NUOVI FARMACI ANTIARITMICI PER IL TRATTAMENTO DELLA FIBRILLAZIONE ATRIALE

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NUOVI FARMACI ANTIARITMICI PER IL TRATTAMENTO
DELLA FIBRILLAZIONE ATRIALE

• G.L. Botto, MD, FACC, FESC
• UO Cardiologia,
• UOS Elettrofisiologia ed Elettrostimolazione
• Ospedale SantAnna, Como

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AFIB Within The Cardiovascular Continuum
AF is NOT a DISEASE, but rather a manifestation
of a number of CLINICAL SYNDROMES, some of which
are curable
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AF Introduction of AAD Chronological Overview
1749 Quinidine 1785 Digitalis 1936 Procainamide 19
54 Disopyramide 1962 Beta Blocking
agents 1972 Amiodarone 1978 Propafenone 1982 Fle
cainide 1984 Sotalolo 1995 Ibutilide (i.v.
only) 1996 Dofetilide (U.S. only)
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Loss of Efficacy of IKr Blockers by
Electrical Remodeling in the Goat
142
Control
Sinus Rhythm
44 ms
186
d-Sotalol
Duytschaever, Blaauw et al.
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AF Investigational Antiarrythmic Agents

• Dronedarone (IKr IKs ICa Ito INa B1)
• Celivarone SSR 149744 C (similar to dronedarone)
• ATI-2042 atrial selective (IKr IKs B1 ICa
  Ito INa)
• Piboserod (5-HT4-receptor antagonist)
• Tedisamil (IV) (IKr Ito IKATP INa IKur)
• Vernakalant (RSD1235) (atrial-selective K
  inhibitor-IKur Ito Ina IKACh)
• ZP-123 rotigaptide (GAP 486) (facilitates
  conduction in gap junction)
• CVT-150 (long-acting IV A-1 adenosine agonist)
• AVE-0118 (atrial-selective K inhibitor-IKur)
• NIP-151 (IKACh blocker)
• GsMtx-4 (blocks stretch activated channels)
• Cariporide (Na/H exchange inhibitor)

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Different Drugs for Remodeled Atria?
Control
Remodeled
Early Class III Drugs?
Present Class III Drugs
Ito
Ito
ICa
ICa
IKur
IKur
IKr
IKs
IKr
IKs
0
100
200
300
400 ms
0
100
200
300
400 ms
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Class III Effect of IKur Blockers NOT Lost by
Electrical Remodeling
162
Control
Sinus Rhythm
46 ms
208
AVE 0118
66
Control
After 48h of AF
90 ms
156
AVE 0118
Courtesy of M. Allessie
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Contractile and Electrical Remodeling Go Hand in
Hand
Refractory Period (ms)
Work Index (mm2Hg)
AF Conversion SR
20
140
Refractory Period
15
Work Index
120
10
100
5
80
0
0
1
2
3
4
5
6
7
8
9
10
Time (days)
Schotten et al. Circulation 2003
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Recent Onset Atrial Fibrillation Intravenous
Flecainide vs Amiodarone
pNS
p0.007
p0.001
Conversion to SR (N)
(hours)
Donovan K.D. Am J Cardiol 75693 1995
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Atrial FibrillationArryhthmia Duration and Drugs
Efficacy
p0.005
106 pt, AFIB lt 6 months


Reisinger J. Am J Cardiol 81 1450 1998
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Out-of-Hospital Treatment of Paroxismal Atrial
Fibrillation With the Pill-In-the-Pocket
Approach
Exclusion Criteria

• Previous MI or IHD
• Dilated or hypertrophic CMP
• History of heart failure
• Moderate/Severe Valvular HD
• LV dysfunction ( EF lt 50)
• Chronic cor pulmonale
• Renal or hepatic insufficiency
• Hypokaliemia (lt 3 mEq/L)

• Long QT or Brugada syndrome
• SSS (SR lt50 bpm)
• 2nd or 3rd degree AV block
• Thromboembolic episodes
• Prophylactic AADs treatment
• Known intolerance to flecainide or propafenone

Botto GL. G Ital Aritm Cardiostim 2001 3 109
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Atrial FibrillationPharmacologic Conversion
When How to Use

• Low-Risk Patients
• Recent-onset AFIB
• Monitored setting
• Caution with some drugs in women (i.e., greater
  risk of torsade de pointes)

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Ibutilide in Atrial Fibrillation
M.F. 56 y.o. Male Valvular HD LVEF 46
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Atrial Target Suitable for Rx in AFIB
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The Concept of Atrial Selective Compounds
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VernakalantAtrial Selective Effect
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Rate-Dependent Sodium Current Blockade by
Vernakalant Based on in vitro Data From Human
Embryonic Kidney Cells
INa IC
43 µM at -80 mV, 1 Hz
50
0.8
0.6
1 Hz
Fractional current
0.4
20 Hz
Range of plasma levels in patients
0.2
0.0
1
10
100
1000
Vernakalant concentration (µM)
Fedida D. Expert Opin Investig Drugs
200716519532 Fedida D et al. J Cardiovasc
Electrophysiol. 20051612271238.
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Vernakalant in Patients With AFIB
Dobrev D., Nattel S. Lancet 2010 375 1212-23
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AVRO TrialBaseline Characteristics
Camm AJ. JACC 2011 57 313-21
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AVRO Study Design
Continuous Heart Rhythm Monitoring
Day 30 FU Call
Continuous Holter Monitoring
Day 7
Randomization
Hour 4 Visit
Dischargec
Screening
Primary End PointEfficacy Period
Time
0
10
25
35
90 min
2 h
4 h
6 h/Discharge
7 d2 d
60
30 d3 d
- 1 h
VernakalantN116
2 mg/kga
3 mg/kg
Electrical cardioversion or rate control permitted
AmiodaroneN116
5 mg/kgb
50 mgb
aInfusion only given if patient in atrial
fibrillation. bInfusion stopped upon conversion
to sinus rhythm. cPatient discharge was at the
discretion of the investigator, but patients
remained in the clinic at least 6 hours after
randomization.
Camm A.J. et al. JACC Vol.57, No 3, 2011
Jan18, 2011313-21
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AVRO TrialTime to Treatment-Induced Cardioversion
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
VER Median time to conversion 11 min Higher
rate of symptoms relief _at_ 90 min VER 53,4 vs
AMI 32,8 p0.0012 SAE or AE leading to
discontinuation uncommon
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Vernakalant Added to 2010 ESC Guidelines Drugs
for Pharmacologic Cardioversion of Recent-Onset 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. 20103123692429.
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Atrial Fibrillation Effect on Mortality of Rate
vs Rhythm Control
Pts with Thromboembolic Risk Factors
Pts with Heart Failure
AFFIRM Trial N Engl J Med 2002 347 1825
AF-CHF Trial N Engl J Med 2008 358 2667
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Amiodarone in 5060 AF Patients Meta-analysis
8 studies compared A with a rate control drug,
either beta-blocker or digoxin 4 trials compared
A with placebo.
Outcome of Interest Relative Risk95 CI p-value(test for overall effect)
Conversion to sinus rhythm per patients-year follow up 3.221.885.53 lt0.0001
Incidence of all-cause mortality per patient-year follow up 0.950.811.11 0.51
Rate of all-cause hospitalisation per patients-year follow up 1.100.572.13 0.77

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

Doyle JFD. Mayo Clin Proc. 2009 84 234-242.
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AFFIRMOn-Treatment AnalysisNormal Sinus
Rhythm is Associate with Better Survival
0.54 (0.42 0.70 plt0.001)
0.47 (0.36 0.61 plt0.001)
1.50 (1.18 1.89 plt0.001)
1.41 (1.10 1.83 plt0.0005)
Other significant factors age, CAD, CHF,
smoking, stroke/TIA, N-LVEF, MR
Corley SD. Circulation 2004 109 1509-1513
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AFFIRMOn-Treatment AnalysisThe Hope of Newer
Antiarrhythmic Drugs
0.54 (0.42 0.70 plt0.001)
0.47 (0.36 0.61 plt0.001)
1.50 (1.18 1.89 plt0.001)
0 (xxx-yyy plt0.000n)
Other significant factors age, CAD, CHF,
smoking, stroke/TIA, N-LVEF, MR
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Dronedarone
Dronedarone
O
(CH2)3CH3
CH3SO2HN
(CH2)3CH3
O(CH2)3N
(CH2)3CH3
O
O
(CH2)3CH3
I
CH2CH3
O(CH2)2N
CH2CH3
O
Amiodarone
I
Kathofer F. Cardiovasc Drug Rev. 2005 23 217-30
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Dronedarone was Less Effective on Maintaining SR
but with more Favorable Safety ProfileResults
From The Dyonisos Study
Dronedarone (n249) Amiodarone (n255)
Number of patients with endpoint 184 (73.9) 141 (55.3)
AF endpoint 158 (63.5) 107 (42.0)
Documented AF after conversion 91 (36.5) 62 (24.3)
Unsuccessful electrical cardioversion 29 (11.6) 16 (6.3)
No spontaneous conversion and no electrical cardioversion on day 10 to day 28 38 (15.3) 29 (11.4)
Premature study drug discontinuation 26 (10.4) 34 (13.3)
Lack of efficacy 1 (0.4) 0
Intolerance 25 (10.0) 34 (13.3)
Loading regimen of amiodarone resulted in a lower
incidence of AF recurrences at the cost of a less
favourable safety profile
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DRONEDARONE STARTS HERE
20-Oct-2011
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EURIDIS ADONISPooled Tolerability and Safety
Data
Incidence of Treatment Emergent Adverse Events (TEAEs) Placebo Dronedarone 400 mg bid
N409 N828
Pts with any TEAE 62,8 67,4
Pts with serious TEAE 15,6 14,3
Serious TEAE leading to death 0,7 1,0
Pts permanently discontinued study drug following any TEAE 6,1 9,7

• No evidence of proarrhythmia, in particular, no
  case of torsade de pointes reported during
  12-month follow-up.
• No detection of thyroid disorders (systematic
  hormonal monitoring) or pulmonary or hepatic
  toxicity

Singh BN, et al. N Engl J Med. 2007 3571039-41
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Dronedarone AF/AFL PoolTime to First Serious
Hepatic Adverse Events
0.10
HR0.875 0.542 1.414
p0.9811
0. 5
Cumulative Incidence
Months
0
6
12
18
24
0
Number at risk
Placebo 2875 2241 1921 1174 460
400mg BID 3282 2551 2221 1165 467
ALT5ULN or hepatic adverse events from SOC
Hepatobiliary disorders and the SMQ Liver
related investigation signs and symptoms All
randomized and treated patients in DRI3550/DAFNE,
EFC3153/EURIDIS, EFC4788/ADONIS, EFC4508/ERATO,
EFC5555/ATHENA
Data on file, sanofi-aventis
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ATHENA Trial Design

• Prospective double-blind trial to assess the
  efficacy of dronedarone in preventing
  cardiovascular hospitalization or death from any
  cause in AF/AFL patients with and additional risk
  factors

Age 75 y or 75 y with Hypertension Diabetes Pri
or Stroke/TIA LAD gt50 mm or LVEF 0.40
Dronedarone 400 mg BID (n2301)
AF/AFL patients with additional risk factors
Double-blind
R
Placebo (n2327)
12 30 Months
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ATHENA TrialCardiovascular Hospitalization or
Death
A
B
a Efficacy population
b Randomized and treated patients
C
D
b Randomized and treated patients
b Randomized and treated patients
Hohnloser S. N Engl J Med. 2009 360 668-78
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ATHENA Post-Hoc AnalysisEffect on Non-AF Related
CV Hospitalizations by 14
30
Placebo
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Dronedarone
20
Cumulative incidence ()
15
10
5
0
Months
Patients at risk
Placebo 2327 2093 1929 1326 497 3
DR 400mg bid 2301 2096 1957 1338 479 2
Mean follow-up 21 5 months - on
Study Torp-Petersen C et al. Circulation.
2008118S_828 (presented at scientific sessins
AHA 2008)
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ATHENA Post-Hoc AnalysisReduction in CV
Hospitalization or Death in Permanent AF
50
Placebo on top of standard therapy
Dronedarone 400 mg b.i.d. on top of standard
therapy
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HR 0.74
30
p0.096
20
10
Mean follow-up 21 5 months
Months
0
Patients at risk
Placebo 295 244 224 151 60 0
DR 400 mg b.i.d. 178 160 150 110 47 1
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Page RL et al. Circulation. 2008118S_827.
(presented at scientific sessions AHA 2008)
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Dronedarone and Risk of StrokeATHENA Subanalysis
Mean follow-up 21 5 months
Connolly SJ. Circulation 2009 120 1174-80
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Algorithm For The Management of AF2010 ESC
Guidelines
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Algorithm For The Management of AF2011
ACCF/AHA/HRS Updated Guidelines
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Summary

• AF is a chronic, 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, risk of 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 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