davos 2011 - antiarrhythmic drugs and cardiovascular...
TRANSCRIPT
Antiarrhythmic Drugs and Cardiovascular Outcomes
Dr. Stuart Connolly MD
McMaster University
Hamilton Ontario
Disclosure: Research grants, speaker fees and consulting honoraria from sanofi aventis
AF associated with significant increase in mortality
* Significantly different from patients with AF, at p < 0.05
Wolf PA, et al. Arch Intern Med. 1998;158:229-234.
0
10
20
30
40
50
60
70
80
With AF (n = 13,558) Without AF (n = 13,195)
Mo
rtality
over
3 y
ears
(%
)
65–74 75–84 85–89
38.6
30.2*34.0
25.4
54.5
47.4* 47.5
36.1*
71.365.1* 62.4
51.1*
Age group (years)
Do antiarrhythmic drugs reduce important cardiovascular
outcomes?
Cardiac Arrhytmia Suppression Trial(CAST) 1991
Echt DS. N Engl J Med. 1991;324:781-788.
Antiarrhythmic drugs can increase mortality (after MI)
85
90
95
100
0 91 182 273 364 455
Time after randomization (days)
Pa
tie
nts
wit
ho
ut
eve
nt
(%)
Placebo
(n = 743)
Encainide
or flecainide
(n = 755)
p = 0.001
Amiodarone trials meta-analysis investigators. Lancet. 1997;350:1417-24.
Test of association p = 0.030;
test of heterogeneity p = 0.058
Test of association p = 0.00026;
test of heterogeneity p = 0.24
Odds ratio Odds ratio
1/8 1/4 1/2 1 2 4 8 1/8 1/4 1/2 1 2 4 8
Total mortality Arrhythmic or sudden deathStudy
EMIATCAMIATGEMICA
PATSSSDBASIS
HOCKINGSCAMIAT-PCHFSTATGESICA
EPAMASANICKLASHAMEROverall0.87 (95% CI 0.78–0.99)
CHF = congestive heart failure.
Meta-analysis of individual data from 6,500 patients in randomized trials
0.71
(95% CI 0.59–0.85)
Amiodarone Trials after Myocardial Infarction or in Heart Failure
Antiarrhythmic Drugs Prevent AF Recurrence
Canadian Trial of Atrial Fibrillation (CTAF)
Roy D, et al. N Engl J Med. 2000;342:913-20.
100
80
60
40
20
0
Time (days)
Pati
en
ts w
ith
sin
us r
hyth
m(%
)
Amiodarone
6005004003002001000
SotalolPropafenone
0
5
10
15
20
25
30
0 1 2 3 4 5
Mo
rtality
(%
)
Rate control
Rhythm control
p = 0.078 unadjusted
Time (years)
p = 0.068 adjusted for interim monitoring
Primary endpoint: mortality
Patients at risk
AFFIRM investigators. N Engl J Med. 2002;347:1825-33.
AFFIRM: Testing the Rate control versus Rhythm Control Hypothesis
Do antiarrhythmic drugs reduce mortality in atrial fibrillation?
Rhythm control 2,033 1,932 1,807 1,316 780 255
Rate control 2,027 1,925 1,825 1,328 774 236
AFFIRM: No effect on stroke
Sherman D, et al. Arch Intern Med. 2005;165:1185-91.
Time (years)
Cu
mu
lati
ve n
um
ber
of
pati
en
ts
wit
h a
ll t
yp
es o
f str
oke (
%)
0 1 2 3 4 5
0
15
20
25
30
10
5
Treatment arm
Rate control group
Rhythm control group
Log rank statistic = 0.01
p = 0.93
Annual mortality 9.9% of which 80% were CV deaths
Rhythm control, n = 182 (27%)
Rate control, n = 175 (25%)
Log rank p = 0.59
Hazard ratio 1.06 (95% CI 0.86–1.30)
Follow-up time (months)
Eve
nt-
fre
e r
ate
(%
)
0 12 24 36 48 60
0
40
60
80
100
20
Roy D, et al. N Engl J Med. 2008;358:2667-77.
AF-CHF: no significant difference in CV mortality between rate and rhythm control arms
No difference in stroke, quality of life or any other important outcome
Clinical understanding regarding treatment of AF around 2008?
Concern post-CAST, that antiarrhythmic drugs are dangerous
No evidence that rhythm control ( i.e. ion channel blocking drugs) improves cardiovascular outcomes
Main treatment goal in AF is symptom suppression
Increased interest in ablation procedures for AF
Dronedarone has key structural differences to amiodarone
Dronedarone
CH3SO2H
N
O(CH2)3N
O
O
(CH2)3CH3
(CH2)3CH3
Amiodarone
O(CH2)2N
O
O
CH2CH3
CH2CH3
(CH2)3CH3
(CH2)3CH3
I
I
Kathofer, et al. Cardiovasc Drug Rev. 2005;23(3):217-30.
Cardiac ionic currents inhibited by dronedarone: Comparison with amiodarone
IC50 (µM)
Channel Dronedarone Amiodarone
KAch 0.01 1
Kr (h) 0.06 0.07
CaL 0.2 10
Na (h) ~0.3 ~3
Kur (h) 1.3 23
Ks 10 30
K1 >30 ~30
to NC 5*
(h) = human; NC = not calculable; * Guo et al JMCC 1997
Ito
IKr
IKs
IK1
INa
ICa
IAch (atrial)
IKur (atrial)
EURIDIS and ADONIS Primary Endpoint:Patients with First Recurrence of AF/Aflutter
Dronedarone 400 mg bidPlacebo
A Significant and Consistent Reduction in First Recurrence of Atrial
Fibrillation/Atrial Flutter
Log-rank test results: p=0.0017
0 60 120 180 240 300 3600 60
Cu
mu
lati
ve
In
cid
en
ce
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Time(days)
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
EURIDIS ADONIS
HR=0.80 p=0.16
95%CI = [0.59; 1.09] SINGH, 2007
ERATO:Primary Study Endpoint
*Treatment effect estimate by ANCOVA
Dronedarone Decreases Ventricular Rate by 12 bpm
(Mean ± SEM)
B D14 D14-B
P<.0001
-15
-10
-5
0
5
Ch
an
ge
fro
m b
as
eli
ne
(b
pm
)
He
art
ra
te (
bp
m)
60
70
80
90
100
Dronedarone
400 mg BID
Placebo
DAVY, 2008
Post-CAST regulatory issues for antiarrhythmic drug development
All antiarrhythmic ( ion-channel) drugs are dangerous until proven otherwise
Thorough QT studies required for most new agents
Mortality data needed to establish safety of new antiarrhythmic agents
ANDROMEDA initiated in part to meet this need
Similar design as used in DIAMOND trial for dofetilide
Placebo 317 256 181 103 50 18 6 1
Dronedarone 400 mg b.i.d.
310 257 174 104 59 22 5 1
Increase in all-cause mortality in CHF patients in ANDROMEDA
Time (days)
Cu
mu
lati
ve
in
cid
en
ce
(%
)
0 30 60 90 120 150 180 210
0.0
0.1
0.2
0.3
0.6
0.8
0.4
0.5
0.7
Placebo
Dronedarone 400 mg b.i.d.
Køber L, et al. N Engl J Med. 2008;358:2678-87.
Placebon = 317
Dronedarone 800 mgn = 310
Number of patients who died 12 25
Hazard ratio 2.13
95% CI 1.07–4.25
Log rank p value 0.03
Patients at risk
ATHENA trial design
Prospective double-blind trial to assess the efficacy of dronedarone in preventing cardiovascular hospitalization or death from any cause in AF and AFL patients with additional risk factors*
AFL = atrial flutter;
TIA = transient ischaemic attack. Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
* Age ≥ 75 years or ≤ 75 years with hypertension, diabetes, prior stroke/TIA, LAD > 50 mm,
or LVEF ≤ 0.40
Dronedarone 400 mg b.i.d. (n = 2,301)
Placebo (n = 2,327)
12–30 months
AF and AFL patients
with additional risk
factors*
Double-blind
All patients treated with standard of care treatment.
R
ATHENA
Baseline characteristics
Placebon = 2,327
Dronedaronen = 2,301
All patientsn = 4,628
Mean age ± SD, years 72 ± 9.0 72 ± 8.9 72 ± 9.0
Female gender 1,038 (45%) 1,131 (49%) 2,169 (47%)
AF/AFL at baseline 586 (25%) 569 (25%) 1,155 (25%)
Structural heart disease 1,402 (61%) 1,330 (58%) 2,732 (60%)
Coronary heart disease 737 (32%) 668 (29%) 1,405 (30%)
Valvular heart disease 380 (16%) 379 (17%) 759 (16%)
Non-ischaemic cardiomyopathy 131 (6%) 123 (5%) 254 (6%)
History of CHF NYHA II or III 515 (22%) 464 (20%) 979 (21%)
LVEF < 0.45 285/2,281 (13%) 255/2,263 (11%) 540/4,544 (12%)
LVEF < 0.35 87/2,281 (4%) 92/2,263 (4%) 179/4,544 (4%)
Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
ATHENA
Primary Outcome: Unplanned cardiovascular hospitalization or death
Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
Patients at risk
Placebo 2,327 1,858 1,625 1,072 385 3
Dronedarone400 mg b.i.d.
2,301 1,963 1,776 1,177 403 2
Mean follow-up 21 ± 5 months
Hazard ratio = 0.76
p < 0.001
0
10
20
30
40
50
Follow-up time, months
0 6 12 18 24 30
Cu
mu
lati
ve i
ncid
en
ce (
%)
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard therapy
NNT =13
Secondary Outcome: Total mortality
Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
Patients at risk
Placebo 2,327 2,290 2,250 1,629 636 7
Dronedarone400 mg b.i.d.
2,301 2,274 2,240 1,593 615 4
ATHENA
Hazard ratio = 0.84
95% CI = 0.64-1.07
P<0.001
0.0
2.5
5.0
7.5
10.0
0 6 12 18 24 30
Cu
mu
lati
ve i
ncid
en
ce (
%)
Mean follow-up 21 ± 5 months
Follow-up time, months
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard therapy
Dronedarone reduces cardiovascular death by 29%
Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
Patients at risk
ATHENA
Hazard ratio = 0.71
p = 0.034
0.0
2.5
5.0
7.5
0 6 12 18 24 30
Cu
mu
lati
ve i
ncid
en
ce (
%)
Mean follow-up 21 ± 5 months
Follow-up time, months
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard therapy
Placebo 2,327 2,290 2,250 1,629 636 7
Dronedarone400 mg b.i.d.
2,301 2,274 2,240 1,593 615 4
Adjudicated Cause of Death in ATHENA
OutcomePlacebon = 2,327
Dronedaronen = 2,301
Hazard ratio
(95% CI)p
value
All deaths 139 116 0.84 0.66–1.08 0.18
Non-cardiovascular death 49 53 1.10 0.74–1.62 0.65
Cardiovascular death 90 63 0.71 0.51–0.98 0.03
Cardiac non-arrhythmic death 18 17 0.95 0.49–1.85 0.89
Cardiac arrhythmic death 48 26 0.55 0.34–0.88 0.01
Vascular non-cardiac death 24 20 0.84 0.47–1.52 0.57
Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
ATHENA
Dronedarone reduced ‘downstream’ cardiovascular complications
Reason for first CV hospitalization
Placebon = 2,327
Dronedarone n = 2,301
HR 95% CI p value
Any reason 859 675 0.74 0.67; 0.82 < 0.001
AF 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
Hohnloser SH, et al. N Engl J Med. 2009;360:668-78.
ATHENA
Dronedarone significantly decreased the rate of unplanned non-AF related CV hospitalizations by 14%C
um
ula
tive i
ncid
en
ce (
%)
6 12 18 24 300
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard therapy
0
10
20
30
Hazard ratio = 0.86
p = 0.016
14%reductionin relativerisk
Mean follow-up 21 ± 5 months
Patients at riskFollow-up time, months
ATHENA Post-hoc Analysis
Placebo 2,327 2,093 1,929 1,326 497 3
Dronedarone 400 mg b.i.d.
2,301 2,096 1,957 1,338 479 2
Data on file.
Torp-Pedersen C, Page RL, Connolly ST. American Heart Association Scientific Sessions 2008. Abstract 4101.
Population N HR [95% CI]Interaction
p-value
All ATHENA 4,628 0.74 [0.67;0.82]
0.48
North America 1,403 0.82 [0.68;0.98]
South America 206 0.59 [0.31;1.13]
Western Europe 1,042 0.74 [0.59;0.93]
Eastern Europe 1,439 0.70 [0.59;0.82]
Asia 268 0.53 [0.31;0.91]
Other* 270 0.89 [0.58;1.36]
Data on file/ Multaq EPAR* Australia, India, Israel, Morocco, New Zealand, South Africa, Tunisia
Dronedarone better
0.1 1.0 10.0
Placebo better
Reduction in unplanned CV hospitalizations consistent across
regions
Primary Outcome: ConsistencyAcross Important Clinical Subgroups
Hohnloser SH et al. ATHENA Investigators. N Engl J Med. 2009 Feb 12;360(7):668-78.
Beta Blocking Agents
ACE/ARB
LVEF (%)
Congestive Heart Failure
Structural Heart Disease
Presence of AF/AFL
Gender
NoYes
NoYes
≥4535-45<35
No
Yes
NoYes
NoYes
FemaleMale
≥75<75
Age (years)
13593269
14123216
4004361179
3263
1365
18532732
34731155
21692459
19252703
N
0.71 [0.58;0.86]0.78 [0.69;0.87]
0.79 [0.66;0.95]0.74 [0.66;0.83]
0.78 [0.70;0.86]0.66 [ 0.47;0.92]0.68 [0.44;1.03]
0.76 [0.68;0.86]
0.75 [0.64;0.88]
0.77 [0.65;0.92]0.76 [0.67;0.85]
0.76 [0.68;0.85]0.74 [0.61;0.91]
0.77 [0.67;0.89]0.74 [0.64;0.85]
0.75 [0.65;0.87]0.76 [0.67;0.87]
HR [95% CI]
0.41
0.59
0.55
0.83
0.85
0.85
0.65
0.93
P-value
Dronedarone better
0.1 1 10
Placebo better
0
10
20
30
HR=0.66
p=0.2472
0 6 12 18 24 30
Cu
mm
ula
tive
In
cid
en
ce (
%)
Placebo 109 103 95 59 18 0
Drinedarone 91 78 84 53 20 0
Months
Placebo
Dronedarone
Mortality in patients with low EF or symptoms of heart failure in ATHENA
Mean follow-up 21 ± 5 months (intent-to-treat)Hohnloser S. Oral presentation, Hotline HRS 2009
Death from Any Cause
NYHA Class III CHF
0
10
20
30
HR=0.55
p=0.1311
0 6 12 18 24 30C
um
mula
tive Incid
ence (
%)
Placebo 87 80 74 54 16 0
Drinedarone 92 78 85 65 26 1
Months
Placebo
Dronedarone
Death from Any Cause
LVEF <0.35
Dronedarone reduces the risk of stroke
Patients at risk
Connolly SJ, et al. Circulation. 2009;120:1174-80.
Placebo 295 244 224 151 60 0
Dronedarone 400 mg b.i.d.
178 160 150 110 47 1
Hazard ratio = 0.66
p = 0.027
0
1
2
3
4
5
0 6 12 18 24 30
Cu
mu
lati
ve i
ncid
en
ce (
%)
Mean follow-up 21 ± 5 months
Follow-up time, months
34%reductionin relativerisk
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard therapy
29
ATHENA: Stroke, ACS, or Cardiovascular death
15
10
5
0
Data on fileConnolly et al; Circulation. 2009;120:1174-1180
Cum
ula
tive I
ncid
ence (
%)
Placebo on top of standard therapy
DR 400mg bid on top of standard therapy
Placebo 2327 2240 2166 1547 599 6
DR 400mg bid 2301 2243 2193 1541 586 4
Patients at risk:
HR=0.75 (0.62-0.90)
P<0.001
Placebo Dronedarone
Number of events 262 196
Months
6 12 18 24 300
Adverse events
OutcomePlacebo
n = 2,313Dronedarone
n = 2,291p value
Patients with any TEAE 1,603 (69%) 1,649 (72%) 0.048
Gastro-intestinal 508 (22%) 600 (26%) < 0.001
Respiratory 337 (15%) 332 (15%) 0.97
Skin 176 (8%) 237 (10%) 0.001
Creatinine increase 31 (1%) 108 (4.7%) < 0.001
Patients with any serious TEAE 489 (2%) 456 (20%) 0.31
Gastro-intestinal 68 (3%) 81 (4%) 0.28
Respiratory 45 (2%) 41 (2%) 0.74
Skin 6 (0.3%) 7 (0.3%) 0.79
Creatinine increase 1 (< 0.1%) 5 (0.2%) 0.12
TEAE = treatment-emergent adverse event. Hohnloser S, et al. N Engl J Med. 2009;360:668-78.
Dronedarone reduces the risk of cardiovascular hospitalization or death in "permanent" AF patients
Cu
mu
lati
ve i
ncid
en
ce (
%)
6 12 18 24 300
Hazard ratio = 0.74
p = 0.096
0
10
50
30
20
40
Mean follow-up 21 ± 5 months
Patients at riskFollow-up time, months
26%reductionin relativerisk
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard therapy
ATHENA Post-hoc Analysis
Placebo 295 244 224 151 60 0
Dronedarone 400 mg b.i.d.
178 160 150 110 47 1
Page R, et al. AHA Scientific Sessions 2008; Page R, et al. Circulation. 2008;118:S_827
Placebo BID
5400 patients
5400 patients
Dronedarone 400 mg BID
PALLAS: 10,800 Patient Vascular Outcome Trial of Dronedarone in
Permanent AF
On top of Standard of CareR
Permanent
AF/FL+
CV Risk
Factor
Co-Primary Outcome:
1. Stroke, MI, SE, CV
Death
2. CV hospitalization
or Death
Coordinated by Population Health Research Institute
at McMaster University
Conclusions
Dronedarone is the only antiarrhythmic agent shown to cardiovascular outcomes
CV hospitalization, CV death
It reduces Unplanned CV hospitalizations both due to AF and to other causes
Multiple Mechanisms of Action