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