ESC

2012

Update on Consensus Statements

ICM
on Management of Atrial Fibrillation
Internationales
European Heart Rhythm
Congress Center
Association
Mnchen

Update of the ESC

Guidelines on
Medical Therapy

2012
John Camm
St. Georges University of London
United Kingdom

ESC

ICM - Internationales Congress Center Mnchen

2012
Update on Consensus Statements on Management of Atrial Fibrillation
European Heart Rhythm Association

Update of the ESC Guidelines on

Medical Therapy 2012

John Camm
Conflicts of Interest: Consultant/Advisor/Speaker
Advisor / Speaker : Astra Zeneca, Gilead, Merck, Menarini, Sanofi Aventis,
Servier, Xention, Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi,
Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion,
GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi,
Novartis, Takeda

Management of Atrial Fibrillation

Focus of 2012 Update
Anticoagulation risk stratification
Use of novel oral anticoagulants (NOACs)
Left atrial appendage occlusion/excision
Pharmacological cardioversion (vernakalant)
Oral antiarrhythmic therapy (dronedarone, and
short term therapy)

Left atrial catheter ablation

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

New /Modified
Recommendations
Topic

Anticoagulation risk stratification

Anticoagulation

Left atrial appendage occlusion

IIa

IIb

III

1
2

Pharmacological cardioversion

Oral antiarrhythmic therapy

Left atrial catheter ablation

Total n (%)

12

20

12

(35%)

(59%)

(9%)

(35%)

17

(50%)

(9%)

(9%)

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

Anticoagulation - General
Recommendations for prevention of thromboembolism in nonvalvular AF - general
Recommendations

Class

Level

Antithrombotic therapy to prevent thromboembolism is

recommended for all patients with AF, except in those
patients (both male and female) who are at low risk (aged <65
years and lone AF), or with contraindications.

The choice of antithrombotic therapy should be based upon

the absolute risks of stroke/thromboembolism and
bleeding and the net clinical benefit for a given patient.

The CHA2DS2-VASc score is recommended as a means of

assessing stroke risk in non-valvular AF.

ESC Update on the Management of AF: European Heart Journal/EP- Europace 2012

CHADS2 vs CHA2DS2VASc
All patients with atrial fibrillation not treated with
VKAs in Denmark 1997- 2006
CHADS2 score = 0
Heart failure
Hypertension

73 538 fulfilled the study inclusion criteria

CHADS2 score = 0
Female sex
Heart failure
Hypertension

Diabetes mellitus
Age 75 years

100
Proportion of patients free
of thromboembolism (%)

Proportion of patients free

of thromboembolism (%)

100

Vascular disease
Age 6574 years
Diabetes mellitus

90
80
70
60
0

90
80
70
60
0

4
6
Years of follow-up

10

Kaplan-Meier estimate of probability of remaining

free of thromboembolism with CHADS2 score 0 and 1. Only
patients with CHADS2 scores 0 and 1 were included, and
patients were censored at death for causes other than
thromboembolism

Olesen JB et al, BMJ 2011;342:d124

4
6
Years of follow-up

10

Kaplan-Meier estimate of probability of remaining

free of thromboembolism with CHA2DS2 score 0 and 1.
Only patients with CHA2DS2 scores 0 and 1 were included,
and patients were censored at death for causes other than
thromboembolism

CHA2DS2-VASc

Assessment of Thromboembolic Risk

Congestive heart failure/

LV dysfunction
Hypertension
Age 75
Diabetes mellitus
Stroke/TIA/TE
Vascular disease
(CAD, AoD, PAD)
Age 65-74
Sex category (female)

Annual stroke
rate, %

Score

1
2
1
2
1

1084

73 538

0.78

1.3

2.01

2.2

3.71

3.2

5.92

4.0

9.27

6.7

15.26

9.8

19.78

9.6

21.50

6.7

22.38

15.2

23.64

1
1

Score 0 9
Validated in 1084 NVAF patients not on OAC with
known TE status at 1 year in Euro Heart Survey

OR for stroke if:

Female: 2.53 (1.08 5.92), p=0.029;
Vascular disease: 2.27 (0.94 5.46), p=0.063

Olesen JB et al.
Lip GYH, et al.
BMJ 2011;342:124
Chest 2009

Recommendations

Class

Level

In patients with a CHA2DS2-VASc score of 0 (i.e., aged <65

years with lone AF) who are at low risk, with none of the
risk factors, no antithrombotic therapy is recommended.

In patients with a CHA2DS2-VASc score 2, OAC therapy with:

adjusted-dose VKA (INR 23); or
a direct thrombin inhibitor (dabigatran); or
an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d
. is recommended, unless contraindicated.

IIa

In patients with a CHA2DS2-VASc score of 1, OAC therapy with:

adjusted-dose VKA (INR 23); or
a direct thrombin inhibitor (dabigatran); or
an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d
. should be considered, based upon an assessment of the risk
of bleeding complications and patient preferences.
d

= pending EMA/FDA approval prescribing information is awaited

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

Stroke Prevention: Anticoagulant

Effect
Meta-analysis of stroke or systemic embolism
Relative Hazard Ratio
(95% CI)

Category
W vs Placebo

ICH
W vs Dabigatran 110
W vs Rivaroxaban

W vs Wlow dose

W vs Dabigatran 150

W vs Aspirin

W vs Apixaban 5

W vs Aspirin + Clop

0.3 0.6 0.9 1.2 1.5 1.8 2.0

W vs Ximelagatran
W vs Dabigatran 110

W vs Rivaroxaban

W vs Dabigatran 110

W vs Rivaroxaban

W vs Dabigatran 150
W vs Apixaban 5

Major bleeding

W vs Dabigatran 150
W vs Apixaban 5

0.3 0.6 0.9 1.2 1.5 1.8 2.0

Favours
Favours other
warfarin
Rx

Modified from Camm AJ. EHJ 2009;30:25545

0.3 0.6 0.9 1.2 1.5 1.8 2.0

Favours
Favours other
warfarin
Rx

Anticoagulation - NOACs
Recommendations for prevention of thromboembolism in nonvalvular AF - NOACs
Recommendations

Class

Level

When adjusted-dose VKA (INR 23) cannot be used in a

patient with AF where an OAC is recommended, due to
difficulties in keeping within therapeutic anticoagulation,
experiencing side effects of VKAs, or inability to attend or
undertake INR monitoring, one of the NOACs, either:
a direct thrombin inhibitor (dabigatran); or
an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d
is recommended.

Where OAC is recommended, one of the NOACs, either:

a direct thrombin inhibitor (dabigatran); or
an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d
should be considered rather than adjusted-dose VKA (INR
23) for most patients with non-valvular AF, based
on their net clinical benefit.

IIa

ESC Update on the Management of AF: European Heart Journal/EP- Europace 2012

Anticoagulation General
Antiplatelet Agents
Recommendations for prevention of thromboembolism in nonvalvular AF - general
Recommendations
When patients refuse the use of any OAC (whether VKAs or
NOACs), antiplatelet therapy should be considered,
using combination therapy with aspirin 75100 mg plus
clopidogrel 75 mg daily (where there is a low risk of bleeding)
or less effectively aspirin 75325 mg daily.

Class

Level

IIa

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

Choice of
Anticoagulant

Atrial fibrillation
Yes

Valvular AF*
Yes

No (i.e. non-valvular AF)

< 65 years and lone AF (including females)
No

Includes rheumatic valvular AF,

hypertrophic cardiomyopathy, etc.

**

Antiplatelet therapy with

aspirin plus clopidogrel, or
less effectively aspirin only,
may be considered in patients
who refuse any OAC

Assess risk of stroke

(CHA2DS2-VASc score)

1**

Oral anticoagulant therapy

Assess bleeding risk (HAS-BLED score)
Consider patient values and preferences

No antithrombotic therapy

NOAC

VKA

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

Dabigatran - Stroke and Systemic

Embolism after Cardioversion
Stroke / Systemic Embolism Rate (%)

1983 cardioversions were performed in 1270 patients

4

3,5

p = 0.71
3

1,5

2,5

p = 0.40

With TEE prior

to cardioversion

0.62

1,5
1
0,5

Without TEE prior

to cardioversion

0.45

0.8

0.6

0,5

0.3

0.15
0

D110 mg BID D150 mg BID

0.30

0.15

Warfarin

Nagarakanti R et al. Circulation. 2011;123:131-136

Anticoagulation - Cardioversion
Recommendations for prevention of thromboembolism in nonvalvular AF Peri-cardioversion
Recommendations

Class

Level

For patients with AF of 48 h duration, or when the duration of

AF is unknown, OAC therapy (e.g., VKA with INR 2-3
or dabigatran) is recommended for 3 weeks prior to and for
4 weeks after cardioversion, regardless of the method
(electrical or oral/i.v. pharmacological).

In patients with risk factors for stroke or AF recurrence, OAC

therapy, whether with dose-adjusted VKA (INR
2-3) or a NOAC, should be continued lifelong irrespective of
the apparent maintenance of sinus rhythm following
cardioversion.

ESC Update on the Management of AF: European Heart Journal/EP- Europace 2012

Stroke Outcome After Ablation vs AAD

Therapy: Propensity-Matched Analysis
Market Scan Research Database
2005-2009
Ablation: n = 3194
AAD: n = 6028
Used in propensity-matched analysis: 801 pairs
Follow-up: 27 months

Ablation
n = 801

AAD
n = 801

Age group, %
35-49
50-64
65-80
> 80

8.49
42.57
44.19
4.0

8.61
46.69
40.57
3.37

Men, %

60.92

62.55

Hypertension, %

42.7

40.7

Diabetes, %

18.73

15.23

CHF, %

17.35

15.73

CAD, %

35.33

33.46

Stroke/TIA, %

2.87

4.12

CHADS2, %
0
1
2
3

36.2
37.95
19.73
6.12

34.83
40.32
17.23
7.61

Warfarin

69.91

69.54

Characteristic

Stroke/TIA free survival

1.00

8.3%

0.90

14.1%
0.80

HR = 0.60 (0.43 0.84)

0.70

AF, ablation
AF, no ablation

0.60

Log-rank p = 0.005
0.50
0

0.5

1.5

Years

2.5

Reynolds MR, et al.

Circ Cardiovasc Qual Outcomes 2012;5 [epub ahead of press]

Warfarin use decline to 50% in both groups

PROTECT-AF
Primary Safety and Efficacy Endpoints
Major bleeding (IC, GI)
Serious procedure
related complications:

Tamponade
Device

embolization
Stroke

1o safety endpoint

0.20

RR = 1.69 (1.01 3.19)

Non-inferiority > 99.9%
Superiority 90%

0.15
0.10

Warfarin
4.4 per 100 pt-yrs

0.05
0.00
0

All strokes
CV deaths
Unexplained death

1o efficacy endpoint

Intention-to-treat analysis

Watchman
7.4 per 100 pt-yrs

0.20

365

Days

730

1,095

RR = 0.62 (0.35 1.25)

Non-nferiority > 99.9%
Superiority 98.6%

0.15

Warfarin
4.4 per 100 pt-yrs

0.10
Watchman
3.0 per 100 pt-yrs

0.05
0.00
0

Holmes DR, et al. Lancet 2009;374:534-42

365

Days

730

1,095

LAA Closure/Occlusion/Excision
Recommendations
for LAA closure/occlusion/excision
Recommendations

Class

Level

Interventional, percutaneous LAA closure may

be considered in patients with a high stroke risk
and contraindications for long-term oral
anticoagulation.

IIb

Surgical excision of the LAA may be

considered in patients
undergoing open heart surgery.

IIb

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

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

Choice of
Anti-coagulant

Atrial fibrillation
Yes

Valvular AF*
Yes

No (i.e. non-valvular AF)

< 65 years and lone AF (including females)

* Includes rheumatic valvular AF,

hypertrophic cardiomyopathy, etc.

**

Antiplatelet therapy with

aspirin plus clopidogrel, or
less effectively aspirin only,
may be considered in patients
who refuse any OAC

No
Assess risk of stroke
(CHA2DS2-VASc score)

1**

Oral anticoagulant therapy

Assess bleeding risk (HAS-BLED score)
Consider patient values and preferences

No antithrombotic therapy

NOAC

VKA

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

Intravenous Vernakalant
Consistent Conversion Rates
*

**

**

**

CRAFT: Dosing was 2+3 mg/kg; data represents % converted at 60 min post last dose; AF duration 3-72 hours
ACT I, III & IV: AF <7 days
** P0.0001
** P0.0001
ACT II: Post CABG and valvular AF study; AF duration 3-72 hours
ACT IV: A placebo group was not included in the ACT IV study

10 and 2 Efficacy Endpoint Results

Time and Rate of Conversion from AF to SR
Within 90 Minutes

51.7%
P < 0.0001 (Log-Rank test)
10 min

25 min

35 min

Vernakalant

24.1%

42.2%

45.7%

Amiodarone

0.9%

2.6%

3.5%

5.2%

Median Time To conversion in Vernakalant Responders was 11 minutes

Pharmacological Cardioversion
Recommendations for pharmacological cardioversion of recent-onset AF

Recommendations

Class Level

When pharmacological cardioversion is preferred and there is

no or minimal structural heart disease, intravenous flecainide,
propafenone, ibutilide, or vernakalant are recommended.

In patients with AF 7 days and moderate structural heart

disease (but without hypotension <100 mm Hg, NYHA class III
or IV heart failure, recent [<30 days] ACS, or severe aortic
stenosis) intravenous vernakalant may be considered.
Vernakalant should be used with caution in patients with NYHA
class III heart failure.

IIb

Intravenous vernakalant may be considered for cardioversion of

postoperative AF 3 days in patients after cardiac surgery.

IIb

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

Recent-onset AF
Haemodynamic instability
yes

no
electrical

Cardioversion
Recent Onset
AF

Patient/physician choice

pharmacological

Emergency

Structural heart disease

Elective

Severe

Electrical
cardioversion

aIbutilide

Intravenous
amiodarone

should not be given when significant left ventricular hypertrophy (1.4 cm) is

present.
bVernakalant should not be given in moderate or severe heart failure, aortic stenosis,
acute coronary syndrome or hypotension. Caution in mild heart failure.
c Pill-in-the-pocket technique preliminary assessment in a medically safe
environment and then used by the patient in the ambulatory setting.

None

Moderate

Intravenous
Ibutilide*
vernakalant
Intravenous
amiodarone

Intravenous
flecainide
propafenone
vernakalant

Pill-in-the
pocket
(high dose oral)

flecainide
propafenone

Intravenous
amiodarone

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

Permanent versus Non-Permanent AF

ATHENA

PALLAS

HR = 0.76
40 P < 0.001
30
Placebo

20

Dronedarone

10

Months
0
0
6
12 18 24 30
50 CV hospitalization or death %
permanent
HR = 0.74
40
P = 0.096
30
20

Mean follow-up
21 5 months

10

Months

0
0

12

18

24

30

Hohnloser SH et al. N Engl J Med. 2009;360:668-78

Cumulative Hazard

50

Stroke, MI, SEE or CV Death %

HR = 2.29
P = 0.002

3
2
1

Months

0
Cumulative Hazard

Cumulative Hazard

Cumulative Hazard

CV hospitalization or death %

CV hospitalization or death %

12

HR = 1.95
P = 0.001

8
4

Months

Connolly S et al. N Engl J Med. 2011;365:2268-76

Dronedarone Therapeutic Indication

September 2009
MULTAQ is indicated in adult clinically stable patients with a history of,
or current non-permanent atrial fibrillation (AF) to prevent recurrence of
AF or to lower ventricular rate (see section 5.1).

September 2011
MULTAQ is indicated for the maintenance of sinus rhythm after
successful cardioversion in adult clinically stable patients with
paroxysmal or persistent atrial fibrillation (AF). Due to its safety profile
(see sections 4.3 and 4.4), Multaq should only be prescribed after
alternative treatment options have been considered.
MULTAQ should not be given to patients with left ventricular systolic
dysfunction or to patients with current or previous episodes of heart
failure.
Multaq (Dronedarone) SmPC Europe, September 2011

Details of the Hepatic Failure Cases

Two cases of liver failure and transplant, 2010

69-year-old female
History: intermittent AF, high BP & stable

72-year-old female
History: paroxysmal AF and Sjgrens

CAD.
Received Dronedarone for 4.5m, no LFTs
during this period.

syndrome.
Received Dronedarone for 6 m, with no
LFTs during this period.

Concomitant medications:

Concomitant medications:

lisinopril, hydrochlorothiazide, bisoprolol,

amlodipine, l-thyroxine, simvastatin, ASA,
alendronic acid, tiotropium, formoterol.

metoprolol, amlodipine, omeprazole,

warfarin, alprazolam, calcium, biotin and
multivitamins.

Presentation:

Presentation:

2 weeks prior to hospitalization was exhausted

and tired. 1 week prior to admission
discontinued Dronedarone, and on admission
had jaundice, coagulopathy, transaminitis and
hyperbilirubinemia; hepatic encephalopathy
after 9 days. She was transplanted
Pre-transplant workup no other cause

Developed weakness, abdominal pain,

coagulopathy, transaminitis and
hyperbilirubinemia. She was transplanted
1 month later.
Pre-transplant no other cause. A liver
biopsy prior to transplant revealed 6070% necrosis.

Joghetaei N, et al. Circ Arrhythm Electrophysiol. 2011;4:592-593.

U.S. FDA Drug Safety Communication. http://www.fda.gov/drugs/drugsafety/ucm240011.htm

Dronedarone
2 year Post-marketing Safety Data
Based on the estimated 440,000 patients treated with dronedarone up to 30 June 2011*

Reporting rate in patient-years x 1000

Reporting rate per 1000 patient-years for serious adverse events per periodic safety update period

1 Jul 2009 31 Jan 2010

1 Feb 2010 - 31 Jul 2010

1 Aug 2010 31 Jan 2011

1 Feb 2011 30 Jun 2011

*Estimated. IMS/MIDAS Worldwide Monthly Database, Standard Units Sold until 30 June 2011, reported Aug 2011

FLEC-SL: Primary outcome (ITT)

Flecainide 4 weeks vs long-term therapy
635 patients,
Mean age 64 years,

Primary outcome:
Time to persistent
AF, or death
Monitored by
telemetric ECG

Kirchhof P et al Lancet. 2012 Jul 21;380(9838):238-46.

Oral Antiarrhythmic Drugs

Recommendations for oral antiarrhythmic agents
Recommendations

Class Level

Dronedarone is recommended in patients with recurrent AF as a

moderately effective antiarrhythmic agent for the maintenance of
sinus rhythm.

Short-term (4 weeks) antiarrhythmic therapy after cardioversion

may be considered in selected patients e.g., those at risk for
therapy associated complications.

IIb

Dronedarone is not recommended in patients with permanent

AF.

III

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

Choice of Oral Antiarrhythmic Drug

Minimal or no structural heart disease

Significant structural heart disease

Treatment of underlying condition and prevention of
remodelling ACE-I / ARB / statin

HHD

No LVH

dronedarone / flecainide /
propafenone / sotalol

amiodarone

CHD

LVH

sotalol

dronedarone

dronedarone

amiodarone

HF

amiodarone

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

Pocket Guidelines

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

Thank you for your attention

Thank you for your attention