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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