John Camm

St. George’s University of London

United Kingdom

Davos, February 14th 2011

A Paradigm Shift in AF Management

From the ECG to Cardiovascular Outcomes

John Camm

Conflicts of Interest: Consultant/Advisor/Speaker

Advisor / Speaker : Ambit, Servier, Novartis, sanofi aventis, Astra Zeneca,

Cardiome, Prism, Astellas, Menarini, Xention, ARYx, Bristol Myers Squibb,

Daiichi, Bayer, Merck, Medtronic, St. Jude, Biotronik, Boehringer Ingleheim,

Takeda, GlaxoSmithKline, Boston Scientific, Pfizer, GlaxoSmithKline, Actelion,

Johnson and Johnson, Solvay Pharma

Davos, February 2011

Paradigm Shift

ECG to Outcomes

“Paradigm Shift”Thomas Kuhn in his influential book “ The Structure of Scientific Revolutions” to

describe a change in basic assumptions within the ruling theory of science.

Vase versus Faces Duck versus Rabbit Young lady v Old lady

A buzzword, popularized as marketing speak and appearing more frequently in print and

publication. In his book, Mind The Gaffe, author Larry Trask advises readers to refrain

from using it, because it is abused and overused to the point of becoming meaningless.

History of Antiarrhythmic Drugs

1914 - Quinidine

1950 - Lidocaine

1951 - Procainamide

1956 – Ajmaline

1962 – Disopyramide

1967 – Amiodarone

1972 – Mexiletine

1973 – Aprindine, Tocainide

1975- Flecainide

1976 – Propafenone

1946 – Digitalis

1962 - Verapamil

1964 - Propranolol

1965 – Bretylium

1969 - Diltiazem

2009 – Dronedarone

2010 – Vernakalant (Europe)

1995 - Ibutilide (US)

2000 – Dofetilide US)

2000 - Sotalol

AF Rhythm Endpoints

x x x

Time to 1st event

Time to last AF event,

if > 24 hours, > 1 month,

CCV resistant, etc.

Time to > 24hrs AF, or AF / unit time

Any AF event

AF event > I hour

Symptomatic AF event

Cumulative AF duration/burden

Persistent (permanent) AF onset

xAF episode Symptomatic AF episode

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

SAFE-T Sotalol Amiodarone AF Efficacy Trial

Singh BN et al. NEJM. 2005;352:1861-1872.

VA Cooperative Study

N=665, 20% AF >1 year:

Amio 267, Sot 261, Placebo 137

Sotalol

Placebo

Amiodarone

Days

Fre

e fr

om

AF

rec

urr

ence

(O

T /

ITT

)

Follow-up 1year with TTM weekly

1o EP: time to 1st AF recn after CV

0

20

40

60

80

Spontaneous DCC Failed CV Total

Co

nve

rsio

n t

o S

R [

%]

AmiodaroneSotalolPlacebo

300 10009008007006005004002001000

Randomized Controlled Studies of AADs: Design, Endpoints, and AF Monitoring

Study#

patientsDrug Design

Rhythm at inclusion and

CVPrimary EP AF monitoring

CTAF, 2000 403Amiodarone,

sotalol, propafenone

Open label, no placebo

AF/SR,CV after Rx

Time to 1st

recurrence

TTM at 4 & 14 days and at symptoms, visits at 3 mo, 6-mo

intervals

RAFT, 2003 523Propafenone

SRDB, PC

All in SR, loading period (days 1-4)

Time to 1st

recurrence

TTM at symptoms, visits at 1,3,6,12,24, 39

weeks

SAFIRE-D 325 Dofetilide DB, PCAF, CV in-hospital (3 days/5 doses)SR maintenance

Time to 1st

recurrence

Visits at 2 weeks, 1,2,3 mo, 3-mo intervals

thereafter

PAFAC, 2004

1182, 848 random-

izedSotalol, Q+V DB, PC SR, CV before Rx

Time to 1st

recurrenceTTM daily and at

symptoms

SAFE-T, 2005

665Amiodarone,

sotalolDB, PC AF, CV at 28 days

Time to 1st

recurrence(After d 28)

TTM weekly confirmed by 2 ECGs

in 2 hours

EURIDIS/ADONIS, 2007

12372:1

Dronedarone DB, PC SR, CV before RTime to 1st

recurrence

TTM days 2, 3, 5 and months 3, 5 7 and 10

and when symptomatic

2 TTMs in 10m)

DIONYSOS, 2009

504Dronedarone, amiodarone

DB, no placebo

AF, CV after Rxday 10-28

Time to 1st

recurrence or drug

discontinua-tion - after CV

12SL ECG

Symptomatic and Any AF Endpoints

Dronedarone 400 mg bidPlacebo

Cu

mu

lati

ve

In

cid

en

ce

0 60 120 180 240 300 360

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Time(days)

Log-rank test results: p=0.0138

10 endpoint: 1st Recurrence of

any AF/A Flutter

Cu

mu

lati

ve

In

cid

en

ce

0 60 120 180 240 300 360

0.3

0.4

0.5

0.6

0.7

0.8

0.0

0.1

0.2

Time(days)

Log-rank test results: p=0.0055

20 endpoint: 1st Symptomatic

AF/AFl Recurrence

Episode lasting 10 minutes,

i.e. two consecutive ECGs

10 minutes apart

TTMwith symptoms and on

preset intervals

EURIDIS – Dronedarone 612 pts with AF in SR

Reduction in AF Burden

http://ClinicalTrials.gov; 2 Jan, 2009

Budiodarone dose, mg bid

8

-10

-54

-75-83

-100

-80

-60

-40

-20

0

20

Placebo 200 400 600 600*

n.s.

p=0.015

p=0.005p=0.009

* at

3 m

onth

s

Overall p=0.0001

p=0.16

(P)aroxysmal (A)trial fibrillation (S)tudy with (C)ontinuous (A)trial fibrillation (L)ogging

Ezekowitz M et al; Abstract

Natural History and Progression from Paroxysmal to Permanent AF

Study No. of pts

Follow-up, years

Progression to permanent

AF

Euro Heart Survey, 2010

1219 1 15%

Tokyo study, 1995 137 1 22%

UK general practice, 2005

525 2.7 17%

CARAF, 2001 899 4.14 19%

Italian study (Pappone), 2008

106 5 28.8%

CARAF, 2005 757 8 25%

Danish study, 1986 426 9 33%

Parkinson, 1930 200 10 25%

Tokyo study, 2004 171 14 77%

Olmsted County (lone AF), 2007

71 25.2 31% Kerr CR, et al. Am Heart J 2005;149:489-96

Canadian Registry

of Atrial Fibrillation

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Years

Cu

mu

lative

in

cid

en

ce

of A

F, %

Permanent AF

1st documented AF recurrence

Sotalol versus Quinidine + Verapamil

Fetsch T, et al, Eur Heart J 2004;25:1385-94

Time (days)

Fre

ed

om

fro

m e

ven

t

Quin + Vera (n = 377)Sotalol (n = 383)Placebo (n = 88)

8007006005004003002001000

1.0

0.8

0.6

0.4

0.2

0.0

Time (days)

1o End-point: AF or death 2o End-point: persistent AF

8007006005004003002001000

1.0

0.8

0.6

0.4

0.2

0.0

62%

51%

23

%

35%

33

%17%

848 patients post DCC

MuscleFibrosis

Mahnkopf et al. Heart Rhythm 2010

The Progression of Atrial Fibrillation

Electrical AF

Electro-anatomical AF

Anatomical AF

ANTIPAF Trial Endpoints

AF Burden

Days when

AF was

documented

Time to first

Recurrence Time to

development

of persistent

AF

All show no

difference

between

Olmesartan

and placebo

AF Burden

Time to first

Recurrence

Time to

development of

persistent AF

Madrid, 2002n = 154, DCCAmio vs Amio+Irbesartan 300 mgFollow-up 254 days

Ueng, 2003n = 145, DCCAmio vs Amio+Enalapril 20 mgFollow-up 270 days

Madrid, 2004 (lone AF)n = 90, DCCAmio vs Amio+Irbesartan 150 mgor Amio+Irbesartan 300 mgFollow-up 220 days

CAPRAF, 2006n = 171, DCCPlacebo vs Candesartan 8-16 mgFollow-up 200 days

Yin, 2006(lone PAF)n = 177Amio vs Amio+Losartan 100 mgvs Amio+Perindopril 4 mgFollow-up 24 months

Fogari, 2006n = 250PAF or DCCAmio vs Amio+Losartan 100 mgFollow-up 12 months

GISSI AF, 2009n = 1442PAF or DCC (88%) Placebo vsValsartan 320 mgFollow-up 12 months

ANTIPAF, 2010n = 225PAF Placebo vsOlmesartan 40 mgFollow-up 12 months

J-RHYTHM II, 2010n = 318PAF Amlodipine 2.5-5 mg vsCandesartan 8-12 mgFollow-up 12 months

Fogari, 2008n = 329PAF or DCCAmlodipine 2.5-10 mg vs Ramipril 5-10 mg vs Valsartan 160-320 mgFollow-up 12 months

*

20 Prevention of AF with ACEIs/ARBs

* freedom from

persistent AF

Prospective Studies No ACEI or ARB

ARBs

ACEIs

Belluzzi, 2009(lone AF)n = 62, DCCPlacebo vsRamipril 5 mgFollow-up 3 years

*

Study (9) # pts Type of AFAF free at 1 year

Ablation AAD

Krittayaphong, et al. 2003

30Paroxysmal, persistent

79% 40%

Wazni, et al. 2005, (RAAFT)

70Mainly

paroxysmal87% 37%

Stabile, et al. 2005 (CACAF)

137Paroxysmal, persistent

56% 9%

Oral, et al. 2006 146 Persistent 74% 4%

Pappone, et al. 2006 (APAF)

198 Paroxysmal 86% 22%

Jais, et al. 2008,(A4 study)

112 Paroxysmal 89% 23%

Forleo, et al. 2008 70† Paroxysmal, persistent

80% 43%

Wilber, et al. 2009 (Thermocool)

167 Paroxysmal 66% 16%

Packer, et al. 2010, (STOP-AF)

245 Paroxysmal 69.9% 7.3%

Modified from Camm J, et al. Nat Rev Cardiol 2009;6:332-4

AF Ablation or Antiarrhythmic Drugs?F

reed

om

fro

m A

F r

ecu

rren

ce [

%]

p = <

0.00166

16

0

20

40

60

80

100

PVI AAD

ThermocoolN = 167

Catheter Ablation: The Truth !

Wokhlu A, et al. J Cardiovasc Electrophysiol. 2010;X:1-8

• N = 774; 45% persistent

• 38% PVI, 62% WACA

0

20

40

60

80

100

0 6 12 18 24 30

Months after ablation

First re

curr

ence

, % Mid-term

Late

Very late

Paroxysmal AF

Persistent AF

37%

27%

57%

39%

p <0.001

0 0.5 1 1.5 2 2.5 3 3.5 4

Hazard ratio

Any recurrenceNo recurrenceAge

Male

PersAF

Hypertension

Diabetes

Hyperlipidemia

CHF/EF < 50%

DCM

Valvular

HOCM

Sleep apnea

BMI

Family Hx of AF

LA 45 mm

WACA

0.05

0.67

<0.001

0.02

<0.001

0.11

0.89

0.11

0.18

0.40

0.50

0.75

0.03

0.003

0.009

• Recurrence rate per months: 3-6 months: 5.8% 6-12 months: 1.3%12-30 months: 0.9%

LA Ablation Long-term Follow-up data

ECG: electrocardiogram; AT: atrial tachycardia; AF: atrial fibrillation; Aflut: atrial flutter. * FU was scheduled at 3 and 6 months in the clinic and at 9 and

12 months by telephone call. FU thereafter was not reported!

AuthorVisit

intervals

Evaluation at FUDefinition Recurrence

(ECG document)

Arrhythmia

free

survival

(%)

ECG

at rest

24h

ECG

48h

ECG

Clinical

observations

Gaita

20081,3,6 and every 6

m thereafter Yes Yes NoYes

+ event recorder>30 sec. 41

Fiala

20081,3,6 and every 6

m thereafter Yes Yes NoYes

+ transtelephonic

ECG monitoring

>30 sec. any AT 56

Bertaglia

20091,3,6 and every 6

m thereafter Yes Yes No Yes >30 sec. (only AF) 58

Bhargava

20093,6,9,12 m* No No Yes

Yes

+ event recorder

Occurrence of

AF, Aflut or AT 73

Tsou

2010

6 w, 6 and 12 m,

thereafter every 6

to 12 mYes No No Yes

Requiring repeat

ablation for AF 71

Wokhlu

2010

3 m and

thereafter

annuallyYes Yes No

Yes

+ event recorderOccurrence of

AF, Aflut or AT 64

Ouyang

20101,3,6 and every 6

m thereafter Yes Yes No No >30 sec. 47

Weerasooriya

2011

1,3,6,12 m,

thereafter at

follow-up endYes Yes No Yes

>30 sec. AF, Aflut

or AT 32

Effect of AF and EF on SurvivalAfter LA Ablation

Nadamanee K et al, J Am Coll Cardiol 2008;51:843–9

AF, LVEF ≤ 40%

SR, LVEF ≤ 40%

AF, LVEF > 40%

SR, LVEF > 40%

Some More On-going TrialsAcronym Study Title PI N Endpoint

SARAStudy of Ablation

versus anti-aRrhythmic drugs

in persistent Atrial fibrillationMont 208

Freedom from AF

> 24 hrs

RAAFT

First line Radiofrequency

Ablation versus Antiarrhythmic

drugs for atrial Fibrillation

Treatment

Natale 400Freedom from AF

> 30 sec

AATACAblation vs Amiodarone for

Treatment of AFib in patients

with CHF and an ICDDiBiase 120 AF > 15sec

CASTLE-

AF

Catheter Ablation versus

Standard conventional

Treatment in patients with LEft

ventricular dysfunction and

Atrial Fibrillation

Brachmann 400

All-cause mortality

and HF

hospitalisations

CABANACatheter ABlation versus

ANtiarrhythmic drug therapy for

Atrial fibrillationPacker 3000 All cause mortality

EASTEarly Atrial fibrillation Stroke

prevention TrialKirchhof 3000

All cause mortality +

CV hospitalisations

Also MANTRA-PAF, TTOP-AF, etc.

0

30

25

20

15

10

5

Rhythm Control

Rate Control

AFFIRMAll-cause Death

27% vs 26% (P=0.058 )

Years

Mo

rtality

(%

pati

en

ts)

0 1 2 3 4 5 6

AFFIRM : Main Results

SR AFFIRM

Warfarin use

Digoxin use

AAD use

Heart failure

Stroke/TIA

Hazard Ratio

p = 0.0007

p = 0.0005

p < 0.0001

p < 0.0001

p < 0.0001

p < 0.0001

0 0.5 1 1.5 2 2.5

Rates of Mortality and Hospitalizations in the AFFIRM Study by Treatment Group

Saksena S, et al. Abstracts, ACC 2010

20

40

60

80

100

0 1 2 3 4 5 6

% W

ith

ou

t e

ve

nt

Rate control

Amiodarone

Other AADs

Years

p <0.0001

Composite endpoint

(ACM + CVM + CVH)

20

40

60

80

100

0 1 2 3 4 5 6

% W

ith

ou

t e

ve

nt

Rate control

Amiodarone

Other AADs

Years

CV hospitalization

AFFIRM Raten=2027

Amion=735

Other AADs

n=1298

Age, yrs 69.6 69.9 69.2

Men, % 59.4 67.3 59.1

CAD,% 37.3 46.0 35.1

CMP,% 8.6 12.7 5.7

CHF,% 23.4 30.1 18.7

p <0.0001

P = 0.023 P = 0.038

Rate control: 7% amiodarone Rhythm control: 82% amiodarone

AF-CHF Trial

Roy et al. New Engl J Med 2008;358:2667-77

Prevalence of AF at follow-up

%

0

20

40

60

80

100

48362412843Base

line

Rhythm

controlRate control

Time (weeks)

Su

rviv

al

pro

bab

ilit

y

Rhythm control

Rate control

Time to CV death (months)

0 12 24 36 6048

100

80

60

40

20

0

Logrank p=0.594

Hazard ratio: 1.058

(95% CI, 0.86 to 1.30)

1376 Randomized

CHF: LVEF 35% and NYHA II-IV

AF: 1 > 6 hrs or 1 > 10 min plus DC

shock within 6m

Rhythm vs Rate Control in CHF: On-

Treatment Analysis of the AF CHF Trial

Talajic M, et al. AHA 2008

0.38 (0.23 – 0.65) <0.0010.48 (0.30 – 0.77) 0.003

2.02 (1.33 – 3.08) 0.001

1.65 (1.15 – 2.35) 0.006

2.47 (1.41 – 4.34) 0.002

2.23 (1.38 – 3.62) 0.001

2.00 (1.29 – 3.08) 0.002

2.23 (1.54 – 3.23) <0.001

1.78 (1.16 – 2.73) 0.008

1.88 (1.31 – 2.69) <0.001

1.22 (0.80 – 1.87) 0.348

1.11 (0.78 – 1.58) 0.568

HR (95% CI) p

Oral anticoagulation

Mitral regurgitation

History of stroke/TIA

CAD

NYHA III-IV

AF vs Sinus rhythm

CV death

All-cause death

AAD Outcome TrialsSafety Studies / Efficacy Studies

Post MI “model”:

− CAST: Flecainide / Encainide / Morizicine

− EMIAT/CAMIAT: Amiodarone, SWORD: d-Sotalol

− DIAMOND-MI: Dofetilide; ALIVE: Azimilide

CHF “model”:

− CHF-STAT: Amiodarone

− DIAMOND-CHF: Dofetilide

− ANDROMEDA: Dronedarone

CV risk “model”:

− ATHENA: Dronedarone

Acute Coronary Syndrome “Model”:

− MERLIN: Ranolazine

Atrial

Fibrillation

Reported

DIAMOND CHF

PlaceboDofetilide

Torp-Pedersen et al. New Engl J Med 1999;341:857-65

Time to hospitalisation for CHFTime to new atrial fibrillation

0 12 24 36

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

Event-

Fre

e P

robabili

ty

Hazard ratio = 0.69

95% CI = 0.51-0.93

p = 0.014

0

5

10

15

0 6 12 18 24 30 36 42

Time (months)

Perc

ent A

F

Conclusions:A Paradigm Shift

A Paradigm Shift in the management of atrial

fibrillation is anticipated

This Paradigm Shift refers to:

− De-emphasising rhythm control (ECG based) for

the management of recurrent atrial fibrillation

− Stressing decreasing symptoms and the reduction

of major cardio-vascular outcomes

Drugs may achieve this by pleiotropic effects,

such as rhythm control, rate control and an

antihypertensive effect.

This dual role for an antiarrhythmic drug has

been demonstrated but it’s clinical use is not

easily implemented.

Young lady v Old lady

More time and

experience may be

needed to see the

paradigm shift which is

obvious to some but not

to others

ATHENA: Primary OutcomeTime to first cardiovascular hospitalization or death

Mean follow-up 21 5 months.

Patients at risk

Placebo 2327 1858 1625 1072 385 3

Dronedarone 2301 1963 1776 1177 403 2

0

10

20

30

40

50

0 6 12 18 24 30

Cu

mu

lati

ve I

ncid

en

ce (

%)

HR = 0.76

P < 0.001

Months

Placebo

Dronedarone

Hohnloser SH et al. ATHENA Investigators. N Engl J Med. 2009 Feb 12;360(7):668-78.

European Approval of Dronedarone

Indication for Dronedarone - US Label

MULTAQ is an antiarrhythmic drug indicated to reduce the risk of

cardiovascular hospitalization in patients with paroxysmal or persistent

atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of

AF/AFL and associated cardiovascular risk factors (i.e., age >70,

hypertension, diabetes, prior cerebrovascular accident, left atrial

diameter ≥50 mm or left ventricular ejection fraction [LVEF] <40%), who

are in sinus rhythm or who will be cardioverted .

WARNING: HEART FAILURE

MULTAQ is contraindicated in patients with NYHA Class IV heart failure or NYHA

Class II – III heart failure with a recent decompensation requiring hospitalization

or referral to a specialized heart failure clinic.

In a placebo-controlled study in patients with severe heart failure requiring recent

hospitalization or referral to a specialized heart failure clinic for worsening

symptoms (the ANDROMEDA Study), patients given dronedarone had a greater

than two-fold increase in mortality. Such patients should not be given

dronedarone.

Canadian Product Monograph

INDICATIONS AND

CLINICAL USE

MULTAQ is indicated for

the treatment of patients

with a history of, or

current atrial fibrillation

to reduce the risk of

cardiovascular

hospitalization due to

atrial fibrillation (see

CLINICALTRIALS).