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).