SPAF3 slideset

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Antithrombotic Therapy For Patients with Atrial
Fibrillation American Heart Association Guideline
s Webinar on Atrial Fibrillation July 17,
2008 Jonathan L. Halperin, M.D., F.A.C.C.,
F.A.H.A. The Cardiovascular Institute Mount
Sinai Medical Center
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DisclosureRelationships with Industry
Consulting fees from the following companies
involved in development of investigational drugs
or devices

• Astellas Pharma, U.S.
• Bayer HealthCare
• Biotronik, Inc.
• Boehringer Ingelheim
• Daiichi Sankyo Pharma
• GlaxoSmithKline
• Johnson Johnson
• Sanofi-Aventis

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Atrial FibrillationA Substantial Threat to the
Brain

• Affects 4 of people aged gt60 years
  9 of those aged gt80 years
• 5/year stroke rate
• 30 lifetime risk of stroke
• 12/year for those with prior stroke
• billions annual cost for stroke care

AF identifies millions of people with a five-fold
increased risk of stroke
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Priorities for Management of AFThe Patient Care
Pathway
Rhythm Control
Prevention of Thromboembolism
Rate Control
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Patterns of Atrial Fibrillation
First detected
Paroxysmal (self-terminating)
Persistent (not self-terminating)
Permanent (accepted)
Fuster V, et al. J Am Coll Cardiol 200648854.
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Newly Discovered AFPharmacological Management
Newly Discovered AF
Paroxysmal
Persistent
No therapy needed, unless severe symptoms (eg,
hypotension, HF,angina pectoris)
Accept permanent AF
Rate control andanticoagulation,as needed
Anticoagulationand rate control,as needed
Consider antiarrhythmicdrug therapy
Anticoagulation, as needed
Cardioversion
Long-term drugprevention unnecessary
Fuster et al. J Am Coll Cardiol 200648854.
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Natural History of Lone Atrial Fibrillation
No Cardiopulmonary Disease lt60 Years Old
97 pts Mean Age 44
14.8 yrs Follow-up
0.35/yr Stroke 0.40/yr Mortality
Kopecky S, et al. N Engl J Med 1987 317669.
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Stroke Risk in Atrial FibrillationUntreated
Control Groups of Randomized Trials
Stroke Rate ( per year)
Age (years)
Atrial Fibrillation Investigators. Arch Intern
Med 19941541449.
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Anticoagulation in Atrial FibrillationStroke
Risk Reductions
Warfarin Better
Control Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
Aggregate
-100
50
100
-50
0
Hart R, et al. Ann Intern Med 2007146857.
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Anticoagulation in Atrial FibrillationThe
Standard of Care for Stroke Prevention
Warfarin Better
Control Better
AFASAK
Unblinded
SPAF
Unblinded
BAATAF
Unblinded
CAFA
Terminated early
SPINAF
Double-blind Men only
EAFT
2o prevention Unblinded
Aggregate
-100
50
100
-50
0
Hart R, et al. Ann Intern Med 2007146857.
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Antithrombotic Therapy for Atrial
FibrillationStroke Risk Reduction
Treatment Better
Treatment Worse
6 Trials n 2,900
Warfarin vs. Placebo/Control
Antiplatelet drugs vs. Placebo
8 Trials n 4,876
50
100
-50
0
Hart R, et al. Ann Intern Med 2007146857.
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Intracranial Hemorrhage The Most Feared
Complicationof Antithrombotic Therapy

• gt10 of intracerebral hemorrhages (ICH) occur in
  patients on antithrombotic therapy
• Aspirin increases the risk of ICH by 40
• Warfarin (INR 2-3) doubles the risk of ICH to
  0.3-0.6/year
• ICH during anticoagulation is catastrophic

Hart RG, et al. Stroke 2005361588.
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Risk Stratification in AF
Stroke Risk Factors

• Moderate-Risk Factors
• Age gt75 years
• Hypertension
• Diabetes mellitus
• Heart failure or ? LV function

• High-Risk Factors
• Mitral stenosis
• Prosthetic heart valve
• History of stroke or TIA

Less Validated Risk Factors
Dubious Factors

• Age 6575 years
• Coronary artery disease
• Female gender
• Thyrotoxicosis

• Duration of AF
• Pattern of AF
• (persistent vs. paroxysmal)
• Left atrial diameter

Singer DE, et al. Chest 2004126429S. Fang MC,
et al. Circulation 2005 112 1687.
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Risk Factors Stroke in Patients with Atrial
Fibrillation Frequency of Variables in 12 Schemes
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Nonvalvular Atrial Fibrillation Stroke Rates
Without Anticoagulation According to Isolated
Risk Factors
Stroke Rate (/year)
Heart Failure ? LVEF
Female
Diabetes
Prior Stroke/TIA
Hypertension
Age gt 75 years
Hart RG et al. Neurology 2007 69 546.
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The CHADS2 Index Stroke Risk Score for Atrial
Fibrillation
Prevalence ()
Score (points)
Prior stroke or TIA 2 10 Age gt75
years 1
28 Hypertension 1
65 Diabetes mellitus 1
18 Heart failure 1
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VanWalraven C, et al. Arch Intern Med 2003
163936.
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The CHADS2 Index Stroke Risk Score for Atrial
Fibrillation
Prevalence ()
Score (points)
Prior stroke or TIA 2 (should be 3)
10 Age gt75 years 1
28 Hypertension 1
65 Diabetes mellitus 1
18 Heart failure 1
32 High
risk gt3
22 Moderate risk 1-2
33-50 Low risk 0-1
18-51
VanWalraven C, et al. Arch Intern Med 2003
163936. Nieuwlaat R, et al. (EuroHeart survey)
Eur Heart J 2006 (E-published).
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The CHADS2 Index Stroke Risk Score for Atrial
Fibrillation
Score (points)
Risk of Stroke (/year)
0 1.9 1 2.8 2 4.0 3 5.
9 4 8.5 5 12.5 6
18.2
Van Walraven C, et al. Arch Intern Med 2003
163936. Go A, et al. JAMA 2003 290 2685. Gage
BF, et al. Circulation 2004 110 2287.
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The CHADS2 Index Stroke Risk Score for Atrial
Fibrillation
Score (points)
Risk of Stroke (/year)
0 1.9 1 2.8 2 4.0 3 5.
9 4 8.5 5 12.5 6
18.2
Approximate Risk threshold for Anticoagulation
3/year
Van Walraven C, et al. Arch Intern Med 2003
163936. Go A, et al. JAMA 2003 290 2685. Gage
BF, et al. Circulation 2004 110 2287.
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Risk Stratification and Anticoagulation Stroke
Reduction with Warfarin Instead of Aspirin
CHADS2 Score 3 2 1
0
Number of patients Needed-to-treat to prevent 1
stroke/year
42
83
13
250
EAFT Study Group. Lancet 1993 3241255.
Zabalgoitia M, et al. J Am Coll Cardiol 1998
311622.
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Antithrombotic Therapy for Atrial
FibrillationACC/AHA/ESC Guidelines 2006
Risk Category
Recommended Therapy
No risk factors CHADS2 0
Aspirin, 81-325 mg qd
Aspirin, 81-325 mg/d or Warfarin (INR 2.0-3.0,
target 2.5)
One moderate risk factor CHADS2 1
Any high risk factor or gt1 moderate risk
factor CHADS2 gt2 or Mitral stenosis
Warfarin (INR 2.0-3.0, target 2.5)
Warfarin (INR 2.5-3.5, target 3.0)
Prosthetic valve
Fuster V, et al. Eur Heart J 2006271979.
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• "Actually, it's more of a guideline than a rule.
• Billy Murray in Ghostbusters? (1984),
• relaxing his rule "never to get involved with
  possessed people" in response to Sigourney
  Weaver's seductive advances.

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Factors Associated with Antithrombotic
TherapyEuro Heart Survey of Atrial Fibrillation
2001 ACC/AHA/ESC guidelines
2004 ACCP guidelines
patients
patients
100
100
80
80
60
60
40
40
20
20
0
0
None
Lowest (n111)
Low (n170)
High (n1796)
Highest (n734)
Low (n149)
Moderate (n118)
High (n2125)
Heparin
Antiplatelet
Framingham score
CHADS2 score
OAC Antiplatelet
patients
patients
100
100
OAC
80
80
60
60
40
40
20
20
0
0
0-1 (n36)
2-7 (n104)
8-13 (n96)
gt13 (n71)
1 (n697)
2 (n722)
0 (n332)
3 (n371)
4 (n172)
5 (n72)
6 (n15)
Nieuwlaat R et al. Eur Heart J 2006 (E-published)
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INR at the Time of Stroke or BleedingEfficacy
and Safety of Warfarin
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15
Ischemic Stroke
Intracranial bleeding
Odds Ratio
10
5
1
5.0
6.0
8.0
1.0
2.0
3.0
4.0
7.0
International Normalized Ratio
Fang MC, et al. Ann Intern Med 2004 141745.
Hylek EM, et al. N Engl J Med 1996 335540.
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Anticoagulation with WarfarinIntensity Often
Outside the Target Range
International Study of Anticoagulation Management
Ansell J, et al. J Thromb Thrombolysis 2007 23
83.
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Warfarin for Atrial Fibrillation Limitations
Lead to Inadequate Treatment
Adequacy of Anticoagulation inPatients with AF
in Primary Care Practice
INR above target6
No warfarin65
INR intarget range15
Subtherapeutic INR 13
Samsa GP, et al. Arch Intern Med 2000160967.
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AF Performance Measures
ACC/AHA Task Force on Performance Measures. J Am
Coll Cardiol 2008 51865.
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Patient Selection for AnticoagulationAdditional
Considerations

• Risk of bleeding
• Newly anticoagulated vs. established therapy
• Availability of high-quality anticoagulation
  management program
• Patient preferences

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Warfarin Dosing and Genomics
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Warfarin Dosing and Genomics

• CYP2C9 Gene encoding cytochrome P450 hepatic
  enzyme responsible for primary clearance of
  S-warfarin, the active enantiomer
• variant alleles are associated with sensitivity
  to warfarin.
• VKORC1 Gene encoding vitamin K epoxide
  reductase complex 1 variant alleles are
  associated with warfarin resistance.

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From Fermented Sweet Cloverto Molecular
Targeting of CoagulationThe Promise of New
Anticoagulants
The Goal To bring effective therapy to many more
patients and prevent thousands of strokes.