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MMS/Mass Coalition Program, Nov. 4, 2008MMS/Mass Coalition Program, Nov. 4, 2008

Patients with AF: Who Should be Patients with AF: Who Should be on Warfarin?on Warfarin?

Daniel E. Singer, MDDaniel E. Singer, MDMassachusetts General HospitalMassachusetts General Hospital

Harvard Medical SchoolHarvard Medical School

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Speaker Disclosure InformationSpeaker Disclosure Information

DISCLOSURE INFORMATION:DISCLOSURE INFORMATION:The following relationships exist related to this presentation:The following relationships exist related to this presentation:

Daniel E. Singer, M.D.:Daniel E. Singer, M.D.:Consultant: AstraZeneca, Bayer, Boehringer Ingelheim, Consultant: AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, GSK, Medtronic, and Johnson and Johnson.Daiichi Sankyo, GSK, Medtronic, and Johnson and Johnson.Research Support: Daiichi SankyoResearch Support: Daiichi SankyoSymposium Presentation: Bristol Myers Squibb, PfizerSymposium Presentation: Bristol Myers Squibb, Pfizer

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Prevalence of Diagnosed Prevalence of Diagnosed AF by Age and SexAF by Age and Sex

Go AS et al. JAMA 2001;285:2370–2375

<55 55–59 60–64 65–69 70–74 75–79 80–84 85

Age (years)

0

1

2

3

4

5

6

7

8

9

10

11

12

Pre

vale

nce

(%

)

WomenMen

0.1 0.20.4

0.9 1.0

1.7 1.7

3.03.4

5.0 5.0

7.3 7.2

10.3

9.1

11.1

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Projected Number of Adults Projected Number of Adults with AF in the US, 1995-2050with AF in the US, 1995-2050

2.942.942.662.66

2.442.442.262.26

2.082.08

3.333.33

3.803.80

4.344.34

4.784.785.165.16

5.425.42 5.615.61

0.00.0

1.01.0

2.02.0

3.03.0

4.04.0

5.05.0

6.06.0

7.07.0

19901990 19951995 20002000 20052005 20102010 20152015 20202020 20252025 20302030 20352035 20402040 20452045 20502050

YearYear

Adults with Atrial Fibrillation, millions Adults with Atrial Fibrillation, millions

*JAMA. 2001;285:2370-2375

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AF and Stroke: Framingham Study,AF and Stroke: Framingham Study,30-Year Follow-up*30-Year Follow-up*

AgeAge Relative risk for stroke:Relative risk for stroke:

AF vs NSRAF vs NSR

60-6960-69 4.74.7

70-7970-79 5.45.4

80-8980-89 5.05.0

* Wolf PA, Abbott RD, Kannel WB, Arch Intern Med 1987;147: 1561-1564; adjusted * Wolf PA, Abbott RD, Kannel WB, Arch Intern Med 1987;147: 1561-1564; adjusted for BPfor BP

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AF: Putative Mechanism for AF: Putative Mechanism for StrokeStroke

AFAF loss of loss of atrialatrialcontractioncontraction

LA thrombusLA thrombus embolismembolism

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Left atrial appendage thrombus

LA

LAA-Thrombus

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RCTs of VKA vs Control to RCTs of VKA vs Control to Prevent Stroke in AFPrevent Stroke in AF

Go AS et al. Progr Cardiovasc Dis 2005;48:108–124

*p<0.05

AFASAK BAATAF SPAF-I CAFA SPINAF EAFT

Ann

ual s

trok

e ra

te (

%)

0

2

4

6

8

10

12

14 Control

Warfarin

–71%* –86%* –69%* –52% –79%*

–66%*

5.5

1.6

3.0

0.4

7.4

2.3

5.2

2.5

4.3

0.9

12.3

3.9

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Efficacy of Anticoagulation for AFEfficacy of Anticoagulation for AF

Trial Target Ranges: INR ~ 1.8-4.2Trial Target Ranges: INR ~ 1.8-4.2

RelativeRelative AbsoluteAbsolute

Risk ReductionRisk Reduction Risk ReductionRisk Reduction

Pooled 1° RCTs Pooled 1° RCTs 68%68% (50-79%) (50-79%) 3.1% 3.1% per yearper year

EAFTEAFT 66%66% (43-80%) (43-80%) 8.4% 8.4% per yearper year

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Safety of Anticoagulation for AFSafety of Anticoagulation for AF

Pooled 1° RCTsPooled 1° RCTs 0.3%0.3% per yr per yr 0.1%0.1% per yr per yr

Intracranial Hemorrhage:Intracranial Hemorrhage:

AnticoagulationAnticoagulation ControlControl

Absolute Rates of Absolute Rates of

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Efficacy of Aspirin for AFEfficacy of Aspirin for AF

Pooled 3 trials versus placebo:Pooled 3 trials versus placebo:

AFASAKAFASAK 75 mg daily75 mg dailySPAF ISPAF I 325 mg daily325 mg dailyEAFTEAFT 300 mg daily300 mg daily

Relative Risk Reduction: Relative Risk Reduction: 21% (0-38%)21% (0-38%)No signif impact on severe/fatal strokeNo signif impact on severe/fatal stroke

*JAMA 2002;288:2441-2448 (AFASAK I &II, EAFT, PATAF, SPAF I-III)*JAMA 2002;288:2441-2448 (AFASAK I &II, EAFT, PATAF, SPAF I-III)

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The Optimal INRThe Optimal INR

For an anticoagulant where toxicity results For an anticoagulant where toxicity results from an exaggeration of the beneficial effect, from an exaggeration of the beneficial effect, choosing the right “dose,” here INR, is crucial.choosing the right “dose,” here INR, is crucial.

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Hylek EM, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation Hylek EM, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with non-rheumatic atrial fibrillation. N Engl J Med 1996;335:540-546.for patients with non-rheumatic atrial fibrillation. N Engl J Med 1996;335:540-546.

INRINR Odds RatioOdds Ratio2.02.0 1.01.01.71.7 2.02.01.51.5 3.33.31.31.3 6.06.0

1.0 1.5 3.0 4.0 7.0

135

10

15

2.0

Od

ds

Ra

tio

Od

ds

Ra

tio

INRINR

Lowest Effective Anticoagulation Lowest Effective Anticoagulation Intensity for Warfarin TherapyIntensity for Warfarin Therapy

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Relative Odds of ICH by INR IntervalsRelative Odds of ICH by INR Intervals

Fang et al. Ann Intern Med 2004;141:745-52

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Antithrombotic Trials in AF: Antithrombotic Trials in AF: Core FindingsCore Findings

Anticoag. at INR 2.0-3.0 Anticoag. at INR 2.0-3.0 veryvery effective effective- - Generally safeGenerally safe- Moderately burdensome- Moderately burdensome

Aspirin is much less effectiveAspirin is much less effective

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Anticoagulation for AF: For Whom?Anticoagulation for AF: For Whom?

Guideline perspective:Guideline perspective:

Anticoagulate AF patients whose risk of Anticoagulate AF patients whose risk of stroke is high enough to “merit” the burden stroke is high enough to “merit” the burden and hemorrhage risk of warfarin therapyand hemorrhage risk of warfarin therapy

ASA for othersASA for others

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Pooled Analysis of AF Trials:Pooled Analysis of AF Trials:Risk Factors for Stroke*Risk Factors for Stroke*

Relative Risk Relative Risk (RR)(RR)

VariableVariable Multivariate Multivariate

Prior stroke/TIAPrior stroke/TIA 2.5 2.5

Hx HBPHx HBP 1.6 1.6

Age**Age** 1.4 1.4

Hx DiabetesHx Diabetes 1.7 1.7

**RR per decade**RR per decade

*Arch Intern Med 1994;154:1449-1457*Arch Intern Med 1994;154:1449-1457

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Echo Risk Factors for Stroke With AF: Pooled Echo Risk Factors for Stroke With AF: Pooled

Analysis of Control Arms of 3 RCTs*Analysis of Control Arms of 3 RCTs*

FeatureFeature RR RR p valuep value

LV dysfunctionLV dysfunction

mildmild 1.41.4 0.0020.002

severesevere 2.92.9 <0.001<0.001

*Arch Intern Med 1998;158:1316-1320, univariate

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Risk of Stroke in AF: Impact of Risk of Stroke in AF: Impact of Paroxysmal AFParoxysmal AF

From pooled trials (~25% had PAF)From pooled trials (~25% had PAF)

RR (PAF/Sust AF) = ~RR (PAF/Sust AF) = ~1.01.0

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CHADSCHADS22 AF Stroke Risk Score* AF Stroke Risk Score*

C = C = CCHFHF 1 point1 point

H = H = HHypertensionypertension 1 point1 point

A = A = AAge >75 yearsge >75 years 1 point1 point

D = D = DDiabetesiabetes 1 point1 point

S = Prior S = Prior SStroke/TIAtroke/TIA 2 points2 points

NB: Applies to persistent or paroxysmal AFNB: Applies to persistent or paroxysmal AF

*Gage, et al. JAMA 2001; 285(22): 2864-70*Gage, et al. JAMA 2001; 285(22): 2864-70

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CHADSCHADS22 AF Stroke Risk Score AF Stroke Risk Score

CHADSCHADS22

ScoreScore

No. of No. of PatientsPatients

(n = 1733)(n = 1733)

No. of No. of StrokesStrokes

(n = 94)(n = 94)

AdjustedAdjusted

Stroke Rate,Stroke Rate,

(95% CI)(95% CI)

00 120120 22 1.9 (1.2-3.0)1.9 (1.2-3.0)

11 463463 1717 2.8 (2.0-3.8)2.8 (2.0-3.8)

22 523523 2323 4.0 (3.1-5.1)4.0 (3.1-5.1)

33 337337 2525 5.9 (4.6-7.3)5.9 (4.6-7.3)

44 220220 1919 8.5 (6.3-11.1)8.5 (6.3-11.1)

55 6565 66 12.5 (8.2-17.5)12.5 (8.2-17.5)

66 55 22 18.2 (10.5-27.4)18.2 (10.5-27.4)

Risk of Stroke in National Registry of Atrial Fibrillation (NRAF) Risk of Stroke in National Registry of Atrial Fibrillation (NRAF) Participants, Stratified by CHADSParticipants, Stratified by CHADS22 Score* Score*

*C=CHF, H=HBP, A=age >75, D=diabetes, S=prior stroke/TIA. Gage, et al. JAMA 2001; 285(22): 2864-70*C=CHF, H=HBP, A=age >75, D=diabetes, S=prior stroke/TIA. Gage, et al. JAMA 2001; 285(22): 2864-70

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What is the case’s What is the case’s CHADSCHADS22 score? score?

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Prevalent warfarin use by age among Prevalent warfarin use by age among ambulatory patients with no ambulatory patients with no

contraindications to warfarin: ATRIA Study*contraindications to warfarin: ATRIA Study*

44.3%

58.1% 60.7% 57.3%

35.4%

0%

20%

40%

60%

80%

100%

<55 55-64 65-74 75-84 >85

Age Group (yrs)

Wa

rfa

rin

Us

e

*Ann Intern Med 1999;131:927

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BAFTA Study: Warfarin, INR 2-3 vs BAFTA Study: Warfarin, INR 2-3 vs ASA, 75mg/d, in the Elderly with AF*ASA, 75mg/d, in the Elderly with AF*

N=973, age >=75: mean age = 81.5 yrsN=973, age >=75: mean age = 81.5 yrs

Outcome: Disabling stroke, SE, ICHOutcome: Disabling stroke, SE, ICH

Relative risk=0.48, (95% CI 0.28-0.80)**Relative risk=0.48, (95% CI 0.28-0.80)**– Annual risk on warfarin = 1.8%Annual risk on warfarin = 1.8%– Annual risk on aspirin = 3.8%Annual risk on aspirin = 3.8%

– Bleeding rates ~same on warfarin and Bleeding rates ~same on warfarin and aspirin in this elderly cohort.aspirin in this elderly cohort.

*Mant JM, et al. Lancet 2007; 370: 493-503; **Analysis by intention to treat

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The Importance of “TTR” in Achieving the The Importance of “TTR” in Achieving the Net Benefit of Warfarin in AFNet Benefit of Warfarin in AF

Doing the right thingDoing the right thing

Doing the right thing Doing the right thing rightright

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Stroke and Systemic Emboli (SE) Stroke and Systemic Emboli (SE) Outcomes by INR Control Category: Outcomes by INR Control Category:

Results from SPORTIF III and V*Results from SPORTIF III and V*

2.1

1.341.07

0.2 0.280.06

0

0.5

1

1.5

2

2.5

Poor Moderate Good

Eve

nts

per

100

pat

ien

t- y

ears

Stroke and SEHemorrhagic stroke

*White, HD et al. Comparison of Outcomes Among Patients Randomized to Warfarin Therapy According to Anticoagulant Control. Arch Intern Med. 2007; 167:239-245.

<60% 60-75% >75%

TTR = % of time spent at INR 2.0-3.0TTR = % of time spent at INR 2.0-3.0

ACCP 2008*ACCP 2008*Antithrombotic Therapy in AF:Antithrombotic Therapy in AF:

The 2008 GuidelinesThe 2008 Guidelines

*Chest 2008;133:546S-592S*Chest 2008;133:546S-592S

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Applying a Risk-based Philosophy Applying a Risk-based Philosophy to Anticoagulation in AFto Anticoagulation in AF

• Assume oral VKA has great efficacy: RRR of Assume oral VKA has great efficacy: RRR of 67% vs no Rx; RRR of 50% vs ASA67% vs no Rx; RRR of 50% vs ASA

• Absolute benefit Absolute benefit proportional to absolute risk, proportional to absolute risk, untreated or treated with ASA. Evidence that untreated or treated with ASA. Evidence that untreated strokes rates are decreasing.untreated strokes rates are decreasing.

• At some low expected benefit, 0.5-1.0%/yr, the At some low expected benefit, 0.5-1.0%/yr, the risk and burden of VKA are not warrantedrisk and burden of VKA are not warranted

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• Incorporate patient preferences particularly for Incorporate patient preferences particularly for lower risk patientslower risk patients

• Assume that the patient is not at high risk for Assume that the patient is not at high risk for bleeding and that good control of anticoagulation bleeding and that good control of anticoagulation will occurwill occur

Underlying Values and AssumptionsUnderlying Values and Assumptions

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Recommendations for Long-Term Recommendations for Long-Term Anticoagulant Therapy in AFAnticoagulant Therapy in AF

• 1.1.11.1.1 For patients with AF (including PAF) with For patients with AF (including PAF) with any of the following:any of the following:– Prior stroke, TIA or systemic embolismPrior stroke, TIA or systemic embolism

• Recommend anticoagulation with an oral VKA Recommend anticoagulation with an oral VKA target INR 2.5 (target range 2.0-3.0), target INR 2.5 (target range 2.0-3.0), (Grade 1A)(Grade 1A)

continuedcontinued

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Recommendations for Long-Term Recommendations for Long-Term Anticoagulant Therapy in AFAnticoagulant Therapy in AF

• 1.1.21.1.2 Patients with AF (including PAF) with two Patients with AF (including PAF) with two or more of the following:or more of the following:– Age >75 yearsAge >75 years– History of hypertensionHistory of hypertension– Diabetes mellitusDiabetes mellitus– Moderately or severely impaired LV systolic Moderately or severely impaired LV systolic

function and/or clinical heart failurefunction and/or clinical heart failure• Recommend anticoagulation with an oral VKA Recommend anticoagulation with an oral VKA

target INR 2.5 (target range 2.0-3.0), target INR 2.5 (target range 2.0-3.0), (Grade 1A)(Grade 1A)

continuedcontinued

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Recommendations for Long-Term Recommendations for Long-Term Anticoagulant Therapy in AFAnticoagulant Therapy in AF

• 1.1.31.1.3 Patients with AF with Patients with AF with only oneonly one of the following of the following (CHADS(CHADS22=1):=1):– Age >75 yearsAge >75 years– History of hypertensionHistory of hypertension– Diabetes mellitusDiabetes mellitus– Moderately or severely impaired systolic function Moderately or severely impaired systolic function

and/or clinical heart failureand/or clinical heart failure

• Recommend anticoagulation with an oral VKA, target Recommend anticoagulation with an oral VKA, target INR 2.5 (target range 2.0-3.0) INR 2.5 (target range 2.0-3.0) (Grade 1A)(Grade 1A),, or with aspirin or with aspirin 75-325 mg/day 75-325 mg/day (Grade 1B)(Grade 1B),, although VKA is suggested although VKA is suggested (Grade 2A)(Grade 2A)..– Emphasize role of informed patient.Emphasize role of informed patient.

continuedcontinued

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RecommendationsRecommendations for Long-Term for Long-Term Anticoagulant Therapy in AFAnticoagulant Therapy in AF

• 1.1.41.1.4 Patients with sustained or paroxysmal AF with Patients with sustained or paroxysmal AF with nonenone of the following (CHADS of the following (CHADS22=0):=0):– Prior stroke, TIA or systemic embolismPrior stroke, TIA or systemic embolism– Age >75 yearsAge >75 years– History of hypertensionHistory of hypertension– Diabetes mellitusDiabetes mellitus– Moderately or severely impaired systolic function Moderately or severely impaired systolic function

and/or clinical heart failureand/or clinical heart failure

• Recommend long-term aspirin therapy at a dose of 75-Recommend long-term aspirin therapy at a dose of 75-325 mg/day, 325 mg/day, (Grade 1B)(Grade 1B)

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Recommendations for AF with Recommendations for AF with mitral stenosis mitral stenosis (1.3.1)(1.3.1) and and

AF with a prosthetic heart valve AF with a prosthetic heart valve (1.3.2)(1.3.2)

• 1.3.11.3.1 For patients with AF and mitral stenosis, For patients with AF and mitral stenosis, we recommend long-term anticoagulation with we recommend long-term anticoagulation with an oral VKA, such as warfarin, target INR 2.5 an oral VKA, such as warfarin, target INR 2.5 (range 2.0-3.0) (range 2.0-3.0) (Grade 1B)(Grade 1B)

• 1.3.21.3.2 For patients with AF and a prosthetic heart For patients with AF and a prosthetic heart valve, we recommend long-term anticoagulation valve, we recommend long-term anticoagulation at an intensity appropriate for the specific type of at an intensity appropriate for the specific type of prosthesis prosthesis (Grade 1B)(Grade 1B)

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Anticoagulation for elective Anticoagulation for elective cardioversion of AF cardioversion of AF ≥≥ 48 hours or 48 hours or

unknown durationunknown duration

• 2.1.1 2.1.1 For patients with AF of ≥48 hours or of For patients with AF of ≥48 hours or of unknown duration for whom pharmacologic or unknown duration for whom pharmacologic or electrical cardioversion is planned, we electrical cardioversion is planned, we recommend:recommend:– Anticoagulation with an oral vitamin K Anticoagulation with an oral vitamin K

antagonist, target INR of 2.5 (range, 2.0-3.0) antagonist, target INR of 2.5 (range, 2.0-3.0) • For 3 weeks before elective cardioversion For 3 weeks before elective cardioversion • And for at least 4 weeks after sinus rhythm And for at least 4 weeks after sinus rhythm

has been maintained has been maintained (Grade 1C)(Grade 1C)

continuedcontinued

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ACCP 8: Key Points for Long-ACCP 8: Key Points for Long-term Antithrombotic Therapyterm Antithrombotic Therapy

• Age 65-75 yrs is no longer considered a risk factorAge 65-75 yrs is no longer considered a risk factor

• Either VKA or aspirin is acceptable for AF patients Either VKA or aspirin is acceptable for AF patients with one stroke risk factor, other than prior with one stroke risk factor, other than prior ischemic stroke, although VKA is favored ischemic stroke, although VKA is favored

• We again stress INR 2-3 as the appropriate target We again stress INR 2-3 as the appropriate target and do not endorse lower INR targets in elderly and do not endorse lower INR targets in elderly (e.g., ACC/AHA/ESC INR 1.6-2.5)(e.g., ACC/AHA/ESC INR 1.6-2.5)

• We recommend broader acceptable dosing range We recommend broader acceptable dosing range for ASA 75-325 mg, not just 325 mg as in ACCP 7 for ASA 75-325 mg, not just 325 mg as in ACCP 7 (2004)(2004)

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Stroke Prevention in AF: Stroke Prevention in AF: What’s needed now?What’s needed now?

1. Optimizing warfarin therapy:1. Optimizing warfarin therapy:• Quality improvement for anticoagulationQuality improvement for anticoagulation• Dedicated anticoagulation unitsDedicated anticoagulation units• Self-testing/self-managementSelf-testing/self-management• Better initiation and maintenance dosingBetter initiation and maintenance dosing

- ?clinical+genotype-guided- ?clinical+genotype-guided

2. With high quality anticoagulation assured, more 2. With high quality anticoagulation assured, more patients can be safely and effectively treated.patients can be safely and effectively treated.

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THE ENDTHE END