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John Camm

St. Georges University of London

United Kingdom

Update of the ESC

Guidelines on

Medical Therapy

2012

Update on Consensus Statements

on Management of Atrial Fibrillation

European Heart Rhythm

Association

ESC 2012

ICM

Internationales

Congress Center

Mnchen

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

ESC 2012

ICM - Internationales Congress Center Mnchen

Update of the ESC Guidelines on

Medical Therapy 2012

Update on Consensus Statements on Management of Atrial Fibrillation

European Heart Rhythm Association

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 A B C I IIa IIb III

Anticoagulation risk stratification 6 7 6 7

Anticoagulation 2 5 1 3 4 1

Left atrial appendage occlusion 1 1 2

Pharmacological cardioversion 1 2 1 2

Oral antiarrhythmic therapy 1 2 1 1 1

Left atrial catheter ablation 2 3 1 4

Total n (%) 12 (35%)

20 (59%)

2 (9%)

12 (35%)

17 (50%)

3 (9%)

2 (9%)


Anticoagulation - General

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

Recommendations for prevention of thromboembolism in non-valvular 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

CHADS2 vs CHA2DS2VASc

Olesen JB et al, BMJ 2011;342:d124

All patients with atrial fibrillation not treated with

VKAs in Denmark 1997- 2006

73 538 fulfilled the study inclusion criteria

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

Pro

po

rtio

n o

f p

ati

en

ts f

ree

of

thro

mb

oe

mb

oli

sm

(%

)

Years of follow-up

0 2 4 6 8 10

100

90

80

70

60

0

CHADS2 score = 0

Heart failure

Hypertension

Diabetes mellitus

Age 75 years

100

90

80

70

60

0

Pro

po

rtio

n o

f p

ati

en

ts f

ree

of

thro

mb

oe

mb

oli

sm

(%

)

Years of follow-up

0 2 4 6 8 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

CHADS2 score = 0

Female sex

Heart failure

Hypertension

Vascular disease

Age 6574 years

Diabetes mellitus

CHA2DS2-VASc Assessment of Thromboembolic Risk

Score Annual stroke

rate, %

n 1084 73 538

0 0 0.78

1 1.3 2.01

2 2.2 3.71

3 3.2 5.92

4 4.0 9.27

5 6.7 15.26

6 9.8 19.78

7 9.6 21.50

8 6.7 22.38

9 15.2 23.64

Congestive heart failure/ 1 LV dysfunction

Hypertension 1 Age 75 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease 1

(CAD, AoD, PAD)

Age 65-74 1 Sex category (female) 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 Lip GYH, et al.

Chest 2009

Olesen JB et al.

BMJ 2011;342:124


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

Stroke Prevention: Anticoagulant Effect

Meta-analysis of stroke or systemic embolism

Modified from Camm AJ. EHJ 2009;30:25545

Favours

warfarin

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

Favours other

Rx

Category Relative Hazard Ratio

(95% CI)

W vs Placebo

W vs Wlow dose

W vs Aspirin

W vs Aspirin + Clop

W vs Ximelagatran

W vs Dabigatran 110

W vs Rivaroxaban

W vs Dabigatran 150

W vs Apixaban 5

Favours

warfarin

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

Favours other

Rx

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

W vs Dabigatran 110

W vs Rivaroxaban

W vs Dabigatran 150

W vs Apixaban 5

W vs Dabigatran 110

W vs Rivaroxaban

W vs Dabigatran 150

W vs Apixaban 5

Major bleeding

ICH

Anticoagulation - NOACs


Recommendations for prevention of thromboembolism in non-valvular AF - NOACs


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.

I B

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 A

Anticoagulation General

Antiplatelet Agents

Recommendations for prevention of thromboembolism in non-

valvular AF - general


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.

IIa B


Choice of Anticoagulant

* 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


Atrial fibrillation

Valvular AF*

VKA No antithrombotic therapy NOAC

1** 2

Yes

No

Yes

No (i.e. non-valvular AF)

0

Oral anticoagulant therapy

Assess bleeding risk (HAS-BLED score)

Consider patient values and preferences

< 65 years and lone AF (including females)

Assess risk of stroke

(CHA2DS2-VASc score)

Dabigatran - Stroke and Systemic Embolism after Cardioversion

p = 0.40

0

0,5

1

1,5

2

2,5

3

3,5

4

D110 mg BID D150 mg BID Warfarin

p = 0.71

Str

oke /

Syste

mic

Em

bo

lism

Rate

(%

)

0.8

0.3

0.6

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

1983 cardioversions were performed in 1270 patients

0

0,5

1

1,5

2

With TEE prior

to cardioversion

Without TEE prior

to cardioversion

0.15

0 0.15

0.62

0.30

0.45

Anticoagulation - Cardioversion


Recommendations for prevention of thromboembolism in non-valvular AF Peri-cardioversion


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).

I B

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.

I B

Stroke Outcome After Ablation vs AAD Therapy: Propensity-Matched Analysis

Reynolds MR, et al.

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

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

Characteristic 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

0.50

0.60

0.70

0.80

0.90

1.00

0 0.5 1 1.5 2 2.5 3

Stroke/TIA free survival

8.3%

Years

AF, ablation

AF, no ablation

14.1%

Log-rank p = 0.005

HR = 0.60 (0.43 0.84)

Warfarin use decline to 50% in both groups

0.00

0.05

0.10

0.15

0.20

0 365 730 1,095

PROTECT-AF Primary Safety and Efficacy Endpoints

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

Intention-to-treat analysis

0.00

0.05

0.10

0.15

0.20

0 365 730 1,095Days

1o s

afe

ty e

nd

po

int

Warfarin 4.4 per 100 pt-yrs

Watchman 7.4 per 100 pt-yrs

RR = 1.69 (1.01 3.19) Non-inferiority > 99.9%

Superiority 90%

1o e

ffic

acy e

nd

po

int RR = 0.62 (0.35 1.25)

Non-nferiority > 99.9%

Superiority 98.6%

Days

Watchman 3.0 per 100 pt-yrs

Warfarin 4.4 per 100 pt-yrs

Major bleeding (IC, GI)

Serious procedure

related complications:

Tamponade Device

embolization

Stroke

All strokes CV deaths Unexplained death

LAA Closure/Occlusion/Excision

Recommendations

for LAA closure/occlusion/excision


Interventional, percutaneous LAA closure may

be considered in patients with a high stroke risk

and contraindications for long-term oral

anticoagulation.

IIb B

Surgical excision of the LAA may be

considered in patients

undergoing open heart surgery. IIb C



Choice of Anti-coagulant

Atrial fibrillation

Valvular AF*

VKA No antithrombotic therapy NOAC

Assess risk of stroke

(CHA2DS2-VASc score)

1** 2

Yes

No

Yes

No (i.e. non-valvular AF)

0

Oral anticoagulant therapy

Assess bleeding risk (HAS-BLED score)

Consider patient values and preferences

< 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


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

10 and 2 Efficacy Endpoint Results Time and Rate of Conversion from AF to SR

Within 90 Minutes

P < 0.0001 (Log-Rank test)

51.7%

5.2%

Median Time To conversion in Vernakalant Responders was 11 minutes

10 min 25 min 35 min

Vernakalant 24.1% 42.2% 45.7%

Amiodarone 0.9% 2.6% 3.5%

Recommendations for pharmacological cardioversion of recent-onset AF


When pharmacological cardioversion is preferred and there is

no or minimal structural heart disease, intravenous flecainide,

propafenone, ibutilide, or vernakalant are recommended. I A

In patients with AF 7 days and moderate structural heart disease (but without hypotension

Cardioversion

Recent Onset

AF

Haemodynamic instability

Structural heart disease

Electrical cardioversion

Recent-onset AF

Intravenous amiodarone

yes no

Patient/physician choice

Emergency Elective

Intravenous Ibutilide* vernakalant

Intravenous flecainide propafenone vernakalant

electrical

pharmacological

Intravenous amiodarone Intravenous

amiodarone

Severe Moderate None

Pill-in-the pocket (high dose oral)

flecainide propafenone

aIbutilide 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.


Permanent versus Non-Permanent AF

CV hospitalization or death %

Months 0

10

20

30

40

50

0 6 12 18 24 30

HR = 0.76

P < 0.001

Placebo

Dronedarone

ATHENA

Cu

mu

lati

ve

Ha

za

rd

PALLAS

Mean follow-up

21 5 months

HR = 0.74 P = 0.096

0

10

20

30

40

50

0 6 12 18 24 30

Cu

mu

lati

ve

Ha

za

rd CV hospitalization or death %

Months

0 1 3 6 2 4 5

Cu

mu

lati

ve H

azard

Months

Stroke, MI, SEE or CV Death %

0

2

4

1

3

Cu

mu

lati

ve

Ha

za

rd CV hospitalization or death %

Months 0

4

8

12

0 1 3 6 2 4 5

Hohnloser SH et al. N Engl J Med. 2009;360:668-78 Connolly S et al. N Engl J Med. 2011;365:2268-76

HR = 2.29 P = 0.002

HR = 1.95 P = 0.001

permanent

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

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

CAD.

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

Concomitant medications: lisinopril, hydrochlorothiazide, bisoprolol, amlodipine, l-thyroxine, simvastatin, ASA, alendronic acid, tiotropium, formoterol.

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

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

syndrome.

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

Concomitant medications: metoprolol, amlodipine, omeprazole, warfarin, alprazolam, calcium, biotin and multivitamins.

Presentation: 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 60-70% necrosis.

Two cases of liver failure and transplant, 2010

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

Re

po

rtin

g r

ate

in

pa

tie

nt-

ye

ars

x 1

00

0

Based on the estimated 440,000 patients treated with dronedarone up to 30 June 2011*

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)

635 patients,

Mean age 64 years,

Primary outcome:

Time to persistent

AF, or death

Monitored by

telemetric ECG

Flecainide 4 weeks vs long-term therapy

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

Recommendations for oral antiarrhythmic agents


Dronedarone is recommended in patients with recurrent AF as a

moderately effective antiarrhythmic agent for the maintenance of

sinus rhythm. I A

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

Dronedarone is not recommended in patients with permanent

AF. III B

Oral Antiarrhythmic Drugs


Choice of Oral Antiarrhythmic Drug

Treatment of underlying condition and prevention of

remodelling ACE-I / ARB / statin

HF 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


Pocket Guidelines


Thank you for your attention

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