anticoagulation – full curriculum. the epidemic of atrial fibrillation projected us prevalence 0...

Anticoagulation – Full Curriculum

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The Epidemic of Atrial FibrillationProjected US Prevalence

0

2

4

6

8

10

12

14

16

18

20002005

20102015

20202025

20302035

20402045

2050Year

Pro

ject

ed N

um

ber

of

Peo

ple

Wit

h A

F

(mil

lio

ns)

Based on Projected Incidence

Based on Current Incidence

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Classification of AFACC/AHA/ESC Guidelines

Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

Persistent(Not self-terminating)

Persistent(Not self-terminating)

Paroxysmal(Self-terminating)

Paroxysmal(Self-terminating)

First Detected

First Detected

PermanentPermanent

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Pharmacologic Management of Patients With Newly Discovered AFACC/AHA/ESC Guidelines


Newly Discovered AFNewly Discovered AFNewly Discovered AFNewly Discovered AF

ParoxysmalParoxysmalParoxysmalParoxysmal

No therapy needed, No therapy needed, unless severe unless severe

symptoms symptoms (eg, hypotension, HF,(eg, hypotension, HF,

angina pectoris)angina pectoris)

No therapy needed, No therapy needed, unless severe unless severe

symptoms symptoms (eg, hypotension, HF,(eg, hypotension, HF,

angina pectoris)angina pectoris)

PersistentPersistentPersistentPersistent

Accept permanent AFAccept permanent AFAccept permanent AFAccept permanent AF

AnticoagulationAnticoagulationand rate control,and rate control,

as neededas needed


as neededas needed

Rate control andRate control andanticoagulationanticoagulation,,

as neededas needed

Rate control andRate control andanticoagulationanticoagulation,,

as neededas needed

Consider antiarrhythmicConsider antiarrhythmicdrug therapydrug therapy

Consider antiarrhythmicConsider antiarrhythmicdrug therapydrug therapy

Long-term drugLong-term drugprevention unnecessaryprevention unnecessary

Long-term drugLong-term drugprevention unnecessaryprevention unnecessary

AnticoagulationAnticoagulation,,

as neededas needed

AnticoagulationAnticoagulation,,

as neededas neededCardioversionCardioversionCardioversionCardioversion

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Pharmacologic Management of Patients With Recurrent Paroxysmal AF Sinus Rhythm Maintenance

Recurrent Paroxysmal AFRecurrent Paroxysmal AFRecurrent Paroxysmal AFRecurrent Paroxysmal AF

Minimal orMinimal orno symptomsno symptoms

Minimal orMinimal orno symptomsno symptoms


as neededas needed


as neededas needed

DisablingDisablingsymptoms in AFsymptoms in AF

DisablingDisablingsymptoms in AFsymptoms in AF


as neededas needed


as neededas needed

AAD therapyAAD therapyAAD therapyAAD therapyNo drug forNo drug for

prevention of AFprevention of AFNo drug forNo drug for

prevention of AFprevention of AF

AF ablation if AAD AF ablation if AAD treatment failstreatment fails

AF ablation if AAD AF ablation if AAD treatment failstreatment fails


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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.

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Studies of Stroke in Patients With AF

00

66

44

22

88MortalityMortalityStrokeStroke

Framingham (overall)

Framingham(no heart disease)

Whitehall

Manitoba

WhitehallRegional Heart Study

Framingham

Re

lati

ve

Ris

k


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Stroke Rates in Placebo-Treated Patients With AFa

5.7

9.0

6.34.7

7.9

23.4

0

5

10

15

20

25

aPatients not anticoagulated; bSecondary prevention.Hart et al. Ann Intern Med. Ann Intern Med. 2007;146:857-867..

Str

ok

e (%

)

AFASAK SPAF BAATAF CAFA SPINAF EAFTb

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Stroke Rates by Age in Patients With AF in Untreated Control Groups

Str

ok

e R

ate

(%

/yea

r)S

tro

ke

Ra

te (

%/y

ear)

99

88

77

55

44

33

11

00<65<65 65-7565-75 >75>75

Age (years)Age (years)

66

22


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Severity of Stroke With AF

1061 patients admitted with acute ischemic stroke20.2% had AF

Bedridden stateWith 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.

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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)

Platelets

• P-selectin

-thromboglobulin

• Platelet factor 4

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

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.

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Anticoagulation in AF: Stroke Risk Reductions

aOnly SPINAF used placebo-controlled, double-blind design; no women included.Hart et al. Ann Intern Med. 1999;131:492-501.

Warfarin Better Control Better

AFASAK

SPAF

BAATAF

CAFA

SPINAFa

EAFT

100%100% 50%50% 00 -50%-50% -100%-100%

Aggregate

Reduction of Reduction of strokestroke

RRR 62% RRR 62%

Reduction of Reduction of strokestroke

RRR 62% RRR 62%

Reduction ofReduction ofall-cause mortality all-cause mortality

RRR 26%RRR 26%

Reduction ofReduction ofall-cause mortality all-cause mortality

RRR 26%RRR 26%

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Anticoagulation in AFThe Standard of Care for Stroke Prevention

Warfarin Better Control Better

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAFaa

EAFTEAFT

100%100% 50%50% 00 -50%-50% -100%-100%

AggregateAggregate

Terminated early

Double-blind; men only

Unblinded

Unblinded

Unblinded

2o prevention; unblinded

aOnly SPINAF used placebo-controlled, double-blind design; no women included.Hart et al. Ann Intern Med. 2007;146:857-867.

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Hylek et al. N Engl J Med. 2003;349:1019-1026.

N=596 patients with AF and ischemic strokeN=596 patients with AF and ischemic strokeN=596 patients with AF and ischemic strokeN=596 patients with AF and ischemic stroke

Fatal stroke 9%1%

Severe (total dependence) 6%4%

Major (not independent) 44%38%

Total 59%43%

Minor (independent) 38%55%

No neurologic sequelae 3% 2%

Total 41%57%

Effect of Intensity of Oral Anticoagulation on Stroke Severity

INR<2INR2

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Gage et al. Stroke. 2000;31:822-827.

597 Medicare patients with AF; Rx at hospital discharge

Underuse of AntithromboticTherapy in AF

Warfarin Aspirin Neither

Age (years)

65-75 >75

42%29%

23%21%

36%53%

Sex

Male Female

38%29%

22%21%

42%51%

Location

Urban Rural

36%30%

23%17%

42%54%

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Samsa et al. Arch Intern Med. 2000;160:967-973.

Use and Adequacy of Anticoagulation in AF Patients in Primary Care Practice

INR above INR above targettarget

6%6%

Subtherapeutic Subtherapeutic INR INR 13%13%

INR inINR intarget rangetarget range

15%15%

No warfarinNo warfarin65%65%

N=660

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Bungard et al. Pharmacotherapy. 2000;20:1060-1065.

Use and Adequacy of Anticoagulation in AF Patients on Hospital Admission

Therapeutic INRTherapeutic INR37%37%

Subtherapeutic Subtherapeutic INRINR45%45%

No warfarin64%

SupratherapeuticSupratherapeuticINRINR19%19%

WarfarinWarfarin35%35%

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Anticoagulation With WarfarinIntensity Often Outside the Target Range

Ansell et al. J Thromb Thrombolysis. 2007;23:83-91.

% T

ime

in T

arg

et R

ang

e

0

20

40

60

80

100

US Canada France Italy Spain

INR<2 INR 2–3 INR>3

International Study of Anticoagulation Management International Study of Anticoagulation Management

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Smith et al. Arch Intern Med. 1999;159:1574-1578.

Warfarin Use in Patients With AF

N=5888 communityresidents with AF

Pe

rce

nta

ge

Us

e

100

90

80

70

60

50

40

30

20

10

0

<80 y

80 y

Examination Year

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=631989-1990 1990-1991 1991-1992 1992-1993 1993-1994 1994-1995 1995-1996

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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

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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 >10-fold 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.

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Physician Concerns About Warfarin for Stroke Prevention in AF

0

20

40

60

80

Risk of Fall History of GI Bleed

History ofNon-CNS Bleed

History of CV Hemorrhage

Risk vs benefit of warfarin 47% benefit greatly outweigh risk 34% risk slightly outweigh benefit 19% risk outweigh benefit

Frequently Cited Contraindications

Per

cen

t

Monette et al. J Am Geriatr Soc. 1997;45:1060-1065.

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Patient Concerns About AF

0

20

40

60

80

100

Stroke Death Major Bleeding

InconvenienceMinor Side Effects

Cost

Man-Son-Hing et al. Arch Intern Med. 1996;156:1841-1848.

Per

cen

t

91%

38%

13%9%

2% 5%

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Lip et al. Stroke. 2002;33:238-242.

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

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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


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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


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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.

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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

2

Rockson et al. J Am Coll Cardiol. 2004;43:929-935.

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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).

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CHADS2 Risk Criteria for Stroke in Nonvalvular AF

Warfarin

Stroke Risk in Patients With Nonvalvular AF Not Treated With Anticoagulation According to the CHADS2 Index

5

65

220

337

523

463

120

Patients (N=1733)

0 5 10 15 20 25 30

(95% CI)

6

5

4

3

2

1

0

CHADS2 Score

Adjusted Stroke Rate (%/y)

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Stroke Risk in New-Onset AFACP/AAFP Guidelines

CHADS2a

ScoreAdjusted 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

a Assessment 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.

Warfarin

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Singer et al. Chest. 2004;126(3 suppl):429S-456S.

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

NoneAspirin 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

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Risk-Based Approach to Antithrombotic Therapy

Patient Features Antithrombotic TherapyClass of

Recommendation

Age <60 y, no HD (lone AF)ASA (81-325 mg/d) or

no therapyI

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 factorsOAC (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.

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Risk Stratification in AF: Stroke Risk Factors

Singer et al. Chest. 2004;126:429S-456S; Fang et al. Circulation. 2005;112:1687-1691.

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

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

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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


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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)


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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.

Antithrombotic Therapy for Patients With AF

Risk Category Recommended TherapyNo risk factors 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 Moderate-Risk Factors High-Risk FactorsFemale sex

Age 65 to 74 years

Coronary artery disease

Thyrotoxicosis

Age 75 years

Hypertension

Heart failure

LV ejection fraction 35% or less

Diabetes mellitus

Previous stroke, TIA, or embolism

Mitral stenosis

Prosthetic heart valvea

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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)


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Relation Between INR on the Day of Cardioversion and Risk of Thromboembolism

Gallagher et al. J Am Coll Cardiol. 2002;40:926-933.

Co

nfi

rme

d E

mb

olis

m (

%) 44

33

22

11

001-1.41-1.4 1.5-1.91.5-1.9 2-2.42-2.4 >2.4>2.4

0/7790/779

4/5304/530

2/1822/182

1/421/42

INR at Time of Cardioversion

N=1950N=1950

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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.

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Anticoagulation Variability Prior to CardioversionN

um

be

r o

f P

ati

en

ts

Days (midpoint) to Subtherapeutic INRKim et al. Am J Cardiol. 2001;88:1428-1431.

Time to Subtherapeutic INR After the First Therapeutic Value

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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.

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Warfarin Dosing and Genomics

Caldwell et al. Clin Med Res. 2007;5:8-16.

Age (years)Age (years)

CYP2C9 = *1/*1

Age (years)

Dai

ly D

ose

(mg/

day)

0

2

4

6

8

10

1

3

5

7

9

40 45 50 55 60 65 70 75 80 85

CG

GGGG

GGGG

GGGG

GGGG

GG

CGCG

CGCG

CGCG

CGCG

CCCCCCCCCCCCCC

CCCC

CYP2C9 = *1/*3

Dai

ly D

ose

(mg/

day)

0

2

4

6

8

10

1

3

5

7

9

40 45 50 55 60 65 70 75 80 85

CG

GGGG

GGGG

GGGG

GG GG GG

CGCG

CGCG

CG CGCG CG

CCCCCCCCCCCCCC

CC CC

CYP2C9 = *1/*2

Dai

ly D

ose

(mg/

day)

0

2

4

6

8

10

1

3

5

7

9

40 45 50 55 60 65 70 75 80 85Age (years)

CG

GGGG

GGGG

GGGG

GGGG

GG

CGCG

CGCG

CG CG CG CG

CCCCCCCCCCCCCC

CC CC

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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?

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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

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Rhythm or Rate Control in AF Evidence Base

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

4 Randomized Trials Comparing2 Treatment Strategies

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.

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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.

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Van Gelder et al. N Engl J Med. 2002;347:1834-1840.

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

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The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Waldo. Am J Cardiol. 1999; 84:698-700.

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 months1 episode documented by ECG in last 12 weeks

1 risk factor for stroke (age 65)

• Randomized to rate vs rhythm control

• Both groups anticoagulated

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AFFIRM: Stroke Rates

74% of all strokes were ischemic44% 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.

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AFFIRM Results

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

Time-Dependent Covariates Associated With Survival

Epstein. Presented at the American Heart Association’s Scientific Sessions 2003. November 2003; Orlando, FL.

HR <1.00: decreased risk of death.

HR >1.00: increased risk of death.

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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.

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Strokes in Patients Converted to SR

nRate

controlRhythm control

RR(95% CI) P

AFFIRM 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

Verheugt et al. J Am Coll Cardiol. 2003;41(suppl):130A.

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Page et al. Circulation. 2003;107:1141-1145.

Azimilide (382)

Pro

po

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n F

ree

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As

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pto

ma

tic

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Placebo (233)

Placebo

100 mg or 125 mg azimilide

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Prevalence of Asymptomatic AF in Drug Trials Patients Studied for 30 Seconds Every 2 Weeks

Time (weeks)

www.HRSonline.org

Detection of Recurrent AF:ECG vs Implanted Device Recording

FU=follow-up.Israel et al. J Am Coll Cardiol. 2004;43:47-52.

Nu

mb

er o

f P

atie

nts

100

80

60

40

20

Baseline FU1 FU2 FU3 FU4 FU5 FU10FU9FU8FU7FU6

n=110 110 110 110 85 73 1525394860

P<.0001

Implanted device

ECG

www.HRSonline.org

Prevalence of Recurrent AF During Follow-up

Israel et al. J Am Coll Cardiol. 2004;43:47-52.

Pa

tie

nts

(%

)

70

60

50

40

30

20

10

0AF >72 h AF >48 h AF >24 h AF >12 h AF <12 h

www.HRSonline.org

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

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.

Estimated Absolute Rates of Primary Intracerebral Hemorrhage

www.HRSonline.org

CNS Bleeding and Anticoagulation

Hart et al. Stroke. 2005;36:1588-1593.

Intracranial Hemorrhage vs Anticoagulation Intensity in AF Patients: 2 Recent Studies

0

2

4

6

8

10

<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 <1.5 1.5-1.9 2.0-3.0 3.1-3.4 3.5-3.9 >4.0

Absolute rate Relative risk

Reference Reference pointpoint

INRINR INRINR

Case Control Studymean age:

cases=78 y; controls 75 y

Longitudinal Cohort Studymean age =71 years

www.HRSonline.org

CNS Bleeding and Anticoagulation

Hart et al. Stroke. 2005;36:1588-1593.

Intracranial Hemorrhage vs Anticoagulation Intensity in AF Patients: 2 Recent Studies

Longitudinal Cohort Study Case Control Study

Absolute Rate Relative Risk

Mean age, 71 yearsMean age, cases=78 years,

controls=75 years

INRRate per 100 Person-Years INR Relative Risk

<1.5 0.5 <1.5 1.4

1.5-1.9 0.3 1.5-1.9 1.2

2.0-2.5 0.3 2.0-3.0 1.0 (reference)

2.6-3.0 0.5 — —

3.1-3.5 0.6 3.1-3.4 1.4

3.6-3.9 0.4 3.5-3.9 4.6

4.0-4.5 2.7 >4.0 8.8

>4.5 9.4 — —

www.HRSonline.org

INR at the Time of Stroke or Bleeding Efficacy and Safety of Warfarin

5.05.0 6.06.0 8.08.01.01.0 2.02.0 3.03.0 4.04.0 7.07.0

55

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bleeding

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www.HRSonline.org

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

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ICH During Long-term Anticoagulation With WarfarinMeta-analysis

aPV=prosthetic valves.Levine et al. Chest. 2001;119:108S-121S.

ICH

(%

/ye

ar)

Fihn (AF)

INR<3.0

INR<3.0

Fihn (>75)

Turpie (PVa)

SPAF-2

(75)

SPAF (AF)

Pengo(PVa)

SPAF-2 (75)

SPAF-3 (AF)

INR2.0-4.5

INR2.0-3.0 INR

2.5-3.5

INR3.0-4.5

INR2.0-4.5

INR2.0-4.5

www.HRSonline.org

Antithrombotic Therapy for AFACC/AHA/ESC Guidelines 2006

Risk Category Recommended Therapy

No risk factorsCHADS2 = 0 Aspirin, 81-325 mg qd

One moderate-risk factorCHADS2 = 1

Aspirin, 81-325 mg/d orwarfarin

(INR 2.0-3.0, target 2.5)

Any high-risk factor or>1 moderate-risk factor

CHADS2 2or mitral stenosis

Warfarin(INR 2.0-3.0, target 2.5)

Prosthetic valveWarfarin

(INR 2.5-3.5, target 3.0)


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)


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)


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)


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)


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)


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)


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)


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)


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/CPatients given anticoagulant at D/CAll patients ≥18 years with ischemic stroke or TIA All patients ≥18 years with ischemic stroke or TIA

and permanent, persistent, or paroxysmal AFand 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) inAF 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.

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