Transcript MOST Trial: Follow-up Results - CCN

Pharmacological Prevention of Atrial
Fibrillation
Mattias F. Duytschaever, MD, PhD
Electrophysiology Unit
AZ St.Jan-Brugge
University Hospital Ghent
Bruxelles 2008
Pharmacological Prevention of AF
Outline of the Presentation
 Atrial Fibrillation: The Clinical Problem
− Changing Epidemiology of AF
− Impact on Morbidity and Mortality
 Pharmacological Prevention of AF
− Conventional Anti-arrhythmic Drugs
− New “Anti-arrhytmic drugs” for AF
Atrial Fibrillation: The Clinical Problem
Clinically AF is a Multi-faceted Disease
Parameters
Par AF
Pers AF
Perm AF
(N=1571)
(N=1167)
(N=1541)
64 ±13
66 ±12
71 ±11
Heart Failure
23%
35%
49%
Valvular Heart Disease
19%
24%
40%
Cardiomyopathy
7%
13%
16%
Diabetes
15%
16%
22%
Symptoms
77%
73%
55%
LAD (mm)
43 ±7
46±8
51±17
Age
Nieuwlaat et al, Eur Heart J 2005;26:2422 (Euro Heart Survey)
Epidemiology of Atrial Fibrillation
Prevalence (1 to 1.5%) and Incidence of AF
Prevalence
(%)
Incidence/1000 person-years
17.8%
60
Framingham Study
Mayo Clinic Study
CHS
Rotterdam Study
15
Framingham Study (men)
CHS (men)
Mayo Clinic (men)
40
10
20
5
40
50
60
70
80
40
Age (yrs)
At 55y Life time risk for AF
= 23.8%
50
60
70
80
90
Age (yrs)
Miyasaka et al, Circ 2006;114:119-125
Heeringa et al, EHJ 2006;27:949-953
Epidemiology of AF is Changing
Estimated Prevalence Pool at 2050
Projected N of Pts with AF (millions)
7
2050: 5.6
million
6
Age-adjusted Incidence/1000 person-year
4
3
3.68
5
4
2
3
2
3.04
2050:12 to 16
million
50% of
AF>80y
2.3
1
1
0
1990
2010
2030
2050
Year
Go et al, JAMA 2001;285:2370
1980
1985
1990
1995
2000
Year
Miyasaka et al, Circulation 2006;114:119
Epidemiology of AF is Changing
Temporal Relations of AF and CHF and their Joint Influence on
Mortality (The Framingham Heart Study)
Cumulative Incidence
of AF in Pts with CHF
Atrial Fibrillation and Heart Failure
Another Vicious Circle
0.4
0.3
Heart
Failure
Incidence of AF
3-4% per year
•Neurohormonal remodeling
•Atrial enlargement
Underlying
•Loss of atrial funct
•Atrial hypertrophy
Heart Disease
•Non-physiologic HR
• atrial pressure
(AHT,
•Irregular V response
LVH,VHD, •Atrial stretch
•Loss of AV synchronicity age,
•Atrial Fibrosis
diabetes,..)
•Electrical Remodeling
0.2
0.1
Atrial
fibrillation
2
4
6
8
10
Years
Wang et al., Circulation 2003;107:2920
Pharmacological Prevention of AF
Outline of the Presentation
 Atrial Fibrillation: The Clinical Problem
− Changing Epidemiology of AF
− Impact on Morbidity and Mortality
 Pharmacological Prevention of AF
− Conventional Anti-arrhythmic Drugs
− New “Anti-arrhytmic drugs” for AF
Impact of Atrial Fibrillation on Stroke
Stroke Prevention in AF is a Pressing Health Concern

Yearly Risk of Stroke in Nonvalvular AF is 5%

AF is Associated with a 2 to 7-fold
Increased Risk for Stroke




Incidence of Dementia/1000
person-years
The risk of Stroke increases
Exponential with Age
80
60
Men with AF
20% of all Ischemic Strokes are
Due to AF
40
40% of Patients with AF have
Silent Brain Infarction
General Men
20
In Patients with AF there is Twice
as much Cognitive Dysfunction or
Dementia
50
60
70
80
90
Age (yrs)
Miyasaka et al, European Heart J 2007;28:1962-1967
Impact of Atrial Fibrillation on Stroke
Long-Term Outcome in Pts with Lone AF: a 30-year Follow-Up Study
Survival Free of Stroke/TIA (%)
100
96%
94%
80
60
40
Survival Free of Death (%)
89% 85%
88%
72%*
100
80
expected
60
observed
40
20
92%
observed
68%
86%
expected
57%
20
10
20
30
Years
10
20
30
Years
Jahangir et al, Circulation 2007;115:3050-3056
Impact of Atrial Fibrillation on Mortality
Mortality in AF Cases and Controls (Framingham Study)
AF
(men)
Control
(men)
Total
deaths
59.2*
34.3
Deaths for
CVS causes
49.9*
21.2
Average time to
death
5.9yr*
7.7yr
Relative Risk of Mortality
4
2
Framingham
Manitoba
Kannel et al, NEJM 1982;306:1018
Whitehall
Fuster et al, Circulation 2006;108:1979
Impact of Atrial Fibrillation on Mortality
Does Atrial Fibrillation Increase Mortality in Heart Failure?
Survival (%)
100
Sinus Rhythm
80
60
40
AF at Baseline
20
P=0.0013
10
20
30
40
50
FU (weeks)
Middlekauff et al., Circulation,1991;84:40
Wellens et al., EHJ 2006;27:2740
Impact of Atrial Fibrillation on Mortality
Studies Adressing Mortality Risk of CHF Pts with AF at Baseline
Study
N of AF
EF(%)
BB
ACE/ARB
Mortality
RR
P-value
V-HeFT II
(1993)
107/795
(FU 30m)
30%
0%
50%
20% vs 21%
0.76
0.18
Stevenson
(1996)
140/750
(FU>24m)
<40%
0%
60%
34% vs 25%
1.12
n.s.
SOLVD
(1998)
419/6517
(FU 33.4m)
<35%
20%
50%
34% vs 23%
1.34
0.002
COMET
(2005)
600/3029
(FU 58m)
<35%
100%
90%
N.R. (higher)
1.07
0.38
670/7599
(FU 37.7m)
<40%
55%
55%
37% vs 28%
1.38
<0.001
478/7599
(FU 37.7m)
>40%
55%
20%
24% vs 14%
1.80
<0.001
CHARM
(2006)
Neuberger et al, Eur H Journal, 2007;Sept 13
Impact of Atrial Fibrillation on Mortality
Significance of AF in Heart Failure
(1) New onset (Incident) AF is an Independent Risk Factor
for Increased Mortality (“pre-terminal phenomenon”)
Swedberg et al., Eur Heart J 2005;26:1303 (COMET)
Wang et al., Circulation 2003;107:2920 (Framingham)
(2) Prevalent AF is an Independent Risk Factor in Mild-tomoderate CHF
Olsson et al., JACC 2006;47:1997 (CHARM)
Crijns et al., Eur Heart J 2000;21:1238 (PRIME II)
(3) Prevalent AF is an Independent Risk Factor in Ischemic
Heart Failure
Pedersen et al., Eur Heart J 2006;27:2866 (DIAMOND)
Wellens et al., Eur Heart J 2006;27:2740
Pharmacological Prevention of AF
Outline of the Presentation
 Atrial Fibrillation: The Clinical Problem
− Changing Epidemiology of AF
− Impact on Morbidity and Mortality
 Pharmacological Prevention of AF
− Conventional Anti-arrhythmic Drugs
− New “Anti-arrhytmic drugs” for AF
Challenges of Therapies in AF
Clinical Objectives for Therapy of AF




Prevention of Stroke
Preservation/improvement of LV Function
Relief of Symptoms
Reduction in Mortality
The Preferred Strategy would be Pharmacological
Rhythm Control, if Obtained Effectively and Safe
Importance of Sinus Rhythm!!
Rhythm vs Rate
Cumulative
Mortality (%)
Sinus vs AF
Endpoint Free
Survival (%) 100
30
n:352
n:306
25
Rhythm
Control
20
15
Sinus Rhythm
80
Atrial Fibrillation
60
Rate Control
40
AFFIRM
20
10
5
0
12
24
36
48
60
FU (months)
Survival in
CHF and AF
100
(%)
80
Amiodarone
0
5
10
Survival in
CHF and AF
100
(%)
15 20
25 30 35
FU (months)
Sinus Rhythm
80
60
60
40
STAF
Placebo
CHF-STAT
20
0
12
24
Atrial Fibrillation
40
20
CHF-STAT
0
36
12
FU (months)
24
36
FU (months)
Conventional Antiarrhythmic Drugs for AF
Vaughan Williams Classification of Antiarrhythmic Agents
Fuster et al., JACC 2001, page 1-70
Conventional Antiarrhythmic Drugs for AF
Efficacy of Class IC and III to Prevent Persistent AF
Predictors for Recurrence
Maintenance of Sinus Rhythm
SR (%)
100
Male Gender
Amiodarone
80
Age >75
Sotalol
60
Amiodarone
Digoxin
Sotalol
40
Propafenone
LA <52
LVEDD
20
25%
Duration>1year
0.001 0.01
0.1
1
10
100
Absence of Recurrence
Duytschaever et al., PACE 1999
100
200
300
400
500
Days of Follow-up
CTAF, Roy et al., NEJM, 2000
Conventional Antiarrhythmic Drugs for AF
Review of RCTs on Prevention of Recurrence of AF after DCC
RCT included into analysis
Total
No. of patients
44
11,322
Placebo controlled
25
Active comparator
14
Persistent AF
38 (60% pts)
PAF/recent onset
6
EF > 50%
Lone AF
41
Follow-up
1 year
1
AF Recurrence
Class IA
Class IC
Metoprolol
Class III
Amio
Dofetilide
Sotalol
Q vs Class I
Q vs Sotalol
Amio vs Class I
Amio vs Sotalol
Sotalol vs Class I
0
Lafuente-Lafuente C, et al, Arch Intern Med 2006;166:719-28
0.5 1 1.5 2
Odds Ratio (95% CI)
Conventional Antiarrhythmic Drugs for AF
Rhythm Control v Rate Control (The AFFIRM Trial)
Cumulative
Mortality (%)
30


4060 patients, FU 5 year


> 65 yr or Other RF for Stroke or Death

Rate Control : heart rate from 80/’ en 110/’ ;
continued coumadin
Paroxysmal or Recurrent
Persistent Asymptomatic AF
Rhythm Control : cardioversion,
antiarrhythmic drugs, Stop coumadin if SR
n:352
n:306
Rhythm
Control
25
20
P=0.08
15
Rate
Control
10
5
Years (%)
0
Primary Endpoint
(Death)
1
2
3
4
5
Wyse et al. NEJM 2002
Conventional Antiarrhythmic Drugs for AF
Rhythm Control v Rate Control (The AF-CHF Trial)
Primary Endpoint
(Cardiovascular Death)




1376 patients, FU >2 year
LVEF ≤ 35% and NYHA II-IV
AF ≥ 6 h within last 6 months or
one episode ≥ 10 min within 6
months and prior D/C shock
82% amiodarone (rhythm
control)
Roy et al, NEJM 2008;358:2667-77
Conventional Antiarrhythmic Drugs for AF
Class I and III Drugs are Not Safe (Certainly not in CHF)
Survival in Patients with
CHF and AF (%)
No Antiarrhythmic
100
Drugs
Survival in Patients with
CHF and AF (%)
100
90
80
80
60
Antiarrhythmic Drugs
70
(Quinidine, Procainamide, Disopyramide, Flecainide, Encainide)
Amiodarone
40
60
20
50
0
90
180 270 360 450 540 630
Follow-up (days)
Flaker et al.(SPAF), JACC, 1992
Placebo
12
24
36
Follow-up (months)
Singh et al.(CHF-STAT),Circulation, 1998
Conventional Antiarrhythmic Drugs for AF
Class I and III Drugs are Not Effective Nor Safe
Efficacy
% of Sinus
Rhythm
Safety
Number
of Deaths
169
160
75
60%
50
40%
25
140
120
130
129
113
100
52
81
Cancer
80
23
39
Pulmonary
60
40
37
35
20
Cardiac
Rate
310 †
Rhythm 352 †
Vascular
Non
Cardiovascular
Steinberg et al, Circulation 2004;109:1973
Conventional Antiarrhythmic Drugs for AF
ACC/AHA/ESC 2006 guidelines for the management of AF
Paroxysmal or Recurrent
Persistent AF
No Symptoms
Antico and
Rate Control
Permanent AF
Symptoms
Antico and
Rhythm Control
Antico and
Rate Control
Fuster et al, Circulation 2006;108:1979
Conventional Antiarrhythmic Drugs for AF
ACC/AHA/ESC 2006 guidelines for the management of AF
No Heart
Disease
Coronary Artery
Disease
Heart Failure or
Hypertension with LVH
Flecainide
Sotalol
Sotalol
Amiodarone
Amiodarone
Catheter
Ablation
Amiodarone
Catheter
Ablation
Catheter
Ablation
Fuster et al, Circulation 2006;108:1979
Pharmacological Prevention of AF
Outline of the Presentation
 Atrial Fibrillation: The Clinical Problem
− Changing Epidemiology of AF
− Impact on Morbidity and Mortality
 Pharmacological Prevention of AF
− Conventional Anti-arrhythmic Drugs
− New “Anti-arrhytmic drugs” for AF
“Antiarrhythmic” Drugs for AF
Disopyramide
Amiodarone
Sotalol
Class
IA
Class
III
b-Blocker
Antiarrhythmic Agents
Class
IC
Dofetilide
Propafenone
Flecainide
New
Class III Agents
Substrate
therapies
b-Blocker
Azimilide
Quinidine
Tedisamil
Dronedarone
Multi-channel blockers
ACEI
ARB
Statins
PUFAs
Pirfenidone
Savelieva and Camm, Europace 2008;647-665
Novel Drugs
Connexin
modulators
SAC
Blockers
Ranolazine
Na+/H+
Inhibitors
Na+/Ca2+
Inhibitor
Adenosine
Agonist
ARDAs
ARDAs
(Vernakalant,
AVE0118)
Novel “Antiarrhythmic” Drugs for AF
Pharmacological Modulation of Atrial Conduction (Rotigaptide)
Inter Cellular
Uncoupling
Modulation of Gap Junctions
16 Weeks AF
Eloff et al., Circulation, dec 2003
Novel “Antiarrhythmic” Drugs for AF
Late and Early Class III Drugs (Experimental)
S1
S1
400
Sinus
Rhythm
After 24 h
of AF
S2
142
186
Control
“Late” versus “ Early “
Class III Drugs
d-Sotalol
‘Early’ Class III
IAAD
to I
102
Control
Ca
IKur
118
d-Sotalol
IKrIKs
74
After 48 h
of AF
Control
78
0
100
200
300
400 ms
d-Sotalol
Duytschaever et al., Cardiovascular Research, 2005,67:69-76
Novel “Antiarrhythmic” Drugs for AF
Savelieva and Camm, Europace 2008;647-665
Novel “Antiarrhythmic” Drugs for AF
‘Early’ Class III Drugg AVE0118 (IKur Blocker)
AVE 0118 (3mg/kg/h)
Δ AERP
(ms)
Remodeled Atria
*
60
*
*
*
ms
220
QT-time
200
180
*
40
160
AERP400
140
20
120
100
0
200
250
300
350
Pacing Cycle Length (ms)
400
-20
-10
0
10
20
30
Time (min)
Blaauw et al, Circulation Oct 2004
“Antiarrhythmic” Drugs for AF
Disopyramide
Amiodarone
Sotalol
Class
IA
Class
III
b-Blocker
Antiarrhythmic Agents
Class
IC
Dofetilide
Propafenone
Flecainide
New
Class III Agents
Substrate
therapies
b-Blocker
Azimilide
Quinidine
Tedisamil
Dronedarone
Multi-channel blockers
ACEI
ARB
Statins
PUFAs
Pirfenidone
Savelieva and Camm, Europace 2008;647-665
Novel Drugs
Connexin
modulators
SAC
Blockers
Ranolazine
Na+/H+
Inhibitors
Na+/Ca2+
Inhibitor
Adenosine
Agonist
ARDAs
ARDAs
(Vernakalant,
AVE0118)
New “Class III” Agents for AF
Dronedarone (Post-Hoc Analysis)
ADONIS (N=630, follow-up 1 year)
Time to First CV Hospitalization or Death
Time to AF Recurrence
Placebo
0.8
Placebo
0.4
0.6
0.5
0.4
0.3
0.2
0.1
Dronedarone 400 mg BID
Cumulative incidence
Dronedarone 400 mg BID
0.7
Cumulative Incidence
EURIDIS and ADONIS Meta-analysis
Log-rank test results: p=0.0017
0.3
HR=0.80 p=0.16
95%CI=[0.59; 1.09]
0.2
0.1
Few adverse events
0.0
0.0
0
60
120
180
240
300
360
0
Time (days)
60
120
180
270
360
Time(days)
? ATHENA
Singh BN et al, NEJM 2008
Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco, CA (A).
New “Class III” Agents for AF
ATHENA and Trial Design
N=4628 patients with a history of paroxysmal or persistent AF
• Age ≥ 75 years with or without additional risk factors
• Age ≥ 70 years and ≥ 1 risk factor (hypertension, diabetes, prior
stroke/TIA, LA ≥ 50 mm, LVEF ≤ .40)
R
Dronedarone (400 mg bid)
Placebo
Phase III RCT: Minimum follow-up 12 months
Primary EP: time to Death or Cardiovascular Hospitalisation
J Cardiovasc Electrophysiol. 2008;19:69-73.
New “Class III” Agents for AF
ATHENA: Patient Characteristics
Placebo
(N=2327)
Dronedarone
(N=2301)
72+/-9
72+/-9
Female gender
45%
49%
AF at baseline
25%
25%
Structural Heart Disease
61%
58%
Arterial Hypertension
86%
87%
Coronary Heart Disease
32%
29%
Valvular Heart Disease
16%
17%
NYHA III/IV
22%
20%
EF<0.35
4%
4%
Lone AF
6%
6%
Age (yrs)
New “Class III” Agents for AF
ATHENA: Baseline Medications
Placebo
(N=2327)
Dronedarone
(N=2301)
Betablocker
71%
71%
Ca-antagonists
13%
14%
Digoxin
13%
14%
ACE/ARB
69%
70%
Statins
39%
38%
Vit.K anatagonists
60%
61%
Aspirin
44%
44%
New “Class III” Agents for AF
ATHENA: Primary Outcome
Time to first cardiovascular hospitalization or death
Cumulative
Incidence (%)
50
40
HR=.76
P<.001
30
Placebo
20
Dronedarone
10
Patients at risk
Placebo
Dronedarone
0
0
6
12
18
24
30
2327
2301
1858
1963
1625
1776
1072
1177
385
403
3
2
Months
Mean follow-up 21  5 months.
Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco, CA (A).
New “Class III” Agents for AF
ATHENA: Fatal Outcomes
Outcome
Placebo
(N=2327)
Dronedarone
(N=2301)
Hazard
Ratio
95% CI
P Value
All death
139
116
0.84
0.66-1.08
.18
Non-CV death
49
53
1.10
0.74-1.62
.65
CV death
90
63
0.71
0.51-0.98
.03
Cardiac non-arrhythmic
death
18
17
0.95
0.49-1.85
.89
Cardiac arrhythmic death
48
26
0.55
0.34-0.88
.01
Vascular non-cardiac
24
20
0.84
0.47-1.52
.57
Hohnloser. Presented at the Heart Rhythm Society. May 2008. San Francisco, California (A).
New “Class III” Agents for AF
ATHENA: Non-Fatal Outcomes
Placebo
(N=2327)
Dronedarone
(N=2301)
Hazard
Ratio
95% CI
P Value
917
734
0.76
0.69-0.84
<.001
859
675
0.75
0.67-0.82
<.001
AF
510
335
0.63
0.55-0.72
<.001
CHF
132
112
0.86
0.67-1.1
.221
ACS
89
62
0.70
0.51-0.97
.030
Syncope
32
27
0.85
0.51-1.42
.542
Ventricular arrhythmia or
non-fatal cardiac arrest
12
13
1.09
0.50-2.39
.828
Outcome
Primary outcome
First hospitalization for
CV reasons
Hohnloser. Presented at the Heart Rhythm Society. May 2008. San Francisco, California (A).
New “Class III” Agents for AF
ATHENA: Summary
•Dronedarone Significantly Prolongs Time to Cardiovascular
Hospitalisation or Death in Moderate to High Risk Elderly AF Pts
• All Cause Mortality was Not Increased in Pts Receiving
Dronedarone
• Cardiovascular Mortality (Specifically Arrhythmic Death) was
Lower in the Dronedarone Compared to the Placebo Group
• The Reduction in CV Hospitalisation was Mainly Due to Fewer
Admissions for AF and Acute Coronary Syndromes
• Discontinuation of Study Drug Was Similar in Both Groups
Indicating Good Tolerability of Dronedarone
• The Development Portfolio of this Drug is Practically Complete
New “Class III” Agents for AF
Increased Mortality after Dronedarone Therapy for Severe Heart Failure
After inclusion of 627
patients (310 in the
dronedarone group and
317 in the placebo
group), the trial was
prematurely terminated
beacuse of increased
early mortality related
to the worsening of
heart failure
ANDROMEDA Study; Kober et al. NEJM 2008, 358:2678-2687
“Antiarrhythmic” Drugs for AF
Disopyramide
Amiodarone
Sotalol
Class
IA
Class
III
b-Blocker
Antiarrhythmic Agents
Class
IC
Dofetilide
Propafenone
Flecainide
New
Class III Agents
Substrate
therapies
b-Blocker
Azimilide
Quinidine
Tedisamil
Dronedarone
Multi-channel blockers
ACEI
ARB
Statins
PUFAs
Pirfenidone
Savelieva and Camm, Europace 2008;647-665
Novel Drugs
Connexin
modulators
SAC
Blockers
Ranolazine
Na+/H+
Inhibitors
Na+/Ca2+
Inhibitor
Adenosine
Agonist
ARDAs
ARDAs
(Vernakalant,
AVE0118)
Substrate Therapies for AF
Atrial Remodeling
Therapies
ACE inhibitors
and ARBs
Aldosterone
antagonists
Statins
Corticosteroids
n-3 PUFA
(fish oil)
Beta blockers
Possible Target
Hypertension
Heart failure
AA effects (anti-fibrotic,
antiarrhythmic?)
Hypertension, heart failure
AA effects (anti-fibrotic,
antiarrhythmic?)
Prevention of Atrial
Remodeling
Disease
Substrate
Coronary artery disease
Systemic atherosclerosis
AA effects (antiinflammatory, antioxidant)
Anti-inflammatory effects
Lipid-lowering effects
Antiarrhythmic effects
AF
Targets:
-Prevention of Heart Disease
-Prevent HD-induced Remodeling
Reduction of BP, CHF MI, etc.
Antiarrhythmic effects
-Prevent AF-induced Remodeling
Substrate Therapies for AF
Prevention of AF by Treating Heart Failure (Primary Prevention)
ACE Inhibitors
AR Antagonists
SR (%)
Enalapril
(5% AF)
100
Cumulative Incidence of AF
0.15
Placebo
(8% AF)
80
Placebo
(24% AF)
60
40
0.10
0.05
Valsartan
(5.1% AF)
20
1
2
3
4
5
Years
6
12
18
FU 2.9y
FU 23m
(SOLVD)
(ValHeFT)
Vermes et al, Circulation 2003;107;2926
24
Months
Maggioni et al, Am Heart J 2005;149:548
Substrate Therapies for AF
Prevention of AF by Treating Heart Failure (Primary Prevention)
Prevalence of recommended HF treatment in
Euro Heart Survey on AF
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Geographic distribution of enrolment in
Euro heart Survey on AF
• 5333 patients
• 35 countries
• 182 hospitals
European Society of Cardiology – Euro Heart Survey
Eurlings L, et al.
Preliminary
results
European Society of Cardiology – Euro Heart Survey
With the courtesy of H Crijns
Substrate Therapies for AF
Prevention of AF by Treating Hypertension (Secondary Prevention)
• N=250
• Mild AHT and
Documented AF in
Previous 6 months
• Amiodarone 200 +
Losartan 50mg
• Amiodarone 200 +
Amlodipine 5mg
Fogari et al Journal of Cardiovasc. Pharmacol 2006
Substrate Therapies for AF
Prevention of AF by Treating Hypertension (Primary Prevention)
Stroke (%)
New Onset AF (%)
8
7
10
RR: 0.67 [95% CI: 0.55-0.83], p<0.001.
Atenolol
8
6
5
6
4
4
3
Losartan
2
Atenolol
2
Losartan
1
0
12
24
36
48
60
Months
LIFE, Kjeldsen et al, JAMA, 2002; 288:1491
12
24
36
48
60
Months
Wachtell et al, JACC; 2005; 45
Substrate Therapies for AF
Prevention of Progression of AF (No Structural Heart Disease)
Natural Hx and Progression of AF
Study
UK general practice,
2005
Tokyo study, 1995
CARAF, 2001
# pts
Follow-up
525 1st PAF age 40-89 yrs
Progression
70/418 (17%)
2.7 yrs; 1606 person- progression
increased risk
yrs
of mortality 1.5 (0.8-2.9)
137 new onset PAF
560 men, 339 women
AF
1 year
1st
30/137 (22%)
19%; time to
4.14 yrs
progression 1138 days
(men), 1092 days
(women)
757 new onset PAF
8 (2-11) yrs
8.6% by 1 year; 25% by
5 yrs; probability of any
AF 63% by 5 yrs
426 1st PAF
9 (0-24) yrs
141 (33%)
Parkinson, 1930
200 PAF
10 yrs
25%
Tokyo study, 2004
171 PAF
14 yrs
132/171 (77%)
(5.5%/year
CARAF, 2005
Danish study, 1986
Substrate Therapies for AF
Secondary Prevention in The Absence of Heart Disease
After ECV of Persistent AF
SR (%)
In Paroxysmal AF
SR (%)
Amiodarone+
Irbesartan
100
Amiodarone+
Losartan
100
80
80
60
60
Amiodarone
Amiodarone
40
40
P:0.007
P:0.006
20
20
*
60
120 180 240 300 360
180
Days
Madrid et al, Circulation 2002;106:331
360
540
720
Days
Yin et al, Eur Heart J 2006;27;1841
Substrate Therapies for AF
ACTIVE Study
Dose-adjusted OAC
(INR 2.0–3.0)
Yes
ACTIVE W
R
with AF
Irbesartan
(150–300
mg/day)
Clopidogrel (75 mg/d)
+ ASA (75–100 mg/day)
n = 14.500
Patients
ACTIVE Investigators, Lancet
2006;367:1903-1912
Willing/able to
take OAC
No
R
R
Clopidogrel (75 mg/day)
+ ASA (75–100 mg/day)
ACTIVE A
Placebo + ASA (75–100 mg/day)
Primary endpoint: Stroke, MI, CV death, Systemic Emboli
ACTIVE I
Placebo
Pharmacological Prevention of AF
AF During the Next Half Decade
 Atrial fibrillation will become much more common
 Conventional therapies are only modesty effective
 New “safer” variations of conventional therapies are almost
available
 Drugs with novel antiarrhythmic actions are in development
 New targets that prevent substrate development or suppress
triggers will become available
 The rate versus rhythm debate will reignite
 Mortality and morbidity will improve