Download p-value - Digital Infomedia Solution

Atrial Fibrillation:
From Sinus Rhythm Maintenance to Improving CV
Outcomes – Should We Redefine Therapy Goals?
Milan Gupta, MD
Department of Medicine
McMaster University
Hamilton, Canada
Overview
 AF Epidemiology
 Antiarrhythmic Drugs and Outcomes
 New AF Treatment Options
AF is the most common cardiac arrhythmia
 AF affects
 1 in 25 adults >60 years1
 1 in 10 adults >80 years1
 7.5 million patients with AF in EU and US2,3
4.5 million
EU
3.0 million
US
0
1
1. Go AS et al. JAMA 2001;285:2370-2375
2. Fuster V et al. J Am Coll Cardiol 2006;38:1231-1265
3. Naccarelli GV et al. Am J Cardiol. 2009;104(11):1534-9
2
3
4
5
3
Lifetime risks for development of AF are 1 in 4 for men
and women 40 years of age and older
Framingham
Women
Men
30
Lifetime risk of AF (%)
26.0
25
25.9
23.4
23.2
23.0
25.8
23.0
24.3
21.6
22.7
20
15
10
5
0
40
50
60
70
80
Age (years)
Lloyd-Jones DM, et al. Circulation 2004;110:1042-46
4
AF is Associated with a High
Prevalence of Co-morbidities
The Record AF registry including 5,604 patients with paroxysmal
or persistent AF
Le-Heuzey J-Y, et al. Am J Cardiol 2010;105:687-93.
AF May Adversely Affect
Quality of Life
SF-36 score from QoL Questionnaire
QoL was significantly worse in AF patients than in controls
(post MI patients and healthy subjects)
Lower scores = poorer QoL
120
*p<0.05 vs. controls
100
88
80
78
68*
60
40
54*
70
85
92
71*
68*
76
81
59
20
0
General health
Physical function
AF patients (n=152)
Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309.
Social function
Post MI patients (n=69)
Mental health
Healthy subjects (n=47)
6
AF increases risk of death and CV outcomes
Renfrew/Paisley
Rate ratio (95% Confidence Interval [CI])*
All-cause mortality
CV events
Women
n=8,354
Fatal or non-fatal stroke
Heart failure
All-cause mortality
CV events
Fatal or non-fatal stroke
Men
n=7,052
Heart failure
-1
0
* Adjusted for age; follow-up 20 years
Stewart S, et al. Am J Med 2002;113:359-64.
1
2
3
4
5
6
7
CV events: death or hospitalisation
8
7
REACH Registry: Association of AF with CV
Outcomes in Atherothrombotic Patients*
The REACH registry
Patients with
AF
Patients
without AF
n
6814
56775
All-cause mortality
4.27 %
2.32 %
＜0.0001
CV death
3.16 %
1.42 %
＜0.0001
Non-fatal MI
1.36 %
1.11 %
0.1205
Non-fatal stroke
2.43 %
1.55 %
＜0.0001
Variable
p value
Major CV events
Adjusted for age, sex, smoking, hypertension, diabetes, hypercholesterolaemia
* out patient population with past history of coronary artery disease and/or past
history of cerebrovascular disease and/or peripheral artery disease
Goto S, et al. Am Heart J 2008; 156:855-63.
8
Studies reveal high hospitalisation rates among AF
patients
%
follow-up
1 year
% hospitalised for CV reasons
80
50
AF control
mean follow-up 21
40
months
follow-up
1 year
30
36.9%
36.9%
AF not controlled
60
40
follow-up
1 year
20
28.1
20
17.0%
10
29.8
0
0
ATHENA*
(placebo arm)1
Euro Heart
Survey2,3
RecordAF Registry4
At least one
cardiovascular event
RealizeAF Registry
* First hospitalisation due to CV event
1.
2.
3.
4.
Hohnloser SH et al. N Engl J Med 2009;360:668-78.
Nieuwlaat R et al. European Heart Journal 2008:29;1181–9.
Multaq European Public Assessment Report.
Camm J. RecordAF Registry. Scientific sessions AHA 2009.
9
Hospitalizations Represent a Major Driver in
Cost of Care of AF Patients (US)
In 2001, AF management cost about 6.65 billion dollars* in
the US and was mainly driven by inpatient care.
Outpatient costs
1.53 billion dollars
(Diagnosis of AF)
Incremental inpatient costs
1.95 billion dollars
(AF as comorbid condition)
Hospitalization
2.93 billion dollars
(Principle discharge diagnosis of AF)
0
* Does not include prescription costs.
Coyne K., et al. Value Health 2006;9(5):348-356.
1
2
3
Patients hospitalised with AF have a higher risk of
death in subsequent years
 AFFIRM trial – 4,060 patients analyzed
 CV hospitalisation highly predictive of death in both rhythm and
rate control arms (p<0.0001)
AFFIRM
Inclusive cohort*
HR (95% CI)
Censored cohort*
HR (95% CI)
Rate control
2.15 (1.69 – 2.74)
2.39 (1.86 – 3.07)
Rhythm control
1.71 (1.37 – 2.13)
1.98 (1.52 – 2.57)
Time to death did not differ between 2 treatment groups
CV hospitalisation, occurring sooner and more often than death,
is highly predictive of death
Wyse, et al. Heart Rhythm 2004;1;531-37.
Camm AJ, Reiffel JA. Eur Heart J Suppl 2008;10:H55-78.
* Inclusive cohort = all CV hospitalisations.
* Censored cohort = cardioversion or drug change excluded.
11
Overview
 AF Epidemiology
 Antiarrhythmic Drugs and Outcomes
 New AF Treatment Options
Traditional Goals in Managing AF
 Restoration of sinus rhythm
 Ventricular rate control
 Identification and treatment of predisposing conditions and underlying
heart disease
 Improvement in symptoms
 Improved exercise tolerance
 Improved quality of life
 Stroke prevention (with antithrombotic drugs)
AF Treatment – A brief history
• Digitalis – 1785, William Withing
• Quinidine – 1951
• Amiodarone and disopyramide – 1970’s
• Vaughan Williams classification – 1984
• Encainide and propafenone – late 1980’s
• And then came 1989
105
Placebo
(n=725)
Survival (%)
100
Encainide
or flecainide
(n=730)
95
90
p=0.0006
85
0
50
100
150
200
250
300
350
Days after randomization
400
450
500
Quinidine Treatment Was Associated With
Increased Total Mortality
RCT
Boissel, et al.
Byrne-Quinn, et al.
Hartel, et al.
Hillestad, et al.
Lloyd, et al.
Sodermark, et al.
TOTAL: ALL STUDIES
N=808
0
Quinidine better
1
2
3
4
5
6
7
8
9 10 11 12
Quinidine worse
Odds ratio (Quinidine:Control)
• There was a significant increase in total mortality in quinidine-treated
group as compared with control group (OR=2.98; p<0.05).
Coplen S., et al. Circulation 1990;82:1106-1116.
16
Patients without recurence (%)
Patients remaining free of recurrence of AF (CTAF)
100
Amiodarone (n=201)
80
60
Propafenone (n=101)
40
Sotalol (n=101)
20
0
0
100
200
300
Days of follow-up
Roy D et al. New Engl J Med 2000;342:913-920.
17
400
500
600
AFFIRM Results Post-hoc Analysis
Covariate
HR 99% CI
P Value
Sinus rhythm
<.0001
Warfarin use
<.0001
Digoxin use
.0007
AAD use
.0005
0
0.5
1
1.5
2
The benefits of sinus rhythm are
offset by the toxicity of AADs used in AFFIRM
Corley et al. Circulation. 2004;109:1509-1513.
2.5
Cumulative noncardiovascular mortality in AFFIRM
Percent death (%)
30
Log rank statistic = 11.2
P=0.0008
25
20
15
Rhythm control
10
5
Rate control
0
0
1
2
3
4
5
Years
No. events (%)
Rate
Rhythm
2027, 0 (100)
2033, 0 (100)
1926, 20 (1)
1932, 33 (2)
Steinberg JS Circulation 2004;109:1973-1980.
1827, 49, (3) 1329, 70 (4)
1807, 76 (4) 1316, 120 (7)
774, 101 (7) 236, 109 (8)
780, 149, (9) 255, 167 (12)
1, 113 (14)
1, 169 (14)
Amiodarone in AF Patients:
Meta-analysis*
 Conversion/maintenance of sinus rhythm not associated with a
reduction of all-cause death or all-cause hospitalisation
Relative Risk
[95% CI]
p-value
(test for overall effect)
Conversion to sinus rhythm
per patients-year follow up
3.22
[1.88–5.53]
<0.0001
Incidence of all-cause mortality
per patient-year follow up
0.95
[0.81–1.11]
0.51
Rate of all-cause hospitalisation
per patients-year follow up
1.10
[0.57–2.13]
0.77
Outcome of Interest
.
* Eight studies compared amiodarone with a rate control drug, either beta-blocker or
digoxin, and 4 trials compared amiodarone with placebo.
Doyle JFD, et al. Mayo Clin Proc. 2009;84(3):234-242
Source of slide: John Camm
21
Overview
 AF Epidemiology
 Antiarrhythmic Drugs and Outcomes
 New AF Treatment Options
AF Increases the Risk of Stroke
Framingham
Relative Risk of Stroke
5
4.5
4.0
4
3.3
3
2.6
2
1
0
50-59
60-69
70-79
Age (years)
p<0.001 vs. Non-AF patients
Wolf et al. Stroke 1991:22:983-988
80-89
Warfarin reduces strokes
RRR 64%;
95% CI: 49-75%
6 trials, n=2,700
Hart RG, et al. Ann Intern Med 2007; 146: 857-867
Underutilization of Warfarin in Atrial
Fibrillation: Results from Recent Studies*
Year
Published
Study
Population
% Treated with
Warfarin
1999
ATRIA
Go et al Ann Intern Med 1999
11,082 US patients from HMO
60 (high-risk)
2000
Samsa et al Arch Intern Med 2000
660 US patients: FP/GIM
35
2005
NABOR
Waldo et al J Am Coll Cardiol 2005
945 US patients
55 (high-risk)
2006
Euro Heart Survey
Nieuwlaat et al Eur Heart J 2006
2706 outpatients in 35 EU countries
64
2006
Hylek et al Stroke 2006
402 US patients, ≥65 years
51
2006
Birman-Deych et al Stroke 2006
16,0007 US Medicare patients
49
2006
Friberg et al Eur Heart J 2006
1898 Swedish patients
54
•Adapted from Connolly SJ, et al. Circulation 2007:116;449-455
ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation
FP/GIM: Family practice / general internal medicine
NABOR: National Anticoagulation Benchmark and Outcomes Report
Connolly SJ, et al. Circulation 2007:116;449-455
25
Stroke or Systemic Embolism
Non-inferiority
p-value
<0.001
Dabigatran 110 vs.
Warfarin
Superiority
p-value
<0.001
Dabigatran 150 vs.
Warfarin
0.34
<0.001
Margin = 1.46
0.50
Dabigatran better
0.75
1.00
1.25
HR (95% CI)
1.50
Warfarin better
Connolly S, et al. N Engl J Med 2009
Apixaban
0
3
6
2791
2809
9
12
18
21
Months
No. at Risk
ASA
Apix
ASA
0.03
0.05
RR= 0.46
95%CI= 0.33-0.64
p<0.001
0.0 0.01
Cumulative Risk
AVERROES: Stroke or
Systemic Embolic Event
(Pts ineligible for warfarin)
2720
2761
2541
2567
2124
2127
preliminary Results
1541
1523
626
617
329
353
27
Traditional Goals in Managing AF
 Restoration of sinus rhythm
 Ventricular rate control
 Identification and treatment of predisposing conditions and underlying
heart disease
 Improvement in symptoms
 Improved exercise tolerance
 Improved quality of life
 Stroke prevention (with antithrombotic drugs)
 What about prevention of cardiovascular events and
hospitalizations?
Dronedarone has Key Structural Differences
to Amiodarone
Dronedarone
O
No iodine-related
toxicity
(CH2)3CH3
CH3SO2HN
Less lipophilic –
shorter t1/2 and
reduced tissue
accumulation
O(CH2)3N
O
I
O(CH2)2N
Kathofer et al. Cardiovasc Drug Rev. 2005;23(3):217-30.
(CH2)3CH3
O
(CH2)3CH3
Amiodarone
(CH2)3CH3
O
CH2CH3
CH2CH3
I
30
Dronedarone
 Multichannel blocker like amiodarone but with structural differences
 Similar electrophysiologic properties to amiodarone
 Low proarrhythmic potential
 Lower potential for organ toxicity
 Shorter half-life (24 hrs)
 Food increases bioavailability by 2- to 4.5-fold
 Metabolized by CYP3A4
 Mostly excreted in feces (84%)
EURIDIS/ADONIS: Primary Endpoint
Time to First AF Recurrence
0.8
Cumulative Incidence
0.7
25% RRR
0.6
0.5
0.4
Placebo + standard therapy
Dronedarone 400 mg BID + standard therapy
0.3
HR: 0.75 (95% CI: 0.65-0.87)
P<0.001
0.2
0.1
0
0
60
120
180
Time (d)
HR = hazard ratio; RRR = relative risk reduction; CI = confidence interval.
Singh BN, et al. N Engl J Med. 2007;357:987-999.
240
300
360
Dronedarone Showed a Significant and Consistent Decrease in
Ventricular Rate at First AF/AFL Recurrence
Placebo + standard therapy*
Dronedarone + standard therapy*
Mean Ventricular Rate (TTEM)
120
116.6
p<0.001
117.5
p<0.001
117.1
p<0.001
115
-15 bpm
-12 bpm
-14 bpm
110
104.6
105
103.4
102.3
100
95
90
n=102
n=188
ADONIS
n=117
n=199
EURIDIS
n=219
n=387
Combined
*Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-thrombotic therapy (oral
anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins.
TTEM=Trans Telephonic Electrocardiogram Monitoring.
Singh BN, et al. N Engl J Med. 2007;357:987-99.
33
ERATO: Ventricular Rate Reduction with
Dronedarone in Permanent AF
Mean Reduction in 24-Hour
Holter Heart Rate (bpm)
All Patients
Beta-Blockers
Digoxin
Calcium Antagonists
0
-4
-5.1
-5.1
95% CI, -11 to 0.92
P=0.10
-8
-12
-11.7
-11.7
-11.5
-11.5
95% CI, -14.8 to -8.5
P<0.0001
95% CI, -17 to -6.4
P<0.0001
-16
-14.9
-14.9
95% CI, -20 to -10
P<0.0001
Concomitant Treatment
Davy JM, et al. Am Heart J. 2008;156:527.e1-527.e9.
DIONYSOS Primary Endpoint: AF Recurrence
or Premature Study Drug Discontinuation
Dronedarone
Cumulative incidence
1.0
Amiodarone
0.8
184 (73.9%)
0.6
141 (55.3%)
0.4
RRR (95%CI) = 1.59 (1.275;1.98)
p-value <0.001
0.2
0.0
0
3
6
9
12
15
AF recurrence after electrical cardioversion: Dronedarone 36.5 % Amiodarone 24.3 %
Premature drug discontinuation:
Dronedarone 10.4 % Amiodarone 13.3 %
Le Heuzey JY, et al. J Cardiovasc Electrophysiol. 2010;21:597-605.
Months
ANDROMEDA: All-cause Mortality in Severe HF
0.8
Number of patients who died
0.7
Cumulative Incidence
Placebo
n=317
12
2.13
Hazard Ratio
95% CI
Log rank p value
0.6
Dronedarone 800mg
n=310
25
[1.07; 4.25]
0.03
0.5
0.4
Placebo
DR 400mg bid
0.3
0.2
0.1
Time (days)
0.0
0
30
60
90
120
150
180
210
Placebo
317
256
181
103
50
18
6
1
DR 400mg bid
310
257
174
104
59
22
5
1
Patients at risk:
Køber L, et al. N Engl J Med. 2008;358:2678-87.
36
ATHENA is a Unique Trial
 The largest single antiarrhythmic drug trial ever conducted in AF
 >4,600 patients with a history of paroxysmal or persistent atrial fibrillation or
atrial flutter (permanent AF and class IV heart failure excluded)
 More than 550 investigational sites in 37 countries
 Aged ≥75 years with or without additional risk factors
 Aged ≥70 years and ≥1 risk factor (hypertension; diabetes; prior
stroke/TIA; LA ≥50 mm;LVEF <0.40)
 Unique endpoints for an AF trial
 Combined endpoint of cardiovascular hospitalisation or death
 First AF trial to use "non-conventional" endpoints
Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.
37
Baseline patient characteristics
Placebo
n=2327
Dronedarone
n=2301
All patients
n=4628
71.7 ±9.0
71.6 ±8.9
72 ±9.0
<65yr
442 (19.0%)
431 (18.7%)
873 (18.9%)
65 to 75yr
907 (39.0%)
923 (40.1%)
1830 (39.5%)
≥75yr
978 (42.0%)
947 (41.2%)
1925 (41.6%)
Female gender
1038 (44.6%)
1131 (49.2%)
2169 (46.9%)
AF/AFL at baseline
586 (25.2%)
569 (24.7%)
1155 (25.0%)
Structural heart disease
1402 (60.9%)
1330 (58.3%)
2732 (59.6%)
Hypertension
1996 (85.8%)
1999 (86.9%)
3995 (86.3%)
737 (31.7%)
668 (29.0%)
Age (mean ±SD, years)
Coronary heart disease
1405 (30.4%)
Valvular heart disease
380 (16.3%)
379 (16.5%)
759 (16.4%)
Non-ischemic cardiomyopathy
131 (5.6%)
123 (5.3%)
254 (5.5%)
History of CHF NYHA II/III
515 (22.1%)
464 (20.2%)
979 (21.2%)
LVEF <0.45
285/2281 (12.5%)
255/2263 (11.3%)
540/4544 (11.9%)
LVEF <0.35
87/2281 (3.8%)
92/2263 (4.1%)
179/4544 (3.9%)
Lone atrial fibrillation
139 (6.0%)
140 (6.1%)
279 (6.0%)
Pacemaker
243 (10.4%)
214 (9.3%)
457 (9.9%)
Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.
38
Dronedarone Significantly Decreased Risk
of CV Hospitalisation or Death by 24%
Cumulative Incidence (%)
50
Placebo on top of standard therapy*
DR 400mg bid on top of standard therapy*
40
24% RRR
30
20
HR=0.76
p<0.001
10
Months
0
0
6
12
Placebo
2327
1858
1625
DR 400mg bid
2301
1963
1776
18
24
30
1072
385
3
1177
403
2
Patients at risk:
*Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-thrombotic therapy (oral
anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins.
Hohnloser SH et al. N Engl J Med 2009;360:668-78.
39
Dronedarone Significantly Decreased
Risk of Cardiovascular Death by 29%
Cumulative Incidence (%)
7.5
Placebo on top of standard therapy*
DR 400mg bid on top of standard therapy*
5.0
29% RRR
2.5
HR=0.71
p=0.03
Months
0
0
6
12
Placebo
2327
2290
2250
DR 400mg bid
2301
2274
2240
18
24
30
1629
636
7
1593
615
4
Patients at risk:
*Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-thrombotic therapy (oral
anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins.
Mean follow-up 21 ±5 months.
Hohnloser SH et al. N Engl J Med 2009;360:668-78.
40
Dronedarone Reduced CV Hospitalisation or All-cause
Death Across Important Subgroups
Characteristic
Age (years)
<75
75
Gender
Male
Female
Presence of AF/AFL
Yes
No
Structural Heart Disease
Yes
No
Congestive Heart Failure
Yes
No
LVEF (%)
<35
[35-45[
45
ACE/ARB
Yes
No
Beta Blocking Agents
Yes
No
n
HR (95% CI)
0.93
2703
1925
0.76 (0.67–0.87)
0.75 (0.65–0.87)
0.65
2459
2169
0.74 (0.64–0.85)
0.77 (0.67–0.89)
1155
3473
0.74 (0.61–0.91)
0.76 (0.68–0.85)
0.85
0.85
2732
1853
0.76 (0.67–0.85)
0.77 (0.65–0.92)
1365
3263
0.75 (0.64–0.88)
0.76 (0.68–0.86)
0.83
0.55
179
361
4004
0.68 (0.44–1.03)
0.66 (0.47–0.92)
0.78 (0.70–0.86)
0.59
3216
1412
0.74 (0.66–0.83)
0.79 (0.66–0.95)
0.41
3269
1359
0.78 (0.69–0.87)
0.71 (0.58–0.86)
0.1
1.0
Dronedarone Better
Hohnloser SH et al. N Engl J Med 2009;360:668-78.
p value
for interaction
10.0
Placebo Better
41
Dronedarone Significantly Decreased CV
Hospitalisations by 26%
Reason for first CV
hospitalisation
Placebo
n=2327
Dronedarone
n=2301
HR
95% CI
p value
859
675
0.74
0.67; 0.82
<0.001
Atrial Fibrillation
510
335
0.63
0.55; 0.72
<0.001
CHF
132
112
0.86
0.67; 1.10
0.22
ACS
89
62
0.70
0.51; 0.97
0.03
Syncope
32
27
0.85
0.51; 1.42
0.54
Ventricular arrhythmia or
cardiac arrest
12
13
1.09
0.50; 2.39
0.83
Any reason
Hohnloser SH et al. N Engl J Med 2009;360:668-78.
42
Adverse Event Rates were Not Significantly Different
Between Dronedarone and Placebo Groups
Placebo
n=2313
Dronedarone
n=2291
p value
1603 (69.3%)
1649 (72.0%)
0.048
221 (9.6%)
260 (11.3%)
0.048
Bradycardia
28 (1.2%)
81 (3.5%)
<0.001
QT-interval prolongation
14 (0.6%)
40 (1.7%)
<0.001
Gastrointestinal
508 (22.0%)
600 (26.2%)
<0.001
Respiratory
337 (14.6%)
332 (14.5%)
0.97
176 (7.6%)
237 (10.3%)
0.001
31 (1.3%)
108 (4.7%)
<0.001
489 (21.1%)
456 (19.9%)
0.31
Cardiac events
15 (0.6%)
15 (0.7%)
1.00
Respiratory
45 (1.9%)
41 (1.8%)
0.74
Gastrointestinal
68 (2.9%)
81 (3.5%)
0.28
Creatinine increase
1 (<0.1%)
5 (0.2%)
0.12
6 (0.3%)
7 (0.3%)
0.79
187 (8.1%)
290 (12.7%)
<0.001
Randomised and treated patients
Patients with any TEAE
Cardiac events
Skin
Creatinine increase
Patients with any serious TEAE
Skin
Patients permanently discontinued study
drug for any TEAE
TEAE=Treatment Emergent Adverse Events.
Adapted from Hohnloser SH et al. N Engl J Med 2009;360:668-78.
43
ATHENA Post-hoc Analysis
Dronedarone reduces the risk of stroke
Cumulative incidence (%)
5
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard therapy
4
34%
reduction
in relative
risk
3
Hazard ratio = 0.66
2
p = 0.027
Mean follow-up 21 ± 5 months
1
0
0
6
12
18
24
30
Follow-up time, months
Patients at risk
Placebo
295
244
224
151
60
0
Dronedarone 400
mg b.i.d.
178
160
150
110
47
1
Connolly SJ, et al. Circulation. 2009;120:1174-80.
44
Stroke Prevention in Rate vs. Rhythm Control Trials
n
AFFIRM
Rate
control
Rhythm
control
RR
(95% CI)
p
4,917
5.7%
7.3%
1.28 (0.95-1.72)
0.12
RACE
522
5.5%
7.9%
1.44 (0.75-2.78)
0.44
STAF
266
1.0%
3.0%
3.01 (0.35-25.3)
0.52
PIAF
252
0.8%
0.8%
1.02 (0.73-2.16)
0.49
Total
5,957
5.0%
6.5%
1.28 (0.98-1.66)
0.08
Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A.
Choice of AAD - Underlying Pathology
www.escardio.org
Normal Ventricular Function
Dronedarone
Flecainide*
Propafenone*
Sotalol
Catheter Ablation
Abnormal Left Ventricular Function
EF > 35%
EF ≤ 35%
Amiodarone
Dronedarone
Sotalol*
Amiodarone
Amiodarone
* Sotalol should be used with caution with EF 35-40%
Contra-indicated in women >65 yrs taking diuretics
47
* Class I agents should be AVOIDED in CAD
They should be combined with an AV-nodal blocking agents
Leadership. Knowledge. Community.
ATHENA: Benefits of dronedarone in ‘permanent’* patients
consistent with overall population
50 Non-significantly
Dronedarone
thetherapy
Risk of Unplanned CV
Placebo onReduced
top of standard
Hospitalisation or DeathDR
in400mg
"Permanent"
Patients
bid on top of AF
standard
therapy
Cumulative Incidence (%)

40
26% RRR
30
20
HR=0.74
p=0.096
10
Months
0
Patients at risk:
0
6
12
18
24
30
Placebo
295
244
224
151
60
0
DR 400mg bid
178
160
150
110
47
1
Dronedarone is not indicated in permanent AF patient
*Patients with AF/AFL at each ECG recording were classified as having "permanent AF"
Any unplanned hospitalisation (i.e., admission with an overnight stay
Mean follow-up 21 ±5 months.
in the hospital) was classified by the investigator as a hospitalisation due to
Page R, et al. AHA Scientific Sessions 2008.
either cardiovascular or non-cardiovascular causes
Page R, et al. Circulation. 2008;118:S_827.
48
PALLAS: Dronedarone in permanent AF
(Primary EP: CV death, MI, CVA)
Dronedarone 400 mg BID
5400 patients
R
On top of Standard of Care
5400 patients
Placebo BID
Baseline
Visit
Registration
at time
of consent
Variable – Event Driven
BL
FFUV
Scheduled visits on D7, M1, M4, M8, M12, M16, M22, M28, M34
and phone contacts on M19, M25, M31
49
Summary
•
•
AF is increasing in prevalence, and is associated with substantial morbidity and
mortality: stroke prevention is the first priority in AF patients
A strategy of rhythm control has not been proven superior to rate control – this
may in part relate to the modest efficacy and significant toxicity of contemporary
antiarrhythmic drugs
•
New oral anticoagulants will offer similar or superior stroke prevention
compared to oral VKA, without excessive bleeding
•
Dronedarone is the first AAD to demonstrate a reduction in cardiovascular
outcomes in AF patients, including a reduction in CV hospitalization, CV death,
and stroke (post-hoc)
Defining Endpoints in Clinical Trials of Atrial
Fibrillation – A New Era with Dronedarone
CV
Events
Adapted from Camm J, et al. Eur Heart J Suppl 2008; 10:H55-H78