Review BB-AF-CHF Oct 2015

7232019 Review BB-AF-CHF Oct 2015

httpslidepdfcomreaderfullreview-bb-af-chf-oct-2015 110

Clinical TherapeuticsVolume 37 Number 10 2015

Review Article

Should β-Blockers Be Used in Patients With Heart Failureand Atrial Fibrillation

Yura Mareev MD PhD and John GF Cleland MD PhD FRCP FESC FACC

National Heart amp Lung Institute Harefield Hospital Imperial College London United Kingdom

ABSTRACT

Purpose There is overwhelming evidence that

β-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 evidencethat β-blockers are not effective in patients with heart

failure and atrial 1047297brillation 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 β-blockers

and other heart ratendashslowing medicines in heart failure

Findings The reasons for the lack of effect of

β-blockers in patients with heart failure are uncertainThere is a substantial body of evidence to suggest that

patients with heart failure and atrial 1047297brillation who have

less stringent ventricular rate control have a better

outcome The most plausible explanation for these

1047297ndings in our view is that β-blockers exert similar

bene1047297ts through similar mechanisms regardless of intrin-

sic heart rhythm but that the bene1047297ts of β-blockers are

neutralized in patients with atrial 1047297brillation due to the

induction of pauses that may impair cardiac function

leading to worsening heart failure or cause arrhythmias

resulting in deathImplications Smaller doses of β-blockers and other

rate lowering agents to achieve a resting clinic heart

rate in the range of 75-89beatsmin might improve

outcome Preventing pauses by pacing or pulmonary

vein ablation of atrial 1047297brillation are strategies that

should be researched (Clin Ther 2015372215ndash

2224) amp 2015 Elsevier HS Journals Inc All rights

reserved

Key words heart failure atrial 1047297

brillation ratecontrol prognosis beta-blockers

INTRODUCTIONHeart failure and atrial 1047297brillation (AF) have common

origins and one often provokes the other1 In possibly

half or more of patients with heart failure clinically

overt persistent or permanent AF will develop during

the course of their disease2ndash4 and as many as one half

of patients with AF have heart failure5 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 apparent6 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)7ndash9

b-Blockers in Heart Failure Effective in SinusRhythm But Not in AF

A series of substantial randomized controlled trials(RCTs) demonstrated that β-blockers could reduce the

rate of hospitalization for heart failure as well as

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Accepted for publication August 19 2015

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amp 2015 Elsevier HS Journals Inc All rights reserved

October 2015 2215



cardiovascular and all-cause mortality in patients with

HFrEF10 Only 1 contemporary trial enrolled a

substantial number of patients with HFpEF with

equivocal results in this group of patients11

Recently an individual patient meta-analysis includ-

ing all the landmark RCTs of HFrEF con1047297rmed the

bene1047297ts of β-blockers for patients with HFrEF in sinus

rhythm but suggested that for patients with AFβ-blockers did not reduce the rate of hospitalization

for heart failure or mortality10 (Figure 1) It is possible

that this is a chance 1047297nding12 but it is exceedingly

likely that there is a strong association between

heart rhythm and the clinical bene1047297ts of β-blockers

However it should be pointed out that β-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

bene1047297ts of nebivolol were also con1047297ned to patients insinus rhythm even in those with a left ventricular

ejection fraction 43513 Thus heart rhythm rather

than left ventricular ejection fraction may be the key

determinant of the bene1047297ts of β-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 0001) an effect that might

have been even larger had follow-up been censored for

patients who developed AF which presumably would

have led to a loss of further bene1047297t from β-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 robust10 However such inaccuracies in

data acquisition only serve to dilute observed effects

Although β-blockers do reduce the risk of the develop-ment of AF14 the annual incidence remains 515

Why Do b-Blockers Not Improve Outcomesin AF

Understanding why β-blockers do not improve

outcome in patients with heart failure and AF is

hampered by uncertainty about the mechanism by

which β-blockers mediate their bene1047297ts β-Blockers

block adrenergic receptors in a variety of tissues

including cardiovascular brain and adiposetissue

Some β-blockers are selective for particular receptorsand others have partial agonist activity Changes in

β1- and β1-receptor regulation and intracellular signaling

and activating antibodies may be important and speci1047297c

mechanisms for the effect of β-blockers16 However

β-blockers also have nonspeci1047297c effects including slow-

ing 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

Number at risk

Placebo group

Sinus rhythm

100

90

80

70

60

50

0

6819

7123 5014

4604

1798 722

561

1521

1542

997 331

346

113

1151020

Time (years) Time (years)

1530

HR 073 (95 Cl 067ndash080) plt0001 HR 097 (95 Cl 083ndash114) p=073

21 3 0 21 3

Atrial fibrillation

β-blocker group

Placebo group

β-blocker group

S u r v i v o

r s ( )

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 β-blockers in heart failureHR frac14 hazard ratio Reproduced with permission10

Clinical Therapeutics

2216 Volume 37 Number 10



Table I Reports investigating the relationship between heart rate and prognosis in patients with heart failure

Study No of Patients Groups Results (Hazard Ratio and 95 CI)

PRIME II26 77 HR median 72 beatsmin

range 57ndash

80vs

HR median 90 beats

min range 81ndash163

On multivariate analysis a lower

HR was associated withincreased all-cause mortality

P frac14 0002

CHARM7 1148 from an RCT of

ARBs

T1 HR 64 (60ndash68)


T3 HR 90 (86ndash100)

All-cause mortality

T1 100

T2 113 (089ndash143)

T3 089 (069ndash115)

WHFH or CV death

T1 100

T2 096 (078ndash119)

T3 079 (063ndash099)



T3 HR 90 (86ndash100)

Hull LifeLab20 488 referred to

outpatient clinic

Increase in resting rate

of 10 beatsmin

From baseline

Q1 o69 beatsmin

Q2 69ndash81 beatsmin


Q4 498 beatsmin

At follow-upQ1 o 62 beatsmin



Q4 482 beatsmin

(Hazard ratio 094 95 CI

088ndash100 P frac14 007)

Q1 Referent

Q2 101 (95 CI 069ndash147) P frac14

Q3 094 (95 CI 064ndash138) P frac14

Q4 068 (95 CI 045-103) P frac14

Q1 Referent

Q2 099 (95 CI 056ndash172) P frac14

Q3 071 (95 CI 039ndash

127) P frac14Q4 107 (95 CI 060ndash190) P frac14

O c t o b er 2 0 1 5

2 2 1 7



Table I (continued)


RACE II

subanalysis of

HF 28

287 in an RCT of rate

control

Strict (o80 beatsmin at

rest and o110 beatsmin

on exercise) vs lenient

(o110 beatsmin at rest)rate control

Primary outcome (cardiovascular morbid

and mortality) was 150 in the lenien

group and 182 in the strict group

(P frac14 053)

GWTG-HF 63 20197 hospitalized

with new or

worsening HF

HR o75 beatsmin If LVEF 440 HR Z75 beatsmin was

associated with higher all-cause morta

(hazard ratio 1080 95 CI 1035ndash1

per 10 beatsmin increase P frac14 0 000

HR Z75 beatsmin

If LVEF r40 HR Z75 beatsmin was

associated with mortality (HR 1005

CI 0953ndash1059 per 10-beatsmin incr

but was associated with a reduced risk

the composite of WHFH or CV death

(hazard ratio 0950 95 CI 0910ndash

0per 10-beatsmin increase P frac14 00183

ARBs frac14 angiotensin II receptor blockers CHARM frac14 Candesartan in Heart Failure Assessment of Reduction in Mortality and

With the Guidelines Heart Failure Program HF frac14 heart failure HR frac14 heart rate HFpEF frac14 heart failure with preserved ejectioreduce ejection fraction LVEF frac14 left ventricular ejection fraction PRIME II frac14 Second Prospective Randomised Study of Ibopquartile RACE II frac14 Comparison between Lenient versus Strict Rate Control II study RCT frac14 randomized controlled study T =stay for worsening heart failure or cardiovascular death

2 2 1 8

V ol um e 3 7 N um b er 1 0



functions that improve calcium handling increase rya-

nodine channel stability and reduce apoptosis Improved

cell and whole-organ function may reduce supraventric-

ular 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 reductionare uncertain A study of β-blockers in patients with

HFrEF who had pacemakers suggested that the improve-

ment in cardiac function with β-blockers was lost when

the pacing rate was increased from 60 to 80 beatsmin

(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 adherence18

A conventional meta-analysis suggests19 that the

magnitude of heart rate reduction but not β-blockerdose is associated with survival bene1047297t the individual

patient data meta-analysis is currently working on this

issue The relationship between heart rate and out-

come is supported by other observational studies20

and post hoc analyses of large clinical trials of

angiotensin II receptor blockers for both HFpEF and

HFrEF721 Ivabradine a sinus node inhibitor exerts

clinical bene1047297ts somewhat similar to those of

β-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 β-blocker whenthe patient is in sinus rhythm and has a heart rate

470 beatsmin2223 It also appears to be effective in

the absence of a β-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

β-blockers and in contrast to β-blockers its use is

associated with an increase in AF24 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 thatslows ventricular rate does not reduce mortality in

patients with heart failure in sinus rhythm and exerts

only a modest effect on hospitalization for heart

failure25

If adrenergic receptor blockade independent of

heart rate is the key mechanism of action of

β-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 bene1047297t

in AF Clearly β-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 rhythm720 In the

Second Prospective Randomised Study of Ibopamine

on Mortality and Ef 1047297cacy study (Table I)26 patients in

AF with a ventricular rate 480 beatsmin (median 90beatsmin) had a better prognosis than those with a

1Heart Rate lt6910

08

06

04

02

00

0 730 1460 2190 2920 3650

0 730 1460 2190 2920

10

08

06

04

02

00

Referent

Time (days)

Time (days)

C u m u l a t i v e S u r v i v a l


HR=101 (95 Cl 069-147) p=097HR=094 (95 Cl 064-138) p=075HR=068 (95 Cl 045-103) p=007

1234

ReferentHR=099 (95 Cl 056-172) p=096HR=071 (95 Cl 039-127) p=024HR=107 (95 Cl 060-190) p=082

1234

2Heart Rate 69ndash813Heart Rate 82ndash984Heart Rate gt98

1Heart Rate lt62 bpm2Heart Rate 62ndash72 bpm

3Heart Rate 73ndash82 bpm4Heart Rate gt82 bpm

Figure 2 Multivariable adjusted survival curvesby heart rate quartiles for patientswith heart failure and atrial fibrillationbefore (A) and after (B) intensificationof therapy for heart failure includingβ-blockers HR frac14 hazard ratio Repro-duced with permission19

Y Mareev and JGF Cleland

October 2015 2219



lower ventricular rate (median 72 beatsmin) In the

Candesartan in Heart Failure Assessment of

Reduction in Mortality and Morbidity study

patients with AF and a ventricular rate of 90

beatsmin had a lower risk of the composite

outcome (cardiovascular death or hospital stay for

the management of worsening heart failure) thanpatients with lower rates although the effect was no

longer signi1047297cant in a multivariable analysis A large

observational study also showed that patients with AF

and ventricular rates o73 beatsmin tended to have a

worse survival20 (Figure 2) In the Comparison

Between Lenient Versus Strict Rate Control II

study27 patients with AF approximately half of

whom also had HFrEF or HFpEF were randomly

assigned to lenient (o110 beatsmin) or strict (o80

beatsmin) resting ventricular rate control28 The

mean ventricular rate at rest in those randomized tolenient control was 85 beatsmin during long-term

follow-up28 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 β-blockers to be effective

Part of the bene1047297t of β-blockers might be mediated

through autonomic effects on the sinus node2930

Perhaps atrial activity is an important mediator of

β-blocker effect31 Alternatively β-blockers might exert

both bene1047297t and harm to varying degrees depending on

heart rhythm The overall effect of a treatment dependson the good that it delivers exceeding the harm that it

does leading to a net bene1047297t 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 bene1047297t clearly out-

weighs the harm for many patients but for those with

AF harm and bene1047297t may be evenly balanced This is

important because if the harm can be taken away the

net bene1047297t of β-blockers would ldquoreappearrdquo

Effects of b-Blockers on Ventricular Rate ControlIn major trials of β-blockers patients with AF had a

ventricular rate of 85 beatsmin at baseline32 and

so it can be anticipated that the ventricular rate during

follow-up would be 15 to 20 beatsmin slower33 and

that for many patients the resting daytime clinic

ventricular rate was reduced to o60 beatsmin The

nocturnal ventricular rate would likely be slower34

still with frequent pauses The presence of AF could

also conceal atrioventricular conduction disease that

could be exacerbated by β-blockers further

prolonging pauses In the Cardiac Arrhythmias and

Risk Strati1047297cation 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 ventriculartachycardia (VT)35 and patients who had episodes of

AF were more likely to have pauses36 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

reported37 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 de1047297brillators show that

those with AF are more prone to irregular ventricular

beats that can trigger ventricular arrhythmias38 It couldbe 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 arrest3940

However the effectiveness of implantable cardioverter

de1047297brillators which offer protection from both brady-

and tachyarrhythmias in preventing sudden death41

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 bucindo-

lol42ndash44 and xamoterol45 β1 partial agonists (ie agents

that act as β-blockers during periods of high sympathetic

activity but as β-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 bene1047297cial in patients with heartfailure 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 outcomes46 Studies

of atrioventricular node ablation comparing subsequent

right ventricular with biventricular pacing suggest that

the latter strategy is superior4748 but do not provide





evidence that biventricular pacing is superior to phar-

macological management alone49

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 pauses34 which may account for

the increase in mortality5051 and sudden death25 insome although not all52ndash54 reports However the

individual patient data meta-analysis did not show an

interaction between β-blockers and digoxin in the

prognosis of patients with AF and heart failure10

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 RhythmThe 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 bene1047297ts of β-blockade No

study has adequately researched this question15

although the best available data suggest not57 One

small study (61 patients) showed that restoration of

sinus rhythm improves cardiac function and quality of

life58 but a much larger study (1300 patients) failed to

con1047297rm this59 although this may have been because

of the inclusion of patients with paroxysmal AF manyof whom remained in sinus rhythm in the rate control

group throughout the study You cannot 1047297x things

that are not ldquobrokenrdquo Amiodarone has been the

principal antiarrhythmic agent used to try and

restore and maintain sinus rhythm60 However in

patients with more advanced heart failure

amiodarone may increase mortality especially since

the widespread introduction of β-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 TheAblation vs Amiodarone for Treatment of Atrial

Fibrillation in Patients with Congestive Heart Failure

and an Implanted ICDCRT-D (AATAC-AF) trial

(203 patients) showed that patients randomly

assigned to AF ablation had better outcomes than

those assigned to amiodarone61 More substantial

evidence that this approach is safe and effective in

improving symptoms and reducing morbidity and

mortality is awaited62

SUMMARY There is no evidence that β-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 β-blocker for apatient with AF they might be prescribed for concom-

itant 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 β-blockers for rate

control and currently there is insuf 1047297cient 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 im-

plantable cardioverter-de1047297brillator

That is the evidencemdashand now for an opinion It islikely that β-blockers are bene1047297cial 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

β-blockers to avoid decreasing the resting ventricular

rate to o75 beatsmin might avoid this harm

ACKNOWLEDGMENTSBoth 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 indi-

cated that they have no other con1047298ict of interest

regarding the content of this article

REFERENCES1 Khand AU Rankin AC Kaye GC Cleland JG Systematic

review of the management of atrial 1047297brillation in patients

with heart failure Eur Heart J 200021614ndash632

2 Guha K McDonagh T Heart failure epidemiology Euro-

pean perspective Curr Cardiol Rev 20139123ndash127

3 Anter E Jessup M Callans DJ Atrial 1047297brillation and heart

failure Treatment considerations for a dual epidemic

Circulation 20091192516ndash2525


October 2015 2221



4 Khand AU Cleland JGF Deedwa-

nia PC Prevention of and medical

therapy for atrial arrhythmias in

heart failure Heart Fail Rev

20027267ndash283

5 Cleland JGF Shelton R Nikitin N

et al Prevalence of markers of heart failure in patients with atrial

1047297brillation and the effects of xime-

lagatran compared to warfarin on

the incidence of morbid and fatal

events a report from the SPORTIF

III and V trials Eur J Heart Fail

20079730ndash739

6 Cleland JGF Swedberg K Follath

F et al The EuroHeart Failure

survey programmendash a survey on

the quality of care among patients

with heart failure in Europe Part 1 patient characteristics and diag-

nosis Eur Heart J 200324442ndash

463

7 Castagno D Skali H Takeuchi M

et al Association of heart rate

and outcomes in a broad spec-

trum of patients with chronic

heart failure Results from the

CHARM (Candesartan in Heart

Failure Assessment of Reduction

in Mortality and morbidity) pro-

gram J Am Coll Cardiol 2012591785ndash1795

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 1047297brillation in Europe

a report from the EURObservational

Research Programme Pilot survey on

Atrial Fibrillation Eur J Heart Fail

201517570ndash582

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 Euro-

Heart Failure Survey Eur Heart J

2004251214ndash1220

10 Kotecha D Holmes J Krum H et al

Ef 1047297cacy of β blockers in patients

with heart failure plus atrial 1047297brill-

ation an individual-patient data

meta-analysis Lancet 2014384

2235ndash2243

11 van Veldhuisen DJ Cohen-Solal A

Boumlhm M et al Beta-Blockade

With Nebivolol in Elderly Heart

Failure Patients With Impaired

and Preserved Left Ventricular Ejec-tion Fraction Data From SENIORS

(Study of Effects of Nebivolol In-

tervention on Outcomes and Re-

hospitalization in Seniors With

Heart Failure) J Am Coll Cardiol

2009532150ndash2158

12 McMurray JJV van Veldhuisen DJ

β Blockers Atrial Fibrillation and

Heart Failure Lancet 2014384

2181ndash2183

13 Mulder BA van Veldhuisen DJ

Crijns HJGM et al Effect of nebi-volol on outcome in elderly

patients with heart failure and

atrial 1047297brillation insights from SE-

NIORS Eur J Heart Fail 201214

1171ndash1178

14 Nasr IA Bouzamondo A Hulot

J-S et al Prevention of atrial

1047297brillation onset by beta-blocker

treatment in heart failure a meta-

analysis Eur Heart J 200728

457ndash462

15 Swedberg K Olsson LG Charles-worth A et al Prognostic rele-

vance of atrial 1047297brillation in

patients with chronic heart failure

on long-term treatment with beta-

blockers Results from COMET

Eur Heart J 2005261303ndash1308

16 Gong H Sun H Koch WJ et al

Speci1047297c beta(2)AR blocker ICI

118551 actively decreases contrac-

tion through a G(i)-coupled form

of the beta(2)AR in myocytes from

failing human heart Circulation20021052497ndash2503

17 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 2006152713e9ndash13

18 Boumlhm M Swedberg K Komajda

M et al Heart rate as a risk factor

in chronic heart failure (SHIFT)

The association between heart rate

and outcomes in a randomised

placebo-controlled trial Lancet

2010376886ndash894

19 McAlister FA Wiebe N Ezekowitz

JA et al Meta-analysis beta-

blocker dose heart rate reductionand death in patients with heart

failure Ann Intern Med 2009

150784ndash794

20 Cullington D Goode KM Zhang J

et al Is heart rate important for

patients with heart failure in atrial

1047297brillation JACC Heart Fail

20142213ndash220

21 Boumlhm M Perez A-C Jhund PS

et al Relationship between heart

rate and mortality and morbidity

in the irbesartan patients withheart failure and preserved systolic

function trial (I-Preserve) Eur J

Heart Fail 201416778ndash787

22 Swedberg K Komajda M Boumlhm

M et al Ivabradine and outcomes

in chronic heart failure (SHIFT) A

randomised placebo-controlled

study Lancet 2010376875ndash885

23 Borer JS Boumlhm M Ford I et al

Effect of ivabradine on recurrent

hospitalization for worsening

heart failure in patients withchronic systolic heart failure the

SHIFT Study Eur Heart J 201233

2813ndash2820

24 Martin RIR Pogoryelova O Koref

MS et al Atrial 1047297brillation associated

with ivabradine treatment meta-

analysis of randomised controlled

trials Heart 20141001506ndash1510

25 The Digitalis Investigation Group

The effect of digoxin on mortality

and morbidity in patients with

heart failure N Engl J Med 1997336525ndash533

26 Rienstra M Van Gelder IC Van

Den Berg MP et al A comparison

of low versus high heart rate in

patients with atrial 1047297brill-

ation and advanced chronic

heart failure Effects on clinical

pro1047297le neurohormones and sur-

vival Int J Cardiol 2006109

95ndash100





27 Van Gelder IC Groenveld HF

Crijns HJGM et al Lenient versus

strict rate control in patients with

atrial 1047297brillation N Engl J Med

20103621363ndash1373

28 Mulder BA Van Veldhuisen DJ

Crijns HJGM et al Lenient vsstrict rate control in patientswith

atrial 1047297brillation and heart failure

A post-hoc analysis of the RACE 2

study Eur J Heart Fail 201315

1311ndash1318

29 Clark DM Plumb VJ Epstein AE

Kay GN Hemodynamic effects of

an irregular sequence of ventricu-

lar cycle lengths during atrial

1047297brillation J Am Coll Cardiol 1997

301039ndash1045

30 Gosselink ATM Blanksma PKCrijns HJGM et al Left ventricular

beat-to-beat performance in atrial

1047297brillation Contribution of Frank-

Starling mechanism after short

rather than long RR intervals J Am

Coll Cardiol 1995261516ndash1521

31 Pellicori P Zhang J Lukaschuk E

et al Left atrial function measured

by cardiac magnetic resonance

imaging in patients with heart fail-

ure clinical associations and prog-

nostic value Eur Heart J 201536733ndash742

32 Rienstra M Damman K Mulder

BA et al Beta-blockers and out-

come in heart failure and atrial

1047297brillation a meta-analysis JACC


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 Carve-

dilol Or Metoprolol European Trial(COMET) randomised controlled

trial Lancet 20033627ndash13

34 Khand AU Rankin AC Martin W

et al Carvedilol Alone or in Com-

bination with Digoxin for the Man-

agement of Atrial Fibrillation in

Patients with Heart Failure

J Am Coll Cardiol 2003421944ndash1951

35 Bloch Thomsen PE Jons C

Raatikainen MJP et al Long-term

recording of cardiac arrhythmias

with an implantable cardiac

monitor in patients with reduced

ejection fraction after acute myo-

cardial infarction the Cardiac Ar-

rhythmias and Risk Strati1047297cation

After Acute Myocardial Infarction(CARISMA) study Circulation

20101221258ndash1264

36 Ruwald ACH Bloch Thomsen PE

Gang U et al New-onset atrial

1047297brillation predicts malignant ar-

rhythmias in post-myocardial in-

farction patients - A Cardiac

Arrhythmias and RIsk Strati1047297ca-

tion after acute Myocardial infarc-

tion (CARISMA) substudy Am

Heart J 2013166855ndash863e3

37 Gang UJO Joslashns C Joslashrgensen RMet al Heart rhythm at the time of

death documented by an implant-

able loop recorder Europace

201012254ndash260

38 Groumlnefeld GC Mauss O Li YG

et al Association between atrial

1047297brillation and appropriate im-

plantable cardioverter de1047297brillator

therapy results from a prospective

study J Cardiovasc Electrophysiol

2000111208ndash1214

39 Kurlykina NV Pevzner AV LitvinAI 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 20094936ndash42

40 Cleland JG Massie BM Packer M

Sudden death in heart failure

vascular or electrical Eur J Heart

Fail 1999141ndash45

41 Santangeli P Di Biase L Dello

Russo A et al Meta-analysis ageand effectiveness of prophylactic

implantable cardioverter-de1047297bril-

lators Ann Intern Med 2010153

592ndash599

42 A trial of the beta-blocker bucin-

dolol in patients with advanced

chronic heart failure N Engl J

Med 20013441659ndash1667

43 Kao DP Davis G Aleong R et al

Effect of bucindolol on heart

failure outcomes and heart rate

response in patients with reduced

ejection fraction heart failure and

atrial 1047297brillation Eur J Heart Fail

201315324ndash333

44 Black-Maier E Steinberg Ba

Piccini JP Bucindolol hydrochlor-ide in atrial 1047297brillation and

concomitant heart failure Expert

Rev Cardiovasc Ther 201513627ndash

636

45 Ang EL Chan WL Cleland JG

et al Placebo controlled trial of

xamoterol versus digoxin in chronic

atrial 1047297brillation Br Heart J 1990

64256ndash260

46 Sweeney MO Hellkamp AS

Ellenbogen KA et al Adverse ef-

fect of ventricular pacing on heart failure and atrial 1047297brillation

among patients with normal base-

line QRS duration in a clinical trial

of pacemaker therapy for sinus

node dysfunction Circulation

20031072932ndash2937

47 Doshi RN Daoud EG Fellows C

et al Left ventricular-based cardiac

stimulation post AV nodal abla-

tion evaluation (The PAVE study)

J Cardiovasc Electrophysiol 200516

1160ndash

116548 Brignole M Botto GL Mont L

et al Predictors of clinical ef 1047297cacy

of lsquoAblate and Pacersquo therapy in

patients with permanent atrial 1047297-

brillation Heart 201298297ndash302

49 Cleland JGF Keshavarzi F Pellicori

P Dicken B Case selection for

cardiac resynchronization in atrial

1047297brillation Heart Fail Clin 20139

461ndash474

50 Ouyang A-J Lv Y-N Zhong H-L

et al Meta-analysis of digoxin useand risk of mortality in patients

with atrial 1047297brillation Am J Cardiol

2015115901ndash906

51 Whitbeck MG Charnigo RJ Khairy

P et al Increased mortality among

patients taking digoxinndashanalysis

from the AFFIRM study Eur Heart

J 2013341481ndash1488

52 Gheorghiade M Fonarow GC van

Veldhuisen DJ et al Lack of


October 2015 2223



evidence of increased mortality

among patients with atrial 1047297brilla-

tion taking digoxin 1047297ndings from

post hoc propensity-matched

analysis of the AFFIRM trial Eur

Heart J 2013341489ndash1497

53 Jorge E Baptista R Martins Het al Digoxin in advanced heart

failure patients A question of rhythm

Rev Port Cardiol 201332303ndash310

54 Oliver Ziff GYL Dipak Kotecha

Monica Samra et alDigoxin -

friend or foe A Comprehensive

review of digoxin use and mortal-

ity abstracts in British Cardiology

Society 2015 [Online] http

wwwbcscomabstracts3marker_

viewaspAbstractID=1230 [Accessed

2015]55 Packer DL Prutkin JM Hellkamp

AS et al Impact of implantable

cardioverter-de1047297brillator amiodar-

one and placebo on the mode

of death in stable patients with

heart failure analysis from the

sudden cardiac death in heart fail-

ure trial Circulation 2009120

2170ndash2176

56 Koslashber L Torp-Pedersen C

McMurray JJV et al Increased

mortality after dronedarone ther-apy for severe heart failure N Engl J

Med 20083582678ndash2687

57 Talajic M Khairy P Levesque S

et al Maintenance of sinus rhythm

and survival in patients with heart

failure and atrial 1047297brillation J Am


58 Shelton RJ Clark AL Goode K

et al A randomised controlled

study of rate versus rhythm control

in patients with chronic atrial 1047297bril-

lation and heart failure (CAFE-IIStudy) Heart 200995924ndash930

59 Roy D Talajic M Nattel S et al

Rhythm control versus rate control

for atrial 1047297brillation and heart

failure N Engl J Med 2008358

2667ndash2677

60 Singh SN Poole J Anderson J

et al Role of amiodarone or im-

plantable cardioverterde1047297brillator

in patients with atrial 1047297brillation

and heart failure Am Heart J

2006152974e7ndash11

61 Luigi Di Biase AN Prasant Mo-

hanty Sanghamitra Mohanty

et al Ablation vs amiodarone

for treatment of persistent atrial

1047297brillation in patients with conges-tive heart failure and an implanted

device Results from the AATAC

multicenter randomized trial Ameri-

can College of Cardiology 2015 Scienti 1047297c

Sessions March 16 2015 San Diego

CA Abstract 408-08 2015 [Online]

httpwwwabstractsonlinecom

pp83658presentation37598

[Accessed 21-Jun-2015]

62 Marrouche NF Brachmann J

Catheter ablation versus standard

conventional treatment in

patients with left ventricular dys-

function and atrial 1047297brillation

(CASTLE-AF) - study design Pac-

ing Clin Electrophysiol Aug 200932987ndash994

63 Laskey WK Alomari I Cox M

et al Heart Rate at Hospital Dis-

charge in Patients With Heart Fail-

ure Is Associated With Mortality

and Rehospitalization J Am Heart

Assoc 20154e001626ndashe001626

httpjahaahajournalsorgcontent

44e001626

Address correspondence to Dr Yura Mareev National Heart amp Lung

Institute Hare1047297eld Hospital Imperial College London UB9 6JH United

Kingdom E-mail mareev84gmailcom





cardiovascular and all-cause mortality in patients with

HFrEF10 Only 1 contemporary trial enrolled a

substantial number of patients with HFpEF with

equivocal results in this group of patients11

Recently an individual patient meta-analysis includ-

ing all the landmark RCTs of HFrEF con1047297rmed the

bene1047297ts of β-blockers for patients with HFrEF in sinus

rhythm but suggested that for patients with AFβ-blockers did not reduce the rate of hospitalization

for heart failure or mortality10 (Figure 1) It is possible

that this is a chance 1047297nding12 but it is exceedingly

likely that there is a strong association between

heart rhythm and the clinical bene1047297ts of β-blockers

However it should be pointed out that β-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

bene1047297ts of nebivolol were also con1047297ned to patients insinus rhythm even in those with a left ventricular

ejection fraction 43513 Thus heart rhythm rather

than left ventricular ejection fraction may be the key

determinant of the bene1047297ts of β-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 0001) an effect that might

have been even larger had follow-up been censored for

patients who developed AF which presumably would

have led to a loss of further bene1047297t from β-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 robust10 However such inaccuracies in

data acquisition only serve to dilute observed effects

Although β-blockers do reduce the risk of the develop-ment of AF14 the annual incidence remains 515

Why Do b-Blockers Not Improve Outcomesin AF

Understanding why β-blockers do not improve

outcome in patients with heart failure and AF is

hampered by uncertainty about the mechanism by

which β-blockers mediate their bene1047297ts β-Blockers

block adrenergic receptors in a variety of tissues

including cardiovascular brain and adiposetissue

Some β-blockers are selective for particular receptorsand others have partial agonist activity Changes in

β1- and β1-receptor regulation and intracellular signaling

and activating antibodies may be important and speci1047297c

mechanisms for the effect of β-blockers16 However

β-blockers also have nonspeci1047297c effects including slow-

ing 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

Number at risk

Placebo group

Sinus rhythm

100

90

80

70

60

50

0

6819

7123 5014

4604

1798 722

561

1521

1542

997 331

346

113

1151020

Time (years) Time (years)

1530

HR 073 (95 Cl 067ndash080) plt0001 HR 097 (95 Cl 083ndash114) p=073

21 3 0 21 3

Atrial fibrillation

β-blocker group

Placebo group

β-blocker group

S u r v i v o

r s ( )

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 β-blockers in heart failureHR frac14 hazard ratio Reproduced with permission10








range 57ndash

80vs

HR median 90 beats




P frac14 0002


ARBs



T3 HR 90 (86ndash100)

All-cause mortality

T1 100

T2 113 (089ndash143)

T3 089 (069ndash115)

WHFH or CV death

T1 100

T2 096 (078ndash119)

T3 079 (063ndash099)



T3 HR 90 (86ndash100)


outpatient clinic


of 10 beatsmin

From baseline

Q1 o69 beatsmin



Q4 498 beatsmin




Q4 482 beatsmin



Q1 Referent

Q2 101 (95 CI 069ndash147) P frac14

Q3 094 (95 CI 064ndash138) P frac14

Q4 068 (95 CI 045-103) P frac14

Q1 Referent

Q2 099 (95 CI 056ndash172) P frac14

Q3 071 (95 CI 039ndash


O c t o b er 2 0 1 5

2 2 1 7



Table I (continued)


RACE II

subanalysis of

HF 28


control








(P frac14 053)


with new or

worsening HF





HR Z75 beatsmin










2 2 1 8














(Table)17





























failure25













1Heart Rate lt6910

08

06

04

02

00

0 730 1460 2190 2920 3650

0 730 1460 2190 2920

10

08

06

04

02

00

Referent

Time (days)

Time (days)




1234


1234






October 2015 2219



















































































































































































October 2015 2221







20027267ndash283








20079730ndash739







463



















201517570ndash582






2004251214ndash1220






2235ndash2243










2009532150ndash2158




2181ndash2183






1171ndash1178






457ndash462

























2010376886ndash894





150784ndash794





20142213ndash220

















2813ndash2820


















95ndash100









20103621363ndash1373






1311ndash1318






301039ndash1045








































20101221258ndash1264













201012254ndash260







2000111208ndash1214










Fail 1999141ndash45





592ndash599




Med 20013441659ndash1667







201315324ndash333





636





64256ndash260








20031072932ndash2937






1160ndash










461ndash474




2015115901ndash906





J 2013341481ndash1488




October 2015 2223




























2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626











range 57ndash

80vs

HR median 90 beats




P frac14 0002


ARBs



T3 HR 90 (86ndash100)

All-cause mortality

T1 100

T2 113 (089ndash143)

T3 089 (069ndash115)

WHFH or CV death

T1 100

T2 096 (078ndash119)

T3 079 (063ndash099)



T3 HR 90 (86ndash100)


outpatient clinic


of 10 beatsmin

From baseline

Q1 o69 beatsmin



Q4 498 beatsmin




Q4 482 beatsmin



Q1 Referent

Q2 101 (95 CI 069ndash147) P frac14

Q3 094 (95 CI 064ndash138) P frac14

Q4 068 (95 CI 045-103) P frac14

Q1 Referent

Q2 099 (95 CI 056ndash172) P frac14

Q3 071 (95 CI 039ndash


O c t o b er 2 0 1 5

2 2 1 7



Table I (continued)


RACE II

subanalysis of

HF 28


control








(P frac14 053)


with new or

worsening HF





HR Z75 beatsmin










2 2 1 8














(Table)17





























failure25













1Heart Rate lt6910

08

06

04

02

00

0 730 1460 2190 2920 3650

0 730 1460 2190 2920

10

08

06

04

02

00

Referent

Time (days)

Time (days)




1234


1234






October 2015 2219



















































































































































































October 2015 2221







20027267ndash283








20079730ndash739







463



















201517570ndash582






2004251214ndash1220






2235ndash2243










2009532150ndash2158




2181ndash2183






1171ndash1178






457ndash462

























2010376886ndash894





150784ndash794





20142213ndash220

















2813ndash2820


















95ndash100









20103621363ndash1373






1311ndash1318






301039ndash1045








































20101221258ndash1264













201012254ndash260







2000111208ndash1214










Fail 1999141ndash45





592ndash599




Med 20013441659ndash1667







201315324ndash333





636





64256ndash260








20031072932ndash2937






1160ndash










461ndash474




2015115901ndash906





J 2013341481ndash1488




October 2015 2223




























2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626








Table I (continued)


RACE II

subanalysis of

HF 28


control








(P frac14 053)


with new or

worsening HF





HR Z75 beatsmin










2 2 1 8














(Table)17





























failure25













1Heart Rate lt6910

08

06

04

02

00

0 730 1460 2190 2920 3650

0 730 1460 2190 2920

10

08

06

04

02

00

Referent

Time (days)

Time (days)




1234


1234






October 2015 2219



















































































































































































October 2015 2221







20027267ndash283








20079730ndash739







463



















201517570ndash582






2004251214ndash1220






2235ndash2243










2009532150ndash2158




2181ndash2183






1171ndash1178






457ndash462

























2010376886ndash894





150784ndash794





20142213ndash220

















2813ndash2820


















95ndash100









20103621363ndash1373






1311ndash1318






301039ndash1045








































20101221258ndash1264













201012254ndash260







2000111208ndash1214










Fail 1999141ndash45





592ndash599




Med 20013441659ndash1667







201315324ndash333





636





64256ndash260








20031072932ndash2937






1160ndash










461ndash474




2015115901ndash906





J 2013341481ndash1488




October 2015 2223




























2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626


















(Table)17





























failure25













1Heart Rate lt6910

08

06

04

02

00

0 730 1460 2190 2920 3650

0 730 1460 2190 2920

10

08

06

04

02

00

Referent

Time (days)

Time (days)




1234


1234






October 2015 2219



















































































































































































October 2015 2221







20027267ndash283








20079730ndash739







463



















201517570ndash582






2004251214ndash1220






2235ndash2243










2009532150ndash2158




2181ndash2183






1171ndash1178






457ndash462

























2010376886ndash894





150784ndash794





20142213ndash220

















2813ndash2820


















95ndash100









20103621363ndash1373






1311ndash1318






301039ndash1045








































20101221258ndash1264













201012254ndash260







2000111208ndash1214










Fail 1999141ndash45





592ndash599




Med 20013441659ndash1667







201315324ndash333





636





64256ndash260








20031072932ndash2937






1160ndash










461ndash474




2015115901ndash906





J 2013341481ndash1488




October 2015 2223




























2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626
























































































































































































October 2015 2221







20027267ndash283








20079730ndash739







463



















201517570ndash582






2004251214ndash1220






2235ndash2243










2009532150ndash2158




2181ndash2183






1171ndash1178






457ndash462

























2010376886ndash894





150784ndash794





20142213ndash220

















2813ndash2820


















95ndash100









20103621363ndash1373






1311ndash1318






301039ndash1045








































20101221258ndash1264













201012254ndash260







2000111208ndash1214










Fail 1999141ndash45





592ndash599




Med 20013441659ndash1667







201315324ndash333





636





64256ndash260








20031072932ndash2937






1160ndash










461ndash474




2015115901ndash906





J 2013341481ndash1488




October 2015 2223




























2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626












20027267ndash283








20079730ndash739







463



















201517570ndash582






2004251214ndash1220






2235ndash2243










2009532150ndash2158




2181ndash2183






1171ndash1178






457ndash462

























2010376886ndash894





150784ndash794





20142213ndash220

















2813ndash2820


















95ndash100









20103621363ndash1373






1311ndash1318






301039ndash1045








































20101221258ndash1264













201012254ndash260







2000111208ndash1214










Fail 1999141ndash45





592ndash599




Med 20013441659ndash1667







201315324ndash333





636





64256ndash260








20031072932ndash2937






1160ndash










461ndash474




2015115901ndash906





J 2013341481ndash1488




October 2015 2223




























2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626












20103621363ndash1373






1311ndash1318






301039ndash1045








































20101221258ndash1264













201012254ndash260







2000111208ndash1214










Fail 1999141ndash45





592ndash599




Med 20013441659ndash1667







201315324ndash333





636





64256ndash260








20031072932ndash2937






1160ndash










461ndash474




2015115901ndash906





J 2013341481ndash1488




October 2015 2223




























2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626

































2170ndash2176




Med 20083582678ndash2687















2667ndash2677






2006152974e7ndash11




























44e001626






Review BB-AF-CHF Oct 2015

Documents

Transcript of Review BB-AF-CHF Oct 2015