Transcript Cards 2000 - Scioto County Medical Society

Heart-to-Heart:
An AF Outcomes Initiative
IMPROVE YOUR PRACTICE
AND EARN MORE CME CREDITS!
 Interactive case-based initiative composed of the
following educational programming:
– Heart-to-Heart: AF Outcomes ACC satellite
symposium
– Heart-to-Heart: AF Outcomes Roundtable Series
– Heart-to-Heart: AF Outcomes National Grand
Rounds and Visiting Professor Series
– Heart-to-Heart: AF Outcomes Performance
Improvement Activity
FIND OUT MORE AT www.AFOutcomes.com
Heart-to-Heart: AF Outcomes
Performance Improvement Activity
Allows Physicians to:
− Measure performance with respect to AF treatment
guidelines
− Personally tailor their educational plan
− Re-evaluate their practice upon completion of activity
− Earn up to 20 CME credits for free
PARTICIPATE NOW ON www.AFOutcomes.com!
Introduction
The Disease Burden of AF
 Affects 2.5 million patients in the United States and 4.5
million in Europe
 Lifetime risk of AF at age 40 is 1:4
 Associated with an increase in aging and chronic heart
disease, such as HF, hypertension, atherosclerosis,
and diastolic dysfunction
 Inflammation and diabetes also associated with AF
 May induce hypercoagulable state
Go et al. JAMA. 2001;285:2370-2375; ACC/AHA/ESC 2006 guidelines for the management of patients with atrial
fibrillation. J Am Coll Cardiol. 2006;48:854-906; Lloyd-Jones et al. Circulation. 2004;110:1042-1046;
Wyse et al. Circulation. 2004;109:3089-3095; Thom et al. Circulation. 2006;113:e85-e151; Peters et al. Lancet.
2002;359:593-603.
The Consequences of AF
Thromboembolism
 Stroke: 4.5 increased risk
 Microemboli: reduced
cognitive function
 Prothrombotic state
Mortality
 2 increased risk independent
of comorbid CV disease
 Sudden death in HF and HCM
Hospitalizations
 Most common arrhythmia
requiring hospitalization
 2-3 increased risk for
hospitalization
Reduced QoL
 Palpitations, dyspnea,
fatigue, reduced exercise
tolerance




Impaired Hemodynamics
Loss of atrial kick
Irregular ventricular
contractions
HF
Tachycardia-induced
cardiomyopathy
HCM=hypertrophic cardiomyopathy.
Van Gelder et al. Europace. 2006;8:943-949; Narayan et al. Lancet. 1997;350:943-950; Wattigney et al.
Circulation. 2003;108:711-716; Wyse et al. Circulation. 2004;109:3089-3095; Favale et al. PACE. 2003;26:637639.
CV Events in AF Patients
Ischemic Cerebrovascular Event
AF group
Relative Riska
(95% CI)
3.0 (2.3-4.0)
PAF
2.6 (1.7-4.2)
CAF
3.2 (2.4-4.4)
Coronary Event
AF group
2.1 (1.6-2.9)
PAF
1.7 (1.0-2.7)
CAF
2.4 (1.7-3.4)
Heart Failure
AF group
6.4 (5.0-8.3)
PAF
4.2 (2.7-6.5)
CAF
7.4 (5.7-9.8)
0
aRR
adjusted by all the variables using COX regression analysis.
PAF=paroxysmal AF; CAF=chronic AF.
Ruigómez et al. Int J Cardiol. 2008 [Epub ahead of print].
2
4
6
8
10
Hospitalizations for AF
Prevalence per 10,000 Persons
National Hospital Discharge Survey
140
120
100
80
60
40
20
0
1985
1987
1989
1991
1993
1995
1997
1999
Year
Age (years)
85+
75-84
Wattigney et al. Circulation. 2003;108:711-716.
65-74
55-64
35 to 54
AF Adversely Affects QoL
AF vs CAD vs healthy controls
a
a
a
a
a
b
a
a
100
a
SF-36 Score
a
b
a
80
60
40
20
0
General Health
Physical Functioning
AF
Social Functioning
CAD
Mental Health
Controls
Higher Scores = Better QoL
aP.05,
patients with AF compared to healthy controls; bP.05, patients with AF compared to those with CAD.
Dorian et al. J Am Coll Cardiol. 2000;36:1303-1309 (B).
AF Prevalence Is Rapidly Increasing
15.2
Projected Number of Persons
With AF (millions)
16
15.9
14.1
13.1
14
11.7
12
8.4
10
8.9
7.7
8
6
4
9.4
6.7
5.1
5.1
5.9
5.5
6.1
6.8
7.5
10.3
11.1
11.7
12.1
8.4
Current age-adjusted AF incidence
Increased age-adjusted AF incidence
2
0
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
Year
Miyasaka et al. Circulation. 2006;114:119-125.
Case 1
 66-year-old woman with history of atypical chest
pain who has had 6 weeks of fatigue, intermittent
shortness of breath, and palpitations
 AF diagnosed on office ECG; ventricular rate
mean 114 bpm
 Anticoagulated with warfarin, sotalol started and
titrated to 120 mg bid; and cardioverted to SR
 Intermittent palpitations became more frequent
and very bothersome
 Visit EP specialist for second opinion
Case 1 — Second Opinion
 Echo: LVEF 45%; LA 4.5 cm, no LVH
 Recent nuclear stress test with inferior wall
reduced uptake
 Performed ECG—AF 107 bpm at rest
 Current symptoms
− Palpitations, fatigue, shortness of breath
on exertion
 What do you do?
LVEF=left ventricular ejection fraction; LA=left atrium; LVH=left ventricular hypertrophy.
Causes of AF: Expanding Etiologies,
Diminishing “Lone AF”
Usual etiologies
−
−
−
−
−
−
−
−
Other etiologies to consider
Mitral valve disease
Ischemic/infarcted LV
HF
HCM
Hypertension
Alcohol
Hyperthyroidism
Others
LV=left ventricle; HCM=hypertrophic cardiomyopathy.
Schoonderwoerd et al. Europace. 2008;10:668-673.
−
−
−
−
−
−
Sleep apnea
Obesity
Inflammation
Extreme sports/exercise
Latent hypertension
Genetic factors
Clinical Perspective
Paroxysmal
Persistent
Relative Importance
Permanent
 APBs
 Tachycardia
 Bradycardia  Others
Trigger/
Initiation
Reentrant Circuits
Substrate/
Maintenance
Modulating
Factors
Duration of AF
APBs=atrial premature beats.
Wyse. Circulation. 2004;109:3089-3095 (B).
Modulating Factors for AF
Modulating
Factors
Non-Modifiable
 Genetic factors
 Age/senescence
Modifiable
Endothelial Dysfunction
 Atherosclerosis
Coagulation Factors
Inflammation
 Pericarditis
 Cardiac surgery
 Interleukin 6
 C-reactive protein
ANS
 Vagal
 Adrenergic
Atrial and PV Stretch
 Hypertension
 LV dysfunction
 Mitral stenosis
 Aortic stenosis
Hormonal
 Thyroid
 Diabetes
Miscellaneous
 Obesity
 Sleep apnea
PV=pulmonary vein; LV=left ventricle; ANS=autonomic nervous system.
Wyse. Circulation. 2004;109:3089-3095 (B).
What Happens When AF Persists?
Structural
Remodeling
• LA and LAA dilatation
• Fibrosis
Electrophysiologic
Remodeling
• Decrease in Ca++ currents
• Shortening of atrial action
potential
• Increased importance of
early activating K+
channels: IKur, IKto
Remodeling explains why
“AF begets AF”
Three Proposed Positive Feedback
Loops of Atrial Remodeling on AF
AFCI 
Electrical
APD 
Cytosolic 
Ca++

Ca++
Channels
AF
WL 
Circuit
Size
Stretch
Contractile
Dilatation
Zig-Zag
Conduction
Structural
Anisotropy
Contractility 
Connexins
Compliance 
APD=action potential duration; WL=wavelength; AFCI=AF cycle length.
Allessie et al. Cardiovasc Res. 2002;54:230-246 (B).
Fibrosis
Timeline of AF Remodeling
I. Paroxysmal AF
Triggered AF
Persistent AF:
(seconds/minutes)
II. Paroxysmal AF
Triggered AF - 1
Substrate - 2
Persistent AF:
(minutes/hours)
LA
LA
RA
RA
Normal
Normal/Abnormal
III. Persistent AF
Cardioversion
Triggered/Substrate AF
IRAF: IV. Persistent AF
Substrate AF
LA
RA
LA
RA
Abnormal
Prystowsky. J Cardiovasc Electrophysiol. 2008;19:575-582 (B).
Cardioversion
Abnormal
SR:
Greater SR Maintenance With Earlier
Cardioversion
AF Duration prior to cardioversion
<3 months
3-12 months
>12 months
Patients in SR (%)
100
80
60
a
40
20
0
1 Month
aP<.02.
Dittrich et al. Am J Cardiol. 1989;63:193-197 (B).
6 Months
What Are the Goals of AF Therapy?
 Improve survival
 Reduce sequelae
− Stroke




Reduce hospitalizations
Improve symptoms
Improve QoL
Restore atrial function/reverse the remodeling
process
Electrical Remodeling Correlates
With Atrial Function
AF
Conversion
SR
Work Index
140
15
120
10
100
5
80
0
0
1
2
3
4
5
6
Time (days)
Schotten et al. Circulation. 2003;107:1433-1439 (B).
7
8
9
10
Atrial Work Index (mm2 Hg)
Refractory Period (ms)
Refractory Period
What Are the Goals of AF Therapy?
 Improve survival
 Reduce sequelae
− Stroke




Reduce hospitalizations
Improve symptoms
Improve QoL
Restore atrial function/reverse the remodeling
process
QoL Improvement With Restoration of SR
SAFE-T Study: Symptomatic Patients
Negative Change
Positive Change
a
SF-36 Physical Functioning
SF-36 Role-Physical
SF-36 General Health
SF-36 Vitality
SF-36 Bodily Pain
SF-36 Social Functioning
SF-36 Role-Emotional
SF-36 Mental Health
a
b
b
SR
AF
SCL Frequency
SCL Severity
Specific Activity Scale
AF Burden
b
a
c
-6
-4
-2
0
2
4
6
8
10
12
14
SR vs AF comparisons on mean changes in QoL scores from baseline to 8 weeks by presence of AF symptoms.
aP=.05; bP=.01; cP=.001. (A) Symptomatic patients. (SR group: n=167; AF group: n=179). SCL=symptom
checklist; SF-36=Short Form-36.
Singh et al. J Am Coll Cardiol. 2006;48:721-730 (A).
QoL Improvement With Restoration of SR
SAFE-T Study: Asymptomatic Patients
SF-36 Physical Functioning
SF-36 Role-Physical
SF-36 General Health
SF-36 Vitality
SF-36 Bodily Pain
SF-36 Social Functioning
SF-36 Role-Emotional
SF-36 Mental Health
b
a
SR
AF
SCL Frequency
SCL Severity
Specific Activity Scale
AF Burden
a
c
-6
-4
-2
0
2
4
6
8
10
12
14
SR versus AF comparisons on mean changes in QoL scores from baseline to 8 weeks by presence of AF
symptoms.
aP=.05; bP=.01; cP=.001. (B) Asymptomatic patients (SR group: n=116; AF group: n=92).
Singh et al. J Am Coll Cardiol. 2006;48:721-730 (A).
Long-Term Maintenance of SR Improves
Functional Capacity: AFFIRM
 Mean New York Heart Association functional class
(NYHA-FC) score significantly better at each visit in
patients in SR
0.50
Mean NYHA-FC Score
0.45
0.40
0.35
0.30
0.25
(Lower NYHA-FC score=less
symptomatic)
0.20
0.15
Adjusted P<.0001
Current AF
No current AF
0.10
0.05
0
Initial 2
4
8
1
1⅓ 1⅔
2
Months
Chung et al. J Am Coll Cardiol. 2005;46:1891-1899 (B).
2⅓ 2⅔
3
3⅓ 3⅔
Years
4
4⅓ 4⅔
5
Maximal Exercise Duration During
SR vs AF
Increase in Duration (seconds)
SR
AF
100
80
P=.01
P=.02
60
40
20
0
8 Weeks
1 Year
SAFE-T: Sotalol Amiodarone AF Efficacy Trial
Singh et al. J Am Coll Cardiol. 2006;48:721-730 (A).
What Are the Goals of AF Therapy?
 Improve survival
 Reduce sequelae
− Stroke




Reduce hospitalizations
Improve symptoms
Improve QoL
Restore atrial function/reverse the remodeling
process
Clinical Trials in AF Therapy
Evidence for Survival Benefit of SR
Probability of Survival
1.0
0.8
0.6
0.4
0.2
0.0
Probability of Survival
Survival rates of patients treated with dofetilide (A)
and placebo (B) who converted or did not convert to SR
1.0
0.8
0.6
0.4
0.2
0.0
(A) Dofetilide Group
SR
Not SR
0
6
12
18
24
30
Time (months)
36
42
48
(B) Placebo Group
SR
Not SR
0
6
12
18
Pedersen et al. Circulation. 2001;104:292-296 (A).
24
30
Time (months)
36
42
48
SR vs AF in Clinical Trials
Evidence Based
5 prospective, randomized, controlled trials comparing
two different treatment strategies
 PIAF
Pharmacological Intervention in Atrial
Fibrillation (pilot)
 STAF
 AFFIRM
STrategies in Atrial Fibrillation (pilot)
 RACE
RAte Control versus Electrical
Cardioversion for Persistent Atrial
Fibrillation
 HOT CAFE
How to Treat Chronic Atrial
Fibrillation)
Atrial Fibrillation Follow-up
Investigation of Rhythm Management
Atrial Fibrillation Follow-up Investigation
of Rhythm Management (AFFIRM) Study
 Long-term treatment of chronic and paroxysmal AF
 Patients  65 years of age or other risk factor
for stroke with
−
−
−
−
AF  6 hours in past 6 months
Not continuous AF for  6 months
 1 episode documented by ECG in past 12 weeks
 1 risk factor for stroke (age  65 years)
 Randomized to rate vs rhythm control
− Patients required to be able to tolerate AF, therefore,
patients were a relatively asymptomatic group
 Both groups anticoagulated
The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Waldo. Am J Cardiol. 1999;84:698-700.
AFFIRM: Primary Endpoint
All-Cause Mortality
Cumulative Mortality (%)
30
Rhythm control
25
Rate control
20
15
10
P=.08
5
0
0
No. of deaths
Rhythm:
Rate:
1
0
0
2
3
Time (years)
Number (%)
80 (4)
175 (9)
257 (13)
78 (4)
148 (7)
210 (11)
The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833 (A).
4
5
314 (18) 352 (24)
275 (16) 306 (21)
AFFIRM Results
Covariate
P Value
HR 99% CI
Time dependent
SR
<.0001
Warfarin use
<.0001
Digoxin use
.0007
AAD use
.0005
0
0.5
1
1.5
2
2.5
The toxicity of AADs counterbalances the benefits of SR.
AADs=antiarrhythmic drugs.
Corley et al. Circulation. 2004;109:1509-1513 (A).
Rhythm Control vs Rate Control
PIAF, STAF, RACE, AFFIRM
 These trials indicate that both strategies are acceptable
but…
 They do not apply to all patients with AF
− Particularly to very symptomatic patients (symptomatic
despite rate control)
− Young patients for whom exercise tolerance
is important
− Patients in whom rate control failed
− Patients with depressed LV function
− Patients with no risk of stroke
 The clinician should adapt the therapeutic
strategy to each individual patient
Position Statement
Rate vs Rhythm (ACC/AHA/ESC)
 “Before choosing rate control as a long-term strategy,
the clinician should consider how permanent AF is likely
to affect the patient in the future. RACE… and AFFIRM…
do not necessarily apply to younger patients without heart
disease or to patients whose dependency upon sinus rhythm
is likely to change appreciably over time. This makes it
important to ensure that a window of opportunity to maintain
sinus rhythm is not overlooked early in the course of
management of a patient with atrial fibrillation.”
Fuster et al. J Am Coll Cardiol. 2006;48:854-906(A).
Rate vs Rhythm and Physician
Characteristics
 Assessed patient and physician characteristics associated
with the choice of rate or rhythm control strategy in hospital
 155,731 hospitalizations from 464 hospitals
− 48% rhythm control
− 52% rate control
 Care by a noncardiologist and increasing age >65 years
were associated with lower odds of rhythm vs rate control
(OR 0.33, 95% CI, 0.31 - 0.36 for family, general, and
internal medicine vs cardiology)
 Warfarin use was greater in the rhythm control group
compared with the rate control group
Lapointe et al. Am J Cardiol. 2008;101(8):1134-1141.
Anticoagulation in AF
Stroke Risk Reductions
Warfarin Better
Control Better
AFASAK
Reduction of
all-cause mortality
RRR 26%
SPAF
BAATAF
CAFA
SPINAF
Reduction of
stroke
RRR 62%
EAFT
All trials=6
100%
50%
Hart et al. Ann Intern Med. 1999;131:492-501(B).
0
-50%
-100%
CHADS2 Risk Stratification Scheme
Risk Factors
Score
C Recent CHF
1
H Hypertension
1
A Age 75 years
1
D Diabetes mellitus
1
S2 History of stroke or transient ischemic
attack (TIA)
2
Rockson et al. J Am Coll Cardiol. 2004;43:929-935(B).
Stroke Risk in New-Onset AF
ACP/AAFP Guidelines
CHADS2a
Score
Adjusted Stroke Rateb
(95% CI)
CHADS2
Risk Level
0
1.9 (1.2-3.0)
Low
1
2.8 (2.0-3.8)
Low
2
4.0 (3.1-5.1)
Moderate
3
5.9 (4.6-7.3)
Moderate
4
8.5 (6.3-11.1)
High
5
12.5 (8.2-17.5)
High
6
18.2 (10.5-27.4)
High
Warfarin
of the following comorbidities: CHF, hypertension, age ≥75, and diabetes
(1 point each); history of stroke or TIA (2 points each).
bExpected rate of stroke per 100 patient-years.
aAssessment
Snow et al. Ann Intern Med. 2003;139:1009-1017 (A).
Stroke Risk in AFFIRM Rate and
Rhythm Control Arms
Rate Control
n (%)
Ischemic strokea
Rhythm Control
n (%)
77 (5.5)
80 (7.1)
INR 2.0
23 (31)
16 (21)
INR <2.0
27 (36)
17 (22)
Not taking warfarin
25 (33)
44 (57)
42 (69)
25 (37)
AF at time of event
INR=international normalized ratio.
aEvent rates derived from Kaplan-Meier analysis, P=.79.
AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833 (A); Sherman et al. Arch Intern Med.
2005;165:1185-1191 (A).
The ACTIVE Trial
Clopidogrel + Aspirin
AF + Risk Factors
ACTIVE - W
Anticoagulation-eligible
VKA
Clopidogrel
(INR 2-3)
+ Aspirin
Open-label
Noninferiority
n=6500
ACTIVE - A
OAC Contraindications or Unwilling
Aspirin
Clopidogrel
+ Placebo
+ Aspirin
Double-blind
Superiority
n~7500
Irbesartan, 300 mg/day vs placebo
ACTIVE - I
n ~9000
Risk Factors:
Age 75, HTN, prior stroke/TIA,
LVEF<45%, PAD, age 55-74 + CAD or
diabetes
Primary outcome:
Stroke, systemic embolism, MI, or
CV death
ACTIVE Investigators. Lancet. 2006;367:1903-1912; ACTIVE Investigators. Am Heart J. 2006;151:1187-1193.
Antithrombotic Therapy for Atrial Fibrillation
Stroke Risk Reductions
Warfarin
Better
Antiplatelet Rx
Better
ACTIVE-W
Anticoagulation vs
aspirin + clopidogrel
n=6706
Anticoagulation vs
antiplatelet drugs
7 Trials
n=4232
100%
50%
0%
-50%
ACTIVE Investigators. Lancet. 2006;367:1903-1912; Hart et al. Ann Intern Med. 2007;146:857-867.
Dabigatran Etexilate
 Competitive inhibitor of thrombin
 Prodrug dabigatran etexilate is converted
completely to active dabigatran
 Orally active; Peak plasma concentration at 2 hours
post-dose; bioavailabiltiy of 3.5-6.5%
 T ½: 14-17 hours
 No known drug/drug interactions; Proton pump
inhibitors reduce absorption
 Eliminated predominantly by kidneys (80%)
Stangier et al. J Clin Pharmacol. 2005;45:555-563; Liesenfeld et al. Br J Clin Pharmacol. 2006;62:527-537;
Stangier et al. Br J Clin Pharmacol. 2007;64:292-303
Dabigatran: RE-LY Study Design
Patient with NVAF
assessed for
eligibility
N=20,240
R
N=18,113
Dabigatran
110 mg bid
Warfarin naїve
start dabigatran
Dabigatran
150 mg bid
On nonstudy
warfarin/VKA at
randomization: once
INR <2.0, start dabigatran
Warfarin naїve
start warfarin
Warfarin
INR 2-3
R=randomization.
Ezekowitz et al. Am Heart J. 2009;157:805-810.e1-2.
On nonstudy
warfarin/VKA at
randomization: once
INR <3.0, start warfarin
Dabigatran: RE-LY Study Primary Outcome
1.0
0.05
Cumulative Hazard Ratio
0.04
0.8
0.03
0.6
0.02
0.01
0.4
0.00
0
0.2
Warfarin
6
12
Dabigatran 110
mg
18
24
30
Dabigatran
150 mg
0.0
No. at Risk
Warfarin
Dabigatran, 110 mg
Dabigatran, 150 mg
0
6
12
6022
6015
6076
5862
5862
5939
5718
5710
5779
Connolly et al. N Engl J Med. 2009;361.
18
Months
4593
4593
4682
24
30
2890
2945
3044
1322
1385
1429
Dabigatran
Event
P Value
Stroke or systemic embolism
<.001a
Stroke
<.001
Hemorrhagic
<.001
Ischemic or unspecified
.03
Nondisabling stroke
.01
Disabling or fatal stroke
.005
Myocardial infarction
.048
Pulmonary embolism
.21
Hospitalization
.34
Death from vascular causes
.04
Death from any cause
.051
0
afor
noninferiority, <.001.
Connolly et al. N Engl J Med. 2009;361.
1
2
3
4
Risk of AF in HF Patients
CONSENSUS (IV)
GESICA (II-IV)
DIAMOND-CHF (II-III)
ATLAS (III)
CHF-STAT (II-III)
In HF, new AF occurs at a rate
of 6% to 8%/year
V-HeFT (II-III)
Overall, AF is present in >15%
of HF patients
SOLVD (II-III)
0
10
20
30
Prevalence of AF (%)
Ehrlich et al. J Cardiovasc Electrophysiol. 2002;13(4):399-405 (B).
40
50
SOLVD: Influence of AF on Mortality
All-Cause Mortality (%)
Death or Hospitalization for HF (%)
AF
100
100
80
80
Survival (%)
Survival (%)
SR
60
40
60
40
P<.001
P<.001
20
20
0
0
0
365
770
Days
1095
1460
Dries et al. J Am Coll Cardiol. 1998;32(3):695-703 (A).
0
365
770 1095
Days
1460
Effect of AF on Sudden Death in HF
Probability of CHF
Hospitalization or Death
AVID
MADIT II
1.0
AF
0.8
Sinus
0.6 Unadjusted P=.004
P=.03
0.4
0.2
0.0
0.0
0.5
1.0
1.5 2.0
Years
2.5
3.0
1.0
Survival
Probability of Death
MADIT II and AVID Studies – Post-Hoc Analysis
AF
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Unadjusted P=.01
Adjusted P=.02
0
0.8 Unadjusted P=.001
0.6
Non-AF
1
2
Years
3
4
0.4
0.2
0.0
P<.01
0.0
0.5
1.0
1.5 2.0
Years
2.5
3.0
Wyse et al. J Interv Card Electrophysiol. 2001;5:267-273 (B); Zareba et al. Heart Rhythm. 2006;3:631-637 (B).
AF-CHF Trial
Study Design
CHF:
Qualifying AF:
AF-CHF
Screening
NYHA class II-IV and EF  35%
NYHA I and prior hospitalization for CHF or EF  25%
One episode  6 hours within last 6 months
One episode  10 minutes within last 6 months and prior D/C shock
Eligible patients’ consent
Randomization (open-label)
Rhythm control
Rate control
Antiarrhythmic drug and/or nonpharmacologic therapy in resistant
patients
Pharmacologic dosing adjustment
Cardioversion if needed
AF nodal ablation for patients with
inadequate rate control
Follow-up 2 years, clinic visits every 4 months
Optimal CHF management with ACEI and BB
Atrial Fibrillation and Congestive Heart Failure (AF-CHF) Trial Investigators. Am Heart J. 2002;144(4):597-607 (B).
AF-CHF Trial: Results
 No difference in primary endpoint of CV death
−
182 (27%) rhythm control vs 175 (25%) rate control (HR 1.06, P=.59)
 No difference in prespecified secondary endpoints
−
−
−
Total mortality, worsening CHF, and stroke
Composite of CV death, worsening CHF, and stroke
CV mortality
 21% crossover from rhythm to rate control
−
Primarily due to inability to maintain SR
 10% crossover from rate to rhythm control
−
Primarily due to worsening HF
 Higher hospitalization rate in rhythm control (46% vs 39% at 1 year;
P=.001)
−
Mainly due to hospitalization for AF (14% vs 9%; P=.001) and
bradyarrhythmias (6% vs 3%; P=.02)
 Higher rate of cardioversions in rhythm control (59% vs 9% P<.001 )
Roy et al. N Engl J Med. 2008;358:2667-2677(A).
Maintenance of SR
No (or minimal)
heart disease
Hypertension
CAD
HF
Flecainide
Propafenone
Sotalol
Substantial
LVH
Dofetilide
Sotalol
Amiodarone
Dofetilide
Amiodarone
Dofetilide
Catheter
ablation
No
Yes
Flecainide
Propafenone
Sotalol
Amiodarone
Amiodarone
Dofetilide
Catheter
ablation
Catheter
ablation
Fuster et al. J Am Coll Cardiol. 2006;48:854-906 (A).
Amiodarone
Catheter
ablation
Catheter
ablation
Effect of AF on Event Rate in Patients
With HF and Preserved EF
CHARM Study
CV Death or Hospitalization for HF
Low EF:
Hazard Ratio 1.29
(95% Cl, 1.14-1.46)
P<.001
0.45
Cumulative Distribution Function
AF at
Baseline
(Low EF)
0.40
No AF at
Baseline
(Low EF)
0.35
AF at
Baseline
(Preserved)
0.30
0.25
No AF at
Baseline
(Preserved)
0.20
0.15
PEF:
Hazard ratio 1.72
(95% Cl, 1.45-2.06)
P<.001
0.10
0.05
0
0
1
2
3
3.5
Year
EF=ejection fraction; PEF=Preserved ejection fraction.
Olsson et al. J Am Coll Cardiol. 2006;47:1997-2004(A).
0.45
Cumulative Distribution Function
0.50
All-Cause Mortality
AF at
baseline
(Low EF)
No AF at
baseline
(Low EF)
AF at
baseline
(Preserved)
No AF at
baseline
(Preserved)
Low EF:
Hazard Ratio 1.38
(95% Cl, 1.21-1.59)
P<.001
0.40
0.35
0.30
0.25
0.20
0.15
PEF:
Hazard Ratio 1.80
(95% Cl, 1.46-2.21)
P<.001
0.10
0.05
0
0
1
2
Year
3
3.5
Maintenance of SR
No (or minimal)
heart disease
Hypertension
CAD
HF
Flecainide
Propafenone
Sotalol
Substantial
LVH
Dofetilide
Sotalol
Amiodarone
Dofetilide
Amiodarone
Dofetilide
Catheter
ablation
No
Yes
Flecainide
Propafenone
Sotalol
Amiodarone
Amiodarone
Dofetilide
Catheter
ablation
Fuster et al. J Am Coll Cardiol. 2006;48:854-906(A).
Catheter
ablation
Amiodarone
Catheter
ablation
Catheter
ablation
Maintenance of SR
No (or minimal)
heart disease
Hypertension
CAD
HF
Flecainide
Propafenone
Sotalol
Substantial
LVH
Dofetilide
Sotalol
Amiodarone
Dofetilide
Amiodarone
Dofetilide
Catheter
ablation
No
Yes
Flecainide
Propafenone
Sotalol
Amiodarone
Amiodarone
Dofetilide
Catheter
ablation
Fuster et al. J Am Coll Cardiol. 2006;48:854-906(A).
Catheter
ablation
Amiodarone
Catheter
ablation
Catheter
ablation
Success Rates With Ablation
Worldwide Survey
Success without AADs
Success with AADs
Overall success
100
90
Rates (%)
80
70
60
50
40
30
20
10
0
0-3
4-6
7-9
10-12
13-18
Range of Follow-up (months)
Cappato et al. Circulation. 2005;111:1100-1105(B).
19-24
>24
Ablation vs AAD Therapy:
Meta-analysis of Clinical Trials
Study
Recurrence in
AAD Group at
1 Year (n/N)
Recurrence in
Ablation Group at
1 Year (n/N)
Krittayaphong et al
9/15
3/15
Wazni et al
22/37
20/77
Stabile et al
63/69
30/68
Jais et al
56/69
13/53
Pappone et al
73/99
14/99
Totala
254/348
84/345
aP<.001
for the comparison of AAD group to ablation group.
Nair et al. J Cardiovasc Electrophys. 2008 [Epub ahead of print].
P<.001
LV End-Diastolic
Diameter (mm)
0
75
70
65
1
P=.001
P<.001
3
Month
P=.03
P<.001
P<.001
40
LV Fractional
Shortening (%)
70
65
60
55
50
45
40
35
30
25
0
6
P=.02
35
P=.001
60
55
50
45
0
P<.001
P<.001
P<.001
P<.001
30
25
20
15
0
0
12
LV End-Systolic
Diameter (mm)
LVEF (%)
Improvement in LV Function/Dimensions
After Ablation in AF Patients With CHF
1
3
Month
6
12
55
P<.001 P<.001
50
P=.001
45
P=.001
40
35
30
0
0
1
3
Month
6
12
0
1
3
Month
6
12
Plotted values are means SD. P values, which are for the comparison with baseline data, were determined
with the use of Fisher’s least-significant-difference test. The numbers of patients included at each time point
were as follows: 0 month, 58; 1 month, 55; 3 months, 48; 6 months, 40; 12 months, 34.
LV=left ventricle; LVEF=left ventricular ejection fraction.
Hsu et al. N Engl J Med. 2004;351:2373-2383(B).
Complication Rates for Catheter Ablation
1.5
Patients (%)
1.22
1
0.53
0.42
0.5
0.16
0.05
0.01
0.02
0
Cappato et al. Circulation. 2005;111:1100-1105(B).
0.11
0.01
0.03
CABANA Trial
Primary Ablation
(technique at
operator discretion)
Recent-onset AF
eligible for ablation
or drug therapy
 65 years old or
< 65 years old with
 1 risk factor for
CAD or stroke
Drug Therapy
(rate or rhythm control
[at operator discretion]
with anticoagulation)
Packer. Presented at: 2005 Scientific Sessions of the American Heart Association;
November 13-16, 2005; Dallas, TX(Ai).
Discontinued
Anticoagulation
Continued
Anticoagulation
Indications for Catheter AF Ablation
 Symptomatic AF refractory or intolerant to at least
one Class I or III antiarrhythmic medication
 In rare clinical situations, it may be appropriate
as first-line therapy
 Selected symptomatic patients with HF and/or
reduced ejection fraction
 Presence of a left atrial thrombus is a
contraindication to catheter ablation of AF
Calkins et al. Heart Rhythm. 2007;4:1-46.
Management After Ablation
 Heparin (UFH or LMWH) as bridge to warfarin
 Warfarin for all patients for  2 months
 Use of warfarin > 2 months following ablation based
on the patient’s risk factors for stroke and not on the
presence or type of AF
− Discontinuation of warfarin therapy postablation
generally not recommended for CHADS2 score  2
Calkins et al. Heart Rhythm. 2007;4:1-46.
New Approaches to Treatment
What Are the Goals of AF Therapy?
 Improve survival
 Reduce sequelae
− Stroke




Reduce hospitalizations
Improve symptoms
Improve QoL
Restore atrial function/reverse the remodeling
process
New AAD Development:
Possible Mechanisms
 BB with class I or III effects
 Amiodarone congeners
 Atrial-selective antiarrhythmic drugs
− IKur and IKAch blockers
− Atrio-selective Na channel blockers
− 5-HT4 receptor antagonists





Stretch-activated channel blockers
ACEIs/ARBs
NCX (Na/Ca exchanger) inhibitors
Anti-inflammatories (statins)
Gap-junction conduction facilitation
Bhakta et al. Expert Opin Ther Targets. 2007;11(9):1161-1178(B).
Electrophysiologic Remodeling
Normal
Ito
ItoICa
IKur
IKAch
ICa
IKur
IKr
0
Remodeled
100
200
ms
IKs
IKr
300
400
0
100
IKs
200
ms
300
400
Vernakalant (RSD1235)
 Unique ion channel–blocking profile
− Frequency- and voltage-dependent INa block
− Early activating K+ channel block
− Blocks IKAch





Rate-enhanced activity on conduction
Atrial-selective APD/ERP prolongation
Activity confirmed in several species
No adverse hemodynamic effects
Novel aminocyclohexyl ether drug
Vernakalant is an investigational drug not yet approved by the FDA.
Beatch et al. Circulation. 2003;108(suppl IV):IV85.
Vernakalant: ACT III
Termination of AF (%)
60
P<.001
Placebo
Vernakalant
52%
50
P=.001
41%
40
n=86
30
n=118
20
10
0
4%
n=84
AF Duration
3 h-7 d
4%
n=121
AF Duration
3 h-45 d
 Conversion of recent-onset AF (3 h-7 d): 52% vs 4% (P<.001)
 8 minutes—median time to conversion
 No drug-related TdP seen
Vernakalant is an investigational drug not yet approved by the FDA.
TdP=torsades de pointes.
Adapted from Roy et al. Presented at: Heart Rhythm Society; May 5, 2006; New Orleans, LA(Ai).
Oral Vernakalant—Phase 2b
(Interim Analysis)
% SR
Related
SAEs
Death
59 days
39%
1%
1
150 mg BID (110)
NS
NS
2%
1
300 mg BID (108)
NS
NS
0%
0
500 mg BID (110)
>90 daysa
52%
1%
0
Placebo (118)
Time to
Recurrence
Vernakalant is an investigational drug not yet approved by the FDA.
No TdP cases or drug-related deaths.
NS=not significant.
aP<.05 (2-tailed).
Hofman. Fierce Biotech Web site. http://www.fiercebiotech.com/press-releases/cardiome-announces-positiveinterim-phase-2b-results-oral-vernakalant-and-engages-m-0. Accessed May 8, 2008 (Ai).
Dronedarone
 Amiodarone-like compound lacking the
iodine moiety
 Similar electrophysiologic properties
− Blocks IKr, IKur, IKs, IKAch, Ica, Ito, INa
− Beta blockade as well
 No evidence of thyroid or pulmonary toxicity
 24-hour half-life
Dale et al. Ann Pharmacother. 2007;41(4):599-605(B); Altomare et al. Br J Pharmacol. 2000;130:1315-1320(B).
Dronedarone: Trials
 EURIDIS (EURopean trial In atrial fibrillation or flutter
patients receiving Dronedarone for the maIntenance
of Sinus rhythm)
 ADONIS (American-Australian trial with DronedarONe
in atrial fibrillation or flutter patients for the maIntenance
of Sinus rhythm)
 ANDROMEDA (ANtiarrhythmic trial with DROnedarone in
Moderate to severe CHF Evaluating morbidity DecreAse)
 ATHENA (A Trial with dronedarone to prevent
Hospitalization or dEath in patieNts with Atrial fibrillation)
Dale et al. Ann Pharmacother. 2007;41(4):599-605(B).
Primary Endpoint: Patients With
Adjudicated First Recurrence of AF/AFL
ADONIS
0.8
0.7
0.6
0.5
0.4
P=.01
0.3
0.2
Cumulative Incidence
Cumulative Incidence
EURIDIS
0.8
0.7
0.6
0.5
0.4
0.3
0.1
0.1
0.0
0.0
0
60 120 180 240 300 360
Time (days)
Placebo
Singh et al. N Engl J Med. 2007;357:987-999(A).
P=.002
0.2
0
60 120 180 240 300 360
Time (days)
Dronedarone 400 mg bid
Pooled Tolerability and Safety Data
EURIDIS and ADONIS
Incidence of Treatment-Emergent
Adverse Events (TEAEs)
Placebo
Dronedarone
400 mg bid
(n=409)
(n=828)
Patients with any AE
65.8%
69.8%
Patients with any SAE
24.4%
19.8%
Deaths
0.7%
1%
Patients who permanently
discontinued study drug following
any TEAE
7.1%
9.7%
 No evidence of proarrhythmia; in particular, no case of TdP reported
during 12-month follow-up
 No detection of dysthyroidism (systematic hormonal monitoring)
Singh et al. N Engl J Med; 2007;357:987-999(A).
ATHENA
Primary Outcome
Cumulative Incidence (%)
Time to first cardiovascular hospitalization or death
HR=0.76
P<.001
50
40
30
Placebo
20
Dronedarone
10
0
0
Patients at risk
Placebo
Dronedarone
2327
2301
6
1858
1963
12
18
24
30
Months
1625
1072
1776
1177
385
403
3
2
Mean follow-up 21  5 months.
Hohnloser et al. N Engl J Med. 2009;360:668-678 (A).
ATHENA
Fatal Outcomes
Outcome
All deaths
Placebo Dronedarone Hazard
(n=2327)
(n=2301)
Ratio
95% CI
P Value
139
116
0.84
0.66-1.08
.18
Non-CV deaths
49
53
1.10
0.74-1.62
.65
CV deaths
90
63
0.71
0.51-0.98
.03
Cardiac nonarrhythmic
deaths
18
17
0.95
0.49-1.85
.89
Cardiac arrhythmic
deaths
48
26
0.55
0.34-0.88
.01
Vascular noncardiac
24
20
0.84
0.47-1.52
.57
Hohnloser et al. N Engl J Med. 2009;360:668-678 (A).
ATHENA
NonFatal Outcomes
Outcome
Primary outcome
Placebo Dronedarone Hazard
(n=2327)
(n=2301)
Ratio
95% CI
P Value
917
734
0.76
0.69-0.84
<.001
859
675
0.74
0.67-0.82
<.001
AF
510
335
0.63
0.55-0.72
<.001
CHF
132
112
0.86
0.67-1.1
.22
ACS
89
62
0.70
0.51-0.97
.03
Syncope
32
27
0.85
0.51-1.42
.54
Ventricular arrhythmia or
nonfatal cardiac arrest
12
13
1.09
0.50-2.39
.83
First hospitalization for
CV reasons
Hohnloser et al. N Engl J Med. 2009;360:668-678 (A).
ATHENA
Primary Outcome in Important Clinical Subgroups
Characteristic
Age (years)
<75
75
Sex
Male
Female
Presence of AF/AFL
Yes
No
Structural heart disease
Yes
No
Congestive HF
Yes
No
LVEF (%)
<35
35-45
45
ACE/ARB
Yes
No
Beta-blocking agents
Yes
No
N
P
HR (95% CI)
2703
1925
0.76 (0.67-0.87)
0.75 (0.65-0.87)
.93
2459
2169
0.74 (0.64-0.85)
0.77 (0.67-0.89)
.65
1155
3473
0.74 (0.61-0.91)
0.76 (0.68-0.85)
.85
2732
1853
0.76 (0.67-0.85)
0.77 (0.65-0.92)
.85
1365
3263
0.75 (0.64-0.88)
0.76 (0.68-0.86)
.83
179
361
4004
0.68 (0.44-1.03)
0.66 (0.47-0.92)
0.78 (0.70-0.86)
.55
3216
1412
0.74 (0.66-0.83)
0.79 (0.66-0.95)
.59
3269
1359
0.78 (0.69-0.87)
0.71 (0.58-0.86)
.41
0.1
Hohnloser et al. N Engl J Med. 2009;360:668-678 (A).
Dronedarone
Better
1
Placebo
Better
10
ATHENA Post-Hoc Analysis
Stroke Reduction
Dronedarone
Placebo
P<.001
Annual Rate
8
6
5.52
5.06
34% Risk Reduction of Stroke
3.80
4
2
P=.002
6.70
P=.020
P=.027
1.79
1.19
2.05
1.37
P=. 247
0.36 0.54
0
Stroke
Stroke or
TIA
Fatal
Stroke
Note: Investigators were encouraged to maintain
anticoagulation according to published guidelines
Stroke,
Stroke,
ACS, or CV ACS, or
Death
All-Cause
Death
Connolly. ATHENA: The effect of dronedarone on cardiovascular outcomes and stroke in patients with atrial
fibrillation. Presented at: European Society of Cardiology Congress 2008; September 3, 2008; Munich, Germany.
Clinical trials update 3. http://www.theheart.org/viewArticle.do?primaryKey=901685. Accessed September 4,
2008(Ai).
ATHENA Post Hoc Analysis
Stroke and Hospitalization Reduction
P=.002
Annual Rate
8
Dronedarone
6
4
2
P=.027
1.19 1.79
P=.020
1.37
2.05
P<.001
Placebo 34% Risk
5.52
Reduction of
3.80
Stroke
6.70
5.06
P=.247
0.36 0.54
0
Stroke
Total hospital
days
Stroke or TIA
Length of CV
hospitalization
Fatal Stroke
AF
hospitalization
Stroke, ACS, or Stroke, ACS, or
CV Death
All-Cause Death
First non-AF
hospitalization
Incidence of
first AF
recurrence
Incidence of
first D/C
cardioversion
0
-10
-14%
-20
-30
-40
-25%
-28%
-35%
-31%
-37%
Note: Investigators were encouraged to maintain anticoagulation according to published guidelines.
Connolly. Presented at: European Society of Cardiology Congress 2008; September 3, 2008; Munich, Germany;
Clinical trials update 3. http://www.theheart.org/viewArticle.do?primaryKey=901685. Accessed September 4,
2008. Page. Presented at: the American Heart Association; November 2008; New Orleans, LA.
Summary
 AF is a common disease that is increasing in prevalence
 There are significant consequences to AF, including stroke,
HF, sudden death, and other CV mortality
 Atrial electrical and structural remodeling take place early
and progress, making the return to SR more difficult with
longer duration of AF
 New agents have properties that are designed to work more
effectively in remodeled atria
 Current guidelines provide algorithms for antiarrhythmic use
in specific clinical conditions
 New agents may provide antiarrhythmic options with
improved outcomes for managing AF
Heart-to-Heart:
An AF Outcomes Initiative
Questions and Answers