New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistApplying Landmark

New Paradigms New Paradigms andand Landscape Changes Landscape Changes in in

Atrial FibrillationAtrial Fibrillation

Emerging Perspectives in Thrombosis Mitigation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular Specialist—Applying for the Cardiovascular Specialist—Applying

Landmark Trials to the Front Lines of Cardiology Landmark Trials to the Front Lines of Cardiology PracticePractice

National Experts National Experts inin Cardiovascular Medicine Cardiovascular Medicine Illuminate Illuminate andand Debate Debate

Program Chairman and ModeratorProgram Chairman and ModeratorPeter Libby, MD, FACCPeter Libby, MD, FACCChief, Cardiovascular MedicineChief, Cardiovascular MedicineBrigham and Women’s HospitalBrigham and Women’s Hospital

Mallinckrodt Professor of MedicineMallinckrodt Professor of MedicineHarvard Medical SchoolHarvard Medical SchoolBoston, MassachusettsBoston, Massachusetts

CME-certified symposium CME-certified symposium jointly jointly sponsored by the University of sponsored by the University of Massachusetts Medical School Massachusetts Medical School and CMEducation Resources, and CMEducation Resources, LLCLLC

Commercial Support: Commercial Support: Sponsored Sponsored by an independent educational by an independent educational grant from Boehringer-grant from Boehringer-IngelheimIngelheim

Faculty disclosures: Faculty disclosures: Listed in Listed in program syllabusprogram syllabus

Welcome and Program Overview Welcome and Program Overview

Program FacultyProgram Faculty

Peter Libby, MD, FACCPeter Libby, MD, FACCProgram Chairman and Program Chairman and Moderator Moderator Chief, Cardiovascular MedicineChief, Cardiovascular MedicineBrigham and Women’s HospitalBrigham and Women’s HospitalMallinckrodt Professor of MedicineMallinckrodt Professor of MedicineHarvard Medical SchoolHarvard Medical SchoolBoston, MassachusettsBoston, Massachusetts

Jonathan L. Halperin, MDJonathan L. Halperin, MDMount Sinai School of MedicineMount Sinai School of MedicineDirector, Clinical Cardiology ServiceDirector, Clinical Cardiology ServiceThe Zena and Michael A. Wiener The Zena and Michael A. Wiener Cardiovascular InstituteCardiovascular InstituteThe Marie-Josée and Henry R. Kravis The Marie-Josée and Henry R. Kravis Center for Cardiovascular HealthCenter for Cardiovascular HealthNew York, New YorkNew York, New York

Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of MedicineDepartment of MedicineDepartment of MedicineBoston University Medical CenterBoston University Medical CenterBoston, MassachusettsBoston, Massachusetts

Jeffrey I. Weitz, MD, FRCP, FACPJeffrey I. Weitz, MD, FRCP, FACPProfessor of Medicine and BiochemistryProfessor of Medicine and BiochemistryMcMaster UniversityMcMaster UniversityDirector, Henderson Research CenterDirector, Henderson Research CenterCanada Research Chair in ThrombosisCanada Research Chair in ThrombosisHeart and Stroke FoundationHeart and Stroke FoundationJ.F. Mustard Chair in Cardiovascular J.F. Mustard Chair in Cardiovascular ResearchResearchOntario, CanadaOntario, Canada

Challenges in Stroke PreventionChallenges in Stroke Preventionfor Patients with Atrial Fibrillationfor Patients with Atrial Fibrillation

Achieving Balance BetweenAchieving Balance BetweenPrevention of Thromboembolism Prevention of Thromboembolism

and Risk of Bleedingand Risk of BleedingRisk Stratification, Current Guidelines and Therapeutic Risk Stratification, Current Guidelines and Therapeutic

ChoicesChoices

New Frontiers in Atrial FibrillationNew Frontiers in Atrial Fibrillation

Jonathan L. Halperin, MDJonathan L. Halperin, MDProfessor of Medicine (Cardiology) Professor of Medicine (Cardiology)

Mount Sinai School of MedicineMount Sinai School of MedicineDirector, Clinical Cardiology ServicesDirector, Clinical Cardiology Services

The Zena and Michael A. Wiener Cardiovascular InstituteThe Zena and Michael A. Wiener Cardiovascular InstituteThe Marie-Josée and Henry R. KravisThe Marie-Josée and Henry R. Kravis

Center for Cardiovascular HealthCenter for Cardiovascular Health

Atrial FibrillationAtrial FibrillationA Substantial Threat to the BrainA Substantial Threat to the Brain

► Affects Affects

~~4% of people aged 4% of people aged >>60 years60 years

~9% of those aged ~9% of those aged >>80 years80 years► 5%/year stroke rate5%/year stroke rate► 12%/year for those with prior stroke12%/year for those with prior stroke► $ billions annual cost for stroke care$ billions annual cost for stroke care► AF-related strokes have worse AF-related strokes have worse

outcomesoutcomesAF identifies millions of people

with afive-fold increased risk of

stroke

Natural History of “Lone” Atrial Natural History of “Lone” Atrial FibrillationFibrillation

No Cardiopulmonary Disease; <60 Years OldNo Cardiopulmonary Disease; <60 Years Old

Kopecky S, et al. Kopecky S, et al. N Engl J MedN Engl J Med 1987; 317:669. 1987; 317:669.

97 PatientsMean Age = 44

14.8 yearsFollow-up

0.35%/yr Stroke0.40%/yr Mortality

Stroke Risk in Atrial FibrillationStroke Risk in Atrial FibrillationUntreated Control Groups of Randomized TrialsUntreated Control Groups of Randomized Trials

Atrial Fibrillation Investigators. Atrial Fibrillation Investigators. Arch Intern MedArch Intern Med 1994;154:1449. 1994;154:1449.

Str

oke

Rat

e (%

per

yea

r)S

trok

e R

ate

(% p

er y

ear)

Age (years)Age (years)

Anticoagulation in Atrial FibrillationAnticoagulation in Atrial FibrillationStroke Risk ReductionsStroke Risk Reductions

Hart R, et al. Hart R, et al. Ann Intern MedAnn Intern Med 2007;146:857. 2007;146:857.

WarfarinWarfarinBetterBetter

ControlControlBetterBetter

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

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

AggregateAggregate

Anticoagulation in Atrial FibrillationAnticoagulation in Atrial FibrillationThe Standard of Care for Stroke PreventionThe Standard of Care for Stroke Prevention


ControlControlBetterBetter

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

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

AggregateAggregate

Terminated earlyTerminated early

Double-blind; Men onlyDouble-blind; Men only

UnblindedUnblinded

UnblindedUnblinded

UnblindedUnblinded

22oo prevention; Unblinded prevention; Unblinded

Hart R, et al. Hart R, et al. Ann Intern MedAnn Intern Med 2007;146:857. 2007;146:857.

Antithrombotic Therapy for Atrial FibrillationAntithrombotic Therapy for Atrial FibrillationStroke Risk ReductionStroke Risk Reduction

Antiplatelet drugsAntiplatelet drugsvs. Placebovs. Placebo

Warfarin vs.Warfarin vs.Placebo/ControlPlacebo/Control

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

6 Trials6 Trialsn = 2,900n = 2,900


TreatmentTreatmentBetterBetter

TreatmentTreatmentWorseWorse

Hart R, et al. Ann Intern Med 2007;146:857.

Efficacy of Warfarin in Trials vs. PracticeEfficacy of Warfarin in Trials vs. PracticeStroke Risk ReductionsStroke Risk Reductions

Warfarin vs.Warfarin vs.No anticoagulationNo anticoagulation

Warfarin vs.Warfarin vs.Placebo/ControlPlacebo/Control

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


Medicare cohortMedicare cohortn = 23,657n = 23,657

TreatmentTreatmentBetterBetter

TreatmentTreatmentWorseWorse

Hart R, et al. Ann Intern Med 2007;146:857Hart R, et al. Ann Intern Med 2007;146:857Birman-Deych E. Stroke 2006; 37: 1070–1074Birman-Deych E. Stroke 2006; 37: 1070–1074

Intracerebral HemorrhageIntracerebral Hemorrhage

► >10% of intracerebral hemorrhages >10% of intracerebral hemorrhages (ICH) occur in patients on (ICH) occur in patients on antithrombotic therapyantithrombotic therapy

► Aspirin increases the risk by ~ 40%Aspirin increases the risk by ~ 40%

► Warfarin (INR 2–3) Warfarin (INR 2–3) doublesdoubles the risk to the risk to 0.3–0.6%/year0.3–0.6%/year

► ICH during anticoagulation is ICH during anticoagulation is catastrophiccatastrophic

Hart RG, et al. Hart RG, et al. StrokeStroke 2005;36:1588 2005;36:1588

The Most Feared Complication of Antithrombotic TherapyThe Most Feared Complication of Antithrombotic Therapy

Risk Stratification in AFRisk Stratification in AFStroke Risk FactorsStroke Risk Factors

High-Risk FactorsHigh-Risk Factors

► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

Singer DE, et al. Singer DE, et al. ChestChest 2004;126:429S. 2004;126:429S.Fang MC, et al. Fang MC, et al. CirculationCirculation 2005; 112: 1687. 2005; 112: 1687.

High-Risk FactorsHigh-Risk Factors

► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or History of stroke or TIATIA

Moderate-Risk FactorsModerate-Risk Factors

►Age >75 yearsAge >75 years

►HypertensionHypertension

►Diabetes mellitusDiabetes mellitus

►Heart failure or Heart failure or ↓↓ LV function LV function

Risk Stratification in AFRisk Stratification in AFStroke Risk FactorStroke Risk Factorss


High-Risk FactorsHigh-Risk Factors► Mitral stenosisMitral stenosis► Prosthetic heart valveProsthetic heart valve► History of stroke or History of stroke or

TIATIA

Moderate-Risk FactorsModerate-Risk Factors► Age >75 yearsAge >75 years► HypertensionHypertension► Diabetes mellitusDiabetes mellitus► Heart failure or Heart failure or ↓↓ LV function LV function

Less Validated Risk FactorsLess Validated Risk Factors► Age 65–75 yearsAge 65–75 years► Coronary artery diseaseCoronary artery disease► Female genderFemale gender► ThyrotoxicosisThyrotoxicosis



High-Risk FactorsHigh-Risk Factors► Mitral stenosisMitral stenosis► Prosthetic heart valveProsthetic heart valve► History of stroke or History of stroke or

TIATIA

Moderate-Risk FactorsModerate-Risk Factors► Age >75 yearsAge >75 years► HypertensionHypertension► Diabetes mellitusDiabetes mellitus► Heart failure or Heart failure or ↓↓ LV function LV function

Less Validated Risk FactorsLess Validated Risk Factors► Age 65–75 yearsAge 65–75 years► Coronary artery diseaseCoronary artery disease► Female genderFemale gender► ThyrotoxicosisThyrotoxicosis

Dubious FactorsDubious Factors► Duration of AFDuration of AF► Pattern of AFPattern of AF

(persistent vs. paroxysmal)(persistent vs. paroxysmal)► Left atrial diameterLeft atrial diameter



The CHADSThe CHADS22 Index IndexStroke Risk Score for Atrial FibrillationStroke Risk Score for Atrial Fibrillation

CCongestive Heart failureongestive Heart failure 1 32 1 32HHypertensionypertension 1 65 1 65AAge >75 yearsge >75 years 1 28 1 28DDiabetes mellitusiabetes mellitus 1 18 1 18SStroke or TIAtroke or TIA 2 2 10 10

Moderate-High riskModerate-High risk >>2 50-602 50-60Low riskLow risk 0-1 40-500-1 40-50

VanWalraven C, et al. VanWalraven C, et al. Arch Intern MedArch Intern Med 2003; 163:936. 2003; 163:936.* Nieuwlaat R, et al. (EuroHeart survey) * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart JEur Heart J 2006 (E-published). 2006 (E-published).

Prevalence (%)*Prevalence (%)*Score (points)Score (points)

Nonvalvular Atrial FibrillationNonvalvular Atrial Fibrillation

PriorPriorStroke/TIAStroke/TIA

AgeAge> 75 years> 75 years

HypertensionHypertension FemaleFemale DiabetesDiabetes Heart FailureHeart Failure LVEFLVEF

Str

oke

Rat

eS

t rok

e R

ate

(%/ y

ear)

(%/y

e ar )

Hart RG et al. Hart RG et al. Neurology Neurology 2007; 69: 546.2007; 69: 546.

Stroke Rates Without AnticoagulationStroke Rates Without AnticoagulationAccording to Isolated Risk FactorsAccording to Isolated Risk Factors

00 1.91.9

1 1 2.82.8

22 4.04.0

33 5.95.9

44 8.58.5

55 12.5 12.5

66 18.2 18.2

Van Walraven C, et al. Van Walraven C, et al. Arch Intern MedArch Intern Med 2003; 163:936. 2003; 163:936.Go A, et al. JAMA 2003; 290: 2685.Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.Gage BF, et al. Circulation 2004; 110: 2287.

Risk of StrokeRisk of Stroke(%/year)(%/year)

ScoreScore(points)(points)

3%/year3%/yearApproximateApproximate

Risk threshold forRisk threshold forAnticoagulationAnticoagulation

The CHADSThe CHADS22 Index IndexStroke Risk Score for Atrial FibrillationStroke Risk Score for Atrial Fibrillation

Risk Stratification and AnticoagulationRisk Stratification and AnticoagulationStroke Reduction with Warfarin Instead of AspirinStroke Reduction with Warfarin Instead of Aspirin

Number of patients Number of patients Needed-to-treatNeeded-to-treatto preventto prevent1 stroke/year1 stroke/year

2502504242 8383

EAFT Study Group. EAFT Study Group. Lancet Lancet 1993; 324:1255. 1993; 324:1255. Zabalgoitia M, et al.Zabalgoitia M, et al. J Am Coll Cardiol J Am Coll Cardiol 1998; 31:1622.1998; 31:1622.

1313

CHADS2 Score ~ 3 2 1 0

Antithrombotic Therapy for Atrial FibrillationAntithrombotic Therapy for Atrial FibrillationACC/AHA/ESC Guidelines 2006ACC/AHA/ESC Guidelines 2006

Risk FactorRisk Factor Recommended Recommended TherapyTherapy

No risk factorsNo risk factors

CHADSCHADS22 = 0 = 0 Aspirin, 81-325 mg qdAspirin, 81-325 mg qd

One moderate risk factorOne moderate risk factor

CHADSCHADS22 = 1 = 1Aspirin, 81-325 mg/d orAspirin, 81-325 mg/d or

WarfarinWarfarin(INR 2.0-3.0, target 2.5)(INR 2.0-3.0, target 2.5)

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

CHADSCHADS22 >>22

or Mitral stenosisor Mitral stenosis

WarfarinWarfarin(INR 2.0-3.0, target 2.5)(INR 2.0-3.0, target 2.5)

Prosthetic valveProsthetic valveWarfarinWarfarin

(INR 2.5-3.5, target 3.0)(INR 2.5-3.5, target 3.0)

""Actually, it's more of a Actually, it's more of a guideline than a rule.”guideline than a rule.”

Bill Murray in GhostbustersBill Murray in Ghostbusters Ⓒ Ⓒ (1984)(1984),,relaxing his rule "never to get involved relaxing his rule "never to get involved with possessed people" in response to with possessed people" in response to Sigourney Weaver's seductive advances.Sigourney Weaver's seductive advances.

Patient Selection for AnticoagulationPatient Selection for AnticoagulationAdditional ConsiderationsAdditional Considerations

► Risk of bleedingRisk of bleeding

► Newly anticoagulated vs. Newly anticoagulated vs. established therapyestablished therapy

► Availability of high-quality Availability of high-quality anticoagulation management anticoagulation management programprogram

► Patient preferencesPatient preferences

The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirClopidogrel + Aspirinin

Atrial Fibrillation + Risk Factors

VKA(INR 2-3)

Clopidogrel+ Aspirin

Aspirin+ Placebo


Double-blindSuperiorityn = 7,554

Open-labelNon-inferiorityn = 6,706

Anticoagulation-eligible OAC Contraindications or Unwilling

Irbesartan, 300 mg/d vs. PlaceboIrbesartan, 300 mg/d vs. Placebon = 9,016n = 9,016

Primary outcomePrimary outcome: Stroke, systemic : Stroke, systemic embolism, MI or cardiovascular embolism, MI or cardiovascular deathdeath

ACTIVE - WACTIVE - W ACTIVE - AACTIVE - A

ACTIVE - IACTIVE - I

Risk FactorsRisk Factors::Age Age 75, hypertension, prior 75, hypertension, prior stroke/TIA, LVEF<45%, PAD, age stroke/TIA, LVEF<45%, PAD, age 55-74 + CAD or diabetes55-74 + CAD or diabetes

The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirinClopidogrel + Aspirin


ACTIVE – W ACTIVE – W

VKA(INR 2-3)


Aspirin+ Placebo






ACTIVE - AACTIVE - A


Antithrombotic Therapy for Atrial FibrillationAntithrombotic Therapy for Atrial FibrillationStroke Risk ReductionsStroke Risk Reductions

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

ACTIVE-WACTIVE-WAnticoagulation vs.Anticoagulation vs.Aspirin + ClopidogrelAspirin + Clopidogrel

Anticoagulation vs.Anticoagulation vs.Antiplatelet drugsAntiplatelet drugs


n = 6,706n = 6,706


Antiplatelet RxAntiplatelet RxBetterBetter

Connolly S, et al. Connolly S, et al. LancetLancet 2006; 367:1903. 2006; 367:1903.Hart R, et al. Hart R, et al. Ann Intern MedAnn Intern Med 2007;146:857. 2007;146:857.

Antithrombotic Therapy for Atrial FibrillationAntithrombotic Therapy for Atrial FibrillationStroke Risk ReductionsStroke Risk Reductions

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

Warfarin vs.Warfarin vs.Aspirin + ClopidogrelAspirin + Clopidogrel


Antiplatelet RxAntiplatelet RxBetterBetter

Prior OACPrior OAC

VKA-naVKA-naïïveve

Connolly S, et al. Lancet 2006; 367:1903.

All patientsAll patients

Major Hemorrhage in Relation toMajor Hemorrhage in Relation toPrior Anticoagulant Therapy: Prior Anticoagulant Therapy: ACTIVE-WACTIVE-W

Interaction Interaction pp=0.028=0.028

YesYes

Anticoagulant Therapy at EntryAnticoagulant Therapy at Entry

NoNo

Connolly S, et al. Connolly S, et al. LancetLancet 2006; 367:1903. 2006; 367:1903.

Eve

nt R

ate

Eve

nt R

ate

(%/y

ear)

(%/y

ear)

““Starters”Starters” ““Switchers”Switchers”

The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirinClopidogrel + Aspirin


ACTIVE – W ACTIVE – W

VKA(INR 2-3)


Aspirin+ Placebo






ACTIVE - ACTIVE - AA


Connolly SJ, et al. N Engl J Med 2009; 360:2066. Connolly SJ, et al. N Engl J Med 2009; 360:2066.

Risk factor for bleeding*Risk factor for bleeding* 23%23%

Physician judgment against Physician judgment against anticoagulation for patientanticoagulation for patient

50%50%

Patient preference onlyPatient preference only 26%26%

* Inability to comply with INR monitoringInability to comply with INR monitoring* Predisposition to falling or head traumaPredisposition to falling or head trauma* Persistent hypertension >160/100 mmHgPersistent hypertension >160/100 mmHg* Previous serious bleeding on VKAPrevious serious bleeding on VKA

* Severe alcohol abuse within 2 yearsSevere alcohol abuse within 2 years* Peptic ulcer diseasePeptic ulcer disease* ThrombocytopeniaThrombocytopenia* Chronic need for NSAIDChronic need for NSAID

* Severe alcohol abuse within 2 yearsSevere alcohol abuse within 2 years* Peptic ulcer diseasePeptic ulcer disease* ThrombocytopeniaThrombocytopenia* Chronic need for NSAIDChronic need for NSAID

Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066. Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066.

The ACTIVE TrialThe ACTIVE TrialReasons for Exclusion from AnticoagulationReasons for Exclusion from Anticoagulation

ACTIVE-AACTIVE-ATotal Stroke RateTotal Stroke Ratess

Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066. Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066.

296 (2.4%/year)296 (2.4%/year)

408 (3.3%/year)408 (3.3%/year)

Cum

ulat

ive

Inci

denc

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umul

ativ

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nce

Cum

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Inci

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28% RRR28% RRR HR 0.72 HR 0.72 (95% CI, 0.62–0.83) (95% CI, 0.62–0.83) p p <0.001<0.001

28% RRR28% RRR HR 0.72 HR 0.72 (95% CI, 0.62–0.83) (95% CI, 0.62–0.83) p p <0.001<0.001

0.00.0

0.050.05

0.100.10

0.150.15

00 11 22 33 44

AspirinAspirin

Clopidogrel + AspirinClopidogrel + Aspirin

YearsYears

The ACTIVE TrialsThe ACTIVE TrialsStroke Rates and Risk ReductionsStroke Rates and Risk Reductions

Connolly SJ, et al. Connolly SJ, et al. LancetLancet 2006; 367:1903. 2006; 367:1903.Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066. Connolly SJ, et al. Connolly SJ, et al. LancetLancet 2006; 367:1903. 2006; 367:1903.Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066.

TreatmentTreatment VKAVKA C+AC+A AspirinAspirin

ACTIVE WACTIVE W(Annual Rate)(Annual Rate)

1.41.4 2.42.4 ~~

ACTIVE AACTIVE A(Annual Rate)(Annual Rate)

~~ 2.42.4 3.33.3

RRRRRRversus Aspirinversus Aspirin

-58%-58% -28%-28% ~~

RRRRRRversus C+Aversus C+A

-42%-42% ~ ~ ~~

VKA VKA = oral anticoagulant= oral anticoagulantC+A C+A = clopidogrel + aspirin= clopidogrel + aspirinVKA VKA = oral anticoagulant= oral anticoagulantC+A C+A = clopidogrel + aspirin= clopidogrel + aspirin

Investigational Anticoagulant TargetsInvestigational Anticoagulant Targets

TFPI (tifacogin)

Idraparinux

RivaroxabanRivaroxabanApixabanApixabanEdoxabanEdoxabanLY517717LY517717YM150YM150BetrixabanBetrixabanTAK 42TAK 42

Dabigatran

ORALORAL PARENTERALPARENTERAL

DX-9065aOtamixaban

Xa Xa

IIa IIa

TF/VIIaTF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

II (thrombin)II (thrombin)

FibrinFibrinFibrinogenFibrinogen

ATAT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz JI.Adapted from Weitz JI. Thromb Haemost Thromb Haemost 2007; 5 Suppl 1:65-7.2007; 5 Suppl 1:65-7.

TTP889

APC activated protein CAPC activated protein CAT antithrombinAT antithrombinsTM soluble thrombomodulinsTM soluble thrombomodulinTF tissue factorTF tissue factorFPI tissue factor pathway FPI tissue factor pathway inhibitorinhibitor

Dose, Concentration, or Intensity of Dose, Concentration, or Intensity of AnticoagulationAnticoagulation

Th

rom

bosi

sT

hro

mbo

sis B

leed

ing

Blee

din

g

Safe TherapeuticSafe TherapeuticRangeRange

ThrombosisThrombosis BleedingBleeding

The Ideal AnticoagulantThe Ideal AnticoagulantWide Therapeutic MarginWide Therapeutic Margin

Emerging AnticoagulantsEmerging AnticoagulantsRegulatory IssuesRegulatory Issues

► Open-label vs. blinded trial designOpen-label vs. blinded trial design

► Issues related to active-control trial Issues related to active-control trial designdesign

► How many trials are needed?How many trials are needed?

► Preventing use for unapproved Preventing use for unapproved indicationsindications

► Assessing patient-oriented outcomesAssessing patient-oriented outcomes

Alternatives to AnticoagulationAlternatives to AnticoagulationAtrial FibrillationAtrial Fibrillation

Restoration and maintenance of sinus rhythmRestoration and maintenance of sinus rhythm• Antiarrhythmic drug therapyAntiarrhythmic drug therapy• Catheter ablationCatheter ablation• Maze operationMaze operation

Current approachesCurrent approaches

Emerging (investigational) approachesEmerging (investigational) approaches

Obliteration of the left atrial Obliteration of the left atrial appendageappendage• Trans-catheter occluding devicesTrans-catheter occluding devices• Thoracoscopic epicardial plicationThoracoscopic epicardial plication• Amputation Amputation

Strokes after Conversion to NSRStrokes after Conversion to NSRRate vs. Rhythm Control TrialsRate vs. Rhythm Control Trials

nnRate Rate

controlcontrolRhythm Rhythm controlcontrol

RRRR(95% CI)(95% CI) pp

AFFIRMAFFIRM 4,9174,917 5.7%5.7% 7.3%7.3% 1.28 1.28 (0.95-1.72)(0.95-1.72) 0.120.12

RACERACE 522522 5.5%5.5% 7.9%7.9% 1.44 1.44 (0.75-2.78)(0.75-2.78) 0.440.44

STAFSTAF 266266 1.0%1.0% 3.0%3.0% 3.01 3.01 (0.35-25.3)(0.35-25.3) 0.520.52

PIAFPIAF 252252 0.8%0.8% 0.8%0.8% 1.02 1.02 (0.73-2.16)(0.73-2.16) 0.490.49

TotalTotal 5,9575,957 5.0%5.0% 6.5%6.5% 1.28 1.28 (0.98-1.66)(0.98-1.66) 0.080.08

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

AFFIRM TrialAFFIRM TrialStroke RatesStroke Rates

► 74% of all strokes were proven 74% of all strokes were proven ischemicischemic 44% occurred after stopping warfarin44% occurred after stopping warfarin 28% in patients taking warfarin with INR 28% in patients taking warfarin with INR

<2.0<2.0 42% occurred during documented AF42% occurred during documented AF

Wyse AG, et al. Wyse AG, et al. N Engl J MedN Engl J Med 2002; 347: 1825 2002; 347: 1825.

ATHENA TrialATHENA TrialDronedarone vs. Placebo in Patients with AFDronedarone vs. Placebo in Patients with AF

Hohnloser SH, et al. Hohnloser SH, et al. N Engl J MedN Engl J Med 2009; 360: 668-78. 2009; 360: 668-78.

EventEvent Placebo Placebo (%/y)(%/y)

Dronedarone Dronedarone (%/y)(%/y)

HR HR (95% CI)(95% CI)

PP

StrokeStroke 1.791.79 1.191.19 0.660.66 0.0270.027

Stroke or Stroke or TIATIA 2.052.05 1.371.37 0.670.67 0.0200.020

Fatal strokeFatal stroke 0.540.54 0.360.36 0.670.67 0.2470.247

Stroke Rates Stroke Rates (Secondary Analysis(Secondary Analysis))

Percutaneous LAA OcclusionPercutaneous LAA OcclusionThe WATCHMANThe WATCHMAN®® DeviceDevice

Syed T, Halperin JL. Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med Nature Clin Prac Cardiovasc Med 2007; 4:4282007; 4:428Holmes DR, et al. Holmes DR, et al. Lancet 2009; 374: 534 Lancet 2009; 374: 534

Alternatives to AnticoagulationAlternatives to AnticoagulationAtrial FibrillationAtrial Fibrillation

Restoration and maintenance of sinus Restoration and maintenance of sinus rhythmrhythm• Antiarrhythmic drug therapyAntiarrhythmic drug therapy• Catheter ablationCatheter ablation• Maze operationMaze operation

Current approachesCurrent approaches

Emerging (investigational) approachesEmerging (investigational) approaches

Obliteration of the left atrial Obliteration of the left atrial appendageappendage• Trans-catheter occluding devicesTrans-catheter occluding devices• Thoracoscopic epicardial plicationThoracoscopic epicardial plication• Amputation Amputation

Is atrial fibrillation the cause of strokeor a marker of a population at risk?

Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismThe Next ChallengesThe Next Challenges

► Better tools to stratify bleeding riskBetter tools to stratify bleeding risk

► Noninvasive imaging and biomarkers of Noninvasive imaging and biomarkers of inflammation and thrombosis to predict inflammation and thrombosis to predict clinical events and guide therapyclinical events and guide therapy

► Confirming successful rhythm control over Confirming successful rhythm control over timetime

► Targeted therapy to prevent AF in patients Targeted therapy to prevent AF in patients at riskat risk

► Defining role and risk stratification Defining role and risk stratification strategies for non-monitored, oral strategies for non-monitored, oral anticoagulants anticoagulants

From Fermented Sweet CloverFrom Fermented Sweet Cloverto Molecular Targeting of Coagulationto Molecular Targeting of Coagulation

The Promise of New ApproachesThe Promise of New Approaches

The Goal:The Goal:To bring effective therapy to many more patients To bring effective therapy to many more patients

and prevent thousands of strokes.and prevent thousands of strokes.

Atrial Fibrillation Case StudyAtrial Fibrillation Case Study


► An 82-year-old man with An 82-year-old man with hypertension and diabetes has hypertension and diabetes has permanent atrial fibrillationpermanent atrial fibrillation

► He has a history of spinal He has a history of spinal stenosis and walks with a walkerstenosis and walks with a walker

Question 1: Question 1: Which regimen would you Which regimen would you prescribe for prophylaxis against prescribe for prophylaxis against thromboembolism?thromboembolism?

a.a. Warfarin (INR 2.0-3.0)Warfarin (INR 2.0-3.0)

b.b. Warfarin (INR 1.5-2.0)Warfarin (INR 1.5-2.0)

c.c. Aspirin, 81 mg dailyAspirin, 81 mg daily

d.d. Aspirin, 81 mg + clopidogrel, 75 mg Aspirin, 81 mg + clopidogrel, 75 mg dailydaily

e.e. No antithrombotic therapyNo antithrombotic therapy


Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyAssessment of Thromboembolic RiskAssessment of Thromboembolic Risk

00 1.91.9

1 1 2.82.8

22 4.04.0

33 5.95.9

44 8.58.5

55 12.5 12.5

66 18.2 18.2

Van Walraven C, et al. Van Walraven C, et al. Arch Intern MedArch Intern Med 2003; 163: 936. 2003; 163: 936.Go A, et al. JAMA 2003; 290: 2685.Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.Gage BF, et al. Circulation 2004; 110: 2287.

Risk of StrokeRisk of Stroke(%/year)(%/year)

ScoreScore(points)(points)

Question 2: Question 2: What if you learn that he has What if you learn that he has tripped and fallen twice in the past two tripped and fallen twice in the past two years?years?



c.c. Aspirin, 81 mg dailyAspirin, 81 mg daily

d.d. Aspirin, 81 mg + clopidogrel, 75 mg Aspirin, 81 mg + clopidogrel, 75 mg dailydaily

e.e. No antithrombotic therapyNo antithrombotic therapy


Question 3: Question 3: If the oral direct thrombin inhibitor If the oral direct thrombin inhibitor dabigatran were available and FDA-approved for dabigatran were available and FDA-approved for stroke prevention in AF, in this patient with a stroke prevention in AF, in this patient with a history of tripping you would treat with:history of tripping you would treat with:



c.c. Dabigatran 110 mg P.O. B.I.DDabigatran 110 mg P.O. B.I.D

d.d. Dabigatran 150 mg P.O. B.I.D.Dabigatran 150 mg P.O. B.I.D.

e.e. Aspirin, 81 mg + clopidogrel, 75 mg Aspirin, 81 mg + clopidogrel, 75 mg dailydaily

f.f. No antithrombotic therapyNo antithrombotic therapy


Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyAnticoagulation in Patients at Risk of FallsAnticoagulation in Patients at Risk of Falls

Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyAnticoagulation in Patients at Risk of FallsAnticoagulation in Patients at Risk of Falls

“…“…persons taking warfarin must fall about 295 persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin (535/1.81) times in 1 year for warfarin notnot to be the to be the optimal therapy…”optimal therapy…”

Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyICH in Patients with AF Prone to FallsICH in Patients with AF Prone to Falls

Gage BF, et al. Gage BF, et al. Am J MedAm J Med 2005; 118:612. 2005; 118:612.

► The risk of ICH was 2.8%/year in The risk of ICH was 2.8%/year in patients at patients at high risk of falls and high risk of falls and 1.1 in other patients.1.1 in other patients.

► Warfarin was associated with an Warfarin was associated with an increased increased risk of mortality risk of mortality among those with ICH (30 day among those with ICH (30 day mortality = 52 vs. 34%, mortality = 52 vs. 34%, p p = = 0.007).0.007).

FactorFactor Hazard ratio Hazard ratio (95% CI)(95% CI) P valueP value

High-risk for fallsHigh-risk for falls 1.9 (1.03-2.9)1.9 (1.03-2.9) 0.0020.002

Prior strokePrior stroke 2.2 (1.7-2.8)2.2 (1.7-2.8) <0.0001<0.0001

Prior bleedPrior bleed 1.8 (1.4-2.4)1.8 (1.4-2.4) <0.0001<0.0001

Neuropsychiatric Neuropsychiatric impairmentimpairment 1.4 (1.0-1.9)1.4 (1.0-1.9) 0.0550.055

Hazard ratios of independent predictors Hazard ratios of independent predictors of intracranial hemorrhageof intracranial hemorrhage

Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyOutcomes in Patients with AF Prone to FalOutcomes in Patients with AF Prone to Fallsls

Gage BF, et al. Gage BF, et al. Am J MedAm J Med 2005; 118:612. 2005; 118:612.

CHADS CHADS 22

scorescoreHazard ratio Hazard ratio

(95% CI)(95% CI) P valueP valueRecommended Recommended antithrombotic antithrombotic

therapytherapy

0-10-1 0.98 (0.56, 1.72)0.98 (0.56, 1.72) 0.940.94 Aspirin or nilAspirin or nil

2-62-6 0.75 (0.61, 0.91)0.75 (0.61, 0.91) 0.0040.004 AnticoagulantAnticoagulant

Hazard ratio of warfarin for composite outcome—out-of-Hazard ratio of warfarin for composite outcome—out-of-hospital death or hospitalization for stroke, MI, or hemorrhagehospital death or hospitalization for stroke, MI, or hemorrhage

—in 1245 patients at high risk for falls—in 1245 patients at high risk for falls

Summary of Case StudySummary of Case Study

► The risk of intracranial hemorrhage is The risk of intracranial hemorrhage is increased in patients who fall.increased in patients who fall.

► The use of oral anticoagulation does not The use of oral anticoagulation does not predict ICH, but mortality is higher among predict ICH, but mortality is higher among patients on anticoagulants who develop patients on anticoagulants who develop ICH.ICH.

► The risk of mortality due to ICH is offset by The risk of mortality due to ICH is offset by the reduction in ischemic events achieved the reduction in ischemic events achieved with anticoagulation in elderly patients with anticoagulation in elderly patients with AF at high risk of thromboembolism.with AF at high risk of thromboembolism.

► Better risk-stratification instruments are Better risk-stratification instruments are needed.needed.

Stroke Prevention in Stroke Prevention in High Risk PopulationsHigh Risk Populations

Optimizing Warfarin Therapy in Optimizing Warfarin Therapy in Challenging Patient PopulationsChallenging Patient Populations


Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of Medicine

Department of MedicineDepartment of MedicineDirector, Thrombosis Clinic and Anticoagulation ServiceDirector, Thrombosis Clinic and Anticoagulation Service

Boston University Medical CenterBoston University Medical CenterBoston, MassachusettsBoston, Massachusetts

Prevalence of AF by AgePrevalence of AF by Age

Feinberg WM. Arch Intern Med. 1995;155(5):469–473Feinberg WM. Arch Intern Med. 1995;155(5):469–473

Framingham StudyFramingham Study

Cardiovascular Health StudyCardiovascular Health Study

Mayo Clinic StudyMayo Clinic Study

Western Australia StudyWestern Australia Study

Pre

vale

nce

(%)

Pre

vale

nce

(%)

Age (years)Age (years)4040 50 50 60 60 70 70 80 80 90 90

2020

1818

1616

1414

1212

1010

88

66

44

22

00

Atrial FibrillationAtrial FibrillationMorbidity and MortalityMorbidity and Mortality

►4- to 5-fold increased risk of stroke4- to 5-fold increased risk of stroke►Doubling of the risk for dementiaDoubling of the risk for dementia►Tripling of risk for heart failureTripling of risk for heart failure►40 to 90% increased risk for overall 40 to 90% increased risk for overall

mortalitymortality►Risk of stroke in AF patients by age Risk of stroke in AF patients by age

groupgroup– 1.5% in 50 to 59 year age group1.5% in 50 to 59 year age group– 23.5% in 80 to 89 year age group23.5% in 80 to 89 year age group

Benjamin EJ, et al. Circulation 2009;119:606-618Benjamin EJ, et al. Circulation 2009;119:606-618

““The graying population will slowly, The graying population will slowly, radically transform society.” radically transform society.” Richard Suzman, Richard Suzman,

NIA NIA

► More than 37 million people are ≥ age More than 37 million people are ≥ age 65.65.

► By 2030, this number will exceed 70 By 2030, this number will exceed 70 million. million.

► By 2040, those aged ≥75 years will By 2040, those aged ≥75 years will exceed the exceed the

population 65 to 74 years old.population 65 to 74 years old.► By 2050, 12%, or 1 in 8 Americans, will By 2050, 12%, or 1 in 8 Americans, will

be be

age 75 or older.age 75 or older.

**Coronary heart disease, heart failure, stroke and hypertensionCoronary heart disease, heart failure, stroke and hypertension

15.9

37.9

73.379.3

7.8

38.5

72.6

85.9

0102030405060708090

100

20-39 40-59 60-79 80+

Per

cen

t of P

op

ula

tion

Men Women

Prevalence of CVD* in Adults by Age and Prevalence of CVD* in Adults by Age and Sex (NHANES: 2005-2006)Sex (NHANES: 2005-2006)

Source: NCHS and NHLBI

AgeAge

Pharmacokinetic and Pharmacodynamic Pharmacokinetic and Pharmacodynamic Changes with AgingChanges with Aging

► MetabolismMetabolism Generally, lower drug doses are required to Generally, lower drug doses are required to

achieve the same effectachieve the same effect Receptor numbers, affinity, or post-receptor Receptor numbers, affinity, or post-receptor

cellular effects may changecellular effects may change Overall decline in metabolic capacityOverall decline in metabolic capacity Decreased liver mass Decreased liver mass Decreased oxidative metabolism Decreased oxidative metabolism

through P450 system through P450 system decreased decreased clearance of drugsclearance of drugs

Kidney Function and AgeKidney Function and Age

Andres and Tobin, 1976Andres and Tobin, 1976

Age (years)Age (years)

Sta

ndar

d C

reat

ine

Cle

aran

ceS

tand

ard

Cre

atin

e C

lear

ance

ml/m

in/1

.73

ml/m

in/1

.73

30 40 50 60 70 8030 40 50 60 70 80

140140

130130

120120

110110

100100

Prevalence of Dementia Prevalence of Dementia

North America: 6.9% prevalence; 63% increase 2010-North America: 6.9% prevalence; 63% increase 2010-2030; 151% increase 2010-2050 2030; 151% increase 2010-2050

Polypharmacy in the ElderlyPolypharmacy in the Elderly

► Elderly = 12% of population; Elderly = 12% of population;

32% of prescriptions32% of prescriptions

► Average of 6 prescription medications;Average of 6 prescription medications;

1 to 3.5 over-the-counter drugs 1 to 3.5 over-the-counter drugs

► Average nursing home patientAverage nursing home patient

takes 7 medicationstakes 7 medications

► Average American senior spends Average American senior spends

$670/year for pharmaceuticals$670/year for pharmaceuticals

Adverse Drug ReactionsAdverse Drug Reactions

► About 15% of hospitalizations in the About 15% of hospitalizations in the elderly are related to adverse drug elderly are related to adverse drug reactionsreactions

► The risk of adverse drug reactions The risk of adverse drug reactions increases with the number of increases with the number of prescription medications prescription medications

Polypharmacy and Non-adherencePolypharmacy and Non-adherence

► Strongest predictor of non-adherence is Strongest predictor of non-adherence is

the number of medicationsthe number of medications► Non-adherence rates estimated 25-50%Non-adherence rates estimated 25-50%► Intentional about 75% of the timeIntentional about 75% of the time

Changes in regimen made by Changes in regimen made by patients to: patients to: - Increase convenience - Increase convenience - Reduce adverse effects or - Reduce adverse effects or - Decrease refill expense- Decrease refill expense

Hazards of Anticoagulant MedicationsHazards of Anticoagulant Medications

► #1 in 2003 and 2004 in the number of #1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse mentions of “deaths for drugs causing adverse effects in therapeutic use”effects in therapeutic use”11

► Warfarin-6% of 702,000 ADEs treated in ED per Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalizationyear; 17% require hospitalization11

► 21 million warfarin prescriptions in 1998>>>31 21 million warfarin prescriptions in 1998>>>31 million in 2004million in 200422

► The incidence AC-related intracranial The incidence AC-related intracranial hemorrhage quintupled during this time periodhemorrhage quintupled during this time period33

11 Wysowski DK, et al. Wysowski DK, et al. Arch Intern Med.Arch Intern Med. 2007;167:1414-1419. 2007;167:1414-1419. 22 Budnitz DS, et al. Budnitz DS, et al. JAMAJAMA. 2006;296:1858-1866. . 2006;296:1858-1866. 33 Flaherty ML, et al. Flaherty ML, et al. Neurology.Neurology. 2007;68:116-121. 2007;68:116-121.

Od

ds

Rat

io

005.05.0 6.06.0 8.08.0

INR1.01.0 2.02.0 3.03.0 4.04.0 7.07.0

5.05.0

15.015.0

10.010.0StrokeStroke Intracranial BleedIntracranial Bleed

1.01.0

Fuster et al. Fuster et al. J Am Coll CardiolJ Am Coll Cardiol. 2001;38:1231-1266.. 2001;38:1231-1266.

Ischemic Stroke and Ischemic Stroke and Intracranial BleedingIntracranial Bleeding

Adjusted Odds in Relation to Intensity of AnticoagulationAdjusted Odds in Relation to Intensity of Anticoagulation

Warfarin Dosing is ComplexWarfarin Dosing is ComplexFactors that Correlate w/ Warfarin DoseFactors that Correlate w/ Warfarin Dose

• AgeAge• Body surface area Body surface area

(BSA) or weight(BSA) or weight• Amiodarone Amiodarone • Other drugs (e.g. Other drugs (e.g.

acetaminophen)acetaminophen)• RaceRace• SexSex• Plasma vitamin K levelPlasma vitamin K level• Decompensated CHFDecompensated CHF• ChemotherapyChemotherapy• Genetic status Genetic status

Other Factors (up to 40%)

Age, Sex, Age, Sex, Weight Weight (10-20%)(10-20%)

CYP2C9 CYP2C9 (up to (up to 15%)15%)

VKORC1 VKORC1 (up to 25%)(up to 25%)

ACTIVE W TrialACTIVE W TrialVKA vs dualVKA vs dual

antiplatelet Rxantiplatelet Rx

Circulation 2008;118. Connolly SJ for Active W InvestigatorsCirculation 2008;118. Connolly SJ for Active W Investigators

Minimum thresholdMinimum threshold TTR TTR necessary to necessary to

realize benefit of warfarin:realize benefit of warfarin:

≥ ≥ 58%58%

Comparison of Outcomes Among Patients Comparison of Outcomes Among Patients Randomized to Warfarin According to Anticoagulant Randomized to Warfarin According to Anticoagulant

Control Control Results From SPORTIF III and VResults From SPORTIF III and V

TTR <60%TTR <60% TTR 60-75%TTR 60-75% TTR TTR >75%>75%

OutcomeOutcome TTR < 60%TTR < 60% TTR 60-75%TTR 60-75% TTR>75%TTR>75%

Mortality, %Mortality, % 4.24.2 1.841.84 1.691.69

Major Bleed, %Major Bleed, % 3.853.85 1.961.96 1.581.58

Stroke/SEE,%Stroke/SEE,% 2.102.10 1.341.34 1.071.07

Arch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers GArch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G

Major Hemorrhage RatesMajor Hemorrhage Rates

Randomized TrialsRandomized Trials INR TargetINR Target ICHICH MajorMajor AgeAge

AFIAFI 1.5-4.51.5-4.5 0.30.3 1.01.0 6969

SPAF IISPAF II 2.0-4.52.0-4.5 0.90.9 1.41.4 7070

AFFIRMAFFIRM 2.0-3.02.0-3.0 -------- 2.02.0 7070

RE-LYRE-LY 2.0-3.02.0-3.0 0.70.7 3.43.4 7272

ObservationalObservational INR TargetINR Target ICHICH MajorMajor AgeAge

Van der Meer, et al. Van der Meer, et al. (1993)(1993) 2.8-4.82.8-4.8 0.60.6 2.02.0 6666

Palareti, et al (1996)Palareti, et al (1996) 2.0-4.52.0-4.5 0.50.5 0.90.9 6262

Go, et al (2003)Go, et al (2003) 2.0-3.02.0-3.0 0.50.5 1.01.0 7171

Historical Historical trialstrials

SPORTIF SPORTIF III/VIII/V

ACTIVE ACTIVE WW

RE-LYRE-LY

Year publishedYear published 1989-19931989-1993 2003-20052003-2005 20062006 20092009

NN 3,7633,763 7,3277,327 6,7066,706 18,11318,113

Age, yrsAge, yrs 6969 7171 7070 7272

FemaleFemale 29%29% 31%31% 33%33% 37%37%

Prior strokePrior stroke 5%5% 21%21% 15%15% 20%20%

HypertensionHypertension 45%45% 77%77% 83%83% 79%79%

CHRCHR 26%26% 18%18% 21%21% 32%32%

DiabetesDiabetes 13%13% 18%18% 21%21% 23%23%

CHADSCHADS22 score score NANA NANA 2.02.0 2.12.1

Baseline Characteristics AF TrialsBaseline Characteristics AF Trials

Cumulative Incidence of Major BleedingCumulative Incidence of Major Bleeding

Hylek EM et al, Hylek EM et al, CirculationCirculation 2007;115(21) 2007;115(21)::2689-2696.2689-2696.

Days of WarfarinDays of Warfarin00 100 200 300 400 100 200 300 400

Age < 80Age < 80 Age >=80 Age >=80

Cum

ulat

ive

Pro

port

ion

Cum

ulat

ive

Pro

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ion

with

Maj

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ajor

Hem

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0.00

0

.02

0.

04

0.06

0.

08

0.10

0.00

0

.02

0.

04

0.06

0.

08

0.10

First Year Among Patients Newly Starting Warfarin by AgeFirst Year Among Patients Newly Starting Warfarin by Age

Risk of Stopping Therapy in the First Year Risk of Stopping Therapy in the First Year Among Among

Patients Newly Starting Warfarin by AgePatients Newly Starting Warfarin by Age

Hylek EM et al, Hylek EM et al, CirculationCirculation 2007;115(21) 2007;115(21)::2689-2696.2689-2696.

Days of WarfarinDays of Warfarin

Ris

k of

Sto

ppin

g W

arfa

rinR

isk

of S

topp

ing

War

farin

00 100 200 300 400 100 200 300 400

0

.000

5

.

001

.001

5

.

002

0

.000

5

.

001

.001

5

.

002

Age < 80Age < 80 Age >=80 Age >=80

HemorrhageHemorrhage ThrombosisThrombosis

Optimizing Benefit and Reducing RiskOptimizing Benefit and Reducing Risk

Strategies To Minimize Strategies To Minimize Risk Of HemorrhageRisk Of Hemorrhage

Incidence of UGIB and LGIB increases with Incidence of UGIB and LGIB increases with age.age.

70% of acute UGIB occur > 60 years of 70% of acute UGIB occur > 60 years of age.age.

Differential mucosal effect of ASA by ageDifferential mucosal effect of ASA by age

Incidence of LGIB increases 200-fold from Incidence of LGIB increases 200-fold from the the 33rdrd to 9 to 9thth decade of life: d decade of life: diverticulosis, iverticulosis, angiodysplasias, ischemic colitis, malignancyangiodysplasias, ischemic colitis, malignancy

THE FACTS:THE FACTS:

Bleeding Risk Scores for Warfarin Bleeding Risk Scores for Warfarin TherapyTherapy

LowLow ModerateModerate HighHigh

Kuijer et al. Kuijer et al. Arch Intern Med Arch Intern Med 1999;159:457-601999;159:457-60

00 1-31-3 >3>3 1.6 x age + 1.3 x sex +2.2 x cancer with 1 point for 1.6 x age + 1.3 x sex +2.2 x cancer with 1 point for ≥60, female or malignancy and 0 if none≥60, female or malignancy and 0 if none

Beyth et al.Beyth et al.Am J Med Am J Med 1998;105:91-91998;105:91-9

00 1-21-2 ≥≥33

≥≥65 years old; GI bleed in last 2 weeks; previous 65 years old; GI bleed in last 2 weeks; previous stroke; comorbidities (recent MI, Hct < 30%, stroke; comorbidities (recent MI, Hct < 30%, diabetes, Creat > 1.5) with 1 point for presence of diabetes, Creat > 1.5) with 1 point for presence of each condition and 0 if absenteach condition and 0 if absent

Gage et al.Gage et al.Am Heart J Am Heart J 2006;151:713-92006;151:713-9

0-10-1 2-32-3 ≥≥44

HEMORR2HAGES score: liver/renal disease, HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low ETOH abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, platelet count or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 points for previous bleedrisk factor present with 2 points for previous bleed

Shireman et al.Shireman et al.ChestChest2006;130:1390-62006;130:1390-6

≤≤1.071.07 >1.07 - >1.07 - <2.19<2.19 >2.19>2.19

(0.49 x age >70) + (0.32 x female) + (0.58 x remote (0.49 x age >70) + (0.32 x female) + (0.58 x remote bleed) + 0.62 x recent bleed) + 0.71 x ETOH/drug bleed) + 0.62 x recent bleed) + 0.71 x ETOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for (0.32 x antiplatelet drug use) with 1 point for presence of each and 0 if absentpresence of each and 0 if absent

Warfarin Dose by Age Warfarin Dose by Age

Derived from two independent Derived from two independent ambulatory populationsambulatory populations

Garcia D, et al. Chest 2005 2005;127:2049-2056Garcia D, et al. Chest 2005 2005;127:2049-2056

Female MaleFemale Male Female MaleFemale MaleAgeAgeAgeAge

War

farin

Wee

kly

Dos

e, m

gW

arfa

rin W

eekl

y D

ose,

mg

War

farin

Wee

kly

Dos

e, m

gW

arfa

rin W

eekl

y D

ose,

mg

<50 50-59 60-69 70-79 80-89 >=90<50 50-59 60-69 70-79 80-89 >=90 <50 50-59 60-69 70-79 80-89 >=90<50 50-59 60-69 70-79 80-89 >=90

5050

4545

4040

3535

3030

2525

2020

5050

4545

4040

3535

3030

2525

2020

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00

Interval (days)

1

2

3

4

6

10

INR

1b

Index INR 7 - 9 (n = 235)Median INR half life = 2.3 daysInterquartile Range = (1.7,3.8)

Median days to INR < 4: 1.5 daysInterquartile Range = (1.1,2.5)

Hylek et al, Ann Intern Med. 2001;135:393-400

Delay in INR Normalization with Delay in INR Normalization with Increasing AgeIncreasing Age

Risk Factors for INR > 4.0 After Risk Factors for INR > 4.0 After Holding Two Doses of WarfarinHolding Two Doses of Warfarin

Adjusted Odds Ratio

Warfarin dose, weekly per 10 mgWarfarin dose, weekly per 10 mg 0.87 (0.79 - 0.97)0.87 (0.79 - 0.97)

Age, per decadeAge, per decade 1.18 (1.01 – 1.38)1.18 (1.01 – 1.38)

Decompensated heart failureDecompensated heart failure 2.79 (1.30 – 5.98)2.79 (1.30 – 5.98)

Active malignancyActive malignancy 2.48 (1.11 – 5.57)2.48 (1.11 – 5.57)

Index INR, per unitIndex INR, per unit 1.25 (1.14 – 1.37)1.25 (1.14 – 1.37)

Risk of UGIB with Different Combinations Risk of UGIB with Different Combinations of Antithrombotic Agentsof Antithrombotic Agents

Hallas J, et al. BMJ doi:10.1136/bmj.38947.697558.AEHallas J, et al. BMJ doi:10.1136/bmj.38947.697558.AE

Mean age=72 yearsMean age=72 years

Evolving Role for AspirinEvolving Role for Aspirin

► Meta-analysis of 10 trials that compared oral Meta-analysis of 10 trials that compared oral anticoagulant (OAC) therapy to ASA+OAC. anticoagulant (OAC) therapy to ASA+OAC.

► 4,180 patients with either heart valve, AF, or CAD4,180 patients with either heart valve, AF, or CAD

► Combination therapy:Combination therapy:● Lower incidence of thromboembolism (OR 0.66), but Lower incidence of thromboembolism (OR 0.66), but

the benefits were limited to patients with valves (OR the benefits were limited to patients with valves (OR 0.27). 0.27).

● Did notDid not benefit patients with AF (OR 0.99) or CAD (OR benefit patients with AF (OR 0.99) or CAD (OR 0.69) nor did it influence all cause mortality. 0.69) nor did it influence all cause mortality.

● DidDid increase the risk of major bleeding (OR 1.43). increase the risk of major bleeding (OR 1.43).

Dentali F, Douketis JD, Lim W, Crowther M.Dentali F, Douketis JD, Lim W, Crowther M.Arch Intern Med 2007; 167:117-124.Arch Intern Med 2007; 167:117-124.

Strategies to Improve Quality of Strategies to Improve Quality of VKA-Based Anticoagulant TherapyVKA-Based Anticoagulant Therapy

► Vigilant monitoring around all transitions Vigilant monitoring around all transitions in carein care

► Initiate lower doses in most susceptible Initiate lower doses in most susceptible patient subsetspatient subsets

► Increase monitoring with medication Increase monitoring with medication changes changes

► Reinforce safety points with patients and Reinforce safety points with patients and caregiverscaregivers

► Justify use of concomitant antiplatelet Justify use of concomitant antiplatelet therapytherapy

Summary Points and ConclusionsSummary Points and Conclusions

► Elderly patients with AF are at the highest risk of Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage.stroke and the highest risk of hemorrhage.

► Rates of ischemic stroke significantly exceed Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage rates of ICH and major extracranial hemorrhage on OAC.on OAC.

► Intensive efforts to optimize OAC will help to Intensive efforts to optimize OAC will help to decrease major bleeding.decrease major bleeding.

► Novel anticoagulants Novel anticoagulants maymay be safer in the elderly be safer in the elderly population due to their wider therapeutic index, population due to their wider therapeutic index, shorter tshorter t1/21/2, lack of dietary interference, and fewer , lack of dietary interference, and fewer drug interactions.drug interactions.


► 85-year-old female with AF, HTN, HF, prior TIA, 85-year-old female with AF, HTN, HF, prior TIA, osteoarthritis and prior diverticular GIB six osteoarthritis and prior diverticular GIB six months ago, on warfarin, who presents to the months ago, on warfarin, who presents to the ED with complaints of SOB for several days and ED with complaints of SOB for several days and black stools.black stools.

► Medications: atenolol, lisinopril, lasix, warfarin, Medications: atenolol, lisinopril, lasix, warfarin, ASA ASA

► Most recent INR 3 weeks ago = 3.1Most recent INR 3 weeks ago = 3.1

Atrial Fibrillation Patient Case StudyAtrial Fibrillation Patient Case Study

Question 1: Question 1: This patient’s estimated This patient’s estimated stroke risk per year without warfarin is:stroke risk per year without warfarin is:

a)a)5%5%

b)b)12%12%

c)c)20%20%

d)d)None of the aboveNone of the above


Exam:Exam: afebrile, HR 110-130, BP 154/90 afebrile, HR 110-130, BP 154/90 lungs-bibasilar raleslungs-bibasilar ralesCOR-irreg irregCOR-irreg irregABD-nontenderABD-nontenderguaiac + guaiac +

ECG:ECG: AF with rapid VRAF with rapid VR

CXR:CXR: mild pulmonary edemamild pulmonary edema

Labs:Labs: Hct=21, INR=8.0, Troponin - Hct=21, INR=8.0, Troponin -

Physical Exam and Pertinent DataPhysical Exam and Pertinent Data

Question 2: Question 2: The most appropriate The most appropriate management strategy for this patient management strategy for this patient would be to:would be to:

a)a)Stop both aspirin and warfarin – Resume Stop both aspirin and warfarin – Resume aspirinaspirin only in one weekonly in one week

b)b)Stop both aspirin and warfarin – Resume Stop both aspirin and warfarin – Resume warfainwarfain

c)c)Stop both aspirin and warfarin – Resume Stop both aspirin and warfarin – Resume bothboth warfarin and aspirin in one weekwarfarin and aspirin in one week

d)d)Stop both aspirin and warfarin permanentlyStop both aspirin and warfarin permanently


Question 3: Question 3: The patient’s bleeding episode The patient’s bleeding episode resolves, she is started back on warfarin, and resolves, she is started back on warfarin, and she returns six months later with an hematocrit she returns six months later with an hematocrit of 35 (her baseline). Her INR is 3.7. If of 35 (her baseline). Her INR is 3.7. If dabigatran were approved by the FDA for SPAF, dabigatran were approved by the FDA for SPAF, at this point you would:at this point you would:

a)a)Stop warfarin and put the patient on clopidogrel and Stop warfarin and put the patient on clopidogrel and aspirinaspirinb)b)Adjust the warfarin to achieve an INR of 2.0 - 3.0Adjust the warfarin to achieve an INR of 2.0 - 3.0c)c)Transition patient to dabigatran 110mg PO BIDTransition patient to dabigatran 110mg PO BIDd)d)Transition patient to dabigatran 150 mg PO BidTransition patient to dabigatran 150 mg PO Bide)e)Start aspirin onlyStart aspirin onlyf)f)Stop all anticoagulationStop all anticoagulation


The Emerging Role of The Emerging Role of New Oral AnticoagulantsNew Oral Anticoagulants

Landmark Trials That MayLandmark Trials That MayAlter the Landscape of Stroke Prevention in AFAlter the Landscape of Stroke Prevention in AF


Jeffrey I. Weitz, MD, FRCP, FACPJeffrey I. Weitz, MD, FRCP, FACPProfessor of Medicine and BiochemistryProfessor of Medicine and Biochemistry

McMaster UniversityMcMaster UniversityDirector, Henderson Research CenterDirector, Henderson Research CenterCanada Research Chair in ThrombosisCanada Research Chair in Thrombosis

Heart and Stroke FoundationHeart and Stroke FoundationJ.F. Mustard Chair in Cardiovascular ResearchJ.F. Mustard Chair in Cardiovascular Research

Overview of PresentationOverview of Presentation

► Limitations of warfarinLimitations of warfarin

► New oral anticoagulantsNew oral anticoagulants

► Role of new agents in AFRole of new agents in AF

Limitations of WarfarinLimitations of Warfarin

LimitationLimitation ConsequenceConsequence

Slow onset of actionSlow onset of action Overlap with a parenteral Overlap with a parenteral anticoagulantanticoagulant

Genetic variation in metabolismGenetic variation in metabolism Variable dose requirementsVariable dose requirements

Multiple food and drug Multiple food and drug interactionsinteractions Frequent coagulation monitoringFrequent coagulation monitoring

Narrow therapeutic indexNarrow therapeutic index Frequent coagulation monitoringFrequent coagulation monitoring

New New Oral Anticoagulants for Stroke Oral Anticoagulants for Stroke Prevention in AFPrevention in AF

Direct Inhibitors of Factor Xa Direct Inhibitors of Factor Xa or Thrombinor Thrombin

Comparison of Features of New OralComparison of Features of New OralAnticoagulants in Advanced Stages of DevelopmentAnticoagulants in Advanced Stages of Development

FeaturesFeatures RivaroxabanRivaroxaban ApixabanApixaban Dabigatran Dabigatran EtexilateEtexilate

TargetTarget XaXa XaXa IIaIIa

Molecular WeightMolecular Weight 436436 460460 628628

ProdrugProdrug NoNo NoNo YesYes

Bioavailability (%)Bioavailability (%) 8080 5050 66

Time to peak (h)Time to peak (h) 33 33 22

Half-life (h)Half-life (h) 99 9-149-14 12-1712-17

Renal excretion Renal excretion (%)(%) 6565 2525 8080

AntidoteAntidote NoneNone NoneNone NoneNone

Comparison of Features of New Comparison of Features of New Anticoagulants With Those of WarfarinAnticoagulants With Those of Warfarin

FeaturesFeatures WarfarinWarfarin New AgentsNew Agents

OnsetOnset SlowSlow RapidRapid

DosingDosing VariableVariable FixedFixed

Food effectFood effect YesYes NoNo

Drug interactionsDrug interactions ManyMany FewFew

MonitoringMonitoring YesYes NoNo

Half-lifeHalf-life LongLong ShortShort

AntidoteAntidote YesYes NoNo

1.1. Oral factor Xa inhibitors have a better safety profile Oral factor Xa inhibitors have a better safety profile than oral thrombin inhibitorsthan oral thrombin inhibitors

2.2. Of the new oral anticoagulants, dabigatran etexilate Of the new oral anticoagulants, dabigatran etexilate is most advanced in developmentis most advanced in development

3.3. Oral factor Xa inhibitors can be safely given to Oral factor Xa inhibitors can be safely given to patients with a creatinine clearance < 30 ml/minpatients with a creatinine clearance < 30 ml/min

4.4. The prothrombin time can be used to monitor all The prothrombin time can be used to monitor all of the new oral anticoagulantsof the new oral anticoagulants

5.5. Fresh frozen plasma will reverse the anticoagulantFresh frozen plasma will reverse the anticoagulant effects of the new oral anticoagulantseffects of the new oral anticoagulants

Which of the Following Which of the Following Statements is trueStatements is true??

RE-LY: A Non-inferiority TrialRE-LY: A Non-inferiority Trial

R

Open

•Atrial Fibrillation with ≥ 1 Risk Factor• Absence of Contraindications• Conducted in 951 centers in 44

countries

WarfarinAdjusted

INR 2.0 – 3.0N=6000

Dabigatran etexilate 110 mg BID

N=6000

Dabigatran etexilate 150 mg BID

N=6000

Blinded Event Adjudication

OpenOpen BlindedBlinded

RR

RE-LY: Baseline CharacteristicsRE-LY: Baseline Characteristics

CharacteristicCharacteristic Dabigatran Dabigatran 110 mg110 mg

Dabigatran Dabigatran 150 mg150 mg WarfarinWarfarin

RandomizedRandomized 60156015 60766076 60226022

Mean age (years)Mean age (years) 71.471.4 71.571.5 71.671.6

Male (%)Male (%) 64.364.3 63.263.2 63.363.3

CHADS2 score CHADS2 score (mean)(mean) 0-1 (%)0-1 (%) 2 (%)2 (%) 3+ (%)3+ (%)

2.12.1

32.632.634.734.732.732.7

2.22.2

32.232.235.235.232.632.6

2.12.1

30.930.937.037.032.132.1

Prior stroke/TIA (%)Prior stroke/TIA (%) 19.919.9 20.320.3 19.819.8

Prior MI (%)Prior MI (%) 16.816.8 16.916.9 16.116.1

CHF (%)CHF (%) 32.232.2 31.831.8 31.931.9

Baseline ASA (%)Baseline ASA (%) 40.040.0 38.738.7 40.640.6

Warfarin Naïve (%)Warfarin Naïve (%) 49.949.9 49.849.8 51.451.4

Connolly et al., Connolly et al., NEJMNEJM, 2009, 2009

RE-LY: Stroke or Systemic EmbolismRE-LY: Stroke or Systemic Embolism

0.500.50 0.750.75 1.001.00 1.251.25 1.501.50

Dabigatran 110 vs. WarfarinDabigatran 110 vs. Warfarin

Dabigatran 150 vs. WarfarinDabigatran 150 vs. Warfarin

Non-inferiorityNon-inferiorityp-valuep-value<0.001<0.001

<0.001<0.001

SuperioritySuperiorityp-valuep-value

0.340.34

<0.001<0.001

Margin = 1.46Margin = 1.46

HR (95% CI)HR (95% CI)Warfarin betterWarfarin betterDabigatran betterDabigatran better


RE-LY: Annual Rates of BleedingRE-LY: Annual Rates of Bleeding

DabigatranDabigatran

110mg110mg

DabigatranDabigatran

150mg150mgWarfarinWarfarin

Dabigatran Dabigatran 110mg vs. 110mg vs. WarfarinWarfarin

Dabigatran Dabigatran 150mg vs. 150mg vs. WarfarinWarfarin

nn 60156015 60786078 60226022RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

TotalTotal 14.6%14.6% 16.4%16.4% 18.2%18.2%0.780.78

0.74-0.830.74-0.83<0.001<0.001

0.910.91

0.86-0.970.86-0.970.0020.002

Major Major 2.7 %2.7 % 3.1 %3.1 % 3.4 %3.4 %0.800.80

0.69-0.930.69-0.930.0030.003

0.930.93

0.81-1.070.81-1.070.310.31

Life- Life- Threatening Threatening 1.2 %1.2 % 1.5 %1.5 % 1.8 %1.8 %

0.680.68

0.55-0.830.55-0.83<0.001<0.001

0.810.81

0.66-0.990.66-0.990.040.04

Gastro-Gastro-intestinalintestinal 1.1 %1.1 % 1.5 %1.5 % 1.0 %1.0 %

1.101.10

0.86-1.410.86-1.410.430.43

1.501.50

1.19-1.891.19-1.89<0.001<0.001


RR 0.40 (95% CI: 0.27–0.60)

p<0.001 (sup)

RE-LY: Intra-cranial Bleeding RatesRE-LY: Intra-cranial Bleeding Rates

RR 0.31 (95% CI: 0.20–0.47)

p<0.001 (sup)

Nu

mb

er o

f ev

ents

Nu

mb

er o

f ev

ents

0,23 %0,23 %

0,74 %0,74 %

0,30 %0,30 %

RRRRRR69%69%

RRRRRR60%60%


► Targeted inhibition of thrombinTargeted inhibition of thrombin

► Consistent and predictable Consistent and predictable anticoagulant effectanticoagulant effect

How can dabigatran be more effective How can dabigatran be more effective than warfarin yet cause less bleeding?than warfarin yet cause less bleeding?

RE-LY: Secondary Efficacy Outcomes RE-LY: Secondary Efficacy Outcomes According to Treatment GroupAccording to Treatment Group

Connolly, et al. N Engl J Med N Engl J Med 2009;361:1139-51

EventEvent Dabigatran Dabigatran 110 mg110 mg

Dabigatran Dabigatran 150 mg150 mg WarfarinWarfarin

Myocardial Myocardial infarctioninfarction 0.7%0.7% 0.7%0.7% 0.5%0.5%

Vascular deathVascular death 2.4%2.4% 2.3%2.3% 2.7%2.7%

All-cause All-cause mortalitymortality 3.8%3.8% 3.6%3.6% 4.1%4.1%

► Chance finding?Chance finding?

► Warfarin superior to dabigatran for Warfarin superior to dabigatran for inhibitionof clotting at sites of plaque inhibitionof clotting at sites of plaque disruption?disruption?

► Other factors?Other factors?

Why is There More MI with Dabigatran?Why is There More MI with Dabigatran?

End pointEnd point Warfarin Warfarin Dabigatran Dabigatran

110 mg 110 mg twice dailytwice daily

RR (95% CI) RR (95% CI) vs warfarinvs warfarin pp

Dabigatran Dabigatran 150 mg150 mg

twice dailytwice daily

RR (95% CI) RR (95% CI) vs warfarinvs warfarin pp

Stroke/ systemic Stroke/ systemic embolism embolism (%/year)(%/year)

2.742.74 2.322.32 0.850.85(0.59–1.22)(0.59–1.22) 0.370.37 2.07 2.07 0.760.76

(0.53–1.10) (0.53–1.10) 0.140.14

Hemorrhagic Hemorrhagic stroke (n)stroke (n) 1818 22

0.110.11(0.03–0.47)(0.03–0.47) 0.0030.003 55

0.270.27(0.10–0.72) (0.10–0.72) 0.0090.009

ICH (n)ICH (n) 3030 660.200.20

(0.08–0.47)(0.08–0.47) 0.0010.001 1313 0.410.41(0.21–0.79) (0.21–0.79) 0.0070.007

RE-LY: Outcomes in Secondary-Prevention RE-LY: Outcomes in Secondary-Prevention Patients with AF by Treatment AssignmentPatients with AF by Treatment Assignment

Diener HC et al. American Stroke Association International Stroke Conference Diener HC et al. American Stroke Association International Stroke Conference 2010; February 26, 2010; San Antonio, TX. 2010; February 26, 2010; San Antonio, TX.

RE-LY: Cumulative Risk of ALT or AST RE-LY: Cumulative Risk of ALT or AST >3x ULN After Randomization>3x ULN After Randomization

Years of follow-up

DabigatranDabigatran 110 mg110 mg

Cu

mu

lati

ve r

isk

0.0

0.01

0.02

0.03

0.04

0 0.5 1.0 1.5 2.0 2.5

Dabigatran 150 mg

Warfarin

Connolly, et al. N Engl J Med N Engl J Med 2009;361:1139-51

Lower-dose regimenLower-dose regimen

► ElderlyElderly

► Renal insufficiencyRenal insufficiency

► Lower stroke risk (CHADSLower stroke risk (CHADS22 score of 1) score of 1)

Higher-dose regimenHigher-dose regimen

► Higher stroke risk (CHADSHigher stroke risk (CHADS22 score ≥ 2) score ≥ 2)

Which Dose for Which Patient?Which Dose for Which Patient?

Camm J.: Oral presentation at ESC on Aug 30th 2009. Camm J.: Oral presentation at ESC on Aug 30th 2009.

Meta-analysis of Ischemic Stroke Meta-analysis of Ischemic Stroke or Systemic Embolismor Systemic Embolism

W vs placeboW vs placebo

W vs W low doseW vs W low dose

W vs ASAW vs ASA

W vs ASA + clopidogrelW vs ASA + clopidogrel

W vs dabigatran 150W vs dabigatran 150

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

FavoursFavours warfarinwarfarin Favours other treatmentFavours other treatment

What About Trials with What About Trials with Other New Oral AnticoagulantsOther New Oral Anticoagulants??

► ROCKETROCKET – Rivaroxaban – Rivaroxaban

► ARISTOTLEARISTOTLE – Apixaban – Apixaban

► ENGAGEENGAGE - Edoxaban - Edoxaban

What about other What about other indications?indications?

RE-COVERRE-COVERTM TM Trial DesignTrial Design

ObjectiveObjectiveconfirmationconfirmation

of VTEof VTE

EE RR

30 days30 daysfollow up follow up

Initial parenteraltherapy

Single-dummyperiod Double-dummy period

7272 hh

6 months6 monthsEnd of treatmentEnd of treatment

Until INR Until INR 2.0 on2.0 ontwo consecutivetwo consecutivemeasurementsmeasurements

(8-11 days)(8-11 days)

WarfarinWarfarin WarfarinWarfarin(INR 2.0–3.0)(INR 2.0–3.0)

Dabigatran etexilate placebo bidDabigatran etexilate placebo bid

Warfarin placeboWarfarin placebo

Dabigatran etexilate 150 mg bidDabigatran etexilate 150 mg bidWarfarinWarfarinplaceboplacebo

E= enrolmentE= enrolmentR= randomizationR= randomization

Efficacy and Safety OutcomesEfficacy and Safety Outcomes

Schulman et al., N Engl J Med, 2009Schulman et al., N Engl J Med, 2009

OutcomeOutcome DabigatranDabigatran DabigatranDabigatran HR (95% CI)HR (95% CI)

Recurrent VTE Recurrent VTE and VTE-related and VTE-related deathdeath

2.4%2.4% 2.1%2.1% 1.10 (0.65-1.84)1.10 (0.65-1.84)

Major bleedingMajor bleeding 1.6%1.6% 1.9%1.9% 0.82 (0.45-1.48)0.82 (0.45-1.48)

Is Warfarin Obsolete?Is Warfarin Obsolete?

► New oral anticoagulants are more New oral anticoagulants are more convenientconvenient

► But, warfarin effective when time But, warfarin effective when time in therapeutic range is highin therapeutic range is high

Cumulative Risk of Stroke, MI, Cumulative Risk of Stroke, MI, Systemic Embolism, or Vascular DeathSystemic Embolism, or Vascular Death

Connolly, S. J. et al. Circulation 2008;118:2029-2037Connolly, S. J. et al. Circulation 2008;118:2029-2037

OACOAC

OACOAC

C+AC+A

C+AC+A

YearsYears YearsYears

Eve

nt R

ate

(%)

Eve

nt R

ate

(%)

Eve

nt R

ate

(%)

Eve

nt R

ate

(%)

TTR < 65%TTR < 65% TTR >= 65%TTR >= 65%

RR=0.93 (0.70-1.24)RR=0.93 (0.70-1.24)p=0.61p=0.61

RR=2.14 (1.61-2.85)RR=2.14 (1.61-2.85)P=0.0001P=0.0001

0.0 0.5 1.0 1.50.0 0.5 1.0 1.5 0.0 0.5 1.0 1.50.0 0.5 1.0 1.5

1212

1010

88

66

44

22

00

1212

1010

88

66

44

22

00

Patients treated at centers with a TTR below or above the study median (65%)Patients treated at centers with a TTR below or above the study median (65%)

Time in Therapeutic Range (TTR) with Time in Therapeutic Range (TTR) with Warfarin in the RE-LY TrialWarfarin in the RE-LY Trial

GroupGroup Relative RiskRelative Risk

OverallOverall 64%64%

VKA ExperiencedVKA Experienced 61%61%

VKA NaVKA Naïveve 67%67%

All patientsLong-term VKA therapy

No

Yes

Region

North America

South America

Western Europe

Central Europe

South Asia

East Asia

Other

0.5 1.0 1.5 0.5 1.0 1.5

Dabigatran Better Dabigatran BetterWarfarin Better Warfarin Better

0.72

0.91

0.81

0.11

18,113 1.53 1.11 1.69

9,123 1.57 1.07 1.67

8,989 1.49 1.15 1.70

6,533 1.19 1.11 1.51

1,134 1.82 0.91 1.68

2,829 1.22 0.78 1.06

3,941 1.53 1.26 1.43

1,134 3.35 0.84 4.00

1,648 1.87 1.77 2.28

1,072 1.95 0.88 2.27

SubgroupPatientstotal no. 110 mg 150 mg

WarfarinDabigatranHazard Ratio withDabigatran, 100

mg (95% CI)

Hazard Ratio withDabigatran,

150 mg (95% CI)

P Valuefor

Interaction

P Valuefor

Interaction

Relative Risk of Stroke or Systemic Embolism Relative Risk of Stroke or Systemic Embolism with According to Geographical Regionwith According to Geographical Region

Connolly et al., Connolly et al., NEJM NEJM 20092009

Dabigatran Versus WarfarinDabigatran Versus Warfarin

► Stable on warfarinStable on warfarin

► Renal impairmentRenal impairment

► Severe hepatic diseaseSevere hepatic disease

► Poor compliance Poor compliance

Who is Not a Candidate for Who is Not a Candidate for Dabigatran?Dabigatran?

► Management of patients with severe Management of patients with severe coronary artery disease or recent GI coronary artery disease or recent GI bleeding?bleeding?

► Will short half-life obviate need for Will short half-life obviate need for antidotes?antidotes?

► Will elimination of monitoring Will elimination of monitoring adversely impact patient care?adversely impact patient care?

Unanswered QuestionsUnanswered Questions

► Dabigatran etexilate is superior to Dabigatran etexilate is superior to warfarin for stroke prevention and warfarin for stroke prevention and non-inferior for VTE treatmentnon-inferior for VTE treatment

► Dosing of new oral anticoagulants is Dosing of new oral anticoagulants is critical; are the doses of factor Xa critical; are the doses of factor Xa inhibitors optimal?inhibitors optimal?

► New oral anticoagulants will replace New oral anticoagulants will replace warfarin, but transition likely to be warfarin, but transition likely to be slowslow

Conclusions: RE-LY and New, Oral Non-Conclusions: RE-LY and New, Oral Non-Monitored AnticoagulationMonitored Anticoagulation


► Mrs. A. is a 78-year-old woman who is Mrs. A. is a 78-year-old woman who is taking warfarin for stroke prevention on the taking warfarin for stroke prevention on the background of atrial fibrillation. She also background of atrial fibrillation. She also takes ASA 81 mg daily. takes ASA 81 mg daily.

► Her risk factors for stroke include Her risk factors for stroke include hypertension and type II diabetes mellitus. hypertension and type II diabetes mellitus. Her INR control has been erratic with values Her INR control has been erratic with values ranging from 1.5 to 6.8. ranging from 1.5 to 6.8.

► For the past two weeks, she has had For the past two weeks, she has had intermittent nosebleeds lasting 5 to 20 intermittent nosebleeds lasting 5 to 20 minutes. She is anxious to stop warfarin. minutes. She is anxious to stop warfarin.


Question 1: Question 1: What is the best approach for What is the best approach for this patient?this patient?

(a)(a)Stop the warfarin and the ASAStop the warfarin and the ASA

(b)(b)Stop the ASA, but continue warfarinStop the ASA, but continue warfarin

(c)(c)Perform CYP2C9 and VKORC1 genotyping to Perform CYP2C9 and VKORC1 genotyping to better identify an appropriate warfarin dosebetter identify an appropriate warfarin dose

(d)(d)Stop the warfarin and add clopidogrel 75 mg Stop the warfarin and add clopidogrel 75 mg dailydaily

(e)(e)Continue warfarin and ASA, but monitor the Continue warfarin and ASA, but monitor the INR more frequentlyINR more frequently


The ASA was stopped, but Mrs. A. still The ASA was stopped, but Mrs. A. still complains of nosebleeds. Despite complains of nosebleeds. Despite weekly monitoring, her INR continues weekly monitoring, her INR continues to range from 1.8 to 4.8. A calculated to range from 1.8 to 4.8. A calculated creatinine clearance is 45 ml/min.creatinine clearance is 45 ml/min.


Question 2Question 2: If dabigatran were approved for : If dabigatran were approved for stroke prevention in patients with atrial stroke prevention in patients with atrial fibrillation, what would you likely do at this fibrillation, what would you likely do at this point?point?

(a)(a)Continue on warfarinContinue on warfarin

(b)(b)Continue on warfarin, but add low-dose Continue on warfarin, but add low-dose vitamin Kvitamin K

(c)(c)Switch from warfarin to dabigatran etexilate Switch from warfarin to dabigatran etexilate 110 mg b.i.d.110 mg b.i.d.

(d)(d)Switch from warfarin to dabigatran etexilate Switch from warfarin to dabigatran etexilate 150 mg b.i.d.150 mg b.i.d.

(e)(e)Switch from warfarin to ASA and clopidogrelSwitch from warfarin to ASA and clopidogrel


Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismCurrent State of the Art and ScienceCurrent State of the Art and Science

► There is a new, quickening rhythm to the pace of There is a new, quickening rhythm to the pace of research and clinical advances in atrial fibrillationresearch and clinical advances in atrial fibrillation

► Etiology of AF is multifactorial and we are just Etiology of AF is multifactorial and we are just beginning to understand the inter-relationship beginning to understand the inter-relationship among myriad factorsamong myriad factors

► Noninvasive imaging and biomarkers of Noninvasive imaging and biomarkers of inflammation and thrombosis can predict clinical inflammation and thrombosis can predict clinical events in AF and may help guide therapyevents in AF and may help guide therapy

► Risk stratification strategies for AF are useful but Risk stratification strategies for AF are useful but imperfect: advances and refinements are required imperfect: advances and refinements are required to help define role for non-monitored, oral to help define role for non-monitored, oral anticoagulants anticoagulants

Atrial Fibrillation and ThromboembolismAtrial Fibrillation and Thromboembolism Current State of the Art and ScienceCurrent State of the Art and Science

► Strategies are being developed to improve the Strategies are being developed to improve the safety and efficacy of vitamin K antagonists safety and efficacy of vitamin K antagonists (VKAs), but achieving acceptable TTRs remains a (VKAs), but achieving acceptable TTRs remains a challengechallenge

► Elderly patients with AF are at the highest risk of Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage, and stroke and the highest risk of hemorrhage, and therefore demand special attentiontherefore demand special attention

► Novel anticoagulants Novel anticoagulants appearappear to be safer in the to be safer in the elderly population due to their wider therapeutic elderly population due to their wider therapeutic index, shorter tindex, shorter t1/21/2, lack of dietary interference, , lack of dietary interference, and fewer drug interactions.and fewer drug interactions.


► Dabigatran etexilate is superior to warfarin for Dabigatran etexilate is superior to warfarin for stroke stroke prevention and non-inferior for VTE treatmentprevention and non-inferior for VTE treatment

► Dosing strategy for new oral anticoagulants is Dosing strategy for new oral anticoagulants is critical:critical: selecting the appropriate dose in the individual selecting the appropriate dose in the individual patient to patient to achieve ideal balance of stroke prevention and achieve ideal balance of stroke prevention and bleeding bleeding minimization is a work in progressminimization is a work in progress

► New oral anticoagulants will replace warfarin, and New oral anticoagulants will replace warfarin, and the the transition will impact the landscape of transition will impact the landscape of anticoagulation anticoagulation managementmanagement

The RE-LY Trial represents the most compelling The RE-LY Trial represents the most compelling evidence evidence to date for revising, reconsidering, and reshaping to date for revising, reconsidering, and reshaping our our current VKA-based paradigm for stroke prevention current VKA-based paradigm for stroke prevention in AFin AF

► Dabigatran etexilate is superior to warfarin for Dabigatran etexilate is superior to warfarin for stroke stroke prevention and non-inferior for VTE treatmentprevention and non-inferior for VTE treatment

► Dosing strategy for new oral anticoagulants is Dosing strategy for new oral anticoagulants is critical:critical: selecting the appropriate dose in the individual selecting the appropriate dose in the individual patient to patient to achieve ideal balance of stroke prevention and achieve ideal balance of stroke prevention and bleeding bleeding minimization is a work in progressminimization is a work in progress

► New oral anticoagulants will replace warfarin, and New oral anticoagulants will replace warfarin, and the the transition will impact the landscape of transition will impact the landscape of anticoagulation anticoagulation managementmanagement

The RE-LY Trial represents the most compelling The RE-LY Trial represents the most compelling evidence evidence to date for revising, reconsidering, and reshaping to date for revising, reconsidering, and reshaping our our current VKA-based paradigm for stroke prevention current VKA-based paradigm for stroke prevention in AFin AF

► At least four trials evaluating the safety and At least four trials evaluating the safety and efficacy of oral, non-monitored anticoagulants efficacy of oral, non-monitored anticoagulants

for SPAF are in progress: stay tunedfor SPAF are in progress: stay tuned


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Documents

New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistApplying Landmark