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Anticoagulation – Full Curriculum
Projected Number of People With AF
(millions)
The Epidemic of Atrial Fibrillation
Projected US Prevalence
18
16
14
12
10
8
6
4
2
0
Year
www.HRSonline.org
Based on Projected Incidence
Based on Current Incidence
Classification of AF
ACC/AHA/ESC Guidelines
First
Detected
Paroxysmal
(Self-terminating)
Persistent
(Not self-terminating)
Permanent
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Pharmacologic Management of Patients With Newly Discovered AF
ACC/AHA/ESC Guidelines
Newly Discovered AF
Paroxysmal
No therapy needed,
unless severe
symptoms
(eg, hypotension, HF,
angina pectoris)
Anticoagulation,
as needed
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Persistent
Accept permanent AF
Rate control and
anticoagulation,
as needed
Anticoagulation
and rate control,
as needed
Consider antiarrhythmic
drug therapy
Cardioversion
Long-term drug
prevention unnecessary
Pharmacologic Management of Patients With Recurrent Paroxysmal AF
Sinus Rhythm Maintenance
Recurrent Paroxysmal AF
Minimal or
no symptoms
Disabling
symptoms in AF
Anticoagulation
and rate control,
as needed
Anticoagulation
and rate control,
as needed
No drug for
prevention of AF
AAD therapy
AF ablation if AAD
treatment fails
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Costs of Stroke in the United States
$3.4 billion paid on behalf of Medicare beneficiaries discharged from
short-stay hospitals for stroke in the United States
$5692 per discharge
Initial hospital stay accounts for over 70% of costs worldwide
American Heart Association. Heart Disease and Stroke Statistics–2004 Update. Caro et al. Stroke. 2000;31:582-590.
www.HRSonline.org
Studies of Stroke in Patients With AF
Stroke
Mortality
Relative Risk
8
6
4
2
0
Whitehall
Regional Heart Study
Framingham
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Whitehall
Framingham
(no heart disease)
Framingham (overall)
Manitoba
Stroke Rates in Placebo-Treated Patients With AFa
25
23.4
Stroke (%)
20
15
9.0
10
7.9
6.3
5.7
4.7
5
0
AFASAK
aPatients
SPAF
BAATAF
CAFA
not anticoagulated; bSecondary prevention.
Hart et al. Ann Intern Med. Ann Intern Med. 2007;146:857-867.
www.HRSonline.org
SPINAF
EAFTb
Stroke Rates by Age in Patients With AF in Untreated Control
Groups
9
Stroke Rate (%/year)
8
7
6
5
4
3
2
1
0
<65
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
65-75
Age (years)
>75
Severity of Stroke With AF
1061 patients admitted with acute ischemic stroke
20.2% 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; P<.0005)
Dulli et al. Neuroepidemiology. 2003;22:118-123.
www.HRSonline.org
Thrombogenicity in AF: Additional Factors
Prothrombotic compounds are increased in
the fibrillating atrium
Coagulation
• Factor VII
• Fibrinogen
• D-dimer
• Prothrombin fragment
• Thrombin-antithrombin complex
• Altered fibrinolytic balance
• Increased superoxides in LAA (which
degrade NO)
NO secretion by arterial endothelium
and atrium reduced

Due to loss of laminar flow
and decreasing stretch
periods
Time course of recovery following SR
restoration unknown
Atrial abnormalities may exist
independently of AF
Platelets
• P-selectin
-thromboglobulin
• Platelet factor 4
Gustafsson et al. Stroke. 1990;21:47-51; Feng et al. Am J Cardiol. 2001;87:168-171; Leong et al. Am J Cardiol.
2000;86:795-797; Heppell et al. Heart. 1997;77:407-411; Mitusch et al. Thromb Haemost. 1996;75:219-223; Nagao et al.
Stroke. 1995;26:1365-1368.
www.HRSonline.org
Anticoagulation in AF: Stroke Risk Reductions
Warfarin Better
Control Better
AFASAK
Reduction of
all-cause mortality
RRR 26%
SPAF
BAATAF
CAFA
SPINAFa
Reduction of
stroke
EAFT
RRR 62%
Aggregate
100%
aOnly
50%
0
-50%
SPINAF used placebo-controlled, double-blind design; no women included.
Hart et al. Ann Intern Med. 1999;131:492-501.
www.HRSonline.org
-100%
Anticoagulation in AF
The Standard of Care for Stroke Prevention
Warfarin Better
Control Better
Unblinded
AFASAK
SPAF
Unblinded
BAATAF
Unblinded
Terminated early
CAFA
SPINAFa
Double-blind; men only
2o prevention; unblinded
EAFT
Aggregate
100%
aOnly
50%
0
-50%
SPINAF used placebo-controlled, double-blind design; no women included.
Hart et al. Ann Intern Med. 2007;146:857-867.
www.HRSonline.org
-100%
Effect of Intensity of Oral Anticoagulation on Stroke Severity
N=596 patients with AF and ischemic stroke
INR<2
INR2
Fatal stroke
Severe (total dependence)
Major (not independent)
9%
6%
44%
1%
4%
38%
Total
59%
43%
Minor (independent)
No neurologic sequelae
38%
3%
55%
2%
Total
41%
57%
Hylek et al. N Engl J Med. 2003;349:1019-1026.
www.HRSonline.org
Underuse of Antithrombotic
Therapy in AF
597 Medicare patients with AF; Rx at hospital discharge
Warfarin
Aspirin
Neither
42%
29%
23%
21%
36%
53%
38%
29%
22%
21%
42%
51%
36%
30%
23%
17%
42%
54%
Age (years)
65-75
>75
Sex
Male
Female
Location
Urban
Rural
Gage et al. Stroke. 2000;31:822-827.
www.HRSonline.org
Use and Adequacy of Anticoagulation
in AF Patients in Primary Care Practice
N=660
No warfarin
65%
INR above
target
6%
INR in
target range
15%
Samsa et al. Arch Intern Med. 2000;160:967-973.
www.HRSonline.org
Subtherapeutic
INR
13%
Use and Adequacy of Anticoagulation
in AF Patients on Hospital Admission
No warfarin
64%
Supratherapeutic
INR
19%
Therapeutic INR
37%
Subtherapeutic
INR
45%
Bungard et al. Pharmacotherapy. 2000;20:1060-1065.
www.HRSonline.org
Warfarin
35%
Anticoagulation With Warfarin
Intensity Often Outside the Target Range
International Study of Anticoagulation Management
% Time in Target Range
100
INR<2
INR 2–3
INR>3
80
60
40
20
0
US
Canada
Ansell et al. J Thromb Thrombolysis. 2007;23:83-91.
www.HRSonline.org
France
Italy
Spain
Warfarin Use in Patients With AF
100
N=5888 community
residents with AF
90
Percentage Use
80
<80 y
80 y
70
60
50
40
30
20
10
0
n=110 n=34 n=79 n=32 n=80 n=34 n=83 n=36 n=78 n=38 n=73 n=57 n=72 n=63
1989-1990 1990-1991 1991-1992 1992-1993 1993-1994 1994-1995 1995-1996
Smith et al. Arch Intern Med. 1999;159:1574-1578.
www.HRSonline.org
Examination Year
The Challenge of Nonadherence to Guidelines for AF Treatment
• AF has the highest prevalence in the elderly
• The elderly are at the highest risk for stroke
• Thus, the elderly are most likely to benefit from anticoagulation;
however, they are the least likely to receive anticoagulation
www.HRSonline.org
Physician Questionnaire Results on AF and Warfarin
• No relationship between perceived benefits of warfarin and its use
• Perceived risk for hemorrhage strongly inversely associated with
warfarin use (P<.001)
• Estimated annual rates of warfarin-associated hemorrhage >10fold higher than literature-based estimates
• Physician attitudes reflect aversion to hemorrhagic risk that
influences responses to treatment recommendations
Gross et al. Clin Ther. 2003;25:1750-1764.
www.HRSonline.org
Physician Concerns About Warfarin for Stroke Prevention in AF
80
Risk vs benefit of warfarin
 47% benefit greatly outweigh risk
 34% risk slightly outweigh benefit
 19% risk outweigh benefit
Percent
60
40
20
0
Risk of Fall
History of
GI Bleed
History of
History of CV
Non-CNS Bleed
Hemorrhage
Frequently Cited Contraindications
Monette et al. J Am Geriatr Soc. 1997;45:1060-1065.
www.HRSonline.org
Patient Concerns About AF
100
91%
80
Percent
60
38%
40
13%
20
0
Stroke
Death
Major Minor Side
Bleeding Effects
Man-Son-Hing et al. Arch Intern Med. 1996;156:1841-1848.
www.HRSonline.org
9%
2%
5%
Cost
Inconvenience
Patient Perceptions of AF and Anticoagulation
• 61% felt that AF was not serious
• 47% unaware that AF predisposed to stroke
• 52% aware of reason for warfarin
• 45% believed some risk associated with warfarin
• 42% stated they were “careless” at times about taking warfarin
Lip et al. Stroke. 2002;33:238-242.
www.HRSonline.org
ACC/AHA/ESC Guidelines
General Considerations for Anticoagulation in AF
• Anticoagulation therapy is the only therapy in AF that has
demonstrated mortality reduction
• As a group, patients with AF are 6 times more likely to sustain stroke
compared with patients in SR
• Risk of stroke varies with risk factors, and decisions regarding
anticoagulation should be based on stroke risk
• Patients treated with rhythm control strategy are still at risk for
stroke—anticoagulation cannot be discontinued indiscriminately
• Anticoagulation guidelines apply to AF and atrial flutter equally
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Risk vs Benefit in Anticoagulation
• Estimating risk of stroke for each individual is crucial for
anticoagulation decision
• Risk threshold warranting anticoagulation is controversial, but most
accept 2%-3% risk/year
• NNT for ≤2%/year = 100 or more
• NNT for ≥6%/year = 25 or less
• Controversy is greatest in 3%-5% risk categories
• Several risk stratification schemes exist:
• AF Investigators, SPAF, Framingham, CHADS2
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Risk Factors for Stroke and Systemic Embolism
Risk Factors
Relative Risk
Previous stroke or TIA
2.5
Diabetes mellitus
1.7
History of hypertension
1.6
Heart failure
1.4
Advanced age (continuous, per decade)
1.4
Data derived from collaborative analysis of 5 untreated control groups in primary prevention
trials. TIA=transient ischemic attack.
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
CHADS2 Risk Stratification Scheme
Risk Factors
Score
C
Recent congestive heart failure
1
H
Hypertension
1
A
Age 75 years
1
D
Diabetes mellitus
1
S2 History of stroke or transient ischemic
attack
Rockson et al. J Am Coll Cardiol. 2004;43:929-935.
www.HRSonline.org
2
The CHADS2 Index Stroke Risk Score for AF
Score (points)
Prevalence (%)
Prior stroke or TIA
2
10
Age >75 years
1
28
Hypertension
1
65
Diabetes mellitus
1
18
Heart failure
1
32
High risk
3
22
Moderate risk
1-2
33-50
Low risk
0-1
18-51
van Walraven et al. Arch Intern Med. 2003;163:936-943; Nieuwlaat et al. Euro Heart Survey. Eur Heart J. 2006 (Epub).
www.HRSonline.org
CHADS2 Risk Criteria for Stroke in Nonvalvular AF
Stroke Risk in Patients With Nonvalvular AF Not Treated With
Anticoagulation According to the CHADS2 Index
Patients
(N=1733)
120
(95% CI)
CHADS2 Score
0
463
1
523
2
337
3
220
4
65
5
5
6
0
5
10
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
15
20
Warfarin
25
30
Adjusted Stroke Rate (%/y)
Stroke Risk in New-Onset AF
ACP/AAFP Guidelines
CHADS2a
Score
Adjusted Stroke Rateb
(95% CI)
CHADS2
Risk Level
0
1.9 (1.2-3.0)
Low
1
2.8 (2.0-3.8)
Low
2
4.0 (3.1-5.1)
Moderate
3
5.9 (4.6-7.3)
Moderate
4
8.5 (6.3-11.1)
High
5
12.5 (8.2-17.5)
High
6
18.2 (10.5-27.4)
High
Warfarin
of the following comorbidities: CHF, hypertension, age ≥75, and diabetes (1 point each);
history of stroke or TIA (2 points each).
b Expected rate of stroke per 100 patient-years.
Snow et al. Ann Intern Med. 2003;139:1009-1017.
a Assessment
www.HRSonline.org
Current Recommendations for Stroke Prevention in AF
American College of Chest Physicians Guidelines
Risk Category
Goal INR
Comment
Age <65 years,
no other risk factors
None
Aspirin
325 mg qd
Age 65-75 years,
no other risk factors
2.5 (2.0-3.0)
Warfarin or aspirin
325 mg qd
Any high-risk factor
2.5 (2.0-3.0)
Warfarin
High-risk factors: previous TIA, systemic embolism, or stroke; HTN, LV dysfunction,
and/or recent CHF; age >75 years; DM; rheumatic heart disease (mitral stenosis); and
prosthetic heart valve
Singer et al. Chest. 2004;126(3 suppl):429S-456S.
www.HRSonline.org
Risk-Based Approach to Antithrombotic Therapy
Patient Features
Antithrombotic Therapy
Class of
Recommendation
Age <60 y, no HD (lone AF)
ASA (81-325 mg/d) or
no therapy
I
Age <60 y, HD but no risk factorsa
ASA (81 to 325 mg/d)
I
Age 60-74 y, no risk factorsa
ASA (81 to 325 mg per day)
I
Age 65-74 y with DM or CAD
OAC (INR 2.0 to 3.0)
I
Age ≥75 y, women
OAC (INR 2.0 to 3.0)
I
Age ≥75 y, men, no other risk factors
OAC (INR 2.0-3.0)
or ASA (81-325 mg/d)
I
Age ≥65, HF
OAC (INR 2.0-3.0)
I
LVEF <35% or fractional shortening <25%,
and hypertension
OAC (INR 2.0-3.0)
I
Rheumatic HD (mitral stenosis)
OAC (INR 2.0-3.0)
I
Prosthetic heart valve
OAC (INR 2.0-3.0 or higher)
I
Prior thromboembolism
OAC (INR 2.0-3.0 or higher)
I
Persistent atrial thrombus on TEE
OAC (INR 2.0-3.0 or higher)
IIa
aRisk
factors for thromboembolism include heart failure (HF), left ventricular ejection fraction (LVEF) less than 35%, and
history of hypertension.
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Risk Stratification in AF: Stroke Risk Factors
High-Risk Factors
•Mitral stenosis
•Prosthetic heart valve
•History of stroke or TIA
Moderate-Risk Factors
•Age >75 years
•Hypertension
•Diabetes mellitus
•Heart failure or ↓ LV function
Less Validated Risk Factors
• Age 65-75 years
• Coronary artery disease
• Female gender
• Thyrotoxicosis
Singer et al. Chest. 2004;126:429S-456S; Fang et al. Circulation. 2005;112:1687-1691.
www.HRSonline.org
ACC/AHA/ESC Guidelines
•
Warfarin (INR range 2-3)
•
Women age 75 years
•
Age 65 to 74 years with DM or CAD
•
LVEF <35% or fractional shortening <25%, and HTN
•
Age 65 years, HF
•
Rheumatic heart disease (mitral stenosis)
•
Warfarin (INR range 2-3, or higher)
•
Prosthetic heart valve
•
Prior thromboembolism
•
Persistent atrial thrombus on TEE
•
Warfarin (INR range 2-3) with optional addition of aspirin (81-325 mg)
•
Men age 75 years with no other risk factors
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
ACC/AHA/ESC Guidelines
• Aspirin (81-325 mg)
• Age <60 years, heart disease but no risk factors
• Age 60-74 years, no risk factors
• Aspirin (81-325 mg) or no treatment
• Age <60 years, no heart disease (lone AF)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Antithrombotic Therapy for Patients With AF
Risk Category
No risk factors
Recommended Therapy
Aspirin, 81 to 325 mg daily
One moderate-risk factor
Aspirin, 81 to 325 mg daily, or warfarin
(INR 2.0 to 3.0, target 2.5)
Any high-risk factor or more than 1
moderate-risk factor
Warfarin (INR 2.0 to 3.0, target 2.5)a
Less Validated or
Weaker Risk Factors
Female sex
Moderate-Risk Factors
Age 75 years
Age 65 to 74 years
Hypertension
Coronary artery disease
Heart failure
Thyrotoxicosis
LV ejection fraction 35%
or less
Diabetes mellitus
aIf
mechanical valve, target international normalized ratio (INR) greater than 2.5.
LV=left ventricular.
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
High-Risk Factors
Previous stroke, TIA,
or embolism
Mitral stenosis
Prosthetic heart valvea
Special Considerations for Anticoagulation Prior to Cardioversion
For patients with AF of ≥48 hours of AF, or when duration is unknown, 3
weeks of anticoagulation with documented INR ≥ 2 are required prior
to cardioversion
It may take longer than 3 weeks to achieve 3 consecutive weeks of
adequate (INR ≥ 2) anticoagulation
Anticoagulation must be continued for at least 4 weeks post
cardioversion
TEE can be used to assess LA for thrombus as alternative to 3-week
anticoagulation (however, anticoagulation must continue for 4 weeks
post cardioversion)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Confirmed Embolism (%)
Relation Between INR on the Day of Cardioversion and Risk of
Thromboembolism
4
N=1950
1/42
3
2/182
4/530
2
1
0
0/779
1-1.4
1.5-1.9
2-2.4
INR at Time of Cardioversion
Gallagher et al. J Am Coll Cardiol. 2002;40:926-933.
www.HRSonline.org
>2.4
Prevalence of Atrial Thrombus With Transiently Subtherapeutic
INR
• 182 consecutive patients with AF and subtherapeutic INR on 2
measurements in the last 3 weeks before the scheduled cardioversion
• Intra-atrial thrombus in 18 (9.9%)
• None (0%) of 21 with LA dimension 4.0 cm
• 11.2% with dilated LA
• No difference in LVEF
Shen. J Am Coll Cardiol. 2002;39(suppl):376A-377A.
www.HRSonline.org
Anticoagulation Variability Prior to Cardioversion
Number of Patients
Time to Subtherapeutic INR After the First Therapeutic Value
Days (midpoint) to Subtherapeutic INR
Kim et al. Am J Cardiol. 2001;88:1428-1431.
www.HRSonline.org
Achieving Adequate Anticoagulation Prior to Cardioversion
n (interquartile range)
INR checks
9 (6-11)
Days to 1st therapeutic INR
7 (4-15)
Days to 3 weeks therapeutic INR
35 (27-47)
Days to cardioversion
58 (41-78)
Kim et al. Am J Cardiol. 2001;88:1428-1431.
www.HRSonline.org
CYP2C9 = *1/*1
Daily Dose (mg/day)
10
9
8
7
6
5
4
3
2
1
0
GG
GG
GG
CG
CC
CG
CC
GG
GG
CG
CC
CG
CC
CG
CC
GG
CG
CC
GG
GG
CG
GG
CG
CC
CG
CC
CC
10
9
8
7
6
5
4
3
2
1
0
40 45 50 55 60 65 70 75 80 85
Age (years)
Daily Dose (mg/day)
Daily Dose (mg/day)
Warfarin Dosing and Genomics
Caldwell et al. Clin Med Res. 2007;5:8-16.
www.HRSonline.org
10
9
8
7
6
5
4
3
2
1
0
CYP2C9 = *1/*2
GG
CG
CC
GG
CG
CC
GG
CG
CC
CG
CC
GG
CG
CC
GG
CG
CC
GG
CG
CC
GG
CG
CC
GG
CG
CC
GG
CG
CC
GG
GG
CG
CG
CC
CC
GG
CG
CC
GG
CG
CC
40 45 50 55 60 65 70 75 80 85
Age (years)
CYP2C9 = *1/*3
GG
GG
GG
CG
CG
CC
CC
GG
GG
CG
CG
CC
CC
40 45 50 55 60 65 70 75 80 85
Age (years)
Unanswered Questions About Anticoagulation in Patients
Restored to SR
• Does restoration of sinus rhythm prevent stroke in patients with AF?
• What is the duration of anticoagulation in patients maintained in SR?
• How should one determine efficacy of maintenance?
www.HRSonline.org
Stroke Rates in AFFIRM
• In AFFIRM, there were 157 ischemic strokes
• At the time of stroke, only 53.5% of patients assigned to rate control
and 30.8% of those assigned to rhythm control were in AF
www.HRSonline.org
Rhythm or Rate Control in AF Evidence Base
4 Randomized Trials Comparing
2 Treatment Strategies
PIAF
Pharmacological Intervention in Atrial Fibrillation (pilot)
STAF
Strategies of Treatment of Atrial Fibrillation (pilot)
AFFIRM
Atrial Fibrillation Follow-up Investigation of Rhythm
Management
RACE
RAte Control versus Electrical Cardioversion for Persistent
Atrial Fibrillation
The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Carlsson et al. J Am Coll Cardiol. 2003;41:1690-1696;
Gronefeld. Card Electrophysiol Rev. 2003;7:113-117; Van Gelder et al. N Engl J Med. 2002;347:1834-1840.
www.HRSonline.org
Rate Control vs Electrical Cardioversion for Persistent AF
(RACE) Study
• 522 patients with persistent AF/AFl 24 hours to 1 year randomized to
rate vs rhythm control
• Rate control to resting rate <100 bpm
• Rhythm control with electrical cardioversion and serial antiarrhythmics
• Follow-up 2 years
• Primary end point: composite of death from cardiovascular events
Van Gelder et al. N Engl J Med. 2002;347:1834-1840.
www.HRSonline.org
RACE: Stroke Rates
Thromboembolic events in 35/522 (6.7%)
5.5% of rate control
7.9% of rhythm control
• 6 patients had events after cessation of warfarin
• 5 of these patients were in SR
23/35 (68%) had events while taking warfarin with INR <2.0
17/21 (81%) bleeding episodes occurred with INR >3.0
Van Gelder et al. N Engl J Med. 2002;347:1834-1840.
www.HRSonline.org
Atrial Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM) Study
• Long-term treatment of chronic and paroxysmal AF
• Patients 65 years old or other risk factor for stroke with
• AF 6 hours in last 6 months
• Not continuous AF for 6 months
• 1 episode documented by ECG
in last 12 weeks
• 1 risk factor for stroke (age 65)
• Randomized to rate vs rhythm control
• Both groups anticoagulated
The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Waldo. Am J Cardiol. 1999; 84:698-700.
www.HRSonline.org
AFFIRM: Stroke Rates
74% of all strokes were ischemic
44% occurred after warfarin discontinuation
28% taking warfarin, but INR <2.0
42% occurred during AF
The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.
www.HRSonline.org
AFFIRM Results
Time-Dependent Covariates Associated With Survival
Covariate
P Value
Hazard Ratio
99% CI
Sinus rhythm
<.0001
0.53
0.39-0.72
Warfarin use
<.0001
0.50
0.37-0.69
Digoxin use
.0007
1.42
1.09-1.86
AAD use
.0005
1.49
1.11-2.01
HR <1.00: decreased risk of death.
HR >1.00: increased risk of death.
Epstein. Presented at the American Heart Association’s Scientific Sessions 2003. November 2003; Orlando, FL.
www.HRSonline.org
AFFIRM and RACE Conclusions
• Trials were to compare end points in rate control vs rhythm control
• One hypothesis was that sinus rhythm will reduce the stroke rate
• Critical finding was that rhythm control did not protect from stroke,
even though patients were thought to be in SR
• Patients may have paroxysms of AF that go undetected
The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Van Gelder et al. N Engl J Med. 2002;347:1834-1840.
www.HRSonline.org
Strokes in Patients Converted to SR
n
Rate
control
Rhythm
control
4917
5.7%
7.3%
1.28 (0.95-1.72)
.12
RACE
522
5.5%
7.9%
1.44 (0.75-2.78)
.44
STAF
266
1.0%
3.0%
3.01 (0.35-25.30)
.52
PIAF
252
0.8%
0.8%
1.02 (0.73-2.16)
.49
Total
5957
5.0%
6.5%
1.28 (0.98-1.66)
.08
AFFIRM
Verheugt et al. J Am Coll Cardiol. 2003;41(suppl):130A.
www.HRSonline.org
RR
(95% CI)
P
Prevalence of Asymptomatic AF in Drug Trials Patients Studied
for 30 Seconds Every 2 Weeks
Proportion Free of
Asymptomatic Event
1.0
Azimilide
(382)
0.9
0.8
Placebo
(233)
0.7
100 mg or 125 mg azimilide
0.6
Placebo
0.5
0
2
4
6
8
10
12
14
16 18 20
Time (weeks)
Page et al. Circulation. 2003;107:1141-1145.
www.HRSonline.org
22
24
26
Detection of Recurrent AF:
ECG vs Implanted Device Recording
Number of Patients
100
80
P<.0001
60
40
Implanted device
20
ECG
Baseline FU1 FU2 FU3 FU4 FU5 FU6
n=110
110
110
110
FU=follow-up.
Israel et al. J Am Coll Cardiol. 2004;43:47-52.
www.HRSonline.org
85
73
60
FU7 FU8 FU9 FU10
48
39
25
15
Prevalence of Recurrent AF During Follow-up
70
Patients (%)
60
50
40
30
20
10
0
AF >72 h
AF >48 h
Israel et al. J Am Coll Cardiol. 2004;43:47-52.
www.HRSonline.org
AF >24 h
AF >12 h
AF <12 h
Intracranial Hemorrhage: The Most-Feared Complication of
Antithrombotic Therapy
• >10% 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% per year
• ICH during anticoagulation is usually catastrophic
Hart et al. Stroke. 2005;36:1588-1593.
www.HRSonline.org
Absolute Rates of Primary ICH
Estimated Absolute Rates of Primary Intracerebral Hemorrhage
General population, age ~70 y
0.15%/y
Aspirin (any dosage)
Atrial fibrillation
0.2%/y
Cerebrovascular disease
0.3%/y
Aspirin plus clopidogrel
Atrial fibrillation
0.3%/y
Cerebrovascular disease
0.4%/y
Warfarin (INR 2.5)
Atrial fibrillation
0.3-0.6%/y
Cerebrovascular disease
0.4-1.0%/y
Warfarin (INR 2.5) plus aspirin
0.5-1.0%/y
Hart et al. Stroke. 2005;36:1588-1593.
www.HRSonline.org
CNS Bleeding and Anticoagulation
Intracranial Hemorrhage vs Anticoagulation
Intensity in AF Patients: 2 Recent Studies
10
Absolute rate
Relative risk
8
Case Control Study
mean age:
cases=78 y; controls 75 y
Longitudinal Cohort Study
mean age =71 years
6
4
Reference
point
2
0
<1.5
1.5-1.9 2.0-2.5 2.6-3.0 3.1-3.5 3.6-3.9 4.0-4.5
INR
Hart et al. Stroke. 2005;36:1588-1593.
www.HRSonline.org
>4.5
<1.5
1.5-1.9 2.0-3.0 3.1-3.4 3.5-3.9
INR
>4.0
CNS Bleeding and Anticoagulation
Intracranial Hemorrhage vs Anticoagulation
Intensity in AF Patients: 2 Recent Studies
Longitudinal Cohort Study
Absolute Rate
Case Control Study
Relative Risk
Mean age, 71 years
Mean age, cases=78 years,
controls=75 years
INR
<1.5
1.5-1.9
2.0-2.5
2.6-3.0
3.1-3.5
3.6-3.9
4.0-4.5
>4.5
Hart et al. Stroke. 2005;36:1588-1593.
www.HRSonline.org
Rate per 100
Person-Years
0.5
0.3
0.3
0.5
0.6
0.4
2.7
9.4
INR
<1.5
1.5-1.9
2.0-3.0
—
3.1-3.4
3.5-3.9
>4.0
—
Relative Risk
1.4
1.2
1.0 (reference)
—
1.4
4.6
8.8
—
INR at the Time of Stroke or Bleeding Efficacy and Safety of
Warfarin
20
Odds Ratio
15
Ischemic stroke
Intracranial
bleeding
10
5
1
1.0
2.0
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
3.0
4.0
5.0
INR
6.0
7.0
8.0
ICH (%/year)
ICH During Long-term Anticoagulation With Warfarin
Meta-analysis
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
INR
2.0-4.5
INR
3.0-4.5
INR
2.0-4.5
INR
<3.0
INR
<3.0
Fihn
(AF)
Fihn
(>75)
aPV=prosthetic
valves.
Levine et al. Chest. 2001;119:108S-121S.
www.HRSonline.org
SPAF
(AF)
INR
2.0-4.5
INR
2.0-3.0
SPAF- SPAF2 (75) 2 (75)
SPAF3 (AF)
INR
2.5-3.5
Turpie
(PVa)
Pengo
(PVa)
Antithrombotic Therapy for AF
ACC/AHA/ESC Guidelines 2006
Risk Category
Recommended Therapy
No risk factors
CHADS2 = 0
Aspirin, 81-325 mg qd
One moderate-risk factor
CHADS2 = 1
Aspirin, 81-325 mg/d or
warfarin
(INR 2.0-3.0, target 2.5)
Any high-risk factor or
>1 moderate-risk factor
CHADS2 2
or mitral stenosis
Warfarin
(INR 2.0-3.0, target 2.5)
Prosthetic valve
Warfarin
(INR 2.5-3.5, target 3.0)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class I Recommendations: Preventing Thromboembolism
• Antithrombotic therapy for all patients with AF, except those with
lone AF or contraindications. (Level of Evidence: A)
• Antithrombotic agent should be based on absolute risk of stroke
and bleeding and RR and benefit for patient. (Level of Evidence: A)
• For patients without mechanical heart valves at high risk of
stroke, warfarin is recommended in a dose adjusted to achieve INR
of 2.0 to 3.0, unless contraindicated. (Level of Evidence: A)
• Anticoagulation with a VKA for patients with >1 moderate-risk
factor (eg, ≥75 y, HTN, HF, impaired LV systolic function, and DM).
(Level of Evidence: A)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class I Recommendations (cont’d)
• INR determined at least weekly during initiation of therapy and
monthly when anticoagulation is stable. (Level of Evidence: A)
• Aspirin, 81-325 mg daily, as an alternative to VKA in
low-risk patients or those with contraindications to oral
anticoagulation. (Level of Evidence: A)
• For patients with AF who have mechanical heart valves, target
intensity of anticoagulation should be based on type of prosthesis,
maintaining an INR of at least 2.5. (Level of Evidence: B)
• Antithrombotic therapy is recommended for patients with AFl as for
those with AF. (Level of Evidence: C)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class IIa Recommendations: Preventing Thromboembolism
• For patients with nonvalvular AF and 1 of the following risk factors,
treatment with aspirin or a VKA is reasonable, based on risk of
bleeding complications, ability to safely sustain adjusted chronic
anticoagulation, and patient preferences: age ≥75 y (especially in
women), HTN, HF, impaired LV function, or DM. (Level of Evidence:
A)
• For patients with nonvalvular AF with ≥1 of the following risk factors,
antithrombotic therapy with aspirin or a VKA is reasonable: age 65 to
74 y, female gender, or CAD. Agent choice should be based upon the
risk of bleeding complications, ability to safely sustain adjusted
chronic anticoagulation, and patient preferences. (Level of Evidence:
B)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class IIa Recommendations (cont’d)
• Select antithrombotic therapy using the same criteria irrespective of
the pattern (ie, paroxysmal, persistent, or permanent) of AF. (Level of
Evidence: B)
• In patients with AF w/o mechanical prosthetic heart valves, it is
reasonable to interrupt anticoagulation for up to 1 wk without
substituting heparin for surgical or diagnostic procedures that carry a
risk of bleeding. (Level of Evidence: C)
• It is reasonable to re-evaluate the need for anticoagulation at regular
intervals. (Level of Evidence: C)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class IIb Recommendations: Preventing Thromboembolism
• In patients ≥75 y at risk of bleeding but w/o contraindications to oral
anticoagulant therapy, and patients with moderate-risk factors who
can’t tolerate anticoagulation at INR 2.0 to 3.0, an INR of 2.0 (range
1.6 to 2.5) may be considered for primary prevention of ischemic
stroke and systemic embolism. (Level of Evidence: C)
• When surgical procedures interrupt oral anticoagulant therapy for
longer than 1 wk in high-risk patients, unfractionated heparin (UH)
may be administered or low-molecular-weight heparin (LMWH) given
by SC injection. (Level of Evidence: C)
• Following PCI or revascularization in patients with AF, low-dose
aspirin (less than 100 mg daily) and/or clopidogrel (75 mg daily) may
be given concurrently with anticoagulation to prevent myocardial
ischemic events. (Level of Evidence: C)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class IIb Recommendations (cont’d)
• During PCI, anticoagulation may be interrupted, but VKA should be
resumed soon after PCI and the dose adjusted to an INR in the
therapeutic range. Aspirin may be given temporarily, but maintenance
should consist of combination of clopidogrel, 75 mg daily, plus
warfarin (INR 2.0 to 3.0). Clopidogrel should be given for ≥1 mo after
implantation of a bare metal stent, ≥3 mo for a sirolimus-eluting stent,
≥6 mo for a paclitaxel-eluting stent, and ≥12 mo in selected patients,
after which warfarin may be given as monotherapy in the absence of a
subsequent coronary event. (Level of Evidence: C)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class IIb Recommendations (cont’d)
• In patients with AF younger than 60 y without heart disease or risk
factors for thromboembolism (lone AF), the risk of thromboembolism
is low without treatment and the effectiveness of aspirin for primary
prevention of stroke relative to the risk of bleeding has not been
established. (Level of Evidence: C)
• In patients with AF who sustain ischemic stroke or systemic embolism
during treatment with low-intensity anticoagulation (INR 2.0 to 3.0),
rather than add an antiplatelet agent, it may be reasonable to raise
the intensity of anticoagulation to a maximum target INR of 3.0 to 3.5.
(Level of Evidence: C)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Class III Recommendations Preventing Thromboembolism
• Long-term anticoagulation with a VKA is not recommended for
primary prevention of stroke in patients <60 y w/o heart disease (lone
AF) or any risk factors for thromboembolism. (Level of Evidence: C)
Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org
Patient Selection for Anticoagulation: Additional Considerations
• Risk of bleeding
• Newly anticoagulated vs established therapy
• Availability of high-quality anticoagulation management program
• Patient preferences
www.HRSonline.org
CMS Physician Quality Reporting Initiative
Measure #33 – Stroke and stroke rehabilitation: anticoagulant therapy at
discharge for AF
Percent of patients ≥18 years with ischemic stroke/TIA and permanent,
persistent, or paroxysmal AF given A/C at D/C:
Report for patients with ischemic stroke/TIA with documented AF at discharge
Patients given anticoagulant at D/C
All patients ≥18 years with ischemic stroke or TIA
and permanent, persistent, or paroxysmal AF
US Department of Health and Human Services. http://www.cms.hhs.gov/PQRI/Downloads/ PQRIMeasuresList.pdf.
Accessed on November 14, 2007.
www.HRSonline.org
CMS Physician Quality Reporting Initiative
Clinical recommendation statements
Antithrombotic therapy (oral A/C or ASA) to all patients with AF, except lone AF
• (ACC/AHA/ESC, 2001) (Class I, Level of Evidence: A)
Long-term oral A/C (target INR 2.5; range 2.0-3.0) in
AF patients with recent stroke/TIA
• (Albers, ACCP, 2001) (Grade 1A)
Oral A/C also beneficial in patients with several other high-risk factors
• (Albers, ACCP, 2001) (Grade 1A)
Oral A/C (target INR, 2.5; range 2.0-3.0) for patients with ischemic stroke/TIA
with permanent, persistent, or paroxysmal AF
• (Sacco, ASA, 2006) (Class I, Level of Evidence: A)
US Department of Health and Human Services. http://www.cms.hhs.gov/PQRI/Downloads/ PQRIMeasuresList.pdf.
Accessed on November 14, 2007.
www.HRSonline.org

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