Arrhythmia/Electrophysiology

Ablation Versus Amiodarone for Treatment of Persistent

Atrial Fibrillation in Patients With Congestive Heart Failure
and an Implanted Device
Results From the AATAC Multicenter Randomized Trial
Luigi Di Biase, MD, PhD; Prasant Mohanty, MBBS, MPH; Sanghamitra Mohanty, MD;
Pasquale Santangeli, MD; Chintan Trivedi, MD, MPH; Dhanunjaya Lakkireddy, MD;
Madhu Reddy, MD; Pierre Jais, MD; Sakis Themistoclakis, MD; Antonio Dello Russo, MD;
Michela Casella, MD; Gemma Pelargonio, MD; Maria Lucia Narducci, MD;
Robert Schweikert, MD; Petr Neuzil, MD; Javier Sanchez, MD; Rodney Horton, MD;
Salwa Beheiry, RN; Richard Hongo, MD; Steven Hao, MD; Antonio Rossillo, MD;
Giovanni Forleo, MD; Claudio Tondo, MD; J. David Burkhardt, MD;
Michel Haissaguerre, MD; Andrea Natale, MD

Background—Whether catheter ablation (CA) is superior to amiodarone (AMIO) for the treatment of persistent atrial
fibrillation (AF) in patients with heart failure is unknown.
Methods and Results—This was an open-label, randomized, parallel-group, multicenter study. Patients with persistent AF, dual-
chamber implantable cardioverter defibrillator or cardiac resynchronization therapy defibrillator, New York Heart Association
II to III, and left ventricular ejection fraction <40% within the past 6 months were randomly assigned (1:1 ratio) to undergo
CA for AF (group 1, n=102) or receive AMIO (group 2, n=101). Recurrence of AF was the primary end point. All-cause
mortality and unplanned hospitalization were the secondary end points. Patients were followed up for a minimum of 24
months. At the end of follow-up, 71 (70%; 95% confidence interval, 60%–78%) patients in group 1 were recurrence free after
an average of 1.4±0.6 procedures in comparison with 34 (34%; 95% confidence interval, 25%–44%) in group 2 (log-rank
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P<0.001). The success rate of CA in the different centers after a single procedure ranged from 29% to 61%. After adjusting for
covariates in the multivariable model, AMIO therapy was found to be significantly more likely to fail (hazard ratio, 2.5; 95%
confidence interval, 1.5–4.3; P<0.001) than CA. Over the 2-year follow-up, the unplanned hospitalization rate was (32 [31%]
in group 1 and 58 [57%] in group 2; P<0.001), showing 45% relative risk reduction (relative risk, 0.55; 95% confidence
interval, 0.39–0.76). A significantly lower mortality was observed in CA (8 [8%] versus AMIO (18 [18%]; P=0.037).
Conclusions—This multicenter randomized study shows that CA of AF is superior to AMIO in achieving freedom from AF at
long-term follow-up and reducing unplanned hospitalization and mortality in patients with heart failure and persistent AF.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729911.  
(Circulation. 2016;133:1637-1644. DOI: 10.1161/CIRCULATIONAHA.115.019406.)
Key Words: amiodarone ◼ atrial fibrillation ◼ catheter ablation ◼ heart failure

T ranscatheter ablation represents a valid treatment option in

patients with drug-refractory symptomatic atrial fibrilla-
tion (AF).1 The majority of catheter ablation trials have mainly
Editorial, see p 1631
Clinical Perspective on p 1644
enrolled patients with preserved left ventricular (LV) systolic shown to be effective in reducing morbidity,2–4 improving the
function. In these patients, the ablative treatment has been quality of life (QoL),3–6 and improving functional capacity.5–7

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received July 29, 2015; accepted February 25, 2016.
From Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin (L.D.B., P.M., S.M., P.S., C.T., J.S., R.H., J.D.B., A.N.); Albert Einstein
College of Medicine, at Montefiore Hospital, New York, NY (L.D.B.); Department of Biomedical Engineering, University of Texas, Austin (L.D.B., A.N.);
Department of Cardiology, University of Foggia, Italy (L.D.B.); University of Kansas, Kansas City (D.L., M.R.); Hôpital Cardiologique du Haut Lévêque,
Université Victor-Segalen Bordeaux, France (P.J., M.H.); Ospedale dell’Angelo, Mestre Venice, Italy (S.T., A.R.); Cardiac Arrhythmia Research Centre,
Centro Cardiologico Monzino IRCCS, Milan, Italy (A.D.R., M.C., C.T.); University of Sacred Heart, Rome, Italy (G.P., M.L.N.); Akron General Hospital,
OH (R.S.); Department of Cardiology, Na Homolce Hospital, Prague, Czech Republic (P.N.); California Pacific Medical Center, San Francisco (S.B.,
R.H., S.H., A.N.); University of Tor Vergata, Rome, Italy (G.F.); Division of Cardiology, Stanford University, Palo Alto, CA (A.N.); Case Western Reserve
University, Cleveland, OH (A.N.); Scripps Clinic, San Diego, CA (A.N.); and Dell Medical School, Austin, TX (A.N.).
Presented at the ACC (American College of Cardiology) Annual Meeting, March 14-16, 2015, San Diego, CA.
Correspondence to Andrea Natale, MD, FACC, FHRS, FESC, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, 3000 N I-35, Suite 720,
Austin, TX 78705. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.115.019406

1637
 1638  Circulation  April 26, 2016

However, a significant number of patients with AF also have flutter, or atrial tachycardia of >30 seconds duration off AADs at
LV systolic dysfunction. AF and heart failure (HF) frequently follow-up.
In the ablation arm, a second ablation procedure could be per-
coexist and are often associated with several common predis- formed during the blanking period (3 months). After the blanking
posing risk factors such as hypertension, coronary artery dis- period, any atrial arrhythmia was considered a recurrence.
ease, structural heart disease (nonischemic, valvular), diabetes Secondary end points included complications, all-cause mortality,
mellitus, obesity, and obstructive sleep apnea .8,9 Importantly, AF- and HF-related unplanned hospitalizations during the postabla-
the prevalence of AF increases with HF severity, ranging from tion follow-up, change in LVEF, 6-minute walk distance (6MWD),
and QoL measured by Minnesota Living with Heart Failure
5% in functional class I patients to ≈50% in class IV patients. Questionnaire (MLHFQ). Unplanned hospitalization was defined as
Also, the prevalence of HF in patients with AF has been a hospital admission during the postindex procedure follow-up for
estimated at 42%.8 The combination of HF and AF leads to arrhythmia-related causes or symptoms, signs, or complications of
deleterious hemodynamic and symptomatic consequences. HF. Planned readmissions, such as hospitalization for repeat ablation
procedures, were not counted as outcomes in this measure.
Rhythm control with antiarrhythmic drugs (AADs) has not
shown satisfactory results in randomized trials both in patients
with or without HF.9–12 Ablation
The Comparison of Pulmonary Vein Isolation Versus AV In brief, dofetilide was discontinued 4 to 5 days before ablation,
whereas patients on low-dose AMIO (up to 200 mg daily) were
Nodal Ablation With Biventricular Pacing for Patients With allowed to discontinue the drug after the blanking period.
Atrial Fibrillation With Congestive Heart Failure (PABA CHF) In all patients, a double transseptal puncture was performed.
trial showed that pulmonary vein isolation (PVI) was superior Intravenous heparin was given with a target activated clotting
to atrioventricular node ablation with biventricular pacing13 time of 300 to 400 seconds. A circular mapping catheter (Lasso,
in patients with AF and HF, improving their cardiac function, Biosense Webster, Diamond Bar, CA) was used to guide the
ablation. Intracardiac echocardiography could be used to guide
exercise capacity, and QoL; however, Jones et al14 showed that transseptal catheterization and for anatomic orientation. An open-
this benefit was achieved after more than a single procedure. irrigation tip catheter (Thermocool, Biosense Webster) was used
We sought to evaluate whether catheter ablation is supe- for ablation.
rior to amiodarone (AMIO) for the treatment of persistent AF The main goal of the ablation procedure was pulmonary vein
antrum isolation. Pulmonary vein antrum isolation was extended
in patients with HF in a randomized controlled trial. down to the coronary sinus and to the left side of the interatrial sep-
tum, along with extensive ablations on the left atrial posterior wall
Methods with the aim to achieve isolation of the entire left atrial posterior wall,
which was defined as complete electric silence on the left atrial pos-
Study Design terior wall confirmed by the absence of near-field atrial activity on
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Ablation vs Amiodarone for Treatment of Atrial Fibrillation in the circular mapping catheter that was placed on the left atrial poste-
Patients With Congestive Heart Failure and an Implanted ICD/CRTD rior wall. In addition, the superior vena cava was empirically isolated
(AATAC) was a randomized study assessing whether catheter ablation when pulmonary vein (PV)–like potentials were found. Additional
is superior to AMIO for the treatment of AF. Patients ≥18 years of linear lesion ablation of complex fractionated electrograms and elimi-
age with persistent AF, dual-chamber implantable cardioverter defi- nation of non-PV triggers were advised but performed according to
brillator or cardiac resynchronization therapy defibrillator, New York the preference of the center or the operator. Antiarrhythmic medica-
Heart Association functional class II to III, and LV ejection fraction tions could be restarted at the discretion of the treating physician dur-
(LVEF) ≤40% within the past 6 months were enrolled at multiple cen- ing the blanking period. A redo procedure within the first 3 months
ters. Patients were excluded if AF was caused by a reversible etiology, follow-up (blanking period) was not considered recurrence.
and if they had valvular or coronary heart disease requiring surgical
intervention, early postoperative AF (within 3 months of surgery), or
a life expectancy ≤2 years. Other exclusions included prolonged QT AMIO Treatment
interval, hypothyroidism, history of severe pulmonary disease, and Treatment with AMIO was initiated in the ambulatory setting.
liver failure. Patients receiving a regular dose of AMIO (≥200 mg/d) AMIO therapy was initiated with a loading dose of ≈10 g in the
were also excluded. The follow-up period of the study was 24 months. first 2 weeks after randomization. This loading dose was given in
A flow chart showing the study design is presented in Figure 1. divided doses: 400 mg given orally twice a day for 2 weeks followed
by 400 mg each day for the next 2 weeks. Once the loading phase
Sample Size and Power was completed, the maintenance dose of AMIO was 200 mg a day.
With the use of a log-rank test, the study was designed to detect at However, 27 patients (12 in the ablation group and 15 in the AMIO
least 20% increase in success rate (30%–50% null hazard rate, 0.6; group) receiving low-dose AMIO (<200 mg/d) were also included in
hazard ratio, 0.575) at 24 months follow-up at a 2-sided type I error the study. Digoxin was discontinued if possible, or the dose was at
(α) of 0.05, and 80% power. With 30% oversampling for attrition, least reduced by 50%.
a total of 200 patients (100 per group) were required to provide the Screening pulmonary function tests and chest radiography were
power. performed at baseline, and pulmonary function tests were performed
yearly thereafter. Liver and thyroid function tests were assessed at
Randomization Procedure baseline and every 6 months thereafter.
Eligible subjects were enrolled after signing informed consent
approved by the institutional review boards of the respective insti-
tutions, and were randomly assigned (1:1 ratio) to undergo catheter Congestive Heart Failure Management
ablation for AF (group 1) or to receive AMIO (group 2). All patients were on the optimal tolerated medical therapy for conges-
A computerized central randomization scheme was generated tive heart failure. Optimal therapy included angiotensin-converting
using block randomization, and sets of randomly selected blocks enzyme inhibitors or angiotensin receptor blockers in angiotensin-
were provided to the investigating sites. converting enzyme–intolerant patients along with β-blockers, diuret-
ics, and digoxin when appropriate.
Primary End Point For those patients intolerant to angiotensin-converting enzyme /
Long-term procedural success was the primary end point for this angiotensin receptor blockers, a combination of hydralazine and iso-
study. Procedural success was defined as freedom from AF, atrial sorbide dinitrate was recommended. New York Heart Association class
 Di Biase et al   Amiodarone and AF Ablation in Heart Failure   1639

Figure 1. Flow chart of the study design showing

enrollment, randomization, and evaluation time
points for outcome measures. AF indicates atrial
fibrillation; CRTD, cardiac resynchronization
therapy defibrillator; ICD, implantable cardioverter
defibrillator; LVEF, left ventricular ejection fraction;
MLHFQ, Minnesota Living with Heart Failure
questionnaire; 6MWD, 6-minute walk distance;
and NYHA, New York Heart Association.

III patients were considered for treatment with spironolactone, whereas Arrhythmia recurrence was evaluated by using remote monitoring
New York Heart Association class IV patients were excluded. capabilities on implanted devices, with device interrogation at 3, 6,
12, and 24 months follow-up. Adverse events were further collected
at the end of the study.
Left Ventricular Ejection Fraction
In all patients standard 2D and Doppler echocardiography was per-
formed. LVEF was quantified by using a modified biplane Simpson Statistical Analysis
rule in 2- and 4-chamber apical views. The LVEF measurements were Demographic Baseline Characteristics
performed by operators blinded to the randomization group and to the Descriptive analysis was performed summarizing the age, sex,
study end points. comorbidities, procedural parameters, and other relevant baseline risk
factors. The continuous variables were reported as mean±standard
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Minnesota Living With Heart Failure Questionnaire deviation. The categorical variables were reported as number of cases
(n) and percentage. Normality of the analysis variables were tested
QoL was measured at baseline and 24 months of follow-up by using
using Shapiro-Wilk test. If the normality assumption was found to be
the MLHFQ survey. It is a 21-item, self-administered, validated ques-
violated, then appropriate nonparametric tests were used.
tionnaire that measures the effects of HF and its treatment on an indi-
vidual’s QoL. The MLHFQ produces a total score ranging from 0 to Efficacy Evaluation
105. Lower scores indicate better QoL.15,16 The efficacy analysis was conducted for the intent-to-treat popula-
tion. The intent-to-treat population consisted of all randomly assigned
6-Minute Walk Distance patients.
Following the same schedule as the MLHFQ survey, 6MWD was Primary End Point
obtained at baseline and 24 months, for objective evaluation of Subjects who were recurrence-free at the end of follow-up were cen-
improvement in functional exercise capacity. It is a widely accepted sored at the analysis time point, and AF-free time was defined as time
test with good reliability in patients with congestive heart failure.17 It from randomization to censor date. Survival curves were constructed
measures the distance that a patient can quickly walk on a flat, hard by using the Kaplan–Meier method, and the primary null hypothesis
surface in a period of 6 minutes.18 was tested using the log-rank test; a 2-sided P value of <0.05 was
considered statistically significant.
Time Course Secondary End Points
The time course for the trial was divided into a treatment period fol- The mortality and unplanned hospitalization rates were summarized
lowed by the trial period. across study groups. Patients requiring at least 1 rehospitalization
The treatment period included the first 3 months postenrollment were counted for this end point; time to first such hospitalization
or postprocedure during which outcome data were not collected, was analyzed by using the survival analysis technique. Death from
repeat ablation could be performed and titration of AMIO dosages any cause within the follow-up period was considered for mortality
could be considered. The trial period started at the end of the treat- analysis and was compared between the groups using the log-rank
ment period and continued for 21 months (the total study duration test. Change in LVEF, 6MWD, and MLHFQ were assessed by using
was 24 months). For patients undergoing repeat ablation, cardiover- analysis of covariance model (SAS GLM procedure) with grouping
sion, or AMIO titration within the first 3 months, the treatment period variable as factor and baseline value as covariate.
started after the repeat procedure or AMIO dosage optimization. All
outcome data were collected during this 21-month trial period. Multivariable Analysis
Multivariable Cox regression model was used for assessing indepen-
Follow-Up dent predictors of AF-free survival and overall survival after adjusting
ECG, echocardiogram, clinical assessment with determination for potential confounders.
of New York Heart Association class, MLHFQ, and 6MWD were Apart from covariates showing significant univariate asso-
obtained at baseline and at 24 months follow-up. Clinic visit at 3 ciation, potential confounders of known or expected clinical rel-
months postprocedure or post-AMIO initiation included echocardio- evance, regardless of their statistical significance at univariate
gram, ECG, and assessment of adverse and serious adverse events. analysis were considered for entering into the multivariable model.
 1640  Circulation  April 26, 2016

Confounders adjusted in the multivariable model included age, At the end of the study, 71 (70%; 95% CI, 60%–78%)
sex, diabetes mellitus, and hypertension. The proportional-hazard patients in group 1 were recurrence free after average 1.4±0.6
assumption was tested by Schoenfeld residual analysis. The hazard
ratio and 95% confidence interval (CI) were computed and pre-
procedures in comparison with 34 (34%; 95% CI, 25%–44%)
sented in the results. in group 2 (log-rank P<0.001). Of the 67 patients having
All tests were 2-sided and a P value <0.05 was considered statisti- recurrence in group 2, treatment failed in 7 (10.4%) after
cally significant. Analyses were performed by using SAS 9.2 (SAS withdrawal of AMIO because of adverse effects (4 had thy-
Institute Inc, Cary, NC). roid toxicity, 2 pulmonary toxicity, and 1 patient developed
liver dysfunction).
Results Because repeat interventions were allowed during the
Patient Characteristics blanking period, and followed up for 24 months after such
In total, 866 patients were screened, 331 were eligible for intervention, these patients accrued a maximum 27 months of
inclusion, and 203 consented and were included in the study follow-up. We performed a sensitivity analysis at the 24-month
and randomly assigned to receive catheter ablation (group cutoff. At this time point, 73 (72%; 95% CI, 62%–79%) in
1, n=102, left atrial diameter 47±4.2 mm, LVEF 29±5%) or group 1 and 37 (37%; 95% CI, 28%–47%) in group 2 were
AMIO (group 2, n=101, left atrial diameter 48±4.9 mm, LVEF arrhythmia free (log-rank P<0.001).
30±8%). Baseline characteristics of the study population are In group 1, higher success was reported in patients under-
presented in Table 1. going PVI and posterior wall isolation in comparison with
In the 102 patients undergoing catheter ablation, PVI was PVI alone (63 [79%; 95% CI, 68%–86%] and 8 [36%; 95%
performed in 22 patients, and PVI plus posterior wall isolation CI, 17%–56%], respectively; P<0.001). Success rate of abla-
was done in 80 patients. The total procedure time and radio- tion in the different centers after a single procedure ranged
frequency time were 168±72 and 66±34 minutes, respectively. from 29% to 61%. No patient was lost to follow-up during the
study period. The Kaplan–Meier curve comparing recurrence
Arrhythmia Recurrence across the study groups is presented in Figure 2.
During the blanking period 52 (51%) in the AMIO group and
3 (3%) in the ablation group underwent cardioversion. After Predictor of Arrhythmia Recurrence
the blanking period, 25 (25%) and 15 (15%) patients had car- We first investigated the association of AF recurrence in an
dioversion in the AMIO and ablation group, respectively. All unadjusted Cox model. In the univariate model, treatment
randomized patients were included in the survival analysis. with AMIO, LVEF, and diabetes mellitus showed significant
association. The results of univariate analysis are presented
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Table 1. Baseline Characteristics of Study Population in Table 2.

After adjusting for covariates in multivariable Cox model,
Group 1 Group 2
(Catheter Ablation, (Amiodarone,
the treatment of patients on AMIO therapy was found to be
n=102) n=101) significantly more likely to fail (hazard ratio, 2.5; 95% CI,
1.5–4.3; P<0.001) in comparison with catheter ablation.
Age, y 62±10 60±11
Besides that, diabetes mellitus showed a statistically signifi-
Male, n (%) 77 (75) 74 (73) cant association with higher recurrence (hazard ratio, 1.1;
AF duration, mo 8.6±3.2 8.4±4.1 95% CI, 1.07–1.26; P=0.01).
BMI, kg/m 2
30±8 29±4
Unplanned Hospitalization and Death
Hypertension, n (%) 46 (45) 48 (48) Over the 2-year follow-up, the unplanned hospitalization rate
Diabetes mellitus, n (%) 22 (22) 24 (24) was substantially lower in group 1 (32 [31%; 95% CI, 20%–
Coronary artery disease, n (%) 63 (62) 66 (65) 41%] and 58 [57%; 95% CI, 51%–69%] in group 2, log-rank
P<0.001), showing 45% relative risk reduction (relative risk,
LA diameter, mm 47±4.2 48±4.9
0.55; 95% CI, 0.39–0.76). The NNT to avoid 1 unplanned
LVEF, % 29±5 30±8 hospitalization was 3.8 patients. In addition, there were sig-
6MWD, meters 348±111 350±130 nificantly fewer deaths (from all causes) in group 1 (8 [8%]
group 1 and 18 [18%] group 2; log-rank P=0.037), with 56%
MLHFQ Score 52±24 50±27
relative risk reduction for mortality in patients receiving cath-
OSA, n (%) 46 (45) 48 (48) eter ablation (relative risk, 0.44; 95% CI, –0.20 to 0.96; NNT
ACEI or ARB, n (%) 94 (92) 89 (88) 10 patients).
Aldosterone antagonists, 46 (45) 51 (50)
n (%) Change in LVEF, 6MWD, and MLHFQ
At baseline, the LVEF, 6MWD, and MLHFQ scores were
β-Blockers, n (%) 78 (76) 81 (80)
not different between the catheter ablation and AMIO groups
Continuous variables are summarized as mean±standard deviation, and (Table 1).
categorical variables are reported as number of cases (n) and percentage.
ACEI indicates angiotensin-converting enzyme inhibitors; AF, atrial fibrillation;
With the exception of the 26 patients who died during
ARB, angiotensin receptor blocker; BMI, body mass index; LVEF, left ventricular the study period, end-of-study measurements were available
ejection fraction; MLHFQ, Minnesota Living with Heart Failure Questionnaire; for all 177 (94 in group 1 and 83 in group 2). In compari-
6MWD, 6-minute walk distance; and OSA, obstructive sleep apnea, son with group 2, better improvement in terms of change in
 Di Biase et al   Amiodarone and AF Ablation in Heart Failure   1641

LVEF (8.1±4 [median, 8.3%] versus 6.2±5.0 [median, 5.0%], survival may reflect the fact that currently available AADs are
P=0.02), 6MWD (22±41 [median, 19 m] versus 10±37 neither highly efficacious nor completely safe. In addition, the
[median, 6 m], P=0.02), and reduction in MLFHQ score results suggested that an effective and safe method to maintain
(11±19 [median, 10] versus 6±17 [median, 5.0]; P=0.04) was sinus rhythm may improve survival. The rationale for a rhythm-
observed in the group 1 population. When stratifying the pop- control approach includes the possibility of fewer symptoms,
ulation by recurrence status, recurrence-free patients (n=91) improved exercise tolerance, lower risk of stroke, superior QoL,
experienced significantly better improvement in all param- and better survival, if sinus rhythm can be maintained.11,12
eters than those who experienced recurrence (n=86; Table 3). In patients with HF and AF, the available AADs to maintain
sinus rhythm recommended by the international guidelines are
Procedural Complications limited to AMIO and dofetilide. These drugs are associated
In group 1, 2 (1.96%) patients had groin hematoma, and 1 with significant adverse side effects and drug interaction that
patient (0.98%) had pericardial effusion that was conserva- often lead to drug discontinuation.19–24 The long-term use of
tively managed with fresh-frozen plasma and protamine. AMIO is associated with significant pulmonary, hepatic, and
thyroid toxicity, in addition to severe bradycardia.24 Dofetilide
Discussion requires hospitalization for careful monitoring because of
severe QT-interval prolongation and torsades de pointes in up
Main Findings to 3% of patients, and its use is limited in patients with renal
This is the first multicenter randomized study showing that in dysfunction, which is a common finding in HF patients.22
patients with HF and persistent AF, catheter ablation is supe- AF ablation might represent the ideal therapy that restores
rior to AMIO in achieving freedom from AF at the long-term sinus rhythm without the adverse effects of AADs. Successful
follow-up. Importantly, ablation improved QoL and exercise AF ablation results in significant improvements of left ventric-
capacity and reduced unplanned hospitalization and overall ular function, exercise tolerance, symptoms, and QoL4 irre-
mortality. These findings are clinically relevant, especially spective of the level of preprocedural rate control, suggesting
in light of the socioeconomic advantages that arise from the that factors other than rate control (eg, loss of atrial contrac-
reduced rehospitalization and mortality in HF patients. tion, atrioventricular dyssynchrony) drive the deterioration of
HF and AF are the most common cardiac conditions in cardiac function.
Western countries and often coexist. Pharmacological rate AF ablation has shown superior outcome achieving free-
versus rhythm control is a controversial topic in the literature dom from AF in comparison with AADs in several random-
for the treatment of AF especially in light of the main results ized controlled trials that enrolled paroxysmal AF patients
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of the Atrial Fibrillation Follow-up Investigation of Rhythm with a normal heart. The success rate in patients who have
Management (AFFIRM) and Rate Control versus Electrical persistent and long-standing persistent AF is variable in the
Cardioversion (RACE) trials.11,12 literature. The variation in procedural outcome depends on
A subanalysis of the AFFIRM trial, however, clearly show- different factors such as age, sex, AF types, structural heart
ing the association of sinus rhythm but not AADs with improved disease, ablation technique, and operator experience.25–29

Figure 2. Kaplan–Meier curve comparing AF-free survival between patients undergoing catheter ablation (group 1) and those receiving
amiodarone therapy (group 2). At end of the study, 71 (70%; 95% CI, 60%–78%) patients in group 1 were recurrence free in comparison with
34 (34%; 95% CI, 25%–44%) in group 2 (log-rank P<0.001). AF indicates atrial fibrillation; AT, atrial tachycardia; and CI, confidence interval.
 1642  Circulation  April 26, 2016

Table 2. Variables Showing Univariate Association With AF higher success rate than their patients who underwent PVI with
Recurrence: Results From Cox Model a roof line and ablation of complex fractionated atrial electro-
95% Confidence grams. Recently published randomized trials have demonstrated
Variables Hazard Ratio Intervals P Value suboptimal outcomes and no added advantage when linear
lesions are performed in conjunction with PVI.34,35 Other factors
Amiodarone 3.00 (1.96–4.61) <0.0001
treatment
responsible for the higher success rate in our study population
could be the operator experience and the improved mapping and
Sex 1.14 (0.92–1.41) 0.22
ablation technology in recent years that resulted in better PV
Age, y 0.99 (0.98–1.019) 0.94 encirclement. The results from this early study also contrast with
BMI 0.99 (0.94–1.03) 0.59 more recent findings from the Catheter Ablation Versus Medical
Rate Control for Atrial Fibrillation in Patients With Heart
LVEF, % 0.96 (0.93–0.99) 0.01
Failure (ARC-HF) and Catheter Ablation Versus Medical
Hypertension 1.12 (0.93–1.36) 0.24 Treatment of Atrial Fibrillation in Heart Failure (CAMTAF)
Left atrial size 1.02 (0.99–1.05) 0.18 trials, which both showed significant improvement in exercise
Diabetes 2.22 (1.31–3.75) 0.003
capacity and QoL with AF ablation in comparison with phar-
mellitus macological rate control.14,36
AF indicates atrial fibrillation; BMI, body mass index; and LVEF, left ventricular
The CAMTAF trial also showed a significant improve-
ejection fraction. ment of LVEF after 6 months of follow-up with AF ablation in
comparison with pharmacological rate control (+8.1 [95% CI,
Overall, a higher recurrence rate has been shown in HF 3.0–13.1] versus –3 [95% CI, –7.7 to 0.5]; P<0.001).36
patients,3–6 and this might explain why AF ablation is not Similarly, the ARC-HF trial reported a trend toward a higher
widely used as a rhythm control strategy in this subset of the LVEF improvement with AF ablation (mean difference, +5.6%
patient population. (95% CI, −0.1 to +11.3; P=0.055) after 12 months of follow-up.14
In agreement with these reports, we observed substantial Our trial shows that, after an average of 1.4 procedures, a
improvement in 6MWD, LVEF, and MLHFQ scores in recur- clinically relevant freedom from AF can be achieved in these
rence-free patients. The pathophysiology underlying HF and AF patients. Of interest is the finding that, when sorting the results
resulting in compromised stroke volume is the likely basis of by ablation technique, a poor success was observed in patients
altered exercise tolerance.15–18,30 Thus, the significant improve- who underwent PV ablation alone in comparison with patients
ment in 6MWD could reflect betterment in cardiac contractility undergoing a more extensive ablation approach.
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and rhythm resulting in restoration of a more efficient cardiac The coexistence of AF and HF increases the risk of
contraction following successful ablation. Our results further cor- unplanned hospitalization and significantly impacts health-
roborated the correlation between ablation success and improve- care costs.37 Therefore, the reduction of unplanned hospi-
ment in QoL. This observation can be attributed to reinstatement talization and mortality are relevant potential benefits of the
of stable sinus rhythm, lesser burden of symptoms, and reduc- ablation strategy.
tion in the use of health care resources and better well-being.31–33
Results from a randomized trial conducted by MacDonald et al7 Study Limitation
comparing ablation versus rate-control medications in patients We acknowledge certain limitations in our trial. (1) Although
with persistent AF and LVEF <35% reported no significant dif- no formal comparison with a rate control strategy was per-
ferences between groups in terms of improvement in ejection formed in this study, we would like to emphasize that AMIO
fraction measured by magnetic resonance (MR), exercise toler- is also considered in the guidelines as a rate control drug. In
ance, or QoL. However, it is difficult to compare our findings addition, 76% of the ablation group and 80% of the AMIO
with their results for several reasons: (1) different study design: group received β-blockers at the tolerated dosage. (2) The 2
ablation versus rhythm control medication in our trial and abla- other alternative AADs available for these patients, sotalol and
tion versus rate-control measures in their study: (2) small sample dofetilide, were not tested in this trial, because dofetilide is
size (n=41); and (3) different ablation approach: majority (78%) not available in countries other than the United States and the
of our patients received PVI and posterior wall isolation plus patients were already on different β-blockers that they could
ablation of complex fractionated atrial electrograms and non-PV tolerate. Moreover, AMIO is the most effective antiarrhythmic
triggers as needed, which was the most likely reason behind the drug; therefore, these results could be extended to dofetilide

Table 3. Change in LVEF, 6MWD, and MLHFQ Score by Recurrence Status

No Recurrence (n=91) Recurrence (n=86)
P (Comparing Change
Baseline Change (Median) Baseline Change (Median) Between Groups)
LVEF, % 28.8±10 9.6±7.4 (9.4) 30.2±9 4.2±6.2 (4.0) <0.001
6MWD, meters 347±113 27±38 (24) 352±128 8±42 (2) <0.001
MLHFQ 53±24 –14±18 (–12) 49±26 –2.9±15 (–2.2) <0.001
Data are summarized as mean±standard deviation. LVEF indicates left ventricular ejection fraction; MLHFQ, Minnesota Living with Heart
Failure Questionnaire; and 6MWD, 6-minute walk distance.
 Di Biase et al   Amiodarone and AF Ablation in Heart Failure   1643

and sotalol. (3) Finally, our patients were followed up for 24 OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B,
Waldo AL; Atrial Fibrillation and Congestive Heart Failure Investigators.
months. Although a longer follow-up would be desirable, the
Rhythm control versus rate control for atrial fibrillation and heart failure.
follow-up duration in our study was longer than many other N Engl J Med. 2008;358:2667–2677. doi: 10.1056/NEJMoa0708789.
studies in the field of ablation. In addition, all patients had an 11. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron
implanted device, and success/failure was obtained by device EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD; Atrial
Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
interrogation. Investigators. A comparison of rate control and rhythm control in patients
with atrial fibrillation. N Engl J Med. 2002;347:1825–1833. doi: 10.1056/
Conclusion NEJMoa021328.
This multicenter randomized study shows that catheter abla- 12. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma
T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ; Rate
tion of AF is superior to AMIO in achieving freedom from Control versus Electrical Cardioversion for Persistent Atrial Fibrillation
AF at long-term follow-up and reducing unplanned hospital- Study Group. A comparison of rate control and rhythm control in patients
ization and mortality in patients with HF and persistent AF. with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347:1834–
1840. doi: 10.1056/NEJMoa021375.
The potential socioeconomic repercussion of these results will 13. Khan MN, Jaïs P, Cummings J, Di Biase L, Sanders P, Martin DO,
require further investigation. Kautzner J, Hao S, Themistoclakis S, Fanelli R, Potenza D, Massaro
R, Wazni O, Schweikert R, Saliba W, Wang P, Al-Ahmad A, Beheiry S,
Santarelli P, Starling RC, Dello Russo A, Pelargonio G, Brachmann J,
Disclosures Schibgilla V, Bonso A, Casella M, Raviele A, Haïssaguerre M, Natale A;
Dr Di Biase is a consultant for Biosense Webster, Stereotaxis and PABA-CHF Investigators. Pulmonary-vein isolation for atrial fibrillation
St Jude Medical. Dr Di Biase received speaker honoraria/travel in patients with heart failure. N Engl J Med. 2008;359:1778–1785. doi:
from Medtronic, EPiEP, Janssen, Pfizer, Bristol Meyers, Boston 10.1056/NEJMoa0708234.
Scientific, and Biotronik. Dr Natale received speaker honoraria from 14. Jones DG, Haldar SK, Hussain W, Sharma R, Francis DP, Rahman-Haley
Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik, SL, McDonagh TA, Underwood SR, Markides V, Wong T. A random-
and Medtronic. Dr Natale is a consultant for Biosense Webster, St ized trial to assess catheter ablation versus rate control in the manage-
Jude Medical, and Janssen. Dr Burkhardt is a consultant for Biosense ment of persistent atrial fibrillation in heart failure. J Am Coll Cardiol.
Webster and Stereotaxis. The other authors report no conflicts. 2013;61:1894–1903. doi: 10.1016/j.jacc.2013.01.069.
15. Supino PG, Borer JS, Franciosa JA, Preibisz JJ, Hochreiter C, Isom
OW, Krieger KH, Girardi LN, Bouraad D, Forur L. Acceptability and
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CLINICAL PERSPECTIVE
Heart failure and atrial fibrillation are common cardiac conditions that often coexist. This is the first randomized study to
show that, in patients with heart failure and persistent atrial fibrillation, catheter ablation is superior to amiodarone (the
most used drug in these patients) in achieving freedom from atrial fibrillation at long-term follow-up. Importantly, ablation
reduced rehospitalization and overall mortality and improved quality of life and exercise capacity. This study suggests that
clinicians should consider catheter ablation sooner in this patient population.

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