Clinical Therapeutics/Volume 37, Number 10, 2015

Review Article

Should -Blockers Be Used in Patients With Heart Failure

and Atrial Fibrillation?
Yura Mareev, MD, PhD; and John G.F. Cleland, MD, PhD, FRCP, FESC, FACC
National Heart & Lung Institute, Harefield Hospital, Imperial College, London, United Kingdom
ABSTRACT
Purpose: There is overwhelming evidence that
-blockers reduce cardiovascular hospitalizations and
mortality in patients with heart failure and a reduced
left ventricular ejection fraction provide they are in
sinus rhythm. However, a recent meta-analysis of
individual patient data provides compelling evidence
that -blockers are not effective in patients with heart
failure and atrial brillation, although neither did they
increase risk. The purpose of this article is to review
the evidence, seek possible explanations for this
observation, and make recommendations based on
the limited evidence available.
Methods: Review and critical analysis of recent
publications and meta-analyses on the use of -blockers
and other heart rateslowing medicines in heart failure.
Findings: The reasons for the lack of effect of
-blockers in patients with heart failure are uncertain.
There is a substantial body of evidence to suggest that
patients with heart failure and atrial brillation who have
less stringent ventricular rate control have a better
outcome. The most plausible explanation for these
ndings, in our view, is that -blockers exert similar
benets through similar mechanisms regardless of intrinsic heart rhythm but that the benets of -blockers are
neutralized in patients with atrial brillation due to the
induction of pauses that may impair cardiac function
leading to worsening heart failure or cause arrhythmias
resulting in death.
Implications: Smaller doses of -blockers and other
rate lowering agents to achieve a resting clinic heart

Accepted for publication August 19, 2015.

http://dx.doi.org/10.1016/j.clinthera.2015.08.017
0149-2918/$ - see front matter
& 2015 Elsevier HS Journals, Inc. All rights reserved.

October 2015

rate in the range of 75-89beats/min might improve

outcome. Preventing pauses by pacing or pulmonary
vein ablation of atrial brillation are strategies that
should be researched. (Clin Ther. 2015;37:2215
2224) & 2015 Elsevier HS Journals, Inc. All rights
reserved.
Key words: heart failure, atrial brillation, rate
control, prognosis, beta-blockers.

INTRODUCTION
Heart failure and atrial brillation (AF) have common
origins and one often provokes the other.1 In possibly
half or more of patients with heart failure, clinically
overt, persistent, or permanent AF will develop during
the course of their disease,24 and as many as one half
of patients with AF have heart failure.5 The prevalence
of AF varies with and may contribute to the severity of
heart failure, from
10% of those with mild to as many
as 50% of those with severe symptoms. Many more
patients will have paroxysmal AF that may or may not
be clinically apparent.6 The prevalence of AF is similar
or greater in patients with heart failure with a preserved
ejection fraction (HFpEF) compared to heart failure with
a reduced ejection fraction (HFrEF).79

b-Blockers in Heart Failure: Effective in Sinus

Rhythm But Not in AF
A series of substantial randomized, controlled trials
(RCTs) demonstrated that -blockers could reduce the
rate of hospitalization for heart failure as well as

Scan the QR Code with your phone to obtain

FREE ACCESS to the articles featured in the
Clinical Therapeutics topical updates or text
GS2C65 to 64842. To scan QR Codes your
phone must have a QR Code reader installed.

2215

Clinical Therapeutics

Atrial fibrillation

Sinus rhythm
-blocker group
Placebo group

100

Survivors (%)

90
80
70
60
HR 0.73 (95% Cl 0.670.80); p<0.001

HR 0.97 (95% Cl 0.831.14); p=0.73

50
0
Number at risk
-blocker group 7123
Placebo group 6819

5014
4604

2
Time (years)
1798
1530

722
561

1521
1542

997
1020

2
Time (years)
331
346

113
115

Figure 1. All-cause mortality in patients with sinus rhythm and atrial fibrillation in an individual patient data
meta-analysis of landmark randomized, placebo-controlled trials of -blockers in heart failure.
HR hazard ratio. Reproduced with permission.10

cardiovascular and all-cause mortality in patients with

HFrEF.10 Only 1 contemporary trial enrolled a
substantial number of patients with HFpEF, with
equivocal results in this group of patients.11
Recently, an individual patient meta-analysis including all the landmark RCTs of HFrEF conrmed the
benets of -blockers for patients with HFrEF in sinus
rhythm but suggested that for patients with AF,
-blockers did not reduce the rate of hospitalization
for heart failure or mortality10 (Figure 1). It is possible
that this is a chance nding,12 but it is exceedingly
likely that there is a strong association between
heart rhythm and the clinical benets of -blockers.
However, it should be pointed out that -blockers did
not increase risk in patients with AF. Interestingly, an
analysis of the Study of the Effects of Nebivolol
Intervention on Outcomes and Rehospitalisation in
Seniors with Heart Failure trial suggested that the
benets of nebivolol were also conned to patients in
sinus rhythm, even in those with a left ventricular
ejection fraction 435%.13 Thus, heart rhythm rather
than left ventricular ejection fraction may be the key
determinant of the benets of -blockers in patients with
heart failure. For patients in sinus rhythm, the reduction
in mortality, hospitalization for heart failure, and their
composite was
30% (P o 0.001), an effect that might
have been even larger had follow-up been censored for
patients who developed AF, which presumably would

2216

have led to a loss of further benet from -blockers,

although because the incidence of AF in these studies was
only 5%, this effect would not be large. Information on
the persistence and duration of AF before enrollment was
not available, and assessment at a single point in time
might not be robust.10 However, such inaccuracies in
data acquisition only serve to dilute observed effects.
Although -blockers do reduce the risk of the development of AF,14 the annual incidence remains
5%.15

Why Do b-Blockers Not Improve Outcomes

in AF?
Understanding why -blockers do not improve
outcome in patients with heart failure and AF is
hampered by uncertainty about the mechanism by
which -blockers mediate their benets. -Blockers
block adrenergic receptors in a variety of tissues,
including cardiovascular, brain, and adiposetissue.
Some -blockers are selective for particular receptors,
and others have partial agonist activity. Changes in
1- and 1-receptor regulation and intracellular signaling
and activating antibodies may be important and specic
mechanisms for the effect of -blockers.16 However,
-blockers also have nonspecic effects, including slowing heart rate, leading to reductions in myocardial
oxygen demand and the propensity to ischemia. This
may divert adenosine triphosphate from consumption in
the actin-myosin cycle to other important cellular

Volume 37 Number 10

October 2015

Table I. Reports investigating the relationship between heart rate and prognosis in patients with heart failure and atrial fibrillation.
Study

No. of Patients

PRIME II26

77

CHARM7

1148 from an RCT of

ARBs

Groups

HR: median, 72 beats/min; On multivariate analysis, a lower

range, 5780
HR was associated with
vs
increased all-cause mortality
HR: median, 90 beats/
P 0.002
min; range, 81163
T1: HR, 64 (6068)
T2: HR, 76 (7280)
T3: HR, 90 (86100)
T1: HR, 64 (6068)
T2: HR, 76 (7280)
T3: HR, 90 (86100)

Hull LifeLab20

488 referred to
outpatient clinic

Results (Hazard Ratio and 95% CI)

At follow-up
Q1: o 62 beats/min
Q2: 6272 beats/min
Q3: 7382 beats/min
Q4: 482 beats/min

LVEF: 23 8%

Study included patients with

HFrEF and HFpEF.
After adjustment for other
variables, these
differences were no longer
signicant. Unadjusted
results may be of greater
relevance to clinical
practice.

(Hazard ratio: 0.94; 95% CI:

LVEF o50%
0.881.00, P 0.07)
Relationship between
Q1: Referent
ventricular rate and
Q2: 1.01 (95% CI: 0.691.47), P 0.97
prognosis studied at time
Q3: 0.94 (95% CI: 0.641.38), P 0.75
of rst clinic referral
Q4: 0.68 (95% CI: 0.45-1.03), P 0.07
(baseline) and again after
Q1: Referent
1 year of treatment
Q2: 0.99 (95% CI: 0.561.72), P 0.96
Q3: 0.71 (95% CI: 0.391.27), P 0.24
Q4: 1.07 (95% CI: 0.601.90), P 0.82

2217

(continued)

Y. Mareev and J.G.F. Cleland

Increase in resting rate

of 10 beats/min
From baseline
Q1: o69 beats/min
Q2: 6981 beats/min
Q3: 8298 beats/min
Q4: 498 beats/min

All-cause mortality
T1: 1.00
T2: 1.13 (0.891.43)
T3: 0.89 (0.691.15)
WHFH or CV death
T1: 1.00
T2: 0.96 (0.781.19)
T3: 0.79 (0.630.99)

Comments

Study

No. of Patients

Groups

Results (Hazard Ratio and 95% CI)

Comments

287 in an RCT of rate Strict (o80 beats/min at

RACE II
Primary outcome (cardiovascular morbidity HFrEF and HFpEF
control
rest and o110 beats/min
subanalysis of
and mortality) was 15.0% in the lenient
on exercise) vs lenient
HF28
group and 18.2% in the strict group
(o110 beats/min at rest)
(P 0.53)
rate control
20,197 hospitalized
HR o75 beats/min
If LVEF 440%, HR Z75 beats/min was
HFrEF and HFpEF
GWTG-HF63
with new or
associated with higher all-cause mortality Investigated association
HR Z75 beats/min
worsening HF
(hazard ratio: 1.080; 95% CI: 1.0351.126
between discharge HR
per 10 beats/min increase; P 0. 0004)
and 12-month all-cause
mortality. Note that heart
If LVEF r40%, HR Z75 beats/min was not
rate at discharge may
associated with mortality (HR: 1.005, 95%
poorly reect heart rate
CI: 0.9531.059 per 10-beats/min increase)
during subsequent followbut was associated with a reduced risk of
up. Heart rate after
the composite of WHFH or CV death
titration of medications
(hazard ratio: 0.950; 95% CI: 0.9100.991
may be a better indicator
per 10-beats/min increase; P 0.0183)
of outcome.
ARBs angiotensin II receptor blockers; CHARM Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity Program; GWTG-HF Get
With the Guidelines Heart Failure Program; HF heart failure; HR heart rate; HFpEF heart failure with preserved ejection fraction; HFrEF heart failure with
reduce ejection fraction; LVEF left ventricular ejection fraction; PRIME II Second Prospective Randomised Study of Ibopamine on Mortality and Efcacy; Q
quartile; RACE II Comparison between Lenient versus Strict Rate Control II study; RCT randomized, controlled study; T = tertile; WHFH or CV death hospital
stay for worsening heart failure or cardiovascular death.

Clinical Therapeutics

2218

Table I. (continued).

Volume 37 Number 10

Y. Mareev and J.G.F. Cleland

October 2015

in AF. Clearly, -blockers will reduce ventricular rate

whether the patient is in sinus rhythm or AF, but the
relationship between ventricular rate and prognosis
appears to differ depending on rhythm.7,20 In the
Second Prospective Randomised Study of Ibopamine
on Mortality and Efcacy study (Table I),26 patients in
AF with a ventricular rate 480 beats/min (median, 90
beats/min) had a better prognosis than those with a

1.0

1.Heart Rate <69

2.Heart Rate 6981
3.Heart Rate 8298
4.Heart Rate >98

Cumulative Survival

0.8

0.6

0.4

0.2

1.
2.
3.
4.

0.0
0

Referent
HR=1.01 (95% Cl 0.69-1.47), p=0.97
HR=0.94 (95% Cl 0.64-1.38), p=0.75
HR=0.68 (95% Cl 0.45-1.03), p=0.07

730

1460
2190
Time (days)

2920

3650

1.Heart Rate <62 bpm

2.Heart Rate 6272 bpm
3.Heart Rate 7382 bpm
4.Heart Rate >82 bpm

1.0

0.8
Cumulative Survival

functions that improve calcium handling, increase ryanodine channel stability, and reduce apoptosis. Improved
cell and whole-organ function may reduce supraventricular and ventricular arrhythmias. How much these
effects depend on heart rate reduction, which could be
achieved by other means, and how much on adrenergic
receptor blockade independent of heart rate reduction
are uncertain. A study of -blockers in patients with
HFrEF who had pacemakers suggested that the improvement in cardiac function with -blockers was lost when
the pacing rate was increased from 60 to 80 beats/min
(Table).17
In sinus rhythm, heart rate is strongly associated
with survival, although evidence that the relationship
is causal is not yet conclusive; it might just be a
marker of disease severity or medication adherence.18
A conventional meta-analysis suggests19 that the
magnitude of heart rate reduction, but not -blocker
dose, is associated with survival benet; the individual
patient data meta-analysis is currently working on this
issue. The relationship between heart rate and outcome is supported by other observational studies20
and post hoc analyses of large clinical trials of
angiotensin II receptor blockers for both HFpEF and
HFrEF.7,21 Ivabradine, a sinus node inhibitor, exerts
clinical benets somewhat similar to those of
-blockers and could be an alternative for patients in
sinus rhythm but with fewer side effects. Ivabradine is
effective when used in addition to a -blocker when
the patient is in sinus rhythm and has a heart rate
470 beats/min.22,23 It also appears to be effective in
the absence of a -blocker, possibly with a similar
magnitude of effect on mortality. It is not thought to
be effective in patients with AF. However, there is
much less experience with ivabradine than with
-blockers, and, in contrast to -blockers, its use is
associated with an increase in AF,24 it does not
control ventricular rate when AF occurs, and it may
provide less protection from ventricular arrhythmias.
On the other hand, digoxin, another medication that
slows ventricular rate, does not reduce mortality in
patients with heart failure in sinus rhythm and exerts
only a modest effect on hospitalization for heart
failure.25
If adrenergic receptor blockade, independent of
heart rate, is the key mechanism of action of
-blockers, then it should not matter what rhythm
the patient is in. If ventricular rate is the key
mechanism, then it might explain the lack of benet

0.6

0.4

0.2

0.0

1.
2.
3.
4.

Referent
HR=0.99 (95% Cl 0.56-1.72), p=0.96
HR=0.71 (95% Cl 0.39-1.27), p=0.24
HR=1.07 (95% Cl 0.60-1.90), p=0.82

730

1460
2190
Time (days)

2920

Figure 2. Multivariable adjusted survival curves

by heart rate quartiles for patients
with heart failure and atrial fibrillation
before (A) and after (B) intensification
of therapy for heart failure including
-blockers. HR hazard ratio. Reproduced with permission.19

2219

Clinical Therapeutics
lower ventricular rate (median, 72 beats/min). In the
Candesartan in Heart Failure: Assessment of
Reduction in Mortality and Morbidity study,
patients with AF and a ventricular rate of
90
beats/min had a lower risk of the composite
outcome (cardiovascular death or hospital stay for
the management of worsening heart failure) than
patients with lower rates, although the effect was no
longer signicant in a multivariable analysis. A large
observational study also showed that patients with AF
and ventricular rates o73 beats/min tended to have a
worse survival20 (Figure 2). In the Comparison
Between Lenient Versus Strict Rate Control II
study,27 patients with AF, approximately half of
whom also had HFrEF or HFpEF, were randomly
assigned to lenient (o110 beats/min) or strict (o80
beats/min) resting ventricular rate control.28 The
mean ventricular rate at rest in those randomized to
lenient control was
85 beats/min during long-term
follow-up.28 No difference in outcome was observed.
Why should the relationship between ventricular rate
and prognosis differ depending on rhythm? Perhaps
sinus rhythm is necessary for -blockers to be effective.
Part of the benet of -blockers might be mediated
through autonomic effects on the sinus node.29,30
Perhaps atrial activity is an important mediator of
-blocker effect.31 Alternatively, -blockers might exert
both benet and harm to varying degrees depending on
heart rhythm. The overall effect of a treatment depends
on the good that it delivers exceeding the harm that it
does, leading to a net benet. All effective medicines are
ultimately poisons when used at the wrong dose or for
the wrong reason or in the wrong patient. For patients
with HFrEF in sinus rhythm, the benet clearly outweighs the harm for many patients, but for those with
AF, harm and benet may be evenly balanced. This is
important because if the harm can be taken away, the
net benet of -blockers would reappear.

Effects of b-Blockers on Ventricular Rate Control

In major trials of -blockers, patients with AF had a

ventricular rate of
85 beats/min at baseline,32 and
so it can be anticipated that the ventricular rate during
follow-up would be 15 to 20 beats/min slower,33 and
that for many patients, the resting daytime clinic
ventricular rate was reduced to o60 beats/min. The
nocturnal ventricular rate would likely be slower34
still, with frequent pauses. The presence of AF could
also conceal atrioventricular conduction disease that

2220

could be exacerbated by -blockers, further

prolonging pauses. In the Cardiac Arrhythmias and
Risk Stratication After Acute Myocardial Infarction
trial, in patients with a reduced left ventricular
ejection fraction subsequent to a myocardial
infarction, pauses proved to be a better predictor of
an adverse prognosis than nonsustained ventricular
tachycardia (VT),35 and patients who had episodes of
AF were more likely to have pauses.36 A similar
number of deaths (8 each) due to bradycardia and
VT were reported, but how many cases of VT were
preceded or precipitated by pauses has not been
reported.37 Cardiac standstill will be lethal, but it is
rare not to have an escape rhythm. Pause-dependent VT
is probably a more common event. Studies of patients
with implantable cardioverter debrillators show that
those with AF are more prone to irregular ventricular
beats that can trigger ventricular arrhythmias.38 It could
be that arrhythmias are innocent bystanders when death
is actually caused by other factors such as congestive
heart failure, myocardial infarction, stroke, pulmonary
embolism, aortic dissection, or respiratory arrest.39,40
However, the effectiveness of implantable cardioverter
debrillators, which offer protection from both bradyand tachyarrhythmias, in preventing sudden death,41
suggests that arrhythmias are a common cause of
sudden death, although it should not be assumed that
this is predominantly by treating tachyarrhythmias!

Do b-Blockers in AF Provoke High-Risk

Bradyarrhythmias?
The importance of pauses as precipitants of death in
AF could be addressed by preventing them. What
interventions could be considered? Studies of bucindolol4244 and xamoterol,45 1 partial agonists (ie, agents
that act as -blockers during periods of high sympathetic
activity but as -agonists when sympathetic activity is
low) suggest that these agents reduce heart rate during
activity and pauses when the patient is at rest or asleep.
Whether these agents are benecial in patients with heart
failure and AF is uncertain, but they appear harmful or
less effective than other agents for patients in sinus
rhythm. An alternative is to implant a pacemaker to
prevent pauses. However, conventional right ventricular
pacing has the potential to exacerbate ventricular
dyssynchrony, resulting in worse outcomes.46 Studies
of atrioventricular node ablation comparing subsequent
right ventricular with biventricular pacing suggest that
the latter strategy is superior47,48 but do not provide

Volume 37 Number 10

Y. Mareev and J.G.F. Cleland

evidence that biventricular pacing is superior to pharmacological management alone.49
Another approach is to consider avoiding agents
that could increase the number or severity of pauses in
AF. Digoxin increases parasympathomimetic tone that
increases nocturnal pauses,34 which may account for
the increase in mortality50,51 and sudden death25 in
some, although not all,5254 reports. However, the
individual patient data meta-analysis did not show an
interaction between -blockers and digoxin in the
prognosis of patients with AF and heart failure.10
Exacerbation of pauses might also be responsible for
the increase in mortality observed in patients with
amiodarone55 and with dronedarone56 in patients
with more advanced heart failure.

Should Sinus Rhythm Be Restored to Regain the

Benefits of Sinus Rhythm?
The onset of AF is certainly associated with an
adverse outcome, although whether this association is
causal remains unclear. Should sinus rhythm be
restored to regain the benets of -blockade? No
study has adequately researched this question,15
although the best available data suggest not.57 One
small study (61 patients) showed that restoration of
sinus rhythm improves cardiac function and quality of
life,58 but a much larger study (1300 patients) failed to
conrm this,59 although this may have been because
of the inclusion of patients with paroxysmal AF, many
of whom remained in sinus rhythm in the rate control
group throughout the study. You cannot x things
that are not broken. Amiodarone has been the
principal antiarrhythmic agent used to try and
restore and maintain sinus rhythm.60 However, in
patients with more advanced heart failure,
amiodarone may increase mortality, especially since
the widespread introduction of -blockers55; this
might again be because it exacerbates pauses. More
recently, pulmonary vein ablation has been applied in
an attempt to restore and maintain sinus rhythm. The
Ablation vs Amiodarone for Treatment of Atrial
Fibrillation in Patients with Congestive Heart Failure
and an Implanted ICD/CRT-D (AATAC-AF) trial
(203 patients) showed that patients randomly
assigned to AF ablation had better outcomes than
those assigned to amiodarone.61 More substantial
evidence that this approach is safe and effective in
improving symptoms and reducing morbidity and
mortality is awaited.62

October 2015

SUMMARY
There is no evidence that -blockers improve prognosis
in patients with heart failure and AF. The ideal range for
resting ventricular rate in patients with heart failure and
AF is uncertain but is probably between 70 and 89 beats/
min, but this requires further exploration. However,
there is no net harm to prescribing a -blocker for a
patient with AF; they might be prescribed for concomitant problems such as angina and hypertension, and
there is no reason to withdraw these agents in patients
who are doing well on them. There is no evidence that
digoxin should be preferred over -blockers for rate
control, and, currently, there is insufcient evidence to
recommend implantation of a pacing device to prevent
pauses in the absence of a conventional indication for
pacing, cardiac resynchronization therapy, or an implantable cardioverter-debrillator.
That is the evidenceand now for an opinion. It is
likely that -blockers are benecial in patients who
have both HFrEF and AF but that excessive rate
control, which is associated with an increase in
pauses, carries a risk. Use of smaller doses of
-blockers to avoid decreasing the resting ventricular
rate to o75 beats/min might avoid this harm.

ACKNOWLEDGMENTS
Both authors contributed to the writing and revision
of the article. Dr. Mareev was supported by a research
grant from the Heart Failure Association. Dr. Cleland
works with the National Institute of Health Research
(UK) as a Senior Investigator.

CONFLICTS OF INTEREST
Dr. Cleland has received support in the form of grants
and honoraria from Servia, Amgen, GlaxoSmithKline,
Ltd., and Biosense-Webster. The authors have indicated that they have no other conict of interest
regarding the content of this article.

REFERENCES
1. Khand AU, Rankin AC, Kaye GC, Cleland JG. Systematic
review of the management of atrial brillation in patients
with heart failure. Eur Heart J. 2000;21:614632.
2. Guha K, McDonagh T. Heart failure epidemiology: European perspective. Curr Cardiol Rev. 2013;9:123127.
3. Anter E, Jessup M, Callans DJ. Atrial brillation and heart
failure: Treatment considerations for a dual epidemic.
Circulation. 2009;119:25162525.

2221

Clinical Therapeutics
4. Khand AU, Cleland JGF, Deedwania PC. Prevention of and medical
therapy for atrial arrhythmias in
heart failure. Heart Fail Rev.
2002;7:267283.
5. Cleland JGF, Shelton R, Nikitin N,
et al. Prevalence of markers of
heart failure in patients with atrial
brillation and the effects of ximelagatran compared to warfarin on
the incidence of morbid and fatal
events: a report from the SPORTIF
III and V trials. Eur J Heart Fail.
2007;9:730739.
6. Cleland JGF, Swedberg K, Follath
F, et al. The EuroHeart Failure
survey programme a survey on
the quality of care among patients
with heart failure in Europe. Part
1: patient characteristics and diagnosis. Eur Heart J. 2003;24:442
463.
7. Castagno D, Skali H, Takeuchi M,
et al. Association of heart rate
and outcomes in a broad spectrum of patients with chronic
heart failure: Results from the
CHARM (Candesartan in Heart
Failure: Assessment of Reduction
in Mortality and morbidity) program. J Am Coll Cardiol. 2012;59:
17851795.
8. Lip GY, Laroche C, Popescu MI,
Rasmussen LH, Vitali-Serdoz Dan
GA, Kalarus Z, Crijns HJ, Oliveira
MM, Tavazzi L, Maggioni AP,
Boriani G. Heart failure in patients
with atrial brillation in Europe:
a report from the EURObservational
Research Programme Pilot survey on
Atrial Fibrillation. Eur J Heart Fail.
2015;17:570582.
9. Lenzen MJ, Scholte op Reimer
WJM, Boersma E, et al. Differences
between patients with a preserved
and a depressed left ventricular
function: a report from the EuroHeart Failure Survey. Eur Heart J.
2004;25:12141220.
10. Kotecha D, Holmes J, Krum H, et al.
Efcacy of blockers in patients
with heart failure plus atrial brillation: an individual-patient data

2222

11.

12.

13.

14.

15.

16.

17.

18.

meta-analysis. Lancet. 2014;384:

22352243.
van Veldhuisen DJ, Cohen-Solal A,
Bhm M, et al. Beta-Blockade
With Nebivolol in Elderly Heart
Failure Patients With Impaired
and Preserved Left Ventricular Ejection Fraction. Data From SENIORS
(Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With
Heart Failure). J Am Coll Cardiol.
2009;53:21502158.
McMurray JJV, van Veldhuisen DJ.
Blockers, Atrial Fibrillation, and
Heart Failure. Lancet. 2014;384:
21812183.
Mulder BA, van Veldhuisen DJ,
Crijns HJGM, et al. Effect of nebivolol on outcome in elderly
patients with heart failure and
atrial brillation: insights from SENIORS. Eur J Heart Fail. 2012;14:
11711178.
Nasr IA, Bouzamondo A, Hulot
J-S, et al. Prevention of atrial
brillation onset by beta-blocker
treatment in heart failure: a metaanalysis. Eur Heart J. 2007;28:
457462.
Swedberg K, Olsson LG, Charlesworth A, et al. Prognostic relevance of atrial brillation in
patients with chronic heart failure
on long-term treatment with betablockers: Results from COMET.
Eur Heart J. 2005;26:13031308.
Gong H, Sun H, Koch WJ, et al.
Specic beta(2)AR blocker ICI
118,551 actively decreases contraction through a G(i)-coupled form
of the beta(2)AR in myocytes from
failing human heart. Circulation.
2002;105:24972503.
Thackray SDR, Ghosh JM, Wright
GA, et al. The effect of altering
heart rate on ventricular function
in patients with heart failure
treated with beta-blockers. Am
Heart J. 2006;152:713.e913.
Bhm M, Swedberg K, Komajda
M, et al. Heart rate as a risk factor
in chronic heart failure (SHIFT):

19.

20.

21.

22.

23.

24.

25.

26.

The association between heart rate

and outcomes in a randomised
placebo-controlled trial. Lancet.
2010;376:886894.
McAlister FA, Wiebe N, Ezekowitz
JA, et al. Meta-analysis: betablocker dose, heart rate reduction,
and death in patients with heart
failure. Ann Intern Med. 2009;
150:784794.
Cullington D, Goode KM, Zhang J,
et al. Is heart rate important for
patients with heart failure in atrial
brillation? JACC Heart Fail.
2014;2:213220.
Bhm M, Perez A-C, Jhund PS,
et al. Relationship between heart
rate and mortality and morbidity
in the irbesartan patients with
heart failure and preserved systolic
function trial (I-Preserve). Eur J
Heart Fail. 2014;16:778787.
Swedberg K, Komajda M, Bhm
M, et al. Ivabradine and outcomes
in chronic heart failure (SHIFT): A
randomised
placebo-controlled
study. Lancet. 2010;376:875885.
Borer JS, Bhm M, Ford I, et al.
Effect of ivabradine on recurrent
hospitalization
for
worsening
heart failure in patients with
chronic systolic heart failure: the
SHIFT Study. Eur Heart J. 2012;33:
28132820.
Martin RIR, Pogoryelova O, Koref
MS, et al. Atrial brillation associated
with ivabradine treatment: metaanalysis of randomised controlled
trials. Heart. 2014;100:15061510.
The Digitalis Investigation Group,
The effect of digoxin on mortality
and morbidity in patients with
heart failure. N Engl J Med.
1997;336:525533.
Rienstra M, Van Gelder IC, Van
Den Berg MP, et al. A comparison
of low versus high heart rate in
patients with atrial brillation and advanced chronic
heart failure: Effects on clinical
prole, neurohormones and survival. Int J Cardiol. 2006;109:
95100.

Volume 37 Number 10

Y. Mareev and J.G.F. Cleland

27. Van Gelder IC, Groenveld HF,
Crijns HJGM, et al. Lenient versus
strict rate control in patients with
atrial brillation. N Engl J Med.
2010;362:13631373.
28. Mulder BA, Van Veldhuisen DJ,
Crijns HJGM, et al. Lenient vs.
strict rate control in patientswith
atrial brillation and heart failure:
A post-hoc analysis of the RACE 2
study. Eur J Heart Fail. 2013;15:
13111318.
29. Clark DM, Plumb VJ, Epstein AE,
Kay GN. Hemodynamic effects of
an irregular sequence of ventricular cycle lengths during atrial
brillation. J Am Coll Cardiol. 1997;
30:10391045.
30. Gosselink ATM, Blanksma PK,
Crijns HJGM, et al. Left ventricular
beat-to-beat performance in atrial
brillation: Contribution of FrankStarling mechanism after short
rather than long RR intervals. J Am
Coll Cardiol. 1995;26:15161521.
31. Pellicori P, Zhang J, Lukaschuk E,
et al. Left atrial function measured
by cardiac magnetic resonance
imaging in patients with heart failure: clinical associations and prognostic value. Eur Heart J. 2015;36:
733742.
32. Rienstra M, Damman K, Mulder
BA, et al. Beta-blockers and outcome in heart failure and atrial
brillation: a meta-analysis. JACC
Heart Fail. 2013;1:2128.
33. Poole-Wilson PA, Swedberg K,
Cleland JGF, et al. Comparison
of carvedilol and metoprolol on
clinical outcomes in patients with
chronic heart failure in the Carvedilol Or Metoprolol European Trial
(COMET): randomised controlled
trial. Lancet. 2003;362:713.
34. Khand AU, Rankin AC, Martin W,
et al. Carvedilol Alone or in Combination with Digoxin for the Management of Atrial Fibrillation in
Patients
with
Heart
Failure?
J Am Coll Cardiol. 2003;42:19441951.
35. Bloch Thomsen PE, Jons C,
Raatikainen MJP, et al. Long-term

October 2015

36.

37.

38.

39.

40.

41.

42.

43.

recording of cardiac arrhythmias

with an implantable cardiac
monitor in patients with reduced
ejection fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk Stratication
After Acute Myocardial Infarction
(CARISMA) study. Circulation.
2010;122:12581264.
Ruwald ACH, Bloch Thomsen PE,
Gang U, et al. New-onset atrial
brillation predicts malignant arrhythmias in post-myocardial infarction patients - A Cardiac
Arrhythmias and RIsk Stratication after acute Myocardial infarction (CARISMA) substudy. Am
Heart J. 2013;166:855863.e3.
Gang UJO, Jns C, Jrgensen RM,
et al. Heart rhythm at the time of
death documented by an implantable loop recorder. Europace.
2010;12:254260.
Grnefeld GC, Mauss O, Li YG,
et al. Association between atrial
brillation and appropriate implantable cardioverter debrillator
therapy: results from a prospective
study. J Cardiovasc Electrophysiol.
2000;11:12081214.
Kurlykina NV, Pevzner AV, Litvin
AI, et al. [Treatment of patients
with long nocturnal asystoles and
obstructive sleep apnea syndrome
by creating continuous positive air
pressure in the upper respiratory
tract]. Kardiologiia. 2009;49:3642.
Cleland JG, Massie BM, Packer M.
Sudden death in heart failure:
vascular or electrical? Eur J Heart
Fail. 1999;1:4145.
Santangeli P, Di Biase L, Dello
Russo A, et al. Meta-analysis: age
and effectiveness of prophylactic
implantable cardioverter-debrillators. Ann Intern Med. 2010;153:
592599.
A trial of the beta-blocker bucindolol in patients with advanced
chronic heart failure. N Engl J
Med. 2001;344:16591667.
Kao DP, Davis G, Aleong R, et al.
Effect of bucindolol on heart

44.

45.

46.

47.

48.

49.

50.

51.

52.

failure outcomes and heart rate

response in patients with reduced
ejection fraction heart failure and
atrial brillation. Eur J Heart Fail.
2013;15:324333.
Black-Maier E, Steinberg Ba,
Piccini JP. Bucindolol hydrochloride in atrial brillation and
concomitant heart failure. Expert
Rev Cardiovasc Ther. 2015;13:627
636.
Ang EL, Chan WL, Cleland JG,
et al. Placebo controlled trial of
xamoterol versus digoxin in chronic
atrial brillation. Br Heart J. 1990;
64:256260.
Sweeney MO, Hellkamp AS,
Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart
failure and atrial brillation
among patients with normal baseline QRS duration in a clinical trial
of pacemaker therapy for sinus
node dysfunction. Circulation.
2003;107:29322937.
Doshi RN, Daoud EG, Fellows C,
et al. Left ventricular-based cardiac
stimulation post AV nodal ablation evaluation (The PAVE study).
J Cardiovasc Electrophysiol. 2005;16:
11601165.
Brignole M, Botto GL, Mont L,
et al. Predictors of clinical efcacy
of Ablate and Pace therapy in
patients with permanent atrial brillation. Heart. 2012;98:297302.
Cleland JGF, Keshavarzi F, Pellicori
P, Dicken B. Case selection for
cardiac resynchronization in atrial
brillation. Heart Fail Clin. 2013;9:
461474.
Ouyang A-J, Lv Y-N, Zhong H-L,
et al. Meta-analysis of digoxin use
and risk of mortality in patients
with atrial brillation. Am J Cardiol.
2015;115:901906.
Whitbeck MG, Charnigo RJ, Khairy
P, et al. Increased mortality among
patients taking digoxinanalysis
from the AFFIRM study. Eur Heart
J. 2013;34:14811488.
Gheorghiade M, Fonarow GC, van
Veldhuisen DJ, et al. Lack of

2223

Clinical Therapeutics

53.

54.

55.

56.

57.

58.

59.

60.

evidence of increased mortality

among patients with atrial brillation taking digoxin: ndings from
post hoc propensity-matched
analysis of the AFFIRM trial. Eur
Heart J. 2013;34:14891497.
Jorge E, Baptista R, Martins H,
et al. Digoxin in advanced heart
failure patients: A question of rhythm.
Rev Port Cardiol. 2013;32:303310.
Oliver Ziff GYL, Dipak Kotecha,
Monica Samra, et al.Digoxin friend or foe? A Comprehensive
review of digoxin use and mortality, abstracts in British Cardiology
Society, 2015. [Online]. http://
www.bcs.com/abstracts3/marker_
view.asp?AbstractID=1230. [Accessed:
2015].
Packer DL, Prutkin JM, Hellkamp
AS, et al. Impact of implantable
cardioverter-debrillator, amiodarone, and placebo on the mode
of death in stable patients with
heart failure: analysis from the
sudden cardiac death in heart failure trial. Circulation. 2009;120:
21702176.
Kber L, Torp-Pedersen C,
McMurray JJV, et al. Increased
mortality after dronedarone therapy for severe heart failure. N Engl J
Med. 2008;358:26782687.
Talajic M, Khairy P, Levesque S,
et al. Maintenance of sinus rhythm
and survival in patients with heart
failure and atrial brillation. J Am
Coll Cardiol. 2010;55:17961802.
Shelton RJ, Clark AL, Goode K,
et al. A randomised, controlled
study of rate versus rhythm control
in patients with chronic atrial brillation and heart failure: (CAFE-II
Study). Heart. 2009;95:924930.
Roy D, Talajic M, Nattel S, et al.
Rhythm control versus rate control
for atrial brillation and heart
failure. N Engl J Med. 2008;358:
26672677.
Singh SN, Poole J, Anderson J,
et al. Role of amiodarone or implantable cardioverter/debrillator
in patients with atrial brillation

2224

and heart failure. Am Heart J.

2006;152:974.e711.
61. Luigi Di Biase AN, Prasant Mohanty, Sanghamitra Mohanty,
et al., Ablation vs. amiodarone
for treatment of persistent atrial
brillation in patients with congestive heart failure and an implanted
device: Results from the AATAC
multicenter randomized trial, American College of Cardiology 2015 Scientic
Sessions; March 16, 2015; San Diego,
CA. Abstract 408-08, 2015. [Online].
http://www.abstractsonline.com/
pp8/!/3658/presentation/37598.
[Accessed: 21-Jun-2015].

62. Marrouche NF, Brachmann J.

Catheter ablation versus standard
conventional
treatment
in
patients with left ventricular dysfunction and atrial brillation
(CASTLE-AF) - study design. Pacing Clin Electrophysiol. Aug. 2009;
32:987994.
63. Laskey WK, Alomari I, Cox M,
et al. Heart Rate at Hospital Discharge in Patients With Heart Failure Is Associated With Mortality
and Rehospitalization. J Am Heart
Assoc. 2015;4:e001626e001626,
http://jaha.ahajournals.org/content/
4/4/e001626.

Address correspondence to: Dr. Yura Mareev, National Heart & Lung
Institute, Hareeld Hospital, Imperial College, London UB9 6JH, United
Kingdom. E-mail: mareev84@gmail.com

Volume 37 Number 10