Comment traiter mйdicalement la Fibrillation Auriculaire aprиs les йtudes AFFIRM, RACE et PIAF?

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Comment traiter médicalement la Fibrillation
Auriculaire après les études AFFIRM, RACE et PIAF?

•  Rhythm Control 
• Ou
•  Rate Control 
• ?

Marc Dubuc MD, FRCPC Institut de Cardiologie de
Montréal
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Comment traiter médicalement la Fibrillation
Auriculaire après les études AFFIRM, RACE et PIAF?

•  Normalisation du Rythme
• Ou
•  Normalisation de la fréquence en FA 
• ?

Marc Dubuc MD, FRCPC Institut de Cardiologie de
Montréal
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Possible mechanisms of AF
LAA
RAA
LAA
RAA
LAA
RAA
AVR
AVR
AVR
Multi-circuit reentry (Mines, Garrey)
Mother wave (Lewis)
Hyperexcitability (Engelmann, Winterberg)

• Rapidly-firing atrial foci
• Macroreentry with fibrillatory conduction
• Multi-circuit reentry

Remodeling acts to make multi-circuit reentry a
common pathway
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"AF Begets AF"
AF causes changes in atrial electrophysiology
that promote AF maintenance
Wijffels et al. Circulation 1995 92 1954-68
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Therapeutic Issues concerning Atrial Fibrillation

• Rate vs Rhythm Control
• Pharmacologic Approaches
• Nonpharmacologic Approaches
• Anticoagulation

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Pharmacologic control of atrial fibrillation

• Prevention of recurrences (Rhythm control)
• Control of ventricular rate (Rate control)
• Acute conversion

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Antiarrhythmic drugs for AF
Class IA
Class IC
Class III
Disopyramide Quinidine Procainamide
Flecainide Propafenone
Amiodarone Dofetilide Sotalol
available in USA only
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Antiarrhythmic drugs for AF
EFFICACY
Sinus rhythm after 1 year
Placebo Class IA , IC , Sotalol Amiodarone
25 40-60 60-70
Concurrent use of AV nodal blocking drug
10
Probability of remainingin sinus rhythm (N 403)
CTAF
sinus rhythm
100

Hazard Ratio
0.43 (0.32-0.57)
plt0.001
Amiodarone
80
60
Propafenone
40
Sotalol
20
0
600
500
400
300
200
100
0
Time (days)
Roy, Talajic, Dorian et al, NEJM 2000342913
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Permanent Discontinuation of Study Medication
CTAF
Amiodarone
Sotalol/propaf
p value
Inefficacy Adverse events Non-compliance Other
Total
8 18 5 3 34
28 11 5 2 46
0.01 0.06 0.83 0.47 0.01
N.E.J.M. 2000342913
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Antiarrhythmic drugs for AF
Risk of therapy
Class I
Class III
Amiodarone
? mortality with SHD TDP class IA Atrial flutter
with 11 AV conduction
TDP Women CHF Bradycardia Low K Diuretic
Non cardiac Thyroid Dermatologic Rx
interaction Pulmonary Ophtalmologic
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Do beta-blockers reduce the recurrence of AF?
Metoprolol 100-200 mg/day (n 197)
Placebo (n 197)
p Value
Relapse of AF HR in AF (bpm) F/U
(days) Adverse events causing withdrawal
96 (49) 98 23 93 20 (10)
118 (60) 107 27 73 6 (3)
0.005
394 patients Persistent AF (enrolled after
cardioversion) Prospective, randomized,
double-blind, placebo-controlled
Kühlkamp et al. JACC 2000 36 139
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Frequency of symptomatic recurrence of AF after
cardioversion in pts treated with metoprolol in
comparison to sotalol
Recurrence of AF ()
OR (95 CI) 2.1 (1.1 - 4.1)
70
178 consecutive patients 1st episode of AF Mean
FU 8 months No ? in baseline characteristics
60
58 (62)
50
40
36 (43)
30
20
"Patients treated with metoprolol had a better
outcome than patients treated with sotalol"
10
0
Metoprolol (n 84)
Sotalol (n 94)
Fischer, F. et al. JACC 2001 37 93A
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Drugs to control atrial fibrillation

• Prevention of recurrence
• Rate control
• Acute conversion

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Rate control

• Poorly defined criteria
• Symptoms
• ECG
• Arbitrary definition
• Resting heart rate 50-80/min
• Moderate exercise 100-115/min
• Tools
• Holter
• Exercise testing

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AF at rest Rx Digoxin
CC5
CM5
ML
71 A- H- S F 60 S7000 8470 CASE 12
004B
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AF during exercise Rx Digoxin
CC5
CM5
ML
71 A- H- S F 60 S7000 8470 CASE 12
004B
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Rate control
ß-blockers (anti-adrenergic activity)

• Effective rate control at rest and during
  exercise
• ? ? exercise capacity
• Frequent side effects in the elderly

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Rate control
Non-dihydropyridine Ca antagonists(verapamil,
diltiazem)

• Effective rate control at rest and during
  activities
• ? exercise duration
• Negative inotropic effect
• ? prevention of electrical remodeling

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Ventricular rate control in AF
Mean HR (bpm)
Exercise duration (min)

• 12 patients with chronic AF
• Crossover open-label study of 5 drug regimens
• Daily activity and programmed exercise

Tx group
Digoxin Diltiazem Atenolol Digoxin
Diltiazem Digoxin Atenolol
175 36 151 27 130 34 146 40 126 29
10.5 4.4 10.8 4.2 10.8 3.7 10.8 4.3 11.0
3.6
p lt 0.01
Digoxin Atenolol produced most effective rate
control
Farshi et al. J Am Coll Cardiol 1999
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Nonpharmacologic Treatment of Atrial Fibrillation

• AV nodal ablation and pacing
• Atrial catheter ablation
• Atrial pacing
• Implantable atrial defibrillator

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Long-term survival after AV node ablation and
implantation of a permanent pacemaker in pts with
AF
100

• 350 patients
• Mayo Clinic 1990-1998(retrospective)
• Mean F/U 36 26 months
• Survival is similar for patients with AFwhether
  they receive ablation or drug therapy.

Expected
80
Ablation
60
Survival () with ablation or drugs and matched
controls
Drug therapy
40
20
0
0
1
2
3
4
5
6
Years of follow-up
Ozcan et al. NEJM April 2001
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AV node ablation

• Does not eliminate AF
• Effective in controlling ventricular rate
• Improves
• QoL
• Exercise tolerance
• Left ventricular function
• No deleterious effect on survival

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Nonpharmacologic Treatment of Atrial Fibrillation

• AV nodal ablation and pacing
• Atrial catheter ablation
• Atrial pacing
• Implantable atrial defibrillator

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Nonpharmacologic Treatment of Atrial Fibrillation

• AV nodal ablation and pacing
• Atrial catheter ablation
• Atrial pacing
• Implantable atrial defibrillator

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Atrial fibrillationRhythm control
Antiarrhythmic drugs
Potential benefits of sinus rhythm

• Fewer symptoms and improved quality of life
• Improved exercise tolerance
• Improved cardiac output
• Reduced embolic risk

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Atrial fibrillationRate control
Advantages

• Avoids proarrhythmic effects of antiarrhythmic
  drugs
• Simpler than rhythm control
• Safer

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Pharmacologic Intervention in Atrial
Fibrillation(PIAF)

• Multicenter German study
• Persistent (? 7 and ? 365 days) AF
• 252 patients
• Primary endpointChange in symptomatic status
  (palpitation, dyspnea, dizzyness)

Heart rate control 125pts
Restoration of SR 127pts
Rx diltiazem Digoxin ?-blockers AVN ablation
Amiodarone Cardioversion
Hohnloser et al ,Lancet 2000
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PIAF
Primary study endpoint improvement in symptoms
Diltiazem 69 73 72 76 responders Amiodarone
73 80 76 70 responders
Lancet 20003561789-94
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PIAF
Secondary study endpoint Maintenance of sinus
rhythm (Holter documented) (intent-to-treat
analysis)
Lancet 20003561789-94
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PIAF
Secondary study endpoint 6-minutes walking
test (intent-to-treat analysis)
Diltiazem 82 72 68
56 63 patients Amiodarone 77
65 63 49
54 patients
Lancet 20003561789-94
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AFFIRMSelected Patient CharacteristicsN 4060

• Age 69.7 9.0 yrs
• 39 female
• Primary diagnosis
• Hypertension 51 (prev 71)
• CAD 26 (prev 38)
• None 13
• gt 2 days of AF in 69
• CHF class gt II in 9
• Symptomatic AF in 88

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AFFIRMPrimary Endpoint Total Mortality
30
25
Rhythm
Rate
20
15
p 0.078 unadjusted
Mortality ()
p 0.068 adjusted
10
5
0
3
0
1
2
4
5
Time (Years)
No difference between strategies, but a late
mortality advantage for rate control starting at
about 2 years after randomization.
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Implications of AFFIRM
for clinical decision making
Rate control is an acceptable primary therapy of
AF.Anticoagulation for all pts with one or more
risk factor for stroke.
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Who is under-represented in AFFIRM?

• Young patients
• Paroxysmal atrial fibrillation
• CHF
• Reduced systolic function
• Isolated diastolic dysfunction
• Disabling symptoms of AF

What therapies are under-represented ?
? Other (newer?) drugs ?Nonpharmacologic therapies
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Rhythm vs Rate control trials

• PIAF AFFIRM
  RACE
• Pts 252 4060
  522
  gt
  Pers gt7 days Pers (69 ), PAF Pers
  (rec/ CVE)
• Age 60 70 68
• F/U yrs 1 3.5 2.3
• Rhythm amio amio, sot
  sot, flec,
• prop, class I prop, amio
• Rate dilt,BB, dig BB, dilt, Ber
  BB, dilt, Ver
• Endpoint symptoms Death
  Death/ bleed/ thromboembolic
• 
  
  events/drug
  adv. events
• Results No ? No ?
  No ?

Expected superiority of rhythm control not
demonstrated Rate control fewer hosp and
adverse drug effect Rhythm control ? better
functional capacity
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The Brent Mitchell classification
Dominant Strategy
Happy Face

• Asymptomatic
• Marginaly symptomatic
• Older
• Relatively sedentary
• Risk of proarrhythmia
• When rate control inefficient
• Moderate severe symptoms
• Younger
• Active
• First episode
• Reversible cause

Rate
Sad /Angry Face
Rhythm
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ACC /AHA/ESC Guidelines for the management of pts
with AF
JACC Oct 2001
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"Two new epidemics of cardiovascular disease are
emerging heart failure and atrial fibrillation."
Braunwald E., N Engl J Med 1997 3371360-5
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AF-CHF Atrial Fibrillation and Congestive Heart
Failure

• HYPOTHESIS
• Restoring and maintaining sinus rhythm will
  improve cardiovascular mortality compared to a
  rate-control treatment strategy in pts with
  congestive heart failure
• PROTOCOL
• Prospective multicenter trial with 1450 pts
  randomly allocated to two treatment arms over 3
  years with a minimum follow-up of 2 years (May
  2001-2006)

AF-CHF trial Investigators Am Heart J 2002144
597
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Study design
AF-CHF
CHF NYHA class II-IV and EF ? 35 NYHA I and
prior hospitalization for CHF or EF ?
25 Qualifying AF one episode ? 6 hours within
last 6 months one episode ? 10 min and prior
D/C shock
Randomization (open-label)
Rate control
Rhythm control
Pharmacologic dosing adjustment ? AV nodal
ablation for pts with inadequate rate control
Antiarrhythmic Class III and/or
non-pharmacologic therapy in resistant
pts ? Cardioversion if needed
Follow-up 2 years ACE inhibitors and
beta-blockers
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What is the preferred treatment strategy
Rhythm vs Rate control Factors to consider

• Symptoms
• Likelihood of maintaining sinus rhythm
• Risk of therapy

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Drugs to control atrial fibrillation

• Prevention of recurrence
• Rate control
• Acute conversion

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Likelihood of spontaneous conversion of AF to SR
Danias, JACC 1998
356 pts AF lt 72 h Symptoms of lt 24 h Predictor
of spontaneous conversion OR 1.8 CI 1.4-2.4
p lt 0.0001
AF duration
Nb of pts
Conversion
lt 24 h 24 - 72 h Total
292 64 356
73 45 68
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Digoxin for converting recent-onset AF to sinus
rhythm
Falk et al. Annals of Intern Medicine 1987
Randomized, double-blind placebo-controlled AF lt
7 days Mean time to conversion Digoxin 5.1
hrs Placebo 3.3 hrs
N 36
Digoxin (n 18)
Placebo (n 18)
AF 9 (50)
NSR 9 (50)
AF 10 (55.6)
NSR 8 (44.4)
 Spontaneous conversion is common   Digitalizat
ion was not shown to affect conversion 
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Conversion of recent-onset AF to sinus
rhythmEffects of different drug protocols
Boriani et al. Pace 1988
Conversion rates to SR
100
417 hospitalized pts AF lt 7 days 119 pts PO
propafenone 600 mg 69 pts PO flecainide 300
mg Mean conversion time Flecainide 2.6
hrs Propafenone 3.0 hrs



80

76
75
60
40
20
0
Placebo
IV Amio
IV Propaf.
Oral Propaf.
Oral Fleca.
p lt 0.05 vs placebo p lt 0.01 vs placebo
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Rate-dependent effects on repolarization

• Tachycardia-dependent prolongation APD
• Class Ic propafenone, flecainide
• Reverse use-dependence
• ? APD and refractoriness to the greatest extent
  at slow rates
• IKr blockers dofetilide, ibutilide, sotalol
• Frequency-independent
• ? APD preserved at rapid rates
• IKs blockers amiodarone, azimilide

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Rate-dependent effectsClinical implications

• Class Ic more effective for acute termination of
  AF
• Class III pro-arrhythmia occurs preferentially at
  lower rates
• Class III agents with IKs-blocking action may
  show less reverse use-dependence
• Less torsadogenic?