Flecainide current role in the treatment of Atrial Fibrillation

1
Flecainide current role in the treatment of
Atrial Fibrillation

• David Bennett, Marketing Centre Cardiology, MEDA

2
Objectives

• The importance of treating AF
• Briefly present the flecainide history - what
  does it tell us
• Treatment guidelines
• Flecainide usage in Western Europe
• Summary
• Czech Republic experience to date

3
Product History

• Tambocor 100 mg immediate-release tablets was
  first registered in Germany in June 1982
• The Original indication was for Ventricular
  Arrhythmias which was extended to
  Supraventricular Arrhythmias from 1986
• Tambocor withdrawn from CAST in April 1989
• Showed that the number of deaths in patients with
  asymptomatic or mildly symptomatic ventricular
  arrhythmias after myocardial infarction was
  greater in those receiving flecainide or
  encainide therapy than in those receiving
  placebo.
• Subsequent to the CAST trial, a retrospective
  study was conducted in patients with
  supraventricular arrhythmias treated with
  flecainide or encainide. This study showed that
  neither drugs were shown to be associated with
  excess mortality.
• Now available in over 50 countries
• Sold officially under a specific treatment
  programme in the Czech Republic since 2008

4
Projected number of people with AF during the
next 50 years
Assuming continued increase in incidence
Assuming no further increase in incidence
15.9
15.2
16
14.3
13.1
14
11.7
12
10.2
12.1
11.7
10
8.9
11.1
Projected number of personswith AF (millions)
10.3
7.7
8
9.4
6.7
N4,618
8.4
5.9
5.1
6
7.5
6.8
Age and sex-adjusted AF increased from 3.04
to 3.68 per 1000 patient years from 1980
to 2000
6.1
5.6
4
5.1
2
0
2000
2005
2010
2015
2020
2025
2030
2035
2040
2045
2050
Year
US model-based prevalence estimates
Upper and lower curves represent the upper and
lower scenarios based on sensitivity analysis
Miyasaka et al, 2006
5
AF is associated with long-term risk of CV events
Men with atrial fibrillation
Women without atrial fibrillation
Women with atrial fibrillation
Men without atrial fibrillation
1.0
0.8
0.6
Age-adjusted event-freesurvival probability
0.4
0.2
0
4
20
14
10
6
0
12
8
2
18
16
Follow-up (year)
Stewart et al., 2002
6
AF an early and late killer
Age 55-75 years
Age 75-94 years
Men AFplt0.0001 vs no AF
80
80
70
70
Men AFplt0.0001 vs no AF
Women AFplt0.0001 vs no AF
60
60
Men no AF
50
50
Women AFplt0.0001 vs no AF
Percent of subjects deadin follow-up ()
40
40
Men no AF
30
30
Womenno AF
20
20
10
10
Womenno AF
0
0
0
4
5
9
8
7
6
3
2
10
4
5
3
2
1
0
1
Follow-up (years)
Benjamin et al., 1998
7
AF impairs QoL
Symptoms occurring during PAF attacks
100
88
87
86
90
70
80
70
59
60
()
50
40
30
20
10
0
Palpitations while exerting
Shortage of breath during exertion
Anxiety
Reduced physical ability
Palpitations at rest
Hansson A et al., 2004
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Paroxysmal Atrial Fibrillation
Recurrent paroxysmal AF
Paroxysmal AF
No therapy unless severe Symptoms (hypotension,
HF, angina pectoris)
Minimal or no symptoms
Disabling AF symptoms
Anticoagulants and rate control as needed
Anticoagulants and rate control as needed
Anticoagulants as needed
No drugs for AF prevention
AADs
AF ablation if AAD treatment fails
Fuster V et al., 2006
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Recurrent persistent AF and permanent AF
Recurrent persistent AF
Permanent AF
Disabling AF symptoms
Minimal or no symptoms
Anticoagulants and rate control as needed
Anticoagulants and rate control
Anticoagulants and rate control as needed
AADs
Electrical Cardioversion as needed
Continue anticoagulants as needed and therapy to
maintain sinus rhythm
Consider ablation for severely symptomatic
recurrent persistent AF after failure of ?1 AAD
plus rate control
Fuster V et al., 2006
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ACC/AHA/ESC guidelines

• Rate control may be a reasonable initial therapy
  in older patients with persistent AF who have
  hypertension or heart disease.
• For younger individuals, especially those with
  paroxysmal lone AF, rhythm control maybe a better
  initial approach.

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AAD therapy to maintain SR in patients with
recurrent paroxysmal or persistent AF
MAINTENANCE OF SINUS RHYTHM
Hypertension
No or minimal heart disease
Flecainide Propafenone Sotalol
Substantial LVH
Yes
No
Amiodarone Dofetilide
Catheter ablation
Amiodarone
Flecainide Propafenone Sotalol
Catheter ablation
Amiodarone Dofetilide
Catheter ablation
Fuster et al., 2006
12
AAD therapy to maintain sinus rhythm in AF
patients with coronary artery disease or heart
failure
13
Flecainide is highly effective in the prevention
of AF recurrence
Relapse rate for different antiarrhythmic drugs
reported in the literature
Relapse Studies (mean,
range) (n) No drug 69
(44-85) 10 Quinidine 59 (46-89) 11 Disopyramid
e 51 (46-56) 3 Propafenone 61 (54-70)
3 Flecainide 38 (19-51) 3 Sotalol 58
(51-63) 3 Amiodarone 47 (17-64) 4
Minimum 6 months follow-up
Levy et al., 1998
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Other Flecainide recommendations

• Flecainide has a  class I recommendation, A
  level of evidence  recommendation for
  pharmacological cardioversion of AF up to 7 days
  duration.
• Flecainide has a  class IIb, B level of
  evidence  recommendation for pharmacological
  cardioversion of AF longer than 7 days duration.
• Flecainide has a  class IIa, B level of
  evidence  Acknowledgement of Flecainide to
  enhance the success of direct current
  cardioversion and prevent recurrence of AF.

Fuster et al., 2006
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Flecainide is highly effective in the acute
cardioversion of AF
Meta-analysis of acute conversion of AF studies
No. of studies
Conversion rate
(n6)
11-86
Quinidine
(n1)
63
Procainamide
Disopyramide
(n1)
23
Flecainide
(n8)
52-95
Propafenone
(n15)
6-91
Amiodarone
(n6)
25-92
(n3)
8-52
Sotalol
Ibutilide
(n3)
10-49
(n25)
0-76
Control treatment
McNamara et al., 2001
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Flecainide produces a low incidence of
extra-cardiac adverse events
Meta-analysis of adverse events
Control
Flecainide
p lt 0.001, p lt 0.05
10.0

9.0
8.0
7.0

6.0
Patients ()
5.0
4.0


3.0

2.0
1.0
0
Central Nervous System
Gastrointestinal
total
diarrhea
nausea
total
headache
dizziness
vertigo
visual disturbances
Wehling, 2002
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Flecainide is safe over the long-term in patients
without structural heart disease
Meta-analysis of cardiac adverse events
Control
Flecainide
Mean exposure time 8 months
1.4
p lt 0.05

1.2
1.0
0.8
Patients ()
0.6
0.4
0.2
0
Anginapectoris
Heartfailure/dyspnea
Bundlebranch block
Hypotension
Sinus nodedysfunction
Palpitations
Syncope
AV-block
Wehling, 2002
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Antiarrhythmic Drug Usage in Western Europe
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11th Tambocor Periodic Safety Update Report25
June 2007 - 24 June 2008

• The estimated patient exposure for the period of
  this report is
• TOTAL (ESTIMATED) 194 MILLION PATIENT-DAYS
• Based on the assumption that the patients are
  treated continuously with Tambocor
• TOTAL (ESTIMATED) 532 000 PATIENTS WERE EXPOSED
  TO TAMBOCOR

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Summary

• Flecainide is a recommended first line treatment
  for patients without structural heart disease
• Flecainide is highly effective for acute
  cardioversion of AF
• Flecainide effectively reduces recurrences of AF,
  maintaining patients in sinus rhythm for longer
• Flecainide is a well-tolerated AAD for patients
  without structural heart disease inducing a low
  incidence of extra-cardiac adverse events
• After 25 years flecainide still remains an
  essential part of a physicians toolkit and with
  new products continuing to fail to meet
  expectations this looks likely to continue