Nuove Prospettive Nel Trattamento AntiaritmicoTrattamento AntiaritmicoDella Fibrillazione Atriale

Gianluca Botto, MD FACC, FESC

U.O. ElettrofisiologiaA.O. Sant’ Anna, Como

Presenter Disclosure InformationPresenter Disclosure Information

� Research support: Boston Scientific, Medtronic; St. Jude Medical, Bayer Healthcare, Gilead, Sanofi

� Advisory Board: � Advisory Board: Biotronik, Medtronic; St. Jude Medical, MSD, Bayer Healthcare, Boehringer, Sanofi

� Speaker Fees: Boston Scientific, Medtronic, St. Jude Medical, SorinGroup, Bayer Healthcare, Boehringer, BMS, Meda, MSD, Pfizer, Sanofi

Long -Term Rhythm Control May Lead to Lower Mortality

Than Rate Control

Long -Term Rhythm Control May Lead to Lower Mortality

Than Rate ControlH

R fo

r rh

ythm

vs

rate

(95

% C

I)

Lower mortality with rate control

No difference

1.2

1.4

26.130 pts >66ys from Quebec, Canada hosp with

Ionescu-Ittu R. Arch Intern Med. 2012; 172: 997-1004.

1 2 3 4 5 6 7 8Treatmentinitiation

HR

for

rhyt

hm v

s ra

te (

95%

CI)

Years since initiation of AF treatment

Lower mortality with rhythm control

No difference

0.8

1.0

0.6

Canada hosp with AF diagnosisfrom ‘99 to ’07who did not have AF-related drug prescriptions in the year before the admission

Comprehensive Management Of AF Should Address The Multiple Impacts Of The Condition

� In addition to stroke prevention and reduction of AF burden, successful management of AF should aim to reduce hospitalisations and CV morbidity

Reduction in the

Preventionof stroke

Reductionof AF burden*

Reduction in CV

mortality

Reduction in the risk of CV- events

and hospitalisations

of AF burden*� QoL

� Symptoms

5

Rhythm Control1 Cardioversion1 Cardioversion

AF in The Acute SettingRHYTHM-AF Registry

AF in The Acute SettingRHYTHM-AF Registry

90%

100%

Primary mode of cardioversion by country

15

Choice of AAD for cardioversion

N°=3943, 200 sites, 26 countries (EU, AU, S-Am)Age 66.4 years, 62% menHTN 63%, CHF 15%, VHD 14%, DM 17%, MI 11%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

All AUS BRA FRA GER ITA HOL POL SPA SWE UK

Phamacological Electrical

Crijns HJGM, et al. ESC Paris 2011

54

31

Amiodarone

Flecainide

Propafenone

The Concept of Atrial Selective Compounds

Different Drugs for Remodeled Atria?Different Drugs for Remodeled Atria?Different Drugs for Remodeled Atria?Different Drugs for Remodeled Atria?

Control

Ito

PresentClass IIIDrugs

Remodeled

Ito

Early Class III Drugs?

0 100 200 300 400 ms

IICaCa

IIKurKur

IIKsKs

IIKrKr

Ito Drugs

0 100 200 300 400 ms

IICaCa

IIKurKur

IIKrKrIIKsKs

Ito

Early Class III AADrugs for AFIBEfficacy of “ Atrial Selectivity ” of AVE 118 in Go ats

Early Class III AADrugs for AFIBEfficacy of “ Atrial Selectivity ” of AVE 118 in Go ats

Blaauw Y, Allessie MA. Circulation 2004_110: 1717-1724

Contractile and Electrical Remodeling‘Go Hand in Hand’

Contractile and Electrical Remodeling‘Go Hand in Hand’

140140Refractory Refractory PPerioderiod

Work Work IIndexndex1515

2020

RefractoryRefractoryPeriodPeriod(ms)(ms)

Work Work IIndexndex(mm(mm22Hg)Hg)AF Conversion SR AF Conversion SR

00 11 22 33 44 55 66 77 88 99 1010

8080

100100

120120 Work Work IIndexndex

00

55

1010

Time (days)Time (days) Schotten et al. Circulation 2003

Effect of AF on Atrial Thrombogenesis in HumansImpact of Rate and Rhythm

• AF and rapid atrial rates significantly increases platelet activation and thrombin generation compared to placebo

• Additionally, AF causes significantly increased

Changes after 15 minutes in prothrombotic markers on 55 pts in SR with a htx of AF randomized to control, atrial pacing or the AF induction group

Lim HSJ Am Coll Cardiol 2013;61:852–60

significantly increased endothelial dysfunction and activation of the inflammatory cascade

TAT= thrombin-antithrombin complexADMA = asymmetric dimethylarginine

Cardioversion Of AF Within 12 Hs From Onset Reduces Thromboembolic Events

Risk Factors for TE Complications

Study Objectives1: Incidence and risk factors of thromboembolic complications after cardioversion of acute atrial fibrillation.

Method1: A retrospective study of total 7,660 cardioversions were performed in 3,143 consecutive patients with atrial fibrillation lasting <48 h in 3 hospitals. Embolic complications were evaluated during the 30 days after 5,116 successful cardioversions in

Risk of thromboembolic complications• Cardioversion ≥ 12 hours from symptom

onset: 1.1%• Cardioversion < 12 hours from symptom onset

0.3%• Absolute risk reduction (< 12 hours) 0,8% p

= 0.004

Odds Ratio (95% CI)a p-value

Time to cardioversion (h)

12-24 vs < 12 4.0 (1.7-9.1) 0.001

24-48 vs < 12 3.3 (1.3-8.9) 0.02

Age, yb 1.06 (1.03-1.09) <0.001

Female sex 2.1 (1.1-4.3) 0.04

Heart failure 3.5 (1.4-8.6) <0.001

Diabetes 2.7 (1.3-5.8) 0.01

Nuotio et al. JAMA 2014; 312: 647-649

a Multivariable logistic regression analysis with a repeated-measure model.

b Treated as a continuous variable without cut points.

Risk Factors for TE Complicationsn = 5116 cardioversions

days after 5,116 successful cardioversions in 2,481 patients with neither oral anticoagulation nor peri-procedural heparin therapy.

Results1: There were 38 (0.7%) definite thromboembolic events (31 strokes) at median 2 days after cardioversion1.

Airaksinen et al. JACC 2013; 62: 1187–92

Vernakalant in Patients With AFIBVernakalant in Patients With AFIB

Dobrev D., Nattel S. Lancet 2010; 375: 1212-23

AVRO TrialTime to Treatment-Induced Cardioversion

AVRO TrialTime to Treatment-Induced Cardioversion

90 min

254 AF pts (3 to 48 h duration)VER 3 mg/Kg in 10 min + 2 mg/Kg in 10 min; AMI 5 mg/Kg in 60 min + 50 mg infusion

VERNAKALANT Median time to conversion = 11 minHigher rate of symptoms relief @ 90 min: VER 53,4% vs AMI 32,8 %; p=0.0012SAE or AE leading to discontinuation uncommon

Real-World Effectiveness Of Vernakalant

86

9387

7065

78

60

70

80

90

100

Ca

rdio

ve

rte

dVernakalant Comparator

Time until

evaluation

displayed in the

10

33,3

0

10

20

30

40

50

% C

ard

iov

ert

ed

Conde et al

vs oral flecainide* 1

n=32

Conde et al

vs oral propafenone 2

n=36

Conde et al

vs I.V.

amiodarone*,3

n=30

1: Conde et al.; Int J Cardiol, 2013;168(3):2423-2425 2: Conde et al.; Cardiovasc Ther, 2013;31(6):377-80

3: Conde et al.; Can J Cardiol, 2013;29(10): 1330.e11–1330.e124: Juul-Möller et al.; Eur J Cardiovasc Med, 2013;2(4). doi 10.5083/ejcm.20424884

5: Presented at ESC 2013

Juul-Möller4**

n=251 (355

treatments)

Kuopio Univ. Hospital Finland5

Preliminary results

*Patients with left ventricular dysfunction

**Retrospective study

2

h

o

u

r

s

8

h

o

u

r

s

1

h

o

u

r

1

h

o

u

r

2

h

o

u

r

s

2

h

INa IC50

= 43 µM at -80 mV, 1 Hz

INa IC50

= 9 µM at -80 mV, 20 Hz

Fra

ctio

nal c

urre

nt

0.6

0.8

1 Hz

Rate-Dependent Sodium Current Blockade by Vernakalant

Based on in vitro Data From Human Embryonic Kidney Cells

Rate-Dependent Sodium Current Blockade by Vernakalant

Based on in vitro Data From Human Embryonic Kidney Cells

17

Vernakalant concentration (µM)

Fra

ctio

nal c

urre

nt

1 10 100 10000.0

0.2

0.4

Range of plasma levels in patients

1 Hz

20 Hz

Fedida D. Expert Opin Investig Drugs 2007;16:519–532

Fedida D et al. J Cardiovasc Electrophysiol. 2005;16:1227–1238.

Cardioversione Della FAFarmaci Antiaritmici di Sicura Efficacia

Cardioversione Della FAFarmaci Antiaritmici di Sicura Efficacia

Linee guida AIAC 2010 per la gestione ed il trattamento della fibrillazione atriale.G Ital Cardiol 2011; 12 (suppl 1)

Vernakalant Added to 2010 ESC Guidelines: Drugs for Pharmacologic Cardioversion of Recent-Ons et AF

Vernakalant Added to 2010 ESC Guidelines: Drugs for Pharmacologic Cardioversion of Recent-Ons et AF

– Vernakalant therapeutic indications:• For non-surgery patients: AF ≤7 days duration• For post-cardiac surgery patients: AF ≤3 days duration

The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369–2429.

Vernakalant should not be given inmoderate or severe heart failure, aorticstenosis, ACS or hypotension. Caution inmild heart failure.

ESC updated guidelines 2012ESC updated guidelines 2012

Rhythm Control2 Long -Term Outcome

ControlControl

High Prevalence Of Concomitant CV Risk Factors In AF Pts

Data from REALISE -AF Registry

%

72.2

AF IN NOT A DISEASE,but rather a manifestation of several CLINICAL SYNDROME S

only some of which are curable

Steg PG. Heart. 2012; 98: 195-201.

Risk factor

Cerebrovascular disease

Hypertension Dyslipidaemia Coronary artery disease

Valvular heart disease

Family history of premature

cardiovascular disease

Diabetes Current smoker

72.2

46.3

32.326.7

23.0 21.314.1 10.2

Increasing Rates Of Hospitalisation Are Associated With Poorer Quality Of Life

Data From Canadian AF Patients

Increasing Rates Of Hospitalisation Are Associated With Poorer Quality Of Life

Data From Canadian AF Patients

2

3

Mea

n nu

mbe

r in

one

yea

r

Hospitalisations ER visits

1.7

2.1

2.6

Dorian P. Circ Arrhythmia Electrophysiol 2009; 2; 218-224.

0

1

0 1 2 3 4

Mea

n nu

mbe

r in

one

yea

r

Mean number of specialist visits and the proportion of patients who had a cardioversion also increased with decreasing QoL

0.10.30.3

0.8

0.4

1.0 0.9

1.7

Severity of AF (SAF) scale (increasing value corresponds to poorer QoL)

Out-of-Hospital Treatment of Paroxysmal Atrial Fibrillation

per

mon

th

45,6

30

35

40

45

50

- 89%

N°

per

mon

th

Alboni P. Botto GL. New Engl J Med 2004; 351: 2384-91

165 pts with 569 episodesduring 15±5 mos of F-U

15

4,91,6

0

5

10

15

20

25

30

Pre-Treatment Out-of-Hospital

ER admissionHospitalization

p<0.0001

ATHENA TrialCardiovascular Hospitalization or Death

ATHENA TrialCardiovascular Hospitalization or Death

A B

SELECTED POPULATION

a Efficacy population b Randomized and treated patients

b Randomized and treated patientsb Randomized and treated patients

C D

Hohnloser SH. N Engl J Med 2009;360:668-78.

Age ≥75 y or ≤75 y with

HypertensionDiabetesPrior Stroke/TIALAD >50 mm or

LVEF ≤0.40

Mean Age 72 ± 9.0

Reduction of Infarct Size by Dronedarone in Pigs

Reduction of Infarct Size by Dronedarone in Pigs

Skyshally A. Cardiovasc Drug Ther 2011

DRONEDARONE STARTED HERE

20-Oct-2010

26-Jul-2011

AF Recurrence in RCT on AFIBAF Recurrence in RCT on AFIB ADONIS, 2007AFFIRM substudy, 2003

Bellandi, 2001Boos, 2008CTAF 2006

Carunchio1995Channer, 2004DAFNE, 2003

DIONYSOS, 2009Dogan, 2004ERAFT, 2002

EURIDIS, 2007FAPIS, 1996

Flecainide AF French Study Group, 1996

Vsdronedarone Odds Ratio Lower 95% CI Upper 95% CI p valu e

Amiodarone 0.405 0.286 0.572 <.0001

Sotalol 0.750 0.520 1.081 0.118

Flecainide 0.574 0.334 0.985 0.0443

Propafenone 0.682 0.464 1.003 0.0518

Control 1.873 1.392 2.521 0.0002

Study Group, 1996Kochiadakis, 1998Kochiadakis, 2000

Kochiadakis, 2004AKochiadakis, 2004B

Lee, 1997Massacci, 1992

PAFAC, 2004RAFT, 2003

Reimold, 1993SAFE-T, 2005SOPAT, 2004

Singh, 1991Stroobandt, 1997VEPARAF, 2003

Van Gelder, 1989Vijayalakshmi, 2006

Freemantle N. EP 2011

Dronedarone Versus PropafenoneIn the Maintenance Of SR In Pts With AF After Electrical CV

Dronedarone Versus PropafenoneIn the Maintenance Of SR In Pts With AF After Electrical CV

25

30

35

Tim

e t

o f

irst

Re

curr

en

ce (

da

ys)

98 pts with AF after electrical CV randomly assigned to receive - dronedarone 400 mg BID - propafenone 150 mg TID

0

5

10

15

20

25

31 32

Tim

e t

o f

irst

Re

curr

en

ce (

da

ys)

- propafenone 150 mg TID

The median ventricular rates at first recurrence of AF were - 76.5 beats/min in DRN Gr. and - 83.0 beats/min in PFN Gr.

(p = 0.059).

Chun KJ. Clin Ther. 2014; 36: 1169-75

AF Control Defined By ECG Does Not Mean Absence Of Symptoms

Data From REALISE -AF

68.4

% %AF control

AF not controlled

At least one symptom* Symptoms in the provious week acco rding to AF control*

AF control AF not controlled

55.7

Palpitation Dyspnea Lighthead-edness/

dizziness

Chest painFatigue Syncope

Steg PG. Heart. 2012; 98: 195-201

27.6

42.8

34.5

48.5

32.6

41.9

14.6 15.9 14.017.6

1.6 2.3

AF control defined as SR (assessed by ECG ) or at-rest AF HR ≤80 beats/m

DYONISOS: Il risultato nell’endpoint primario combinato di

recidiva di FA e interruzione prematura del trattamento è a

favore di amiodarone

L’incidenza dell’endpointprimario è stata del 75% nel gruppo dronedarone e del 59% nel gruppo amiodarone a 12 mesi

0.5

1.0

0.9

0.8

0.7

0.6

0.4

Dronedarone 400 mg bid

Amiodarone 600 mg/200 mg qd

Inci

de

nza

cu

mu

lati

va

(%

)

Dronedarone mantiene una larga parte dell’efficacia di amiodarone nel mantenimento del ritmo sinusale dopo cardioversione riuscita nella FA

persistente

● La differenza relativa a recidiva di FA post-cardioversione tra dronedarone e amiodarone è di 36,5 vs. 24,3%

● L’interruzione prematura del farmaco in studio dovuta a intolleranza si verifica meno frequentemente nel gruppo dronedarone (10,4 vs.

13,3% del gruppo amiodarone)

RR(95% CI) = 1,589 (1,275;1,98)

Log-rank p< 0,0001

Le Heuzey J-Y et al. J Cardiovasc Electrophysiol 2010;21:597-605

1512963

0.2

0.0

0.4

0.3

0.1

0

Mesi

Inci

de

nza

cu

mu

lati

va

(%

)

31

Outcome of Interest 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

Amiodarone in 5060 AF Patients Meta-analysis

Amiodarone in 5060 AF Patients Meta-analysis

8 studies compared A with a rate control drug, either beta-blocker or digoxin4 trials compared A with placebo.

Doyle JFD. Mayo Clin Proc. 2009; 84: 234-242.

per patients-year follow up [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

Conversion/maintenance of SR is NOT associated with a reduction of all-cause death or all-cause hospitalisation

Morbidity/Mortality Studies With DronedaroneAntiarrhythmic Effect Not The Main Espected Driver

Morbidity/Mortality Studies With DronedaroneAntiarrhythmic Effect Not The Main Espected Driver

CV Death, Stroke, Sistemic Embolism, MIHR 2.29; P=0.002

ANDROMEDASevere HF population (25% AF)

PALLASHigh Risk Permanent AF population

Kober L. N Engl J Med 2008 Connolly S. New Engl J Med 2011

HR 2.13; P=0.03

Recommendations (not recommended) Class LevelDronedarone is not recommended for treatment of AF in patients with

2012 Update of the ESC Guidelines on The Management of Atrial Fibrillation

Dronedarone IS NOT Recommended

Dronedarone is not recommended for treatment of AF in patients with NYHA class III and IV, or with recently unstable (decompensation within the prior month) NYHA class II heart failure.

III B

Dronedarone is not recommended in patients with permanent AF III B

Camm AJ. Eur Heart J 2012; 33: 2719-2747 (modif.)

All Cause Mortality in RCT on AFIB Trials > 100 Subjects Per Group, And ≥1 Event per Group

All Cause Mortality in RCT on AFIB Trials > 100 Subjects Per Group, And ≥1 Event per Group

Between Trial Heterogeneity P = 0.12

8 trials 8252 patients349 deaths

A-COMET-II, 2006A-COMET-II, 2006ADONIS, 2007

AFFIRM substudy, 2003ATHENA, 2009

DIONYSOS, 2009EURIDIS, 2007

SAFE-T, 2003SOPAT, 2004

Compared withdronedarone

Odds Ratio Lower 95% CI Upper 95% CI p value

amiodarone 3.191 1.163 8.758 0.032

sotalol 5.051 1.839 13.871 0.009

placebo 1.170 0.913 1.498 0.165 Freemantle N. Europace 2011

…the risk of unplanned CV hospitalisation or death by 27% …the risk of overall mortality by 36%

ATHENA: Coronary Heart Disease Sub -GroupDronedarone Reduced …

ATHENA: Coronary Heart Disease Sub -GroupDronedarone Reduced …

…the risk of CV mortality by 40% …the time to first ACS

Pisters R. Europace Advance Access published September 26, 2013

All-Cause Mortality in RCTs of Dronedarone vs Place boMeta-Analysis Excluding and Including the PALLAS St udy

Iannone P. JAMA Intern Med. Published online February 17, 2014.

ATHENA, PALLAS, ANDROMEDA Demographics, Clinical Characteristics and Outcomes of Study Pts

ATHENA, PALLAS, ANDROMEDA Demographics, Clinical Characteristics and Outcomes of Study Pts

Variable ATHENA PALLAS ANDROMEDAMean age (ys) 72 75 (52% ≥ 75y) 72

Baseline AF 25 100 (70% perm AF > 2ys)

25

Hypertension 86 83 37

Coronary Artery D. 30 41 65

Heart Failure II-III 21 54 97Heart Failure II-III 21 54 97

LVEF 12 <45% 20<40% 100 < 35%

Previous stroke 13 27 NA

Beta-blocker

ACE-i or AT-II-iDigoxin

717014

747833

618631

Oral anticoagulant 60 84 31

Death Any

Death CVDeath Arrhythmic

0.840.710.55

1.942.113.26

2.132.751.68

Stroke 0.66 2.32 NA

Congestive HF 0.86 1.89 1.22

2012

Department of Defense Health Outcome ResultsDeath From Any Cause (Propensity Match )

DronedaroneN = 2,079

Other AADsN = 4,158 P value

Number of events (%) 7 (0.34)Ref. 30 (0.73) 0.079

Event rate/10,000 PM 5.16Ref. 12.11 0.044

Hazard ratio (95% CI) Ref. 2.28 (1.00–5.20) 0.049

100.0

DoD

� A significantly higher risk of death is observed in the “other AADs” cohort compared to dronedarone

Months after index date

0 2 4 6 8 10 12 14 16 18 20 22 24

98.298.498.698.899.099.299.499.699.8

100.0

Pat

ient

s re

mai

ning

ev

ent f

ree

(%)

DronedaroneOther AAD; P < 0.05

Goehring E, et al. J Am Coll Cardiol. 2013;(abstract 1106-45), in press.

Retrospective cohort design, the HRs of the outcome events were analyzed from 10,455 adult patients with a diagnosis of AF/AFL and a new treatment with

dronedarone (comparison drug), amiodarone, sotalol, flecainide, or propafenone

Who is The Ideal Candidate for Dronedarone ?The ATHENA Lesson Revised After PALLASWho is The Ideal Candidate for Dronedarone ?The ATHENA Lesson Revised After PALLAS

ATHENA Study All patients(N=4628)

Age (mean; SD, years) 72 ± 9.0

Female gender 2169 (47%)

AF/AFI at baseline 1155 (25%)

Structural heart disease 2732 (60%)

“Ideal” Candidate for Drone� Older pts (60-80)� Paroxysmal/Persistent AF� Structural HD

- HypertensionStructural heart disease 2732 (60%)

Hypertension 3995 (86%)

Coronary heart disease 1405 (30%)

Valvular heart disease 759 (16%)

Non-ischemic cardiomyopathy

254 (6%)

History of CHF NYHA II/III

979 (21%)

LVEF< 0.45LVEF< 0.35

540/4544 (12%)179/4544 (4%)

Lone atrial fibrillation 279 (6%)

� Structural HD- Hypertension- CAD

� Lone AF (safety)

� No systolic dysfunction� No liver or lung toxicity

related to AMIO

Ion Channel Inhibition by DronedaronePlasma Concentration vs. IC 50

Ion Channel Inhibition by DronedaronePlasma Concentration vs. IC 50

100

120

140

160

Pla

sma

Con

c or

IC

50 (ng

/mL)

Reduce cardiac contractility ► HF safety issue

Plasma Concentration Ion Current IC50

Reduce cardiac contractility ► HF safety issue

Plasma Concentration Ion Current IC50

0

20

40

60

80

100

Dron 400 Dron225-Ran750

Dron150-Ran750

ICa Ikr IKAch

Pla

sma

Con

c or

IC

50 (ng

/mL)

Mean Cmax

Mean Cmin

GILEAD data on file

Heart Rhythm 2013;10:121–127

balloon occlusion of the LCx CA to reduce flow by 75%

during AP @ 150 beats/min

SummarySummary• AF is a CV disease with increasing socioeconomic impact

– Prevalence of AF is projected to be 5.6 million by 2050– AF is associated with increased risk of mortality, stroke, and compromised QoL– Hospitalizations for AF have increased 2 to 3 fold and are projected to continue rising

• Early restoration and maintenance of SR has an integral role in overall AF treatment strategy– AF causes several types of remodeling over time that have adverse physiologic – AF causes several types of remodeling over time that have adverse physiologic

consequences– Sustaining SR may be associated with decreased mortality

• Decreasing AF burden offers potential to successfully treat pts– Successful management of AF includes the reduction of symptoms during

episodes

A measure of success can be defined by decreased mortality, decreased hospitalizations, and increased QoL