial. Lancet.
Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group. Effect 2008;372:1174–1183.
of dofetilide in patients with recent myocardial infarction and left-ventricular 7
4. NAVIGATOR Study Group, McMurray JJ, Holman RR, Haffner SM, et al.
dysfunction: a randomised trial. Lancet. 2000;356:2052–2058. Effect of valsartan on the incidence of diabetes and cardiovascular events. N
5
2. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in Engl J Med. 2010;362:1477–1490.
converting to and maintaining sinus rhythm in patients with chronic atrial 7
5. Massie BM, Carson PE, McMurray JJ, et al.; I-PRESERVE Investigators.
fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative Irbesartan in patients with heart failure and preserved ejection fraction. N Engl
research on dofetilide (SAFIRE-D) study. Circulation. 2000;102:2385–2390. J Med. 2008;359:2456–2467.
5
3. Kafkas NV, Patsilinakos SP, Mertzanos GA, et al. Conversion efficacy of intra- 7
6. Cleland JG, Daubert JC, Erdmann E, et al.; Cardiac Resynchronization-
venous ibutilide compared with intravenous amiodarone in patients with recent- Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resyn-
onset atrial fibrillation and atrial flutter. Int J Cardiol. 2007;118:321–325. chronization on morbidity and mortality in heart failure. N Engl J Med.
5
4. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intrave- 2005;352:1539–1549.
nous ibutilide compared with procainamide during human atrial flutter and 7
7. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrio-
fibrillation: electrophysiological determinants of enhanced conversion effi- ventricular delay on acute systolic function of paced patients with conges-
cacy. Circulation. 1997;96:4298–4306. tive heart failure. The Pacing Therapies for Congestive Heart Failure Study
5
5. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of Group. The Guidant Congestive Heart Failure Research Group. Circulation.
repeated intravenous doses of ibutilide for rapid conversion of atrial flut- 1999;99:2993–3001.
ter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation. 7
8. Gras D, Leclercq C, Tang AS, et al. Cardiac resynchronization therapy in
1996;94:1613–1621. advanced heart failure the multicenter InSync clinical study. Eur J Heart Fail.
5
6. Fragakis N, Bikias A, Delithanasis I, et al. Acute beta-adrenoceptor blockade 2002;4:311–320.
improves efficacy of ibutilide in conversion of atrial fibrillation with a rapid 7
9. Abraham WT, Fisher WG, Smith AL, et al.; MIRACLE Study Group. Multi-
ventricular rate. Europace. 2009;11:70–74. center InSync Randomized Clinical Evaluation. Cardiac resynchronization in
5
7. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in chronic heart failure. N Engl J Med. 2002;346:1845–1853.
patients with left ventricular dysfunction after recent and remote myocardial 80. Young JB, Abraham WT, Smith AL, et al.; Multicenter InSync ICD Randomized
infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet. Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac
1996;348:7–12. resynchronization and implantable cardioversion defibrillation in advanced
5
8. Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de chronic heart failure: the MIRACLE ICD Trial. JAMA. 2003;289:2685–2694.
pointes with d,l-sotalol. Circulation. 1996;94:2535–2541. 8
1. Bristow MR, Saxon LA, Boehmer J, et al.; Comparison of Medical Therapy,
5
9. Fuster V, Ryden LE, Cannom DS, et al. American College of Cardiology/ Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators.
American Heart Association/European Society of Cardiology 2006 Guide- Cardiac-resynchronization therapy with or without an implantable defibrilla-
lines for the management of patients with atrial fibrillation. J Am Coll Cardiol. tor in advanced chronic heart failure. N Engl J Med. 2004;350:2140–2150.
2006;48:e149–e246. 8
2. Moss AJ, Hall WJ, Cannom DS, et al.; MADIT-CRT Trial Investigators.
6
0. Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-onset Cardiac-resynchronization therapy for the prevention of heart-failure events.
atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med. N Engl J Med. 2009;361:1329–1338.
2004;351:2384–2391. 8
3. Fung JW, Yu CM, Chan JY, et al. Effects of cardiac resynchronization therapy
6
1. Khan IA. Single oral loading dose of propafenone for pharmacological cardio- on incidence of atrial fibrillation in patients with poor left ventricular systolic
version of recent-onset atrial fibrillation. J Am Coll Cardiol. 2001;37:542–547. function. Am J Cardiol. 2005;96:728–731.
6
2. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients 8
4. Gasparini M, Steinberg JS, Arshad A, et al. Resumption of sinus rhythm in
receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppres- patients with heart failure and permanent atrial fibrillation undergoing cardiac
sion Trial. N Engl J Med. 1991;324:781–788. resynchronization therapy: a longitudinal observational study. Eur Heart J.
3. Dobrev D, Nattel S. New antiarrhythmic drugs for treatment of atrial fibrilla-
6 2010;31:976–983.
tion. Lancet. 2010;375:1212–1223. 8
5. Molhoek SG, Bax JJ, Bleeker GB, et al. Comparison of response to cardiac
6
4. GISSI-HF Investigators Tavazzi, L, Maggioni, AP, Marchioli R, et al Effect resynchronization therapy in patients with sinus rhythm versus chronic atrial
of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the fibrillation. Am J Cardiol. 2004;94:1506–1509.
GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 6. Cazeau S, Leclercq C, Lavergne T, et al.; Multisite Stimulation in Cardio-
8
2008;372:1223–1230. myopathies (MUSTIC) Study Investigators. Effects of multisite biventricular
5. Liu T, Korantzopoulos P, Shehata M, et al. Prevention of atrial fibrillation
6 pacing in patients with heart failure and intraventricular conduction delay.
with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart. N Engl J Med. 2001;344:873–880.
2011;97:1034–1040. 7. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biven-
8
66. Rahimi K, Emberson J, McGale P, et al.; PROSPER Executive. Effect of statins tricular and right-univentricular pacing in heart failure patients with chronic
on atrial fibrillation: collaborative meta-analysis of published and unpublished atrial fibrillation. Eur Heart J. 2002;23:1780–1787.
evidence from randomised controlled trials. BMJ. 2011;342:d1250. 8
8. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resyn-
7. Pedersen OD, Bagger H, Kober L, et al. Trandolapril reduces the incidence of
6 chronization therapy on exercise tolerance and disease progression: the impor-
atrial fibrillation after acute myocardial infarction in patients with left ven- tance of performing atrioventricular junction ablation in patients with atrial
tricular dysfunction. Circulation. 1999;100:376–380. fibrillation. J Am Coll Cardiol. 2006;48:734–743.
8. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus
6 9. Wilton SB, Leung AA, Ghali WA, et al. Outcomes of cardiac resynchroniza-
8
rhythm in patients with long-lasting persistent atrial fibrillation: a prospective tion therapy in patients with versus those without atrial fibrillation: a system-
and randomized study. Circulation. 2002;106:331–336. atic review and meta-analysis. Heart Rhythm. 2011;8:1088–1094.
© 2012 Lippincott Williams & Wilkins www.cardiologyinreview.com | 295
CRD_v20n6.indb 295 10/1/2012 10:38:52 AM

9. Shaikh et al Cardiology in Review • Volume 20, Number 6, November/December 2012
90. Fuster V Rydén LE, Cannom DS, et al.; American College of Cardiology/
, 1
05. Gaynor SL, Schuessler RB, Bailey MS, et al. Surgical treatment of atrial
American Heart Association Task Force on Practice Guidelines; European fibrillation: predictors of late recurrence. J Thorac Cardiovasc Surg.
Society of Cardiology Committee for Practice Guidelines; European Heart 2005;129:104–111.
Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guide- 1
06. Stulak JM, Dearani JA, Daly RC, et al. Left ventricular dysfunction in atrial
lines for the Management of Patients with Atrial Fibrillation: a report of the fibrillation: restoration of sinus rhythm by the Cox-maze procedure signifi-
American College of Cardiology/American Heart Association Task Force on cantly improves systolic function and functional status. Ann Thorac Surg.
Practice Guidelines and the European Society of Cardiology Committee for 2006;82:494–500;discussion 500.
Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the 1
07. Comtois P, Sakabe M, Vigmond EJ, et al. Mechanisms of atrial fibrilla-
Management of Patients With Atrial Fibrillation): developed in collaboration tion termination by rapidly unbinding Na+ channel blockers: insights from
with the European Heart Rhythm Association and the Heart Rhythm Society. mathematical models and experimental correlates. Am J Physiol Heart Circ
Circulation. 2006;114:e257–e354. Physiol. 2008;295:H1489–H1504.
91. Natale A, Raviele A, Arentz T, et al. Venice Chart international consen- 1
08. Naccarelli GV, Wolbrette DL, Samii S, et al. Vernakalant–a promising ther-
sus document on atrial fibrillation ablation. J Cardiovasc Electrophysiol. apy for conversion of recent-onset atrial fibrillation. Expert Opin Investig
2007;18:560–580. Drugs. 2008;17:805–810.
92. Calkins H, Yong P, Miller JM, et al. Catheter ablation of accessory path- 1
09. Roy D, Rowe BH, Stiell IG, et al.; CRAFT Investigators. A randomized, con-
ways, atrioventricular nodal reentrant tachycardia, and the atrioventricular trolled trial of RSD1235, a novel anti-arrhythmic agent, in the treatment of
junction: final results of a prospective, multicenter clinical trial. The Atakr recent onset atrial fibrillation. J Am Coll Cardiol. 2004;44:2355–2361.
Multicenter Investigators Group. Circulation. 1999;99:262–270. 1
10. Roy D, Pratt CM, Torp-Pedersen C, et al.; Atrial Arrhythmia Conversion
93. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, Trial Investigators. Vernakalant hydrochloride for rapid conversion of atrial
efficacy, and safety of catheter ablation for human atrial fibrillation. Circula- fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation.
tion. 2005;111:1100–1105. 2008;117:1518–1525.
4. Hsu LF, Jaïs P, Sanders P, et al. Catheter ablation for atrial fibrillation in
9 1
11. Kowey PR, Dorian P, Mitchell LB, et al.; Atrial Arrhythmia Conversion
congestive heart failure. N Engl J Med. 2004;351:2373–2383. Trial Investigators. Vernakalant hydrochloride for the rapid conversion of
atrial fibrillation after cardiac surgery: a randomized, double-blind, placebo-
95. Chen MS, Marrouche NF, Khaykin Y, et al. Pulmonary vein isolation for controlled trial. Circ Arrhythm Electrophysiol. 2009;2:652–659.
the treatment of atrial fibrillation in patients with impaired systolic function. 1
12. Camm AJ, Capucci A, Hohnloser SH, et al.; AVRO Investigators. A random-
J Am Coll Cardiol. 2004;43:1004–1009. ized active-controlled study comparing the efficacy and safety of vernaka-
96. Lutomsky BA, Rostock T, Koops A, et al. Catheter ablation of paroxysmal lant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol.
atrial fibrillation improves cardiac function: a prospective study on the 2011;57:313–321.
impact of atrial fibrillation ablation on left ventricular function assessed by 1
13. Cardiome Pharma Corp. Cardiome announces positive phase 2b results for
magnetic resonance imaging. Europace. 2008;10:593–599. oral vernakalant. Available at: http://cardiome.com/wordpress/?p=443. 2008.
97. Efremidis M, Sideris A, Xydonas S, et al. Ablation of atrial fibrillation in Accessed February 5, 2011.
patients with heart failure: reversal of atrial and ventricular remodelling. 1
14. Torp-Pedersen C, Raev DH, Dickinson G, et al. A randomized, placebo-
Hellenic J Cardiol. 2008;49:19–25. controlled study of vernakalant (oral) for the prevention of atrial fibril-
98. Gentlesk PJ, Sauer WH, Gerstenfeld EP, et al. Reversal of left ventricular lation recurrence after cardioversion. Circ Arrhythm Electrophysiol.
dysfunction following ablation of atrial fibrillation. J Cardiovasc Electro- 2011;4:637–643.
physiol. 2007;18:9–14. 1
15. Murdock DK, Kersten M, Kaliebe J, et al. The use of oral ranolazine to con-
99. Khan MN, Jaïs P, Cummings J, et al.; PABA-CHF Investigators. Pulmonary- vert new or paroxysmal atrial fibrillation: a review of experience with impli-
cations for possible “pill in the pocket” approach to atrial fibrillation. Indian
vein isolation for atrial fibrillation in patients with heart failure. N Engl
Pacing Electrophysiol J. 2009;9:260–267.
J Med. 2008;359:1778–1785.
1
16. Murdock DK, Overton N, Kersten M, et al. The effect of ranolazine on main-
1
00. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in taining sinus rhythm in patients with resistant atrial fibrillation. Indian Pac-
patients with drug-refractory atrial fibrillation: a prospective, multi-centre, ing Electrophysiol J. 2008;8:175–181.
randomized, controlled study (Catheter Ablation For The Cure Of Atrial
Fibrillation Study). Eur Heart J. 2006;27:216–221. 1
17. Burashnikov A, Antzelevitch C. Atrial-selective sodium channel blockers: do
they exist? J Cardiovasc Pharmacol. 2008;52:121–128.
1
01. Pappone C, Augello G, Sala S, et al. A randomized trial of circumfer-
1
18. Miles RH, Passman R, Murdock DK. Comparison of effectiveness and safety
ential pulmonary vein ablation versus antiarrhythmic drug therapy
of ranolazine versus amiodarone for preventing atrial fibrillation after coro-
in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol. nary artery bypass grafting. Am J Cardiol. 2011;108:673–676.
2006;48:2340–2347.
1
19. Burashnikov A, Sicouri S, Di Diego JM, et al. Synergistic effect of the com-
1
02. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation bination of ranolazine and dronedarone to suppress atrial fibrillation. J Am
for chronic atrial fibrillation. N Engl J Med. 2006;354:934–941. Coll Cardiol. 2010;56:1216–1224.
1
03. Jaïs P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic 1
20. Arya A, Silberbauer J, Teichman SL, et al. A preliminary assessment of the
drugs for atrial fibrillation: the A4 study. Circulation. 2008;118:2498–2505. effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using
1
04. Wilber DJ, Pappone C, Neuzil P, et al.; ThermoCool AF Trial Investigators. implanted pacemaker methodology. Europace. 2009;11:458–464.
Comparison of antiarrhythmic drug therapy and radiofrequency catheter 1
21. Gautier P, Serre M, Cosnier-Pucheu S, et al. In vivo and in vitro antiarrhyth-
ablation in patients with paroxysmal atrial fibrillation: a randomized con- mic effects of SSR149744C in animal models of atrial fibrillation and ven-
trolled trial. JAMA. 2010;303:333–340. tricular arrhythmias. J Cardiovasc Pharmacol. 2005;45:125–135.
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