Atrial Fibrillation Guideline Update

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Atrial Fibrillation Guideline Update
DRO-062811000 Approved 6-30-11

• Focus on Pharmacotherapy and New Paradigms of
  Therapy
• Dennis J. Jacobsen, Ph.D. FAHA, FACSM
• Medical Affairs, sanofi

2
Background/Disclosures

• UNK (Chemistry/Biology)
• University of MN (MS, Physiology)
• Texas AM (Ph.D., Physiology)
• Faculty/Research
• UNK
• KU
• Medical Affairs sanofi

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Atrial Fibrillation Disease State Awareness
Objectives
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• Describe prevalence and epidemiology
• Define clinical presentation and evaluate the
  risk factors for developing AF
• Discuss the mechanisms and pathophysiology of AF
• Atrial remodeling
• Classification of AF
• Review ACC/AHA/ESC 2011 Guidelines for the
  Management of Patients With AF
• Stroke prevention
• Update on rate control
• Rhythm management
• Review new consideration in AF management

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Prevalence
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Epidemiology of Atrial Fibrillation in the US
Rising Prevalence of the Disease
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• As of 2010, 2.66 million Americans are estimated
  to have AF1
• Lifetime risk for developing AF is high2
• 1 in 4 for men and women aged ?40 years
• Prevalence increases rapidly with age3
• 3.8 for persons aged ?60 years
• 9 for persons aged ?80 years

AF affects 1 in 25 adults aged gt60 years and 1 in
10 adults gt80 years3
1. Lloyd-Jones D et al. Circulation.
2010121e46-e215. 2. Lloyd-Jones DM et al.
Circulation. 20041101042-1046. 3. Go AS et al.
JAMA. 20012852370-2375.
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Projected Prevalence of AF Through 2050
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15.9
15.2
14.3
13.1
11.7
10.2
12.1
11.7
8.9
11.1
7.7
10.3
9.4
Projected Number of Persons With AF (millions)
6.7
8.4
5.9
7.5
5.1
6.8
6.1
5.6
Current age-adjusted AF incidence
5.1
Increased age-adjusted AF incidence
Year
Miyasaka Y et al. Circulation. 2006114119-125.
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Pathophysiology
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AF Disease Progression Can Lead to Cardiac
Remodeling
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Electrical1

• Shortening of atrial refractory periods2
• Loss of normal adaptation of atrial
  refractoriness to heart rate3

Contractile1
Structural1

• Histologic changes4
• Left atrium and LA appendage enlargement5
• Decrease in cardiac output6

• Reduced atrial contractility4

1. Allessie M, et al. Cardiovasc Res.
200254230-246 2. Prystowsky EN, et al.
Circulation. 1996931262-1277 3. Hobbs WJC, et
al. Circulation. 20001011145-1151 4. Thijssen
VLJL, et al. Cardiovasc Pathol. 2000917-28 5.
Sanfilippo AJ, et al. Circulation.
199082792-797 6. Fuster V, et al. Circulation.
2006114e257-e354.
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The Chronic Progressive Nature of Untreated AF
May Explain the Need for Early Intervention
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The AF Continuum of Disease
Diagnosis
AF episode
Sinus rhythm (SR)
Kirchhof P et al. Europace. 200791006-1023.
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Atrial Remodeling and Persistent Atrial
Fibrillation
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• AF induces electrophysiologic changes that
  promote further AF and both cause and are a
  consequence of electrical, contractile, and
  structural atrial remodeling

Wijffels MC et al. Circulation. 1995921954-1968.
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Patients Converted to SR Within 3 Months of AF
Onset are More Likely to Remain in SR
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Plt0.02
82
36
Dittrich HC et al. Am J Cardiol. 198963193-197.
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Goals of Therapy
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Classification and Patterns of Atrial
FibrillationACC/AHA/ESC Guidelines
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First detected
gt7 d
?7 d
May be recurrent
Paroxysmal (self-terminating)
Persistent (not self-terminating)
Permanent
Cardioversion failed or not attempted
Cardioversion failed or not attempted
Lone AF generally applies to younger individuals
(lt60 years) without clinical or echocardiographic
evidence of cardiopulmonary disease, including
hypertension Recurrent AF defined as ?2
episodes termination with pharmacologic or
direct-current cardioversion does not change
designation. Adapted from Fuster V et al.
Circulation. 2006114e257-e354.
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Clinical Presentation of Atrial Fibrillation
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• AF presents with a wide range of symptoms1
• May also be asymptomatic
• Impact of asymptomatic AF2
• Potential for underlying electrical and
  structural damage to atrial myocardium
• While AF symptoms alone may not always be severe,
  untreated disease can result in significant
  morbidity and mortality3

LIGHT-HEADEDNESS
PALPITATIONS
DYSPNEA
SYNCOPE
CHEST PAIN
FATIGUE
THROMBO-EMBOLISM
DEATH
1. Fuster V et al. Circulation.
2006114e257-e354. 2. Page RL et al.
Circulation. 20031071141-1145. 3. Stewart S et
al. Am J Med. 2002113359-364.
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The ALFA StudyPrevalence of Symptoms
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Total Population(N756)
ALFA Étude en Activité Libérale de la
Fibrillation Auriculaire. Lévy S et al.
Circulation. 1999993028-3035.
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Severity of Stroke with AF
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• 1061 patients admitted with acute ischemic stroke
• 20.3 had AF
• Bedridden state
• With AF 41.2
• Without AF 23.7
• Odds ratio for bedridden state following stroke
  due to AF, 2.23 (95 CI, 1.87-2.59 Plt0.0005)

CI confidence interval. Dulli DA et al.
Neuroepidemiology 200322118-123.
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CHADS2 Stroke Risk Stratification Scheme for
Patients With Nonvalvular AFib
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Relationship between CHADS2 score and annual risk
of stroke
Adapted from Hersi A et al. Curr Probl Cardiol.
200530175-234.
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Vaughan-Williams Classification

• AADs have distinct characteristics based on which
  ionic currents they block
• Vaughan-Williams classification based on their
  dominant electrophysiological effect
• There are 3 Class I subtypes 1a, 1b, and 1c

AADs antiarrhythmic drugs. Adapted from
http//www.cvpharmacology.com/antiarrhy/sodium-blo
ckers.htm.
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Vaughan Williams Classification1
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• Multiple mechanisms contribute to the occurrence
  of AF2
• Balance between safety and efficacy is critical
  to choosing an appropriate AAD3
• Agent selection should consider severity of AF
  Burden, safety, CV comorbidities, and dosing
  convenience to improve compliance with therapy3,4

1. Vaughan Williams EM. J Clin Pharmacol.19842412
9-147.2. Nattel S, et al. Circ Arrhythm
Electrophysiol.2008162-73.3. Fuster V, et al.
Circulation. 2006114e257-e354. 4. Naccarelli
GV, et al. US Cardiology.20041-5.
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Class III AgentsPrimary effect on K channel,
most have additional drug-specific effects on
other ion channels
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AF Guideline Focus Update
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• Stroke Prevention
• Rate Control Update
• Anti-Arrhythmic Update

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Recommendation for Combining Anticoagulant with
Antiplatelet Therapy
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• Multiple studies have shown that oral
  anticoagulation with warfarin is effective for
  prevention of thromboembolism in AF1
• Aspirin offers only modest protection against
  stroke in AF and is less efficacious than
  adjusted-dose oral anticoagulation1
• The ACTIVE-W trial showed that oral
  anticoagulation with warfarin was superior to the
  combination of clopidogrel plus aspirin for
  prevention of vascular events in AF with similar
  bleeding risks2

1. Wann LS et al. Circulation. 2011123104-123. 2
. Connolly S et al. Lancet. 20063671903-1912.
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ACTIVE A Atrial fibrillation Clopidogrel Trial
with Irbesartan for prevention of Vascular Events
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• Patient Population
• Afib (Afib at enrollment or at least 2 episodes
  of intermittent Afib in the prior 6 months) and
  at least 1 predetermined risk factor for stroke
• Cannot take VKA (eg, warfarin)

n3,772
Clopidogrel 75 mg ASA (75100 mg)
Placebo ASA (75100 mg)
n3,782
Median follow up 3.6 years

• Primary Endpoint
• First occurrence of a composite of stroke,
  non-CNS systemic embolism, MI, or vascular death
• Safety Endpoints
• Major and minor bleeding

Connolly SJ et al. N Engl J Med. 2009 360
2066-2078.
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ACTIVE A Primary Endpoint Stroke, MI,
Non-CNS-embolism or Vascular Death
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0.4
924 (7.6/year)
RR0.89 (0.81-0.98) P0.01
832 (6.8/year)
0.3
Aspirin
0.2
Cumulative Incidence
Clopidogrel Aspirin
0.1
0.0
0
1
2
3
4
Years

Connolly SJ et al. N Engl J Med.
20093602066-2078.
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ACTIVE A Bleeding
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Connolly SJ et al. N Engl J Med.
20093602066-2078.
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Recommendation for Combining Anticoagulant With
Antiplatelet Therapy
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• Class IIb
• The addition of clopidogrel to aspirin (ASA) to
  reduce the risk of major vascular events,
  including stroke, might be considered in patients
  with AF in whom oral anticoagulation with
  warfarin is considered unsuitable due to patient
  preference or the physicians assessment of the
  patients ability to safely sustain
  anticoagulation. (Level of Evidence B)
• Comments New Recommendation

Wann LS et al. Circulation. 2011123104-123.
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RE-LY A Noninferiority Trial
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Atrial fibrillation ?1 Risk Factor Absence of
contra-indications 951 centers in 44 countries
Blinded Event Adjudication
R
Blinded
Blinded
Open
Warfarin adjusted (INR 2.0-3.0) N6022
Dabigatran Etexilate 110 mg BID N6015
Dabigatran Etexilate 150 mg BID N6076
Connolly SJ et al. N Engl J Med.
20093611139-1151.
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RE-LYStroke or Systemic Embolism
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Noninferiority P Value
Superiority P Value
Dabigatran 110 vs Warfarin
lt0.001
0.34
Dabigatran 150 vs Warfarin
lt0.001
lt0.001
Margin 1.46
Warfarin better
Dabigatran better
0.50
0.75
1.00
1.25
1.50
HR (95 CI)
Connolly SJ et al. N Engl J Med.
20093611139-1151.
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RE-LYBleeding Results
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Connolly SJ et al. N Engl J Med.
20093611139-1151.
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Recommendations for Emerging Antithrombotic Agents
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• Class I
• Dabigatran is useful as an alternative to
  warfarin for the prevention of stroke and
  systemic thromboembolism in patients with
  paroxysmal to permanent AF and risk factors for
  stroke or systemic embolization who do not have a
  prosthetic heart valve or hemodynamically
  significant valve disease, severe renal failure
  (creatinine clearance lt15 mL/min), or advanced
  liver disease (impaired baseline clotting
  function). Level of evidence B)
• Comments New Recommendation

Wann LS et al. Circulation. 2011123104-123.
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Current Trials of Anticoagulant Treatments in the
Prevention of Stroke in Patients With AF
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Medi C et al. Stroke. 2010412705-2713.
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Rate Control During Atrial Fibrillation
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• Rate control usually targets heart rate of 60-80
  bpm resting and 90-115 bpm during moderate
  exercise1
• AFFIRM definition of adequate rate control2
• Up to 80 bpm at rest
• Average of up to 100 bpm over 18 hours of
  ambulatory Holter monitoring with no rate greater
  than 100 of maximum age-predicted exercise heart
  rate
• or
• Maximum of 110 bpm during 6 minute walk test

1. Wann LS et al. Circulation. 2011123104-123. 2
. Olshansky B et al. J Am Coll Cardiol
2004431201-1208.
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RACE II RAte Control Efficacy in Permanent
Atrial Fibrillation
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Permanent AF gt80 bpm
Strict Rate Control n303
Lenient Rate Control n311
HR lt110 bpm (12 lead ECG)
HR lt 80 bpm (12 lead ECG) and HR lt110 bpm (at
25 duration of maximal exercise time)
Van Gelder IC et al. N Engl J Med.
20103621363-1373.
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RACE II RAte Control Efficacy in Permanent
Atrial Fibrillation
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Cumulative Incidence of Primary Composite Endpoint
20
Strict
14.9
15
Cumulative Incidence ()
10
Lenient
12.9
5
0
0
6
12
18
24
30
36
months
No. At Risk Strict 303 282 273 262 246 212 131 Len
ient 311 298 290 285 255 218 138
Van Gelder IC et al. N Engl J Med.
20103621363-1373.
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Recommendations for Rate Control During Atrial
Fibrillation
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• Class III No Benefit
• Treatment to achieve strict rate control of
  heart rate (lt80 bpm at rest or lt110 bpm during a
  6-minute walk) is not beneficial compared to
  achieving a resting heart rate of lt110 bpm in
  patients with persistent AF who have stable
  ventricular function (left ventricular ejection
  fraction gt0.40) and no or acceptable symptoms
  related to the arrhythmia, though uncontrolled
  tachycardia may over time be associated with a
  reversible decline in ventricular performance.
  (Level of Evidence B)
• Comments New recommendation

Wann LS et al. Circulation. 2011123104-123.
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ATHENAStudy Design
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• Randomization was stratified to center, and by
  the presence or absence of AF (or AFL) at the
  time of randomization

R
Dronedarone Placebo 400 mg BID
Minimum treatment and follow-up of 12 months
Hohnloser SH et al. J Cardiovasc Electrophysiol.
20081969-73.
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ATHENAPrimary Outcome Time to First
Cardiovascular Hospitalization or Death
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100 75 50 25 0
Hazard ratio 0.76 (0.69-0.84) Plt0.001
Cumulative Incidence ()
Placebo
Dronedarone
0 6 12 18 24 30 Months
No. at Risk Placebo 2327 1858 1625 1072 385 3 Dron
edarone 2301 1963 1776 1177 403 2
Hohnloser SH et al. N Engl J Med.
2009360668-678.
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ATHENASelected AEs and Laboratory Abnormalities
in Patients Who Received the Study Drug
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TEAE treatment-emergent adverse event, defined
as an AE occurring between first dose of study
drug and 10 days after the last dose. Hohnloser
SH et al. N Engl J Med. 2009360668-678.
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Recommendations for Use of Dronedarone in Atrial
Fibrillation
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• Class IIa
• Dronedarone is reasonable to decrease the need
  for hospitalization for cardiovascular events in
  patients with paroxysmal AF or after conversion
  of persistent AF. Dronedarone can be initiated
  during outpatient therapy. (Level of Evidence B)
• Comment New Recommendation

Wann LS et al. Circulation. 2011123104-123.
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ANDROMEDAStudy Design and Inclusion Criteria
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Dronedarone 400 mg BID
Treatment for minimum of 12 months
Placebo

• Patients hospitalized with new or worsening heart
  failure and
• At least 1 episode of shortness of breath on
  minimal exertion or at rest (NYHA class III or
  IV) or paroxysmal nocturnal dyspnea within the
  month before admission and
• Wall-motion index of no more than 1.2
  (approximating an ejection fraction of no more
  than 35)

Patients were assigned no later than day 7 after
hospital admission. Inclusion could be postponed
if the patient was on a respirator. NYHA New
York Heart Association. Køber L et al. N Engl J
Med. 20083582678-2687.
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ANDROMEDAPrimary Endpoint Time to Death or
Hospitalization for Worsening Heart Failure
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• Prematurely terminated due to imbalance in death
  between the 2 arms

CI confidence interval. Køber L et al. N Engl J
Med. 20083582678-2687.
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Recommendations for Use of Dronedarone in Atrial
Fibrillation
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• Class IIIHarm
• Dronedarone should not be administered to
  patients with class IV heart failure or patients
  who have had an episode of decompensated heart
  failure in the past 4 weeks, especially if they
  have depressed left ventricular function (left
  ventricular ejection fraction ?35) (Level of
  evidence B)
• Comment New Recommendation

Wann LS et al. Circulation. 2011123104-123.
43
2011 ACCF/AHA/HRS Focused Update on the
Management of Patients with Atrial Fibrillation
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Maintenance of Sinus Rhythm
No (or minimal)heart disease
Hypertension
Coronary Artery Disease
Heart Failure
Substantial LVH
Dofetilide Dronedarone Sotalol
Dronedarone Flecainide Propafenone Sotalol
Amiodarone Dofetilide
Yes
No
Amiodarone Dofetilide
Catheter ablation
Amiodarone
Catheter ablation
Catheter ablation
Amiodarone
Catheter ablation
Drugs are listed alphabetically and not in order
of suggested use. The seriousness of heart
disease progresses from left to right, and
selection of therapy in patients with multiple
conditions depends on the most serious condition
present. LVH indicates left ventricular
hypertrophy. Wann LS et al. Circulation.
2011123104-123.
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New Approaches toAtrial Fibrillation Management
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• Considerations Beyond Being Just a Rhythm

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Changing the Paradigm of Goals of AF Therapy
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Old Paradigm
New Paradigm

• Rate vs rhythm control
• Binary outcome SR or AF
• First recurrence of AF failure of therapy
• Focus on the ECG result

• Rate and rhythm control
• Flexible outcome mostly SR
• Recurrence pattern over time
• Focus on the patients symptoms and well-being

Pinter A et al. Cardiovasc Ther. 201028302-310.
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Atrial Fibrillation Treatment Options
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Maintenance of SR1
Stroke Prevention1
Rate Control1
Pharmacologic
Nonpharmacologic

• Pharmacologic
• Warfarin
• Thrombin inhibitor
• Aspirin
• Nonpharmacologic
• Removal/isolation
• LA appendectomy

• Pharmacologic
• Ca2 blockers
• ß-blockers
• Digitalis
• Amiodarone
• Nonpharmacologic
• Ablate and pace

Class IA Class IC Class III New AADs
Catheter ablation Pacing Surgery (maze procedure,
pulmonary veinisolation) Implantable atrial
defibrillator
Ca2 blockers2 ACE-I2 ARB2 PUFA2 Statins2
Prevent remodeling2

• AAD antiarrhythmic drug ACE-1
  angiotensin-converting enzyme inhibitors ARB
  angiotensin-receptor blocker LA left
  ventricle PUFA polyunsaturated fatty acids
  (fish oils) SR sinus rhythm.
• Adapted from Prystowsky EN. Am J Cardiol.
  2000853D-11D.
• Benjamin EJ et al. Circulation. 2009119606-618.

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Utilizing a Comprehensive Approach
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Quality of Life
AF on Electrogram
Symptoms
Potential overlap between ECG-documented presence
of AF, symptoms, and quality of life. Quality of
life may be impaired in the absence of symptoms
or by symptoms related to concomitant disorders
rather than AF. Adapted from Grönefeld GC et al.
Eur Heart J Suppl. 20035(suppl H)H25-H33. Camm
AJ et al. Eur Heart J Suppl. 200810(suppl
H)H55-H78.
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Defining Success With Management of Atrial
Fibrillation
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• Current common measures of success1,2
• Any AF recurrence
• Time to first recurrence of AF
• Reduction of AF burden
• Redefining the best measure of success reduction
  in AF burden and symptoms
• Mortality1,2
• Cardiovascular hospitalization3
• Quality of life4

Symptomsduringepisodes
Duration ofepisodes
Frequency ofepisodes
1. Prystowsky EN. J Cardiovasc Electrophysiol.
200617(suppl 2)S7-S10. 2. Fuster V et al.
Circulation. 2006114e257-e354. 3. Wyse DG et
al. Heart Rhythm. 20041531-537. 4. Dorian P et
al. J Am Coll Cardiol. 2000361303-1309.
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Summary
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• Nonvalvular atrial fibrillation is managed with
• Rate agents
• Rhythm agents
• Stroke prevention
• Recent focus updates incorporate new therapies
  into existing guidelines
• Management of nonvalvular AF should include
  outcomes other than just rhythm management (eg,
  hospitalization, QOL, etc)

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END
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