2012 update of the esc guidelines on the management of atrial

2012 Update of the ESC Guidelines on the

Management of Atrial Fibrillation

Stefan H. Hohnloser

J.W. Goethe University

Frankfurt am Main

S.H.H. has served as a consultant, member of the steering committee, or speaker for:

Bayer Healthcare, BMS, Boehringer Ingelheim, Boston Scientific, Cardiome, Forest RI,

J&J, Medtronic, Pfizer, Portola, Sanofi aventis, St. Jude Medical

Antiarrhythmic drug therapy for the prevention

of atrial fibrillation recurrences

European Heart Journal

doi:10.1093/eurheartj/ehs253

European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253

2012 focused update of the ESC Guidelines for the

Management of Atrial Fibrillation An update of the 2010 ESC Guidelines for the Management of Atrial Fibrillation

Developed with the special contribution of the European Heart Rhythm Association

Authors/Task Force Members: A. John Camm (Chairperson) (UK)*, Gregory Y. H. Lip (UK), Dan Atar (Norway), Raffaele

De Caterina (Italy), Gerhard Hindricks (Germany), Stefan H. Hohnloser (Germany), Paulus Kirchhof (Germany/UK), Irene

Savelieva (UK)

ESC Committee for Practice Guidelines (CPG): Jeroen J. Bax (CPG Chairperson) (The Netherlands),

Helmut Baumgartner (Germany), Claudio Ceconi (Italy), Veronica Dean (France), Christi Deaton (UK),

Robert Fagard (Belgium), Christian Funck-Brentano (France), David Hasdai (Israel), Arno Hoes (The Netherlands), Paulus Kirchhof (Germany/UK),

Juhani Knuuti (Finland), Philippe Kolh (Belgium), Theresa McDonagh (UK), Cyril Moulin (France), Bogdan A. Popescu (Romania), Željko Reiner

(Croatia), Udo Sechtem (Germany), Per Anton Sirnes (Norway), Michal Tendera (Poland), Adam Torbicki (Poland), Alec Vahanian (France),Stephan

Windecker (Switzerland).

Document Reviewers: Panos Vardas (Review Coordinator) (Greece), Nawwar Al-Attar (France), Ottavio Alfieri† (Italy), Annalisa Angelini (Italy),

Carina Blömstrom-Lundqvist (Sweden), Paolo Colonna (Italy), Johan De Sutter (Belgium), Sabine Ernst (UK), Andreas Goette (Germany), Bulent

Gorenek (Turkey), Robert Hatala (Slovak Republic), Hein Heidbüchel (Belgium), Magnus Heldal (Norway), Steen Dalby Kristensen (Denmark),

Philippe Kolh† (Belgium), Jean-Yves Le Heuzey (France), Hercules Mavrakis (Greece), Lluís Mont (Spain), Pasquale Perrone Filardi (Italy), Piotr

Ponikowski (Poland), Bernard Prendergast (UK), Frans Rutten (The Netherlands), Ulrich Schotten (The Netherlands), Isabelle C. Van Gelder (The

Netherlands), Freek Verheugt (The Netherlands)

European Heart Journal (2010) 31, 2369-2429

Principles of antiarrhythmic drug therapy to maintain sinus rhythm

1. Treatment is motivated by attempts to reduce AF-related

symptoms.

2. Efficacy of antiarrhythmic drugs to maintain sinus rhythm is modest.

3. Clinically successful antiarrhythmic drug therapy may reduce rather

than eliminate recurrence of AF.

4. If one antiarrhythmic drug ‘fails’ a clinically acceptable response

may be achieved with another agent.

5. Drug-induced proarrhythmia or extra-cardiac side-effects are

frequent.

6. Safety rather than efficacy considerations should primarily guide

the choice of antiarrhythmic agent.

AF = atrial fibrillation; AV = atrioventricular; bpm = beats per minute; CYP = cytochrome P; ECG = electrocardiogram;

LV = left ventricular; NYHA = New York Heart Association.

Drug Dose Main contraindications and precautions

ECG monitoring AV nodal slowing

Disopyramide 100-250 mg t.i.d.

Contraindicated in systolic heart failure, SND, and AVB II and III without PM. Caution when using concomitant medication with QT-prolonging drugs.

QT interval None

Flecainide 100-200 mg b.i.d.

Contraindicated if creatinine clearance < 50 mg/mL, in coronary artery disease, reduced LV ejection fraction, heart failure.

QRS duration increase > 25% above baseline

None

Flecanide XL 200 mg o.d. Caution in the presence of conduction system disease.

Propafenone 150-300 mg t.i.d.

Contraindicated in coronary artery disease, heart failure.

QRS duration increase > 25% above baseline

Slight

Propafenone SR

225-425 mg b.i.d.

Caution in the presence of conduction system disease and renal impairment.

Changes from 2010 Guidelines

Suggested doses and main caveats for commonly used antiarrhythmic drugs





ECG features prompting lower dose or discontinuation

AV nodal slowing

d,l-Sotalol

80-160 mg b.i.d..

Contraindicated in the presence of significant LV hypertrophy, systolic heart failure, pre-existing QT prolongation, hypokalaemia, significant renal impairment Creatinine clearance < 50 mg/mL. Moderate renal dysfunction requires careful adaptation of dose.

QT interval > 500 ms

Similar to high-dose β-blockers

Amiodarone

600 mg o.d. for 4 weeks, 400 mg o.d. for 4 weeks then 200 mg o.d.

Caution when using concomitant medication with QT-prolonging drugs, heart failure. Dose of vitamin K antagonists and of digitoxin/digoxin should be reduced. Creatinine, liver enzymes, thyroid hormones, & lung function should be monitored

QT interval >500 ms 10–12 bpm in AF







ECG features prompting lowerdose or discontinuation

AV nodal slowing

Dronedarone 400 mg b.i.d. Contraindicated in NYHA class III–IV or unstable heart failure, during concomitant medication with QT-prolonging drugs, powerful CYP 3A4 inhibitors, if creatinine clearance < 30 mg/mL. Not advised in other forms of heart failure, unless no appropriate alternative. Cautious use in CHD. Regular monitoring of liver function.

Dose of digitoxin/digoxin should be reduced.

Elevations in serum creatinine of 0.1–0.2 mg/dL are common and do not reflect reduced renal function.

QT interval > 500 ms 10–12 bpm in AF





Choice of antiarrhythmic for the patient with no or minimal structural heart disease

No or minimal structural heart disease

Adrenergically

mediated

β-blockers

Sotalol

Dronedarone Amiodarone

Dronedarone

Flecainide

Propafenone

Sotalol

Undetermined Vagally

mediated

Disopyramide


Choice of antiarrhythmic drug according to underlying pathology

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CAD = coronary artery disease; CHF = congestive heart failure;

HT = hypertension; LVH = left ventricular hypertrophy; NYHA = New York Heart Association; unstable = cardiac decompensation within the prior

4 weeks. Antiarrhythmic agents are listed in alphabetical order within each treatment box. ? = evidence for ‘upstream’ therapy for prevention of atrial

remodelling still remains controversial.

? Prevention of remodeling

ACE/ARB/statin

β-blockade where appropriate

Treatment of underlying condition and ? Prevention/reversal

of remodelling - ACEI/ARB/statin. β-blockade where appropriate

HT CAD CHF

No LVH LVH Stable

NYHA I/II

NYHA III/IV

or ‘unstable’

NHYA II

Dronedarone Dronedarone

Sotalol

Dronedarone

Amiodarone Amiodarone Amiodarone

Dronedarone / Flecainide /

Propafenone / Sotalol

Minimal or no heart disease Significant underlying heart disease

Antiarrhythmic drug management

of non-permanent AF

Treatment of underlying condition and prevention of

remodelling – ACE-I / ARB / statins

CHF CHD

Significant structural heart disease Minimal or no structural heart disease

HHD

amiodarone

LVH No LVH

amiodarone

dronedarone / flecainide /

propafenone / sotalol

dronedarone

amiodarone

dronedarone

sotalol

AC

E-I

= a

ngio

tensin

convert

ing e

nzym

e inhib

itor;

AR

B =

angio

tensin

II re

cepto

r blo

cker;

CH

D =

coro

nary

heart

dis

ease; C

HF

= c

ongestive h

eart

failu

re; H

HD

=

hyp

ert

ensiv

e h

eart

dis

ease; LV

H =

left

ventr

icula

r hyp

ert

rophy.


Choice of an antiarrhythmic drug for AF control (I)

Recommendations Classa Levelb

The following antiarrhythmic drugs are recommended for rhythm control in

patients with AF, depending on underlying heart disease:

● amiodarone I A

● dronedarone I A

● flecainide I A

● propafenone I A

● d,I-sotalol I A

Amiodarone is more effective in maintaining sinus rhythm than sotalol,

propafenone, flecainide (by analogy) or dronedarone (LoE A), but because

of its toxicity profile should generally be used when other agents have failed

or are contraindicated (LoE C).

I A C

In patients with heart failure amiodarone should be the drug of choice. I B

Dronedarone is recommended in patients with recurrent AF as a moderately

effective antiarrhythmic agent for the maintenance of sinus rhythm. I A

In patients without significant structural heart disease, initial antiarrhythmic

therapy should be chosen from dronedarone, flecainide, propafenone, and

sotalol. I A


0 60 120 180 240 300 360

Cum

ula

tive incid

ence

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Cum

ula

tive incid

ence

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

EURIDIS ADONIS

Time (days) Time (days)

1,237 patients (409 randomized to placebo, 828 to dronedarone)

EURIDIS & ADONIS: Primary Endpoint

HR = 0.78 (0.64 – 0.96)

P = 0.0138

HR = 0.73 (0.59 – 0.89)

P = 0.0017

Singh BN, et al. N Engl J Med. 2007;357:987-999.

0 60 120 180 240 300 360

Placebo

Dronedarone 400 mg BID

Hohnloser SH, et al. N Engl J Med. 2009;360:668-678.

Patients at risk:

Placebo 2,327 1,858 1,625 1,072 385 3

Dronedarone 2,301 1,963 1,776 1,117 403 2

Months

Placebo

Dronedarone

HR = 0.76

P < 0.001

0 6 12 18 24 30

0

10

20

30

40

50

Cu

mu

lative

in

cid

en

ce (

%)

0

10

20

30

40

50

2301

1858

1963

1625

1776

1072

1177

385

403

3

2

2327

Placebo

PlaceboDronedarone

MonthsPatients at risk

Dronedarone

HR=0.76P<0.001

0 6 12 18 24 30

Cu

mm

ula

tive

In

cid

en

ce

(%

)

0

10

20

30

40

50

2301

1858

1963

1625

1776

1072

1177

385

403

3

2

2327

Placebo

PlaceboDronedarone

MonthsPatients at risk

Dronedarone

HR=0.76P<0.001

0 6 12 18 24 30

Cu

mm

ula

tive

In

cid

en

ce

(%

)10 Outcome: Time to First Cardiovascular Hospitalization or Death

ATHENA: Morbidity/Mortality

Study in 4,628 Patients with AF

Choice of an antiarrhythmic drug for AF control (II)


If one antiarrhythmic drug fails to reduce the recurrence of AF to a clinically

acceptable level, the use of another antiarrhythmic drug should be

considered. IIa C

Dronedarone should be considered in order to reduce cardiovascular

hospitalizations in patients with non-permanent AF and cardiovascular risk

factors. IIa B

ß-blockers should be considered for rhythm (plus rate) control in patients

with a first episode of AF. IIa C

Short-term (4 weeks) antiarrhythmic therapy after cardioversion may be

considered in selected patients e.g., those at risk for therapy-associated

complications. IIb B

aClass of recommendation. bLevel of evidence.

AF = atrial fibrillation; LoE = level of evidence.


635 patients, mean age 64 years, flecainide 4 weeks vs long-term therapy

Primary outcome: time to persistent AF or death, monitored by telemetric ECG S

urv

iva

l p

rob

ab

ility

Time to event (days)

Short- vs long-term AAD Rx after cardioversion

Kirchhof et al, www.thelancet.com Published online

June 18, 2012 DOI:10.1016/S0140-6736(12)60570-4 1

Timefrom 1 month to event (days)

Su

rviv

al p

rob

ab

ility

Short- vs long-term AAD Rx after cardioversion

Short-term AAD Rx after cardioversion prevents approximately 80% of AF

recurrences, although long-term therapy is statistically more effective.

Landmark analysis after 1 month

Kirch

ho

f e

t a

l, w

ww

.th

ela

nce

t.co

m P

ub

lish

ed

on

line

June 1

8, 2012 D

OI:

10.1

016/S

0140

-6736(1

2)6

0570-4

1

Choice of an antiarrhythmic drug for AF control (III)


Dronedarone is not recommended for treatment of AF in patients with NYHA

class III and IV, or with recently unstable (decompensation within the prior

month) NYHA class II heart failure. III B

Dronedarone is not recommended in patients with permanent AF III B

Antiarrhythmic drug therapy is not recommended for maintenance of sinus

rhythm in patients with advanced sinus node disease or AV node

dysfunction unless they have a functioning permanent pacemaker. III C




N Engl J Med 2011;365:2268-76

PALLAS: First co-primary outcome (stroke, MI, SEE, CV death)

Dronedarone

Placebo

0 1 3 6

0 1 3 6

Months

Cu

mu

lative

Ha

za

rd

1.0

0.8

0.6

0.4

0.2

0.0

0.04

0.03

0.02

0.01

0.00

Placebo 1617 1445 908 377

Dronedarone 1619 1421 930 353

No. at Risk

Median follow-up

3.5 months

HR 2.29 (1.34-

3.94; p = 0.002)

PALLAS: Second co-primary outcome (unplanned CV hospitalization or death)

Dronedarone

Placebo

0 1 3 6

Months

0 1 3 6

Cu

mu

lative

Ha

za

rd

1.0

0.8

0.6

0.4

0.2

0.0

0.12

0.08

0.04

0.00

No. at Risk

Placebo 1617 1429 882 361

Dronedarone 1619 1389 879 334

Median follow-up

3.5 months

HR 1.95 (1.45-

2.62; p < 0.001)

N Engl J Med 2011;365:2268-76

Summary of Recommendations Regarding the Use of Dronedarone


Dronedarone is recommended in patients with recurrent AF as a moderately

effective antiarrhythmic agent for the maintenance of sinus rhythm. I A

Dronedarone should be considered in order to reduce cardiovascular

hospitalizations in patients with non-permanent AF and cardiovascular risk

factors. IIa B

Dronedarone is not recommended for treatment of AF in patients with NYHA

class III and IV, or with recently unstable (decompensation within the prior

month) NYHA class II heart failure. III B

Dronedarone is not recommended in patients with permanent AF III B





Choice between ablation and antiarrhythmic drug therapy

for patients with and without structural heart disease

†More extensive LA ablation may be needed; *usually PVI is appropriate.

AF = atrial fibrillation; CAD = coronary artery disease; CHF = congestive heart failure; HT = hypertension; LVH = left ventricular hypertrophy;

NYHA = New York Heart Association; PVI = pulmonary vein isolation. Antiarrhythmic agents are listed in alphabetical order within each treatment box.

CHF

Stable

NYHA III

NYHA III/IV

or unstable

NHYA II

Dronedarone Dronedarone

Sotalol Dronedarone

Catheter

ablation for AF

Amiodarone

CAD Hypertension

with LVH

Relevant underlying

heart disease

Dronedarone

Flecainide

Propafenone

Sotalol

Amiodarone

Paroxysmal

AF

Persistent

AF

Catheter

ablation for AF*

No or minimal heart disease

(including HT without LVH)

Antiarrhythmic drugs and/or left atrial ablation

for rhythm control in AF

* = usually PVI is appropriate ‡ = more

extensive LA ablation may be needed;

* = not recommended in LVH;

ǂ caution with coronary heart disease;

HF = heart failure.

No or minimal structural heart disease

Paroxysmal Persistent

amiodarone

dronedarone,

flecainide,

propafenone,

sotalol

Catheter

ablation

Patient choice

‡

*

Patient choice

Relevant structural heart disease

HF

dronedaroneǂ, sotalol *

Due to AF

Catheter ablation ‡

No Yes

amiodarone

Patient choice

Yes

No


European Heart Journal

doi:10.1093/eurheartj/ehs253


2012 focused update of the ESC Guidelines for the

Management of Atrial Fibrillation An update of the 2010 ESC Guidelines for the Management of Atrial Fibrillation

Developed with the special contribution of the European Heart Rhythm Association

Authors/Task Force Members: A. John Camm (Chairperson) (UK)*, Gregory Y. H. Lip (UK), Dan Atar (Norway), Raffaele

De Caterina (Italy), Gerhard Hindricks (Germany), Stefan H. Hohnloser (Germany), Paulus Kirchhof (Germany/UK), Irene

Savelieva (UK)

ESC Committee for Practice Guidelines (CPG): Jeroen J. Bax (CPG Chairperson) (The Netherlands),

Helmut Baumgartner (Germany), Claudio Ceconi (Italy), Veronica Dean (France), Christi Deaton (UK),

Robert Fagard (Belgium), Christian Funck-Brentano (France), David Hasdai (Israel), Arno Hoes (The Netherlands), Paulus Kirchhof (Germany/UK),

Juhani Knuuti (Finland), Philippe Kolh (Belgium), Theresa McDonagh (UK), Cyril Moulin (France), Bogdan A. Popescu (Romania), Željko Reiner

(Croatia), Udo Sechtem (Germany), Per Anton Sirnes (Norway), Michal Tendera (Poland), Adam Torbicki (Poland), Alec Vahanian (France),Stephan

Windecker (Switzerland).

Document Reviewers: Panos Vardas (Review Coordinator) (Greece), Nawwar Al-Attar (France), Ottavio Alfieri† (Italy), Annalisa Angelini (Italy),

Carina Blömstrom-Lundqvist (Sweden), Paolo Colonna (Italy), Johan De Sutter (Belgium), Sabine Ernst (UK), Andreas Goette (Germany), Bulent

Gorenek (Turkey), Robert Hatala (Slovak Republic), Hein Heidbüchel (Belgium), Magnus Heldal (Norway), Steen Dalby Kristensen (Denmark),

Philippe Kolh† (Belgium), Jean-Yves Le Heuzey (France), Hercules Mavrakis (Greece), Lluís Mont (Spain), Pasquale Perrone Filardi (Italy), Piotr

Ponikowski (Poland), Bernard Prendergast (UK), Frans Rutten (The Netherlands), Ulrich Schotten (The Netherlands), Isabelle C. Van Gelder (The

Netherlands), Freek Verheugt (The Netherlands)

2012 update of the esc guidelines on the management of atrial

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