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JACC: CLINICAL ELECTROPHYSIOLOGY
VOL. 2, NO. 2, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
ISSN 2405-500X/$36.00
http://dx.doi.org/10.1016/j.jacep.2015.11.001
Rhythm Control Versus Rate Control
and Clinical Outcomes in Patients
With Atrial Fibrillation
Results From the ORBIT-AF Registry
Amit Noheria, MBBS, SM,a Peter Shrader, MA,b Jonathan P. Piccini, MD, MHS,b Gregg C. Fonarow, MD,c
Peter R. Kowey, MD,d Kenneth W. Mahaffey, MD,e Gerald Naccarelli, MD,f Peter A. Noseworthy, MD,g
James A. Reiffel, MD,h Benjamin A. Steinberg, MD, MHS,b Laine E. Thomas, PHD, MPH,b Eric D. Peterson, MD, MPH,b
Bernard J. Gersh, MBCHB, DPHIL,g on behalf of the ORBIT-AF Investigators and Patients
ABSTRACT
OBJECTIVES The study sought to evaluate clinical outcomes in clinical practice with rhythm control versus rate control
strategy for management of atrial fibrillation (AF).
BACKGROUND Randomized trials have not demonstrated significant differences in stroke, heart failure, or mortality
between rhythm and rate control strategies. The comparative outcomes in contemporary clinical practice are not well
described.
METHODS Patients managed with a rhythm control strategy targeting maintenance of sinus rhythm were retrospectively compared with a strategy of rate control alone in a AF registry across various U.S. practice settings. Unadjusted and
adjusted (inverse-propensity weighted) outcomes were estimated.
RESULTS The overall study population (N ¼ 6,988) had a median of 74 (65 to 81) years of age, 56% were males, 77% had
first detected or paroxysmal AF, and 68% had CHADS2 score $2. In unadjusted analyses, rhythm control was associated with
lower all-cause death, cardiovascular death, first stroke/non–central nervous system systemic embolization/transient ischemic
attack, or first major bleeding event (all p < 0.05); no difference in new onset heart failure (p ¼ 0.28); and more frequent
cardiovascular hospitalizations (p ¼ 0.0006). There was no difference in the incidence of pacemaker, defibrillator, or cardiac
resynchronization device implantations (p ¼ 0.99). In adjusted analyses, there were no statistical differences in clinical
outcomes between rhythm control and rate control treated patients (all p > 0.05); however, rhythm control was associated
with more cardiovascular hospitalizations (hazard ratio: 1.24; 95% confidence interval: 1.10 to 1.39; p ¼ 0.0003).
CONCLUSIONS Among patients with AF, rhythm control was not superior to rate control strategy for outcomes of
stroke, heart failure, or mortality, but was associated with more cardiovascular hospitalizations.
(J Am Coll Cardiol EP 2016;2:221–9) © 2016 by the American College of Cardiology Foundation.
From the aCardiovascular Division, Washington University, St. Louis, Missouri; bDuke Clinical Research Unit, Durham, North
Carolina; cDepartment of Medicine, University of California Los Angeles, Los Angeles, California; dLankenau Medical Center and
Jefferson Medical College, Wynnewood, Pennsylvania; eStanford Center for Clinical Research, Department of Medicine, Stanford
University, Palo Alto, California; fPenn State Heart and Vascular Institute, Hershey, Pennsylvania; gDivision of Cardiovascular
Listen to this manuscript’s
Diseases, Mayo Clinic, Rochester, Minnesota; and the hDivision of Cardiology, Columbia University, New York, New York. The
audio summary by JACC:
ORBIT-AF registry is sponsored by Janssen Scientific Affairs, LLC, Raritan, New Jersey. Dr. Piccini has received grants for clinical
Clinical Electrophysiology
research from ARCA Biopharma, Boston Scientific, Johnson & Johnson, Gilead, St. Jude Medical, and ResMed; and has served as a
Editor-in-Chief
Dr. David J. Wilber.
consultant to Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr. Fonarow has
served as a consultant to Janssen (modest) and Medtronic (significant). Dr. Kowey is a consultant for Johnson & Johnson. Dr.
Mahaffey has received research grants from Amgen, Daiichi-Sankyo, Johnson & Johnson, Medtronic, St. Jude, and Tenax; has
received consultant fees from the American College of Cardiology, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb,
Cubist, Eli Lilly, Elsevier, Epson, Forest, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Mt. Sinai, Myokardia, Orthera,
Portola, Purdue Pharma, Spring Publishing, The Medicines Company, Vindico, and WebMD; and has equity in BioPrint Fitness. Dr.
Naccarelli has served on the steering committee for Janssen, Biotechnology Inc., and Otsuka; as a consultant to Janssen,
GlaxoSmithKline, Pfizer, Daiichi-Sankyo, Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi, AstraZeneca, and Otsuka; and on the
222
Noheria et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 2, NO. 2, 2016
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Rhythm Versus Rate Control for AF
M
any patients with atrial fibrilla-
electrophysiologists. The ORBIT-AF registry enrolled
tion (AF) warrant maintenance
patients from a nationally representative sample of
of sinus rhythm to control symp-
176 U.S. practices between June 29, 2010 and August
toms and improve the quality of life (1–3).
9, 2011. The rationale and design of the registry have
Randomized clinical trials including the
been previously described (14). In brief, patients were
AFFIRM (Atrial Fibrillation Follow-up Inves-
eligible if they were $18 years of age with electro-
HR = hazard ratio
tigation of Rhythm Management) (4), RACE
cardiographic (ECG) evidence of AF and were able to
TIA = transient ischemic attack
(Rate Control Versus Electrical Cardioversion
provide informed consent and follow-up. Exclusion
for Persistent Atrial Fibrillation Study) (5), and the
criteria included <6 months of life expectancy or AF
AF-CHF (Atrial Fibrillation and Congestive Heart Fail-
due to a reversible cause such as pulmonary embo-
ure) trials (6) failed to demonstrate that rhythm con-
lism. Data were collected by inputting data from the
trol improved cardiovascular outcomes or mortality
clinical chart into a web-based case report form and
relative to rate control (7). Further, rhythm control
included data on age, sex, race/ethnicity, insurance
was associated with higher hospitalizations (4–6).
status, education level, cardiovascular risk factors,
ABBREVIATIONS
AND ACRONYMS
AF = atrial fibrillation
CI = confidence interval
CNS = central nervous system
However, post hoc nonrandomized analysis of the
date of diagnosis, type of AF (first detected, parox-
AFFIRM trial suggested that patients who success-
ysmal or persistent), pharmacologic treatment strat-
fully maintained sinus rhythm had lower mortality
egy (rhythm control vs. rate control), AF ablation
than those who failed to maintain sinus rhythm (8).
history, cardioversion history, vital signs, laboratory
findings,
It is unclear if adverse effects of antiarrhythmic
data,
drug therapy mitigated benefits of maintaining sinus
esophageal
rhythm, or if sinus rhythm was just a correlate of
rombotic
other confounding predictors of survival not captured
normalized ratios), concomitant medications, insur-
in the analysis.
ance status and provider information, comorbidities,
SEE PAGE 230
Contemporary observational data on hospitalized
patients with AF suggest that rhythm control may
have a marginal mortality benefit over rate control
during long-term follow-up (9). Overall, in the U.S.
clinical practice, one-third of AF patients are on a
rhythm control strategy (10). Both international and
ECG
transthoracic
echocardiographic
therapy
and
and
findings,
monitoring
transantith-
(international
and outcomes. Follow-up data were collected every
6 months and follow-up duration was 24 to 36
months.
The
Duke
Institutional
Review
Board
approved the ORBIT-AF registry, and all participating
sites
have
obtained
institutional
review
board
approval pursuant to local requirements. All subjects
provided written, informed consent.
U.S. data suggest that there are significant differences
STUDY POPULATION. For the purpose of this anal-
in the population of patients selected for rhythm
ysis, the cohort included patients with first detected/
control versus rate control (10–13). Results from the
new onset, or paroxysmal, or persistent AF, who had
aforementioned trials have presumably impacted
at least 1 follow-up. Patients were classified based on
clinical practice and approach towards use of antiar-
the AF treatment strategy selected for management
rhythmic drugs, and we sought to evaluate the
by the treating physician, rhythm control versus rate
contemporary clinical practice of rhythm control
control, captured through the mutually exclusive
versus rate control. We utilized data from the ORBIT-
check box in the case-report form. The goal of
AF (Outcomes Registry for Better Informed Treatment
rhythm control is to attempt maintenance of sinus
of Atrial Fibrillation) registry to evaluate comparative
rhythm using any therapeutic plan that could
outcomes for rhythm control versus rate control in a
include cardioversions, antiarrhythmic drugs, and/or
broad practice-based cohort of patients with AF.
atrial ablation. From the ORBIT-AF registry population of 10,135, patients were excluded if information
METHODS
on treatment strategy was missing (n ¼ 24, 0.002%),
they had permanent AF (n ¼ 2,827, 27.9%), or if they
The ORBIT-AF registry is a registry of U.S. patients
did not have any follow-up (n ¼ 296, 2.9%)
with AF who are treated by internists, cardiologists or
(Figure 1).
adjudications committee for GlaxoSmithKline. Dr. Steinberg has served as a consultant to Bristol-Myers Squibb. Dr. Peterson has
served as a consultant for Janssen, AstraZeneca, Bayer, Merck, and Boehringer Ingelheim. All other authors have reported that
they have no relationships relevant to the contents of this paper to disclose.
Manuscript received April 23, 2015; revised manuscript received September 25, 2015, accepted November 5, 2015.
Noheria et al.
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Rhythm Versus Rate Control for AF
STUDY OUTCOMES. We assessed the following out-
comes at follow-up: 1) all-cause death; 2) cardiovascular death; 3) first cardiovascular hospitalization;
F I G U R E 1 Flow Diagram Showing Exclusions and the Treatment Strategy Assignments
for the Study Population
4) cardiovascular hospitalization or death; 5) first
stroke, non–central nervous system (CNS) systemic
embolism, or transient ischemic attack (TIA); 6) the
composite of death, stroke, non-CNS embolism, and
TIA; 7) new onset heart failure; and 8) first major
bleeding (15).
STATISTICAL ANALYSES. Statistical analyses were
performed using SAS software (version 9.3, SAS
Institute, Cary, North Carolina), and 2-tailed p value
of 0.05 was considered the significance threshold for
all statistical tests. Baseline characteristics are presented as percentages for categorical variables, and
median (interquartile range) for continuous variables,
stratified by AF management strategy. Characteristics
are compared using chi-square tests for categorical
variables and the Wilcoxon rank sum test for continuous variables. The association of AF management
strategy with outcomes of interest was assessed using
Cox proportional hazards models with a robust
sandwich covariance estimate in order to account for
the covariance within participating sites. First,
unadjusted models were used to analyze the associations
of
AF
management
strategy
with
AF ¼ atrial fibrillation; ORBIT-AF ¼ Outcomes Registry for Better Informed Treatment of
Atrial Fibrillation.
each
outcome. Second, the model predicting each outcome
was adjusted for the propensity to receive either
ventricular systolic function were assessed as poten-
treatment by inverse propensity weighting. The pro-
tial effect modifiers. For these analyses, interaction
pensity score predicting AF management strategy was
terms are added to the propensity model. The inverse
derived using logistic regressions using imputed data.
propensity weighted model was repeated once for
The propensity score was adjusted for all indepen-
each potential modifier. An interaction term for the
dent predictors of AF management strategy identified
modifier and AF management strategy was added into
in our prior publication describing the clinical prac-
the models. Any significant interaction (p # 0.05) was
tice of rhythm versus rate control (10) and all addi-
followed up with additional models stratified by the
tional
backward
effect modifier. In order to avoid any bias associated
selection, as associated with any of the outcomes of
independent
predictors
using
with prior failed rhythm control therapy, we per-
interest for this paper (p < 0.05 required to stay in
formed sensitivity analyses excluding any rate con-
model). Continuous covariates in the propensity
trol patients with a prior history of antiarrhythmic
model were checked for linearity (no nonlinear re-
drug therapy (n ¼ 1,385).
lationships were detected). All subjects with a propensity below the 1 percentile were excluded from
RESULTS
the adjusted models. The hazard ratio (HR) of rhythm
control subjects relative to rate control subjects is
BASELINE
reported for all models, along with the corresponding
tients with first detected/new onset or recurrent
CHARACTERISTICS. Among
95% confidence interval (CI) and p value.
paroxysmal AF, 2,858 (40.9%) were treated with
6,988 pa-
Incidence rates per 100-subject years are presented
rhythm control and 4,130 (59.1%) with a rate control
for incident cardioversions, implanted devices, and
strategy. The baseline characteristics of the cohort
interventional therapy for AF. The HR and p value from
according to treatment strategy are shown in Table 1.
unadjusted Cox proportional hazards models with
Patients in the rhythm control group were younger
a robust sandwich covariance estimate are presented.
than the rate control group (71 [63 to 79] years vs. 75 [67
Age, AF type (first detected/new onset vs. recur-
to 82] years) and had a marginal but statistically lower
rent paroxysmal versus recurrent persistent), and left
prevalence of hypertension, diabetes, chronic kidney
223
224
Noheria et al.
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Rhythm Versus Rate Control for AF
T A B L E 1 Baseline Characteristics by AF Management Strategy
Level
Overall
(N ¼ 6,988)
Rhythm Control
(n ¼ 2,858)
Rate Control
(n ¼ 4,130)
p Value*
74 (65–81)
71 (63–79)
75 (67–82)
<0.0001
90.13
91.99
88.84
<0.0001
Demographics
Age, yrs†
Race
Sex
White
Black or African American
4.78
4.13
5.23
Hispanic
3.56
2.38
4.38
Other
1.37
1.29
1.43
Male
56.27
56.86
55.86
0.4082
Nonsmoker
52.99
51.64
53.92
0.1764
Recent or former smoker
41.17
42.30
40.39
Medical history
Smoking
Current smoker
5.82
6.02
5.69
Hyperlipidemia
Yes
71.29
70.71
71.69
0.3728
Hypertension
Yes
81.84
79.29
83.61
<0.0001
Diabetes
Yes
28.32
26.14
29.83
0.0008
Chronic kidney disease
(MDRD criteria)
Yes
33.16
31.53
34.29
0.0069
Peripheral vascular disease
Yes
12.32
11.13
13.15
0.0115
History of stroke/transient
ischemic attack
Yes
14.18
13.09
14.94
0.0290
History of coronary artery
disease
Yes
35.22
33.48
36.42
0.0117
Significant valvular disease
Yes
22.34
20.12
23.87
0.0002
Obstructive sleep apnea
Yes
18.30
19.80
17.26
0.0069
Chronic obstructive
pulmonary disease
Yes
15.33
14.35
16.00
0.0584
Liver disease
Yes
1.77
1.96
1.65
0.3300
Anemia
Yes
17.07
15.64
18.06
0.0081
Cancer
Yes
22.50
21.20
23.39
0.0314
Cognitive
impairment/dementia
Yes
2.80
2.10
3.29
0.0030
Frailty
Yes
5.18
3.25
6.51
<0.0001
Overall
25.89
23.90
27.26
0.0016
Pacemaker
17.57
15.50
19.01
0.0002
Implanted
cardioverter-defibrillator
4.67
4.93
4.48
0.3745
Cardiac resynchronization
therapy-pacemaker
0.69
0.56
0.77
0.2853
Cardiac resynchronization
therapy-defibrillator
3.35
3.32
3.37
0.9264
<0.0001
Implanted device
Implanted device
Congestive heart failure
Etiology of cardiomyopathy
Functional status
Ischemic
11.95
9.94
13.34
Nonischemic
17.26
16.13
18.04
No congestive heart failure
70.62
73.83
68.40
NYHA functional class I
9.89
8.64
10.75
NYHA functional class II
13.01
12.00
13.70
NYHA functional class III/IV
6.33
5.39
6.97
Yes
5.78
6.23
5.47
0.1831
0.0150
Heart failure hospitalizations
in past year
Left ventricular ejection
fraction type†
<0.0001
Missing
10.02
8.71
10.92
Normal ($50%)
72.05
74.53
70.34
Mild dysfunction
(>40% to <50%)
5.37
4.72
5.81
Moderate dysfunction
($30% to 40%)
8.51
7.91
8.93
Severe dysfunction (<30%)
4.05
4.13
4.00
Continued on the next page
Noheria et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 2, NO. 2, 2016
APRIL 2016:221–9
Rhythm Versus Rate Control for AF
T A B L E 1 Continued
Level
Overall
(N ¼ 6,988)
Rhythm Control
(n ¼ 2,858)
Rate Control
(n ¼ 4,130)
p Value*
29.09 (25.35–33.98)
29.53 (25.75–34.51)
28.78 (25.08–33.74)
<0.0001
70 (62–78)
68 (60–76)
71 (64–80)
<0.0001
6.24
5.56
6.71
<0.0001
70.46
76.42
66.34
Vital signs and AF status
Body mass index, kg/m2†
Heart rate, beats/min†
Type of AF
First detected/new onset
Paroxysmal atrial fibrillation
European Heart Rhythm
Association Score
Persistent atrial fibrillation
23.30
18.02
26.95
No symptoms
34.89
30.16
38.16
Mild (normal daily
activity not affected)
46.41
47.97
45.33
Severe (normal daily
activity affected)
16.23
18.82
14.43
2.19
2.69
1.84
Disabling (normal daily
activity discontinued)
<0.0001
Catheter ablation of AF
Yes
6.67
10.29
4.16
<0.0001
Oral anticoagulant therapy
(warfarin or dabigatran)
Yes
72.21
68.37
74.87
<0.0001
<0.0001
CHADS2 risk score†
0
7.68
9.90
6.15
1
23.88
27.50
21.38
$2
68.43
62.60
72.47
0–3
81.37
83.45
79.93
4
6.01
6.02
6.00
5 or more
12.62
10.53
14.07
ATRIA score
<0.0001
Values are median (interquartile range) or percent unless otherwise indicated. All tests treat the column variable as nominal. *The p values do not correspond to the table
exactly as it is presented here. More appropriately, p values were calculated by comparing only nonmissing row values; p values are based on Pearson chi-square tests for all
categorical row variables. †The p values are based on chi-square rank based group means score statistics for all continuous/ordinal row variables. This is equivalent to
Wilcoxon tests. Bolded values reflect 2-tailed p < 0.05.
AF ¼ atrial fibrillation; MDRD ¼ Modification of Diet in Renal Disease formula; NYHA ¼ New York Heart Association.
disease, vascular disease, valvular heart disease,
new onset congestive heart failure (p ¼ 0.28). Rhythm
anemia, cancer, dementia, and frailty. CHA 2DS2-VASc
control was however associated with a higher rate
risk score was #1 among 8.4% patients in the rhythm
of a first cardiovascular hospitalization (p ¼ 0.0006)
control group versus 14.4% patients on rate control
(Table 2). In the adjusted analyses, there were no sta-
(p < 0.0001). The rhythm control group was less likely
tistical differences in clinical outcomes between the
to have an implanted pacemaker and less likely to have
2 groups, except for a higher risk of a first cardiovas-
a diagnosis of cardiomyopathy (ischemic or non-
cular hospitalization (HR: 1.24; 95% CI: 1.10 to 1.39;
ischemic). Furthermore, the rhythm control group had
p ¼ 0.0003) with rhythm control. The adjusted relative
a higher proportion of paroxysmal AF, higher Euro-
hazard of the composite endpoint of death, stroke,
pean Heart Rhythm Association symptom class, were
non-CNS embolism, and TIA was 0.90 (95% CI: 0.77 to
more likely to have had prior catheter ablation of AF,
1.06; p ¼ 0.20) (Table 2).
but less likely to be on oral anticoagulation therapy
As shown in Table 3, the rhythm control strategy
(Table 1). Among the rhythm control group, 23.6% of
was associated with a higher rate of pharmacologic
patients were on amiodarone and 49% were on other
and electrical cardioversions, transesophageal echo-
antiarrhythmic drugs.
cardiography, and catheter ablation of AF (all
CARDIOVASCULAR OUTCOMES. The median (inter-
quartile range) follow-up was 2.3 (1.8 to 2.9) years.
The proportional hazards assumption was statis-
p < 0.0001). The 2 groups had similar rates of
pacemaker, cardiac resynchronization therapy or
implantable cardioverter-defibrillator insertion.
tically tested and satisfied. In unadjusted analyses,
SENSITIVITY ANALYSES. There was no evidence of
the rhythm control patients as compared to the
modification of the association between AF manage-
rate
death
ment strategy and the adjusted clinical outcomes by
(p < 0.0001), lower cardiovascular death (p ¼ 0.015),
control
group
had
lower
all-cause
age or left ventricular systolic function. However,
fewer first stroke/non-CNS systemic embolization/
there was evidence of an interaction between AF type
TIA (p ¼ 0.028), and fewer first major bleeding events
(first detected/new onset vs. recurrent paroxysmal
(p ¼ 0.0039). There was no statistical difference in
versus recurrent persistent AF) and AF management
225
Noheria et al.
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Rhythm Versus Rate Control for AF
T A B L E 2 Incidence of Outcomes by AF Management Strategy and Associations Between AF Management Strategy and Outcomes
(N ¼ 6,988)
Rhythm Control
Outcome
All-cause death
Events
Rate†
247
3.81
Rate Control
Events
515
Rate†
Unadjusted Results
Adjusted Results*
HR‡ (95% CI)
p Value
HR‡ (95% CI)
5.79
0.65 (0.55–0.77)
<0.0001
0.87 (0.72–1.04)
0.1161
p Value
0.7947
CV death
101
1.56
197
2.23
0.69 (0.52–0.93)
0.0149
0.96 (0.69–1.32)
First CV hospitalization
992
19.41
1,175
15.92
1.22 (1.09–1.37)
0.0006
1.24 (1.10–1.39)
0.0003
CV hospitalization or death
1,121
21.93
1,477
20.01
1.10 (0.99–1.21)
0.0664
1.16 (1.05–1.29)
0.0032
First stroke, non-CNS embolism, or TIA
Composite of death, stroke,
non-CNS embolism, and TIA
New-onset congestive heart failure§
First major bleeding event
73
1.14
135
1.54
0.73 (0.56–0.97)
0.0282
0.87 (0.66–1.16)
0.3452
308
4.80
602
6.86
0.69 (0.60–0.80)
<0.0001
0.90 (0.77–1.06)
0.2032
54
1.13
84
1.38
0.83 (0.59–1.17)
0.2796
0.92 (0.63–1.34)
0.6742
185
2.94
323
3.77
0.78 (0.66–0.92)
0.0039
0.91 (0.76–1.08)
0.2699
*Adjusted results are from inverse propensity weighted models. †Incidence rate presents the number of events per 100 subject-years follow-up. ‡Hazard ratio (HR) is for
rhythm control relative to rate control. §Congestive heart failure at baseline is excluded. Bolded values reflect 2-tailed p < 0.05.
AF ¼ atrial fibrillation; CI ¼ confidence interval; CNS ¼ central nervous system; CV ¼ cardiovascular; MDRD ¼ Modification of Diet in Renal Disease formula; TIA ¼ transient
ischemic attack.
strategy with respect to first cardiovascular hospital-
with inclusion of baseline oral anticoagulation status
ization (p ¼ 0.012), with a trend toward a higher
as an additional covariate for the propensity scores
adjusted risk of cardiovascular hospitalizations with
used in the adjusted models.
rhythm control strategy in patients with recurrent
persistent AF (HR: 1.49; 95% CI: 1.20 to 1.84) versus
DISCUSSION
recurrent paroxysmal AF (HR: 1.17; 95% CI: 1.03 to
In this analysis of AF management in contemporary
1.34) (Table 4).
All of our results remained qualitatively similar
clinical practice, we did not find an independent
when we excluded all rate control patients with a
difference in mortality, heart failure, or systemic
prior history of antiarrhythmic drug therapy. Simi-
embolic events with rhythm or rate control strategies.
larly, there was no appreciable change in the results
However, we did observe a higher rate of cardiovascular hospitalization in those treated with rhythm
T A B L E 3 Incidence Rate of Interventions During Follow-Up Period by AF Management
Strategy (N ¼ 6,988)
control. These observational findings from community practices largely reflect the findings from older
randomized controlled comparisons of rhythm and
Rhythm
Control
Outcome
Rate
Control
rate control therapies.
COMMUNITY PERSPECTIVE ON MANAGEMENT OF AF. A
Events
Rate*
Events
Rate*
HR† (95% CI)
p Value
98
1.55
60
0.68
2.29 (1.56–3.37)
<0.0001
ferences in mortality over initial 4 years of follow-up
DC cardioversion
427
7.33
263
3.11
2.37 (1.96–2.86)
<0.0001
for newly diagnosed AF among hospitalized patients
TEE
139
2.21
97
1.11
2.01 (1.48–2.73)
<0.0001
114
1.80
153
1.77
1.03 (0.80–1.33)
0.8025
ICD
37
0.57
48
0.54
1.06 (0.67–1.70)
0.7921
BiV (CRT-P)
15
0.23
19
0.21
1.09 (0.59–2.02)
0.7881
based on drug prescriptions within 1 week of hospital
Quebec population database study showed no dif-
Cardioversion
Pharmacologic
Implanted device
Pacemaker
initially prescribed rhythm control versus rate control
drugs (9). This analysis was limited to $66-year-old
hospitalized patients with AF, implied rhythm control
41
0.64
59
0.67
0.96 (0.61–1.50)
0.8612
discharge, and was affected by changes in treatment
198
3.19
274
3.22
1.00 (0.81–1.23)
0.9916
practice during follow-up due to publication of the
246
4.03
105
1.20
3.37 (2.60–4.36)
<0.0001
Atrial flutter ablation
52
0.81
37
0.42
1.98 (1.25–3.13)
0.0035
Surgical Maze/hybrid Maze
33
0.51
20
0.23
2.30 (1.32–3.99)
0.0032
AV node/HIS bundle ablation
44
0.68
34
0.38
1.80 (1.11–2.92)
0.0173
BiV-ICD (CRT-D)
Overall
Interventional therapy
Catheter ablation of AF
AFFIRM trial (4). In contrast, our analysis has a wider
applicability to the larger population of AF patients
managed outside the hospital, and directly assesses
the intended strategy of rhythm versus rate control
for management of AF. Another registry from 532
*Incidence rate presents the number of events per 100 subject-years follow-up. †Hazard ratio (HR) and p value
are from Cox proportional hazards model with robust sandwich covariance estimate. Bolded values reflect 2tailed p < 0.05.
sites in 21 countries in Europe, America, and Asia, the
AF ¼ atrial fibrillation; AV ¼ atrioventricular; BiV ¼ biventricular pacemaker; CI ¼ confidence interval; CRT ¼
cardiac resynchronization therapy; D ¼ defibrillator; DC ¼ direct current; ICD ¼ implantable cardioverterdefibrillator; P ¼ pacemaker; TEE ¼ transesophageal echocardiogram.
Assessing the Control of Atrial Fibrillation) registry,
RECORDAF (Registry on Cardiac Rhythm Disorders
followed 3,076 patients on rhythm control and 2,528
patients on rate control (11). The therapeutic target of
Noheria et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 2, NO. 2, 2016
APRIL 2016:221–9
Rhythm Versus Rate Control for AF
T A B L E 4 Adjusted Association Between First Cardiovascular Hospitalization and AF Management Strategy, Stratified by AF Type
First Cardiovascular Hospitalization
Subgroup
Rhythm Control
Rhythm Control
Rate Control
Rate Control
Events
Rate*
Events
Rate*
Adjusted HR*
(95% CI)
p Value
17.71
88
20.60
0.81 (0.54–1.21)
0.2964
First detected/new onset AF
47
Recurrent paroxysmal AF
745
18.72
816
16.55
1.17 (1.03–1.34)
0.0164
Recurrent persistent AF
200
23.07
271
13.40
1.49 (1.20–1.84)
0.0003
*Hazard ratio of rhythm control relative to rate control. Results are from inverse propensity weighted models. The p value for interaction between atrial fibrillation (AF) type
and AF management strategy for outcome of first cardiovascular hospitalization, 0.012. Bolded values reflect 2-tailed p < 0.05.
CI ¼ confidence interval; HR ¼ hazard ratio.
the respective strategies in suppressing atrial fibril-
observe a difference in the new diagnosis of heart
lation or controlling heart rate was much more likely
failure between the rhythm control and rate control
with rhythm control. RECORDAF had fewer incident
groups. This finding, however, does not preclude a
cardiovascular events during a shorter 1-year follow-
role for rhythm control in patients presenting with
up, and unsurprisingly the AF management strategy
congestive heart failure presumed secondary to pre-
did not independently predict occurrence of adverse
viously undiagnosed AF.
clinical events pooled together. Interestingly, the
RECORDAF registry had a majority of patients on
ANTIARRHYTHMIC DRUGS AND CONGESTIVE HEART
rhythm control strategy (54.9%), in contrast to our
FAILURE. We did not observe any increase in new-
ORBIT-AF registry with a smaller proportion on
onset congestive heart failure with rhythm control
rhythm control (40.9%).
strategy. In the RECORDAF registry the rate of hospitalizations for heart failure was lower with rhythm
ROLE FOR A RHYTHM CONTROL STRATEGY. Rando-
control strategy, presumably on account of better
mized clinical trials on AF have shown no influence on
controlled heart rates (11). Regardless, antiarrhythmic
survival, stroke or heart failure with rhythm control
drugs should be used in patients with structural heart
using antiarrhythmic drugs and/or cardioversions for
disease with caution due to risk of ventricular
paroxysmal or persistent AF (4–7). Antiarrhythmic
proarrhythmia. In the AF-CHF trial of AF patients
drugs can have cardiovascular adverse effects and
with left ventricular ejection fraction #35%, there
these trials should have impacted the approach to us-
was no evidence of increased mortality with rhythm
ing them to minimize unfavorable outcomes. Howev-
control (6). Notably, 82% of patients received amio-
er, after adjusting for confounders, our results support
darone as the antiarrhythmic drug, and literature
the applicability of prior clinical trials and guideline
supports no increased mortality with amiodarone in
recommendations in contemporary practice (1). Cur-
AF patients (16).
rent guidelines do not routinely recommend a rhythm
control strategy for reducing the risk of mortality,
RHYTHM
stroke or heart failure (1). Rhythm control, however,
HOSPITALIZATIONS. There were 24% independently
CONTROL
AND
CARDIOVASCULAR
may lead to improvements in quality of life, and in
higher first cardiovascular hospitalizations in the
physical/metal disability scores (1–3); and current
rhythm control group compared to rate control. The
guidelines state that rhythm control should be
increase in hospitalizations among rhythm control
considered for alleviating symptoms due to AF (1).
patients was more marked for those with persistent
Although rhythm control was not statistically
AF. It is unclear if the cause for excess hospitaliza-
superior to rate control strategy in our registry, we
tions was for initiating/switching antiarrhythmic
observed trends towards improvements in all out-
drugs with in-hospital heart rhythm monitoring or
comes except cardiovascular hospitalizations. In
need
particular, there was a trend toward reduction in
related to increase in cardiovascular adverse events.
overall mortality as well as reduction in composite of
Our results are consistent with the RECORDAF regis-
death, stroke, non-CNS embolism, and TIA. Although
try, where there were higher elective hospitalizations
we cannot exclude the influence of chance or
with rhythm control strategy, though there was no
unmeasured confounding, these trends may suggest a
increase in hospitalizations due to adverse cardio-
role for rhythm control strategy in specific subgroups
vascular events, and in fact a lower risk of heart
of patients that need to be identified. We did not
failure hospitalizations (11).
for
cardioversions/ablation
procedures,
or
227
228
Noheria et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 2, NO. 2, 2016
APRIL 2016:221–9
Rhythm Versus Rate Control for AF
ROLE OF LEFT ATRIAL ABLATION. Catheter-based
CONCLUSIONS
or surgical left atrial ablation has emerged as
an alternative to antiarrhythmic drug therapy for
This community-based evaluation of rhythm control
maintenance of sinus rhythm, potentially with higher
versus rate control strategy for management of AF
efficacy and few long-term complications (1,17,18).
supports and reaffirms the evidence garnered from
Only a minority (13.1%) of our rhythm control patients
randomized clinical trials. Rhythm control is not
had undergone catheter or surgical ablation of AF and
associated with reduction in cardiovascular death,
most (72.6%) received antiarrhythmic drug therapy.
thromboembolism, new-onset heart failure, major
Therefore, this analysis largely is a comparison of
bleeding, or all-cause mortality relative to rate con-
antiarrhythmic drugs to rate control drugs. Thus,
trol.
even though rhythm control was not independently
cardiovascular hospitalizations, possibly related to
associated with improved survival, reduction of
elective
embolic events, or heart failure, these conclusions
rhythmic drug regimen or procedures (e.g., cardio-
cannot be applied to an ablative approach to maintain
version, catheter ablation). Therefore, these findings
sinus rhythm. Catheter ablation improves AF symp-
support current guideline recommendations that
toms and quality of life and may result in reduced risk
the primary indication for rhythm control therapy is
of thromboembolism (2,3,19–22). Several ongoing
for the reduction of symptoms and improvement
large clinical trials will assess the impact of ablation
in quality of life.
Rhythm
control
patients
hospitalizations
for
experience
changes
in
more
antiar-
on cardiovascular outcomes and mortality, including
the
CABANA
(Catheter
Ablation
versus
Antiar-
rhythmic Drug Therapy for Atrial Fibrillation Trial)
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Bernard J. Gersh, Mayo Clinic, 200 First Street
trial (NCT00911508) comparing AF ablation with
Southwest, Rochester, Minnesota 55905. E-mail:
antiarrhythmic drugs, and the EAST (Early Treatment
[email protected]
of Atrial Fibrillation for Stroke Prevention Trial) trial
comparing a graduated rhythm control strategy with
drugs followed by AF ablation with standard rate
PERSPECTIVES
control based management (NCT01288352).
STUDY LIMITATIONS. The ORBIT-AF registry is a
voluntary, observational study and susceptible to
inherent limitations of such methods including
residual confounding and confounding by unmeasured variables. The treatment assignment was not
randomized and is quite likely influenced by baseline
confounding factors that can be accounted for only
partially. Even though the ORBIT-AF trial was
designed to include a wide spectrum of AF patients
across different practice setting, selection bias may
exist. While the cohort is a contemporary population,
nonpharmacologic methods of rhythm control, which
may provide superior outcomes compared with antiarrhythmic drugs, remained a relatively small percentage of rhythm control therapies. ORBIT-AF is
an observational registry, and choice of therapeutic
treatment and drug selection may or may not have
COMPETENCY IN MEDICAL KNOWLEDGE: Physicians can educate their patients that there is no benefit in
terms of incident stroke, heart failure, and death with a
rhythm control strategy with antiarrhythmic drugs when
compared to rate control for AF. Notwithstanding the
circumstances of hospital admission, elective or otherwise, rhythm control with antiarrhythmic drugs entails a
higher rate of hospitalizations.
TRANSLATIONAL OUTLOOK: The findings from
analysis of this prospectively maintained contemporary AF registry are consistent with results from prior
randomized trials comparing rhythm control with rate
control. Whether catheter ablation of atrial fibrillation
instead of use of antiarrhythmic drugs impacts hard
clinical outcomes is being evaluated with ongoing
large multicenter randomized clinical trials.
been consistent with the recommended guidelines.
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KEY WORDS antiarrhythmic drugs, atrial
fibrillation, rate control, rhythm control
229

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