Antithrombotic Antithrombotic Therapy Therapy

for for

Stroke Stroke PreventionPrevention inin

Atrial Atrial FibrillationFibrillation

““To this variety of apoplexy those are To this variety of apoplexy those are most liable who lead an idle life, who most liable who lead an idle life, who are obese, whose face and hands are are obese, whose face and hands are

constantly livid and whose pulse constantly livid and whose pulse constantly unequal.”constantly unequal.”

Wepfer, 1658Wepfer, 1658

Left Atrial Appendage (LAA)Left Atrial Appendage (LAA)Left Atrial Appendage (LAA)Left Atrial Appendage (LAA)

Thromboembolic EventsThromboembolic EventsControl Patients in AF TrialsControl Patients in AF Trials

Thromboembolic EventsThromboembolic EventsControl Patients in AF TrialsControl Patients in AF Trials

Cerebral Cerebral 49 (91%)49 (91%)

Systemic Systemic 5 (9%)5 (9%)

Severity of Ischemic StrokesSeverity of Ischemic Strokes in Atrial Fibrillation in Atrial Fibrillation

Severity of Ischemic StrokesSeverity of Ischemic Strokes in Atrial Fibrillation in Atrial Fibrillation

Fatal: Fatal: 5 (10%)5 (10%)

Moderate to Moderate to severe: severe: 23 (45%)23 (45%)

Mild: Mild: 23 (45%)23 (45%)

Number of events in 1,092 control patientsNumber of events in 1,092 control patients

Age Distribution of People With AFAge Distribution of People With AFCompared With U.S. General PopulationCompared With U.S. General Population

Age Distribution of People With AFAge Distribution of People With AFCompared With U.S. General PopulationCompared With U.S. General Population

30,00030,000

20,00020,000

10,00010,000

00

Arch Int Med. Arch Int Med. 1995;155:471.1995;155:471.

5–9

5–9

5–9

5–9

Population withPopulation withAtrial FibrillationAtrial Fibrillation

U.S. PopulationU.S. Population

500500

400400

300300

200200

100100

00

Age, yearsAge, years

U.S

. Po

pu

lati

on

(x

10

00

)U

.S. P

op

ula

tio

n (

x 1

00

0)

<5<5

10–1

4

10–1

415

–19

15–1

920

–24

20–2

425

–29

25–2

930

–34

30–3

435

–39

35–3

940

–44

40–4

450

–54

50–5

460

–64

60–6

470

–74

70–7

480

–84

80–8

490

–94

90–9

4

45–4

9

45–4

955

–59

55–5

965

–69

65–6

975

–79

75–7

985

–89

85–8

9

>95

>95

AF

Po

pu

lati

on

(x

10

)A

F P

op

ula

tio

n (

x 1

0)

Efficacy of WarfarinEfficacy of WarfarinCompared with Control in Five StudiesCompared with Control in Five Studies

AFASAKAFASAK 2727 811811

BAATAFBAATAF 1515 922922

CAFACAFA 1414 478478

SPAFSPAF 2323 508508

SPINAFSPINAF 2929 972972

Combined*Combined* 108108 36913691

No. ofNo. ofEventsEvents

Patient-Patient-yearsyears

100 50100 50 0 0 -50 -50 -100 -100

Warfarin BetterWarfarin Better Warfarin WorseWarfarin Worse

Risk Reduction, %Risk Reduction, %

*Total risk reduction for all 5*Total risk reduction for all 5 studies combined is 68%studies combined is 68%

Patients Assigned toPatients Assigned to Warfarin in AF Trials Warfarin in AF Trials

Intensity of Anticoagulation When Stroke OccurredIntensity of Anticoagulation When Stroke Occurred

AFASAKAFASAK SPAF ISPAF I BAATAFBAATAF SPINAFSPINAFCAFACAFA1.01.0

2.02.0

3.03.0

4.04.01.71.7

1.61.6

1.51.51.41.41.31.31.21.21.11.11.01.0

INRINRRatioRatio

PTPTRatioRatio

(ISI 2.4)(ISI 2.4)

ACCP recommendation: INR: 2.0–3.0ACCP recommendation: INR: 2.0–3.0

1.81.8

Target range for individual studyTarget range for individual study

Efficacy of Aspirin Compared with Efficacy of Aspirin Compared with ControlControl

AFASAKAFASAK 3535 807807

SPAFSPAF 6565 14571457

EAFTEAFT 130130 838838

CombinedCombined** 230230 31023102

No. ofNo. ofEventsEvents

Patient-Patient-yearsyears

100 50 0 -50100 50 0 -50 -100 -100

Aspirin BetterAspirin Better Aspirin WorseAspirin Worse

Risk Reduction (%)Risk Reduction (%)

*Total risk reduction for all 3 studies combined is 21%*Total risk reduction for all 3 studies combined is 21%

SPAF III StudySPAF III Study

Atrial FibrillationAtrial Fibrillation

Clinical Assessment Clinical Assessment Echocardiography (TTE)Echocardiography (TTE)

Female > 75 yearsFemale > 75 years Systolic hypertensionSystolic hypertension Impaired LV functionImpaired LV function Prior thromboembolismPrior thromboembolism

Low Risk CohortLow Risk Cohort

AspirinAspirin 325 mg/day 325 mg/day

High Risk CohortHigh Risk Cohort

WarfarinWarfarinCombinationCombination

INR 2–3INR 2–3 1–3 mg 1–3 mg Warfarin +Warfarin +Monthly INR toMonthly INR to 325 mg 325 mg AspirinAspirinadjust doseadjust dose fixed fixed

dosedose

– +

SPAF III ResultsSPAF III ResultsHigh Risk CohortHigh Risk Cohort

SPAF III ResultsSPAF III ResultsHigh Risk CohortHigh Risk Cohort

Lancet 1996; 348; 633-638.Lancet 1996; 348; 633-638.

00

11

22

33

44

55

66

77

88

Stroke orStroke orSystemic EmbolismSystemic Embolism

Major BleedingMajor Bleeding IntracranialIntracranialHemorrhageHemorrhage

Aspirin Plus Fixed-Dose WarfarinAspirin Plus Fixed-Dose WarfarinAdjusted-Dose Warfarin (INR 2-3)Adjusted-Dose Warfarin (INR 2-3)

Even

t Rat

e, %

per

Pat

ient

-yea

rEv

ent R

ate,

% p

er P

atie

nt-y

ear

SPAF III StudySPAF III Study

Atrial FibrillationAtrial Fibrillation

Clinical Assessment Clinical Assessment Echocardiography (TTE)Echocardiography (TTE)

Female > 75 yearsFemale > 75 years Systolic hypertensionSystolic hypertension Impaired LV functionImpaired LV function Prior thromboembolismPrior thromboembolism

Low Risk CohortLow Risk Cohort

AspirinAspirin 325 mg/day 325 mg/day

High Risk CohortHigh Risk Cohort

WarfarinWarfarinCombinationCombination

INR 2–3INR 2–3 1–3 mg 1–3 mg Warfarin +Warfarin +Monthly INR toMonthly INR to 325 mg 325 mg AspirinAspirinadjust doseadjust dose fixed fixed

dosedose

– +

SPAF III Non-RandomizedSPAF III Non-Randomized Aspirin-Only Arm Aspirin-Only Arm

Low Stroke Risk CohortLow Stroke Risk Cohort**

SPAF III Non-RandomizedSPAF III Non-Randomized Aspirin-Only Arm Aspirin-Only Arm

Low Stroke Risk CohortLow Stroke Risk Cohort**

% per year% per year 95% CI95% CI % per year% per year 95% CI95% CI

Stroke or syst.Stroke or syst. 1.1%1.1% (0.6%–2.0%)(0.6%–2.0%) 3.6%3.6% (2.5%–5.2%)(2.5%–5.2%) embolismembolism

No History of Hypertension History of HypertensionNo History of Hypertension History of Hypertension

*Patients enrolled had none of these high risk features: female >75 *Patients enrolled had none of these high risk features: female >75 years, impaired LV function, current SBP >160 mm Hg, years, impaired LV function, current SBP >160 mm Hg,

prior thromboembolismprior thromboembolism

Risk Factors for Stroke and Risk Factors for Stroke and Efficacy of Efficacy of

Antithrombotic Therapy Antithrombotic Therapy in Atrial Fibrillationin Atrial Fibrillation

Archives of Internal MedicineArchives of Internal MedicineJuly 11, 1994July 11, 1994

Predicting Stroke Risk in AF—Who Predicting Stroke Risk in AF—Who Benefits Most?Benefits Most?

Multivariate Analysis of Pooled DataMultivariate Analysis of Pooled Data

Clinical risk factorsClinical risk factors Relative riskRelative risk

Previous stroke or TIAPrevious stroke or TIA 2.5 x2.5 x

History of hypertensionHistory of hypertension 1.6 x1.6 x

DiabetesDiabetes 1.7 x1.7 x

Increasing age (per decade)Increasing age (per decade)1.4 x1.4 x

Transthoracic Echocardiographic Transthoracic Echocardiographic Predictors of Stroke in Patients with AFPredictors of Stroke in Patients with AF

Transthoracic Echocardiographic Transthoracic Echocardiographic Predictors of Stroke in Patients with AFPredictors of Stroke in Patients with AF

Atrial Fibrillation InvestigatorsAtrial Fibrillation Investigators

Combined databases from 3 randomized trials Combined databases from 3 randomized trials (N=1,066)(N=1,066)

Moderate to severe LV dysfunction was the only Moderate to severe LV dysfunction was the only independent predictor of stroke (RR 2.5, p<0.001)independent predictor of stroke (RR 2.5, p<0.001)

Left atrial size did not predict stroke riskLeft atrial size did not predict stroke risk

Atrial Fibrillation Follow-up Atrial Fibrillation Follow-up Investigation of Rhythm ManagementInvestigation of Rhythm Management

AFFIRMAFFIRM

Atrial Fibrillation Follow-up Atrial Fibrillation Follow-up Investigation of Rhythm ManagementInvestigation of Rhythm Management

AFFIRMAFFIRM

Multicenter, randomized clinical trialMulticenter, randomized clinical trial

NHLBI-NIH supportedNHLBI-NIH supported

Patients with AF at high risk of stroke Patients with AF at high risk of stroke or deathor death

Randomized to either rate-control or rhythm-Randomized to either rate-control or rhythm-control strategycontrol strategy

Primary endpoint: all-cause mortalityPrimary endpoint: all-cause mortality

The AFFIRM Investigators. The AFFIRM Investigators. N Engl J MedN Engl J Med. 2002;347:1825-1833.. 2002;347:1825-1833.

AFFIRMAFFIRM Stroke EventsStroke Events

AFFIRMAFFIRM Stroke EventsStroke Events

0

1

2

3

4

5

6

7

8

9

Ischemicstroke

ICH SDH/SAH All stroke

Rate Rhythm

5.55.5

7.17.1

1.11.1 1.31.30.80.8 0.80.8

7.47.4

8.98.9PP=.79=.79

PP=.73=.73PP=.68=.68

PP=.93=.93

The AFFIRM Investigators. The AFFIRM Investigators. N Engl J MedN Engl J Med. 2002;347:1825-1833.. 2002;347:1825-1833.

Pe

rce

nt

Pe

rce

nt

7th ACCP 7th ACCP Consensus Consensus

Conference on Conference on Antithrombotic Antithrombotic

TherapyTherapyCHEST Supplement: 2004CHEST Supplement: 2004

ACCP Recommendations 2004ACCP Recommendations 2004Risk Factors for StrokeRisk Factors for Stroke

ACCP Recommendations 2004ACCP Recommendations 2004Risk Factors for StrokeRisk Factors for Stroke

Prior stroke, TIA, systemic embolismPrior stroke, TIA, systemic embolism

HypertensionHypertension

Moderate or severely impaired LV Moderate or severely impaired LV systolic function and / or CHFsystolic function and / or CHF

Age >75 yearsAge >75 years

Rheumatic mitral valve diseaseRheumatic mitral valve disease

Prosthetic heart valvesProsthetic heart valves

Diabetes mellitusDiabetes mellitus

Age 65-75Age 65-75Moderate RiskModerate Risk

High RiskHigh Risk

ACCP 2004 Recommendations for ACCP 2004 Recommendations for Stroke Prevention in Atrial Fibrillation*Stroke Prevention in Atrial Fibrillation*

ACCP 2004 Recommendations for ACCP 2004 Recommendations for Stroke Prevention in Atrial Fibrillation*Stroke Prevention in Atrial Fibrillation*

Risk FactorsRisk Factors Recommended TherapyRecommended Therapy

Any High Risk Factor WarfarinAny High Risk Factor Warfarin (target INR 2.5, range 2.0-3.0)**(target INR 2.5, range 2.0-3.0)**

Age 65-75 years and Aspirin 325 mg qdAge 65-75 years and Aspirin 325 mg qd No high risk factors or WarfarinNo high risk factors or Warfarin

(target INR 2.5, range 2.0-3.0)**(target INR 2.5, range 2.0-3.0)**

No Risk Factors and age < 65 Aspirin 325 mg qdNo Risk Factors and age < 65 Aspirin 325 mg qd

*Applies to persistent (sustained or permanent) and paroxysmal (intermittent) AF*Applies to persistent (sustained or permanent) and paroxysmal (intermittent) AF

**target INR > 2.5 for patients with mechanical heart valves**target INR > 2.5 for patients with mechanical heart valves

ACCP Recommendations 2004ACCP Recommendations 2004

CardioversionCardioversion

ACCP Recommendations 2004ACCP Recommendations 2004

CardioversionCardioversion

Continuation of anticoagulation beyond 4 Continuation of anticoagulation beyond 4 weeks after successful pharmacological or weeks after successful pharmacological or electrical cardioversion is based on whether electrical cardioversion is based on whether the patient has experienced more than 1 the patient has experienced more than 1 episode of AF and on their risk factor status.episode of AF and on their risk factor status.

Patients experiencing more than 1 episode of Patients experiencing more than 1 episode of AF should be considered as having AF should be considered as having paroxysmal AF paroxysmal AF

0

20

40

60

80

Warfarin for Atrial FibrillationWarfarin for Atrial FibrillationLimitations Lead to Under-treatmentLimitations Lead to Under-treatmentWarfarin for Atrial FibrillationWarfarin for Atrial FibrillationLimitations Lead to Under-treatmentLimitations Lead to Under-treatment

<55<55 55-6455-64 65-7465-74 75-8475-84 8585

44%44%

58%58%61%61%

57%57%

35%35%

Age (years)Age (years)

Wa

rfa

rin

Us

e in

Wa

rfa

rin

Us

e in

Elig

ible

Pat

ien

ts (

%)

Elig

ible

Pat

ien

ts (

%) 55% 55%

Overall Overall UseUse

Go A et al. Go A et al. Ann Intern MedAnn Intern Med 1999;131:927. 1999;131:927.

Warfarin for Atrial FibrillationWarfarin for Atrial Fibrillation Limitations Lead to Inadequate TreatmentLimitations Lead to Inadequate Treatment

Warfarin for Atrial FibrillationWarfarin for Atrial Fibrillation Limitations Lead to Inadequate TreatmentLimitations Lead to Inadequate Treatment

Samsa GP, et al. Arch Intern Med 2000;160:967.

INR above targetINR above target6%6%

Subtherapeutic INR Subtherapeutic INR 13%13%

INR inINR intarget rangetarget range

15%15%

No No warfarinwarfarin

65%65%

Adequacy of Anticoagulation inAdequacy of Anticoagulation inPatients with AF in Primary Care PracticePatients with AF in Primary Care Practice

XimelagatranXimelagatranOral Direct Thrombin InhibitorOral Direct Thrombin Inhibitor

XimelagatranXimelagatranOral Direct Thrombin InhibitorOral Direct Thrombin Inhibitor

Prompt onset and offset of anticoagulationPrompt onset and offset of anticoagulation

Wider Wider therapeutic margin than warfarintherapeutic margin than warfarin

Predictable pharmacokineticsPredictable pharmacokinetics

Low potential for food and drug interactionsLow potential for food and drug interactions

No dose adjustmentNo dose adjustment

No coagulation monitoringNo coagulation monitoring

Sarich TC, et al. Sarich TC, et al. J Am Coll CardiolJ Am Coll Cardiol 2003;41:557. 2003;41:557.Eriksson H, et al. Eriksson H, et al. Drug Metab DispDrug Metab Disp 2003;31:294. 2003;31:294.

SStroke troke PPrevention Using anrevention Using anORORal Direct al Direct TThrombin hrombin IInhibitor in nhibitor in AAtrial trial

FFibrillationibrillationThe SPORTIF III and V TrialsThe SPORTIF III and V Trials

SStroke troke PPrevention Using anrevention Using anORORal Direct al Direct TThrombin hrombin IInhibitor in nhibitor in AAtrial trial

FFibrillationibrillationThe SPORTIF III and V TrialsThe SPORTIF III and V Trials

Fixed-doseFixed-doseXimelagatranXimelagatran(36 mg bid)(36 mg bid)

Adjusted-doseAdjusted-doseWarfarinWarfarin(INR 2-3)(INR 2-3)

Patients with Nonvalvular AFPatients with Nonvalvular AFand Risk Factors for Strokeand Risk Factors for Stroke

n=7,320 n=7,320

SPORTIF IIISPORTIF III 23 nations23 nations open-label open-label ((nn=3,407)=3,407)

SPORTIF VSPORTIF V US, CanadaUS, Canada double-blinddouble-blind ((nn=3,913)=3,913)

SPORTIF ProgramSPORTIF ProgramPrimary AnalysesPrimary Analyses

Intention-to-treat AnalysisIntention-to-treat Analysis

SPORTIF ProgramSPORTIF ProgramPrimary AnalysesPrimary Analyses

Intention-to-treat AnalysisIntention-to-treat Analysis

Difference in Absolute Event Rates(Ximelagatran – Warfarin)

Ximelagatran Better Warfarin Better

-1-1 00 11 22

SPORTIF IIISPORTIF IIISPORTIF IIISPORTIF III

SPORTIF VSPORTIF VSPORTIF VSPORTIF V

-0.66-0.66

+0.45+0.45

pp=0.10=0.10

pp=0.13=0.13

PooledPooledPooledPooled-0.03-0.03

pp=0.94=0.94

33 44-2-2-3-3-4-4

SPORTIF VSPORTIF VHemorrhageHemorrhage

SPORTIF VSPORTIF VHemorrhageHemorrhage

3.1%

47%

0.1% 0.1% 2.4%

37%

0

10

20

30

40

50

ICH Major Bleeding Major + MinorBleeding

Warfarin

Ximelagatran

Ev

ent

Ra

te (

% /y

ea

r)E

ven

t R

ate

(%

/ye

ar)

pp<0.0001 <0.0001

p=p=0.160.16p=p=NSNS

SPORTIF VSPORTIF VLiver Enzyme ElevationLiver Enzyme Elevation

ALT >3 x ULNALT >3 x ULN

SPORTIF VSPORTIF VLiver Enzyme ElevationLiver Enzyme Elevation

ALT >3 x ULNALT >3 x ULN

0

10

20

30

40

50

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

MonthsMonths

Nu

mb

er o

f P

atie

nts

Ximelagatran

Warfarin

Inci

den

ce (

%)

Inci

den

ce (

%)

ALT >3x ALT >3x ULNULN

pp<0.001<0.001

0.8%

6.0%

0

2

4

6

8

10

12

14 Warfarin

Ximelagatran

ConclusionsConclusionsConclusionsConclusions

Fixed oral dosing without coagulation monitoringFixed oral dosing without coagulation monitoring

Effectiveness non-inferior to well-controlled warfarin in Effectiveness non-inferior to well-controlled warfarin in preventing stroke and systemic embolic eventspreventing stroke and systemic embolic events

Less bleeding than warfarinLess bleeding than warfarin

Elevated liver enzymes in ~6% of patientsElevated liver enzymes in ~6% of patients

A promising treatment option for prevention of A promising treatment option for prevention of thromboembolismthromboembolism

In high-risk patients with atrial fibrillation, In high-risk patients with atrial fibrillation, ximelagatran offers:ximelagatran offers: