please take this time to complete the pre-program performance

Please take this time to complete the Pre-Program Performanceand Knowledge Gap Assessment Tool in your syllabus. Thank you.

New Frontiers New Frontiers inin

Thrombosis Reduction Thrombosis Reduction forfor Heart Heart DiseaseDisease

Focus on Novel Agents Across the ACS and AF Risk Focus on Novel Agents Across the ACS and AF Risk Spectrum—Spectrum—

A Year 2010 Advanced Practice Summit A Year 2010 Advanced Practice Summit for the Cardiovascular Specialistfor the Cardiovascular Specialist

Thrombosis Risk Reduction: An OverviewThrombosis Risk Reduction: An Overview

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIProgram ChairmanProgram Chairman

Chief of Cardiology, VA Boston Healthcare SystemChief of Cardiology, VA Boston Healthcare SystemDirector, Integrated Interventional Cardiovascular ProgramDirector, Integrated Interventional Cardiovascular Program

Brigham and Women’s Hospital and the VA Boston Healthcare SystemBrigham and Women’s Hospital and the VA Boston Healthcare SystemAssociate Professor of Medicine, Harvard Medical SchoolAssociate Professor of Medicine, Harvard Medical School

Senior Investigator, TIMI GroupSenior Investigator, TIMI Group

CME-certified symposium CME-certified symposium jointly jointly sponsored by the Postgraduate sponsored by the Postgraduate Institute of Medicine and Institute of Medicine and CMEducation Resources, LLCCMEducation Resources, LLC

Commercial Support: Commercial Support: Sponsored by Sponsored by an independent educational grant an independent educational grant from from the Bristol-Myers Squibb/Pfizer the Bristol-Myers Squibb/Pfizer PartnershipPartnership

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

Welcome and Program Overview Welcome and Program Overview Welcome and Program Overview Welcome and Program Overview

Program FacultyProgram Faculty

Deepak L. Bhatt, MD, MPH, FACC, Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIFAHA, FSCAIProgram ChairmanProgram ChairmanChief of Cardiology, VA Boston Chief of Cardiology, VA Boston Healthcare Healthcare SystemSystemDirector, Integrated Interventional Director, Integrated Interventional Cardiovascular ProgramCardiovascular ProgramBrigham and Women’s Hospital and the Brigham and Women’s Hospital and the VA VA Boston Healthcare SystemBoston Healthcare SystemAssociate Professor, Harvard Medical Associate Professor, Harvard Medical School Senior Investigator, TIMI GroupSchool Senior Investigator, TIMI GroupBoston, Massachusetts USABoston, Massachusetts USA Gregory Y.H. Lip, MD, FRCP, FACC, Gregory Y.H. Lip, MD, FRCP, FACC, FESCFESCConsultant Cardiologist and Professor of Consultant Cardiologist and Professor of Cardiovascular MedicineCardiovascular MedicineDirector, Haemostasis Thrombosis & Director, Haemostasis Thrombosis & Vascular Biology UnitVascular Biology UnitUniversity of Birmingham Centre for University of Birmingham Centre for Cardiovascular SciencesCardiovascular SciencesCity HospitalCity HospitalBirmingham, EnglandBirmingham, England

Shamir Mehta, MD, MSc, FACC, FRCPCShamir Mehta, MD, MSc, FACC, FRCPCDirector, Interventional CardiologyDirector, Interventional CardiologyHamilton Health SciencesHamilton Health SciencesAssociate ProfessorAssociate ProfessorMcMaster UniversityMcMaster UniversityHamilton, Ontario, CanadaHamilton, Ontario, Canada David A. Garcia, MDDavid A. Garcia, MDAssociate Professor, Division of General Associate Professor, Division of General Internal Internal MedicineMedicineUniversity of New MexicoUniversity of New MexicoCo-Director, University of New Mexico Co-Director, University of New Mexico Anticoagulation Management ServiceAnticoagulation Management ServicePresident, Anticoagulation ForumPresident, Anticoagulation ForumAlbuquerque, New Mexico USAAlbuquerque, New Mexico USA

Richard C. Becker, MDRichard C. Becker, MDProfessor of MedicineProfessor of MedicineSchool of MedicineSchool of MedicineDuke UniversityDuke UniversityDirector, Duke Cardiovascular Thrombosis Director, Duke Cardiovascular Thrombosis CenterCenterDuke Clinical Research InstituteDuke Clinical Research InstituteDurham, North Carolina USADurham, North Carolina USA

Issues We Will AddressIssues We Will Address

► Changing landscape for AFIB with Factor II and Xa Changing landscape for AFIB with Factor II and Xa inhibitors, and how cardiologists will respondinhibitors, and how cardiologists will respond

► The various risk groups for AFIB including de novo The various risk groups for AFIB including de novo patients, patients who have failed coumadin for one patients, patients who have failed coumadin for one reason or another (erratic TTRs or bleeding) and patients reason or another (erratic TTRs or bleeding) and patients who do not want to take coumadin or are not deemed who do not want to take coumadin or are not deemed suitable candidatessuitable candidates

► Pushing the envelope on ACS prevention with triple Pushing the envelope on ACS prevention with triple therapy and whether non-coumadin systemic therapy and whether non-coumadin systemic anticoagulation might offer the opportunity to more anticoagulation might offer the opportunity to more favorably balance the benefit-to-risk ratio, a possibility favorably balance the benefit-to-risk ratio, a possibility given the reduced ICH and major bleed rate with low-given the reduced ICH and major bleed rate with low-dose dabigatrandose dabigatran

► Will "milder, gentler" but non-inferior, and perhaps Will "milder, gentler" but non-inferior, and perhaps superior oral, non-monitored anticoagulation offer new superior oral, non-monitored anticoagulation offer new opportunities and new challenges for risk stratifying opportunities and new challenges for risk stratifying subsets of patients with AF and ACS?subsets of patients with AF and ACS?

► Is warfarin on the path to extinction or will it reinvent Is warfarin on the path to extinction or will it reinvent itself with the aid of pharmacogenomic guidance, itself with the aid of pharmacogenomic guidance, algorithm-directed care, patient self-monitoring, and a algorithm-directed care, patient self-monitoring, and a host of “let's make coumadin as good as we can” host of “let's make coumadin as good as we can” maneuvers?maneuvers?

Issues We Will AddressIssues We Will Address

Atrial Fibrillation and ACS: Atrial Fibrillation and ACS: The Changing Antithrombotic The Changing Antithrombotic

LandscapeLandscape

New Dimensions and New Dimensions and Landmark Practice AdvancesLandmark Practice Advances

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIChief of Cardiology,VA Boston Healthcare SystemChief of Cardiology,VA Boston Healthcare System

Director, Integrated Interventional Cardiovascular Program, Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System Brigham and Women’s Hospital and the VA Boston Healthcare System

Associate Professor of Medicine, Harvard Medical SchoolAssociate Professor of Medicine, Harvard Medical SchoolSenior Investigator, TIMI GroupSenior Investigator, TIMI Group

Boston, MassachusettsBoston, Massachusetts

Atherothrombosis:Atherothrombosis:Clinical ManifestationsClinical Manifestations

StrokeStrokeTIATIAIntracranial stenosisIntracranial stenosis

Carotid artery stenosisCarotid artery stenosisCEACEACarotid stentingCarotid stenting Renal artery stenosisRenal artery stenosisRenal artery stentingRenal artery stenting

Peripheral arterial diseasePeripheral arterial diseaseAcute limb ischemiaAcute limb ischemiaClaudicationClaudicationAmputationAmputationEndovascular stentingEndovascular stentingPeripheral bypassPeripheral bypassAbnormal ABIAbnormal ABI

Acute coronary syndromesAcute coronary syndromes– STEMISTEMI– NSTEMINSTEMI– Unstable anginaUnstable anginaStable CADStable CADAtrial FibrillationAtrial FibrillationAngioplastyAngioplastyBare metal stentBare metal stentDrug eluting stentDrug eluting stentCABGCABG

Abdominal aortic Abdominal aortic aneurysm (AAA)aneurysm (AAA)

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

Polyvascular Disease: ~15% of Polyvascular Disease: ~15% of Patients with Stable Patients with Stable

AtherosclerosisAtherosclerosis

CADCAD

PADPAD

8.4%8.4%

1.6%1.6% CVDCVD

CAD = coronary artery diseaseCAD = coronary artery diseasePAD = peripheral arterial diseasePAD = peripheral arterial diseaseCVD = cerebrovascular diseaseCVD = cerebrovascular disease

4.7%4.7%

~25% of Patients with CAD Also Have Disease in ~25% of Patients with CAD Also Have Disease in Other Arterial TerritoriesOther Arterial Territories

Bhatt DL, Steg PG, Ohman EM, et al, on behalf of the REACH Investigators. Bhatt DL, Steg PG, Ohman EM, et al, on behalf of the REACH Investigators. JAMAJAMA 2006;295:180-189. 2006;295:180-189.

One-Year CV Event Rates Increase with One-Year CV Event Rates Increase with Number of Symptomatic Disease Number of Symptomatic Disease

LocationsLocations

MI=myocardial infarction;*Such as transient ischemic attack, unstable angina, worsening of peripheral arterial disease; adjusted for age and gender

Steg PG, Bhatt DL, Wilson PF, et al, on behalf of the REACH Investigators. JAMA 2007;297:1197-1206.

Pat

ient

s (%

)P

atie

nts

(%)

CV DeathCV Death Non-Fatal MINon-Fatal MI Non-Fatal StrokeNon-Fatal Stroke CV Death/CV Death/MI/StrokeMI/Stroke

CV Death/CV Death/MI/Stroke/Hosp*MI/Stroke/Hosp*

ATRIA: Prevalence of AF Increases with ATRIA: Prevalence of AF Increases with AgeAge

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

Pre

vale

nce

(%)

Pre

vale

nce

(%)

Age (years)Age (years)

Men (n = 10,173) Women (n = 7801)

0

2

4

6

8

10

12

Go AS et al. Go AS et al. JAMAJAMA. 2001;285:2370-5.. 2001;285:2370-5.

AF = atrial fibrillationAF = atrial fibrillation

Atrial Fibrillation and Atrial Fibrillation and Atherothrombosis: Risks and Atherothrombosis: Risks and

ManagementManagement

Goto S, Bhatt DL, RGoto S, Bhatt DL, Rööther J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D’Agostino R, Ohman EM, Liau ther J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D’Agostino R, Ohman EM, Liau C-S, Hirsch AT, Mas J-L, Wilson PWF, CorbalC-S, Hirsch AT, Mas J-L, Wilson PWF, Corbaláán R, Aichner F, Steg Ph G, on behalf of the REACH n R, Aichner F, Steg Ph G, on behalf of the REACH Registry Investigators. Registry Investigators. Am Heart JAm Heart J 2008;156:855-863. 2008;156:855-863.

Atrial Fibrillation in CAD: Atrial Fibrillation in CAD: Prevalence in the REACH RegistryPrevalence in the REACH Registry

37,724 stable outpatients with CAD37,724 stable outpatients with CAD

AF, atrial fibrillation.AF, atrial fibrillation.Goto S et al, on behalf of the REACH Registry Investigators. Goto S et al, on behalf of the REACH Registry Investigators. Am Heart JAm Heart J 2008;156:855-863. 2008;156:855-863.

Atrial Fibrillation Rates by Atrial Fibrillation Rates by Patient GroupPatient Group

Greater incidence of AF in patients with vascular disease compared Greater incidence of AF in patients with vascular disease compared with patients with risk factors onlywith patients with risk factors only

Goto S et al, on behalf of the REACH Registry Investigators. Goto S et al, on behalf of the REACH Registry Investigators. Am Heart JAm Heart J 2008;156:855-863. 2008;156:855-863.

CV CV Event Frequency in AF and Event Frequency in AF and non-AF Patientsnon-AF Patients

Eve

nt r

ate

of C

V

Eve

nt r

ate

of C

V

deat

h/M

I/Str

oke

(%)

deat

h/M

I/Str

oke

(%)

Time (months)Time (months)

AF

Non-AF

Patients with a history of AF

Combined event of CV death and/or nonfatal MI and/or nonfatal stroke in patients Combined event of CV death and/or nonfatal MI and/or nonfatal stroke in patients with vs without history of AF are shown after adjustment of age, gender, and with vs without history of AF are shown after adjustment of age, gender, and

classical risk factorsclassical risk factors

0

5

10

0 6 122 4 108


Atrial Fibrillation in CADAtrial Fibrillation in CAD

P < 0.0001

37,724 patients with CAD: 12.5% prevalence of atrial fibrillation37,724 patients with CAD: 12.5% prevalence of atrial fibrillation

P < 0.0001

P < 0.0001

Pat

ient

s (%

)P

atie

nts

(%)


Annual Rate of CV Death inAnnual Rate of CV Death inAF and Non-AF PatieAF and Non-AF Patientsnts

*p<0.05**p<0.01

**

*

****

**

Multivariate analysis

CHADSCHADS22 Score Defined and Validated to Score Defined and Validated to Predict Stroke in Atrial Fibrillation PatientsPredict Stroke in Atrial Fibrillation Patients

pointspoints

CCongestive HF ongestive HF 11

HHypertension ypertension 11

AAge > 75 yrge > 75 yr 11

DDiabetes iabetes 11

SStroke troke 22

Gage BF, JAMA 2001;285(22):2864-2870Gage BF, Circulation 2004;110;2287-2292

CHADS2 1-y Stroke rate1-y Stroke rate

66 13.7%13.7%

55 12.3%12.3%

44 10.9%10.9%

33 8.6%8.6%

22 4.5%4.5%

11 2.2%2.2%

00 0.8%0.8%

SumSum

Annual CV Event Risk in Annual CV Event Risk in AF Patients by CHADSAF Patients by CHADS2 2 ScoreScore

CHADSCHADS22 score classification was useful in predicting not only stroke but also CV death score classification was useful in predicting not only stroke but also CV death

in stable outpatients with or at high-risk for atherothrombosis, but not as useful in the in stable outpatients with or at high-risk for atherothrombosis, but not as useful in the prediction of nonfatal MIprediction of nonfatal MI

Ann

ual e

vent

rat

e (%

)A

nnua

l eve

nt r

ate

(%)

CHADSCHADS22 score score


Annual Rate Annual Rate of Serious Bleeding in of Serious Bleeding in AF Patients with/without AnticoagulantAF Patients with/without Anticoagulant

P = 0.0025

4,725 stable CAD outpatients with atrial fibrillation4,725 stable CAD outpatients with atrial fibrillation


Medication Use and Risk Factor Control in Medication Use and Risk Factor Control in AF and Non-AF PatientsAF and Non-AF Patients

Variable, %Variable, % AF + AF + (n=6,814)(n=6,814)

AF – AF – (n=56,775)(n=56,775)

P valueP value

AspirinAspirin 49.5149.51 69.4469.44 < 0.0001< 0.0001

Any two antiplatelet agentsAny two antiplatelet agents 9.669.66 13.5813.58 < 0.0001< 0.0001

Oral anticoagulantsOral anticoagulants 36.1736.17 3.833.83 < 0.0001< 0.0001

At least one lipid lowering agentAt least one lipid lowering agent 87.7487.74 89.7789.77 < 0.0001< 0.0001

At least one CV agentAt least one CV agent 97.5897.58 95.6795.67 < 0.0001< 0.0001

At least one anti-diabetic agentAt least one anti-diabetic agent 81.7681.76 86.8586.85 < 0.0001< 0.0001

Approximately 50% of patients with AF receive anticoagulation therapy. Oral Approximately 50% of patients with AF receive anticoagulation therapy. Oral anticoagulants are underused in patients who have a history of AFanticoagulants are underused in patients who have a history of AF


SummarySummary

► High prevalence of AF among patients with or at high-risk of High prevalence of AF among patients with or at high-risk of atherothrombosisatherothrombosis

► Lower use of oral anticoagulants in AF patients even though Lower use of oral anticoagulants in AF patients even though they have risk factors for ischemic stroke, probably due to the they have risk factors for ischemic stroke, probably due to the use of antiplatelet agents for the treatment of use of antiplatelet agents for the treatment of atherothrombosisatherothrombosis

► 1-year follow-up data show that the presence of AF was 1-year follow-up data show that the presence of AF was associated with serious and multiple CV events including a associated with serious and multiple CV events including a higher rate of all-cause and CV mortality, nonfatal stroke and higher rate of all-cause and CV mortality, nonfatal stroke and a modest increase in the risk of nonfatal MI and unstable a modest increase in the risk of nonfatal MI and unstable anginaangina

► There is a need for the optimal antithrombotic therapy among There is a need for the optimal antithrombotic therapy among AF patients to be clarified to balance the increased risk of AF patients to be clarified to balance the increased risk of thrombotic events and the increased risk of bleeding thrombotic events and the increased risk of bleeding associated with combined anticoagulant and antiplatelet associated with combined anticoagulant and antiplatelet therapytherapyGoto S et al, on behalf of the REACH Registry Investigators. Am Heart J

2008;156:855-863.

Design of ACTIVE ProgramDesign of ACTIVE Program

Documented AF + 1 risk factor for stroke

Unsuitable for VKA

ACTIVE WC and ASA vs VKA

ACTIVE AC and ASA vs ASA

No exclusion criteria for ACTIVE

ACTIVE Iirbesartan vs placebo

Annual Event Rate, %Annual Event Rate, %

ASA + ClopidogrelASA + Clopidogrel OACOAC RRR RRR (%)(%) P P ValueValue

Primary outcomePrimary outcome 5.65.6 3.93.9 3030 0.00030.0003

Ischemic strokeIschemic stroke 2.152.15 1.01.0 5353 <0.0001<0.0001

MIMI 0.860.86 0.550.55 3636 0.090.09

Major bleedMajor bleed 2.42.4 2.22.2 8.68.6 0.530.53

ACTIVE-W ResultsACTIVE-W Results

► Stopped early because OAC was clearly Stopped early because OAC was clearly superiorsuperior

ACTIVE Writing Group of the ACTIVE Investigators et al. ACTIVE Writing Group of the ACTIVE Investigators et al. Lancet.Lancet. 2006;367:1903. 2006;367:1903.

0

0.1

0.2

0.3

0.4

ACTIVE A: Primary OutcomeACTIVE A: Primary Outcome

ACTIVE Investigators et al. ACTIVE Investigators et al. N Engl J Med.N Engl J Med. 2009;360:2066. 2009;360:2066.

YearsYears

P=0.01

Stroke, MI, Non-CNS Systemic Embolism, Vascular DeathStroke, MI, Non-CNS Systemic Embolism, Vascular Death

Cum

ulat

ive

inci

denc

eC

umul

ativ

e in

cide

nce

ASA onlyASA only Clopidogrel + ASAClopidogrel + ASA

0 1 2 3 4

0

0.05

0.10

0.15

ACTIVE A: StrokeACTIVE A: Stroke


YearsYears

P<0.001

0 1 2 3 4

ASA onlyASA onlyClopidogrel + ASAClopidogrel + ASA

Cum

ulat

ive

inci

denc

eC

umul

ativ

e in

cide

nce

ACTIVE A: Bleeding RatesACTIVE A: Bleeding Rates

ASA (%/year)ASA (%/year) Clopidogrel + Clopidogrel + ASA (%/year)ASA (%/year) PP Value Value

MajorMajor

SevereSevere

FatalFatal

1.31.3

1.01.0

0.20.2

2.02.0

1.51.5

0.30.3

<0.001<0.001

<0.001<0.001

0.070.07

MinorMinor 1.41.4 3.53.5 <0.001<0.001

AnyAny 5.75.7 9.79.7 <0.001<0.001


Annual Event Rates in Warfarin GroupAnnual Event Rates in Warfarin Group

TrialTrial YearYearPublishedPublished

BaselineBaselineSystolic BPSystolic BP

INR in Therapeutic INR in Therapeutic Range (%)Range (%)

Warfarin-Warfarin-Naive (%)Naive (%)

Ischemic Ischemic Stroke (%)Stroke (%)

Total Total Stroke (%)Stroke (%)

Hemorrhagic Hemorrhagic Stroke (%)Stroke (%)

SPAF IIISPAF III 19961996 140140 6161 4444 1.91.9 2.42.4 0.50.5

SPORTIF IIISPORTIF III 20032003 139139 6666 2727 1.91.9 2.32.3 0.40.4

SPORTIF VSPORTIF V 20052005 132132 6868 1616 1.11.1 1.21.2 0.10.1

ACTIVE WACTIVE W 20062006 133133 6464 2323 1.01.0 1.41.4 0.40.4

Therapeutic INRs With Warfarin Therapeutic INRs With Warfarin in in

Clinical TrialsClinical Trials

Connolly et al. Connolly et al. Circulation.Circulation. 2007;116:449. 2007;116:449.

ACTIVE W: Benefit of OAC by ACTIVE W: Benefit of OAC by Time in Therapeutic Range Time in Therapeutic Range

Connolly et al. Connolly et al. Circulation.Circulation. 2008;118:2029. 2008;118:2029.

StrokeStroke

No. at RiskC + ASA 1598 1527 1156 439

OAC 1600 1525 1152 417

1737 1625 1233 488

1771 1697 1306 507

1598 1533 1164 441

1600 1531 1156 419

1737 1635 1255 500

1771 1702 1311 511

0

2

4

6

8

10

12

0 0.5 1.0 1.5

0

2

4

6

8

10

12

0 0.5 1.0 1.5

OAC

OAC

C + ASA

C + ASA OAC

C + ASA

OAC

Eve

nt

rate

(%

)

TTR <65% TTR ≥65% TTR <65%

Eve

nt

rate

(%

)

Years Years

RR = 0.93 (0.70-1.24)P=0.61

RR = 2.14 (1.61-2.85)P<0.0001

RR = 1.22 (0.75-1.97)P=0.42

0

1

2

3

4

0 0.5 1.0 1.5

0

1

2

3

4

0 0.5 1.0 1.5

C + ASA

TTR ≥65%

RR = 2.25 (1.45-3.49)P=0.0003

Years Years

Stroke, MI, Non-CNS Systemic Embolism, Vascular Death

Stroke

RE-LY: A Noninferiority TrialRE-LY: A Noninferiority Trial

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

R

Open

•Atrial Fibrillation with ≥ 1 Risk Factor for Stroke• 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

0

0.01

0.02

0.03

0.04

0.05

0 6 12 18 24 30

RE-LY: Primary OutcomeRE-LY: Primary Outcome

aaPP=0.34 vs warfarin.=0.34 vs warfarin.bbPP<0.001 vs warfarin.<0.001 vs warfarin.

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

Stroke or Systemic EmbolismStroke or Systemic Embolism

MonthsMonths

Cum

ulat

ive

haza

rd r

ate

Cum

ulat

ive

haza

rd r

ate

DabigatranDabigatran150 mg150 mgbb

DabigatranDabigatran110 mg110 mgaa

WarfarinWarfarin

Oral Direct Factor Xa Inhibitors Oral Direct Factor Xa Inhibitors Currently in DevelopmentCurrently in Development

DrugDrug Half-life Half-life (Hours)(Hours) BioavailabilityBioavailability

Elimination (%)Elimination (%)

DosingDosingRenalRenal HepaticHepatic

ApixabanApixaban 1212 5050 2525 7575 Twice DailyTwice Daily

BetrixabanBetrixaban 1919 4747 00 100100 Once DailyOnce Daily

EdoxabanEdoxaban 6-126-12 100%100% 6262 3535 Once DailyOnce Daily

RivaroxabanRivaroxaban 5-95-9 8080 3333 6767 Once DailyOnce Daily

YM150YM150 18-2018-20 25-8225-82 NRNR NRNR Once/TwiceOnce/Twice

TrialTrial NN Treatment ArmsTreatment Arms Primary End Primary End Point(s)Point(s)

ROCKET-AFROCKET-AF 14,00014,000 Rivaroxaban 20 mg qdRivaroxaban 20 mg qdvs warfarinvs warfarin

Stroke and systemic Stroke and systemic embolism embolism

ARISTOTLEARISTOTLE 18,00018,000 Apixaban 5 mg bidApixaban 5 mg bidvs warfarin vs warfarin

Stroke and systemic Stroke and systemic embolismembolism

AVERROESAVERROES 56005600

Apixaban 5 mg bidApixaban 5 mg bidvs aspirin vs aspirin

(in patients deemed (in patients deemed unsuitable or inappropriate unsuitable or inappropriate for warfarin: superiority trial)for warfarin: superiority trial)

Stroke and systemic Stroke and systemic embolismembolism

ENGAGE AF – ENGAGE AF – TIMI 48TIMI 48 16,50016,500 Edoxaban 30 mg qd and Edoxaban 30 mg qd and

60 mg qd vs warfarin60 mg qd vs warfarinStroke and systemic Stroke and systemic

embolismembolism

Novel Oral Direct Factor Xa Inhibitors for Novel Oral Direct Factor Xa Inhibitors for Stroke Prevention in AFStroke Prevention in AF

www.clinicaltrials.gov. www.clinicaltrials.gov.

Thrombosis Risk Reduction in AFThrombosis Risk Reduction in AF

► Need to weigh thrombotic, ischemic, and Need to weigh thrombotic, ischemic, and bleeding risks in atrial fibrillation patientsbleeding risks in atrial fibrillation patients

► Anticoagulation preferred if it can be done Anticoagulation preferred if it can be done wellwell

► Antiplatelet therapy has a role in some Antiplatelet therapy has a role in some patientspatients

► Novel agents likely to provide more Novel agents likely to provide more options, perhaps even better efficacy and options, perhaps even better efficacy and safety; including in patients who are not safety; including in patients who are not suitable candidates for VKAsuitable candidates for VKA


Challenges Challenges andand Emerging Emerging Dimensions Dimensions ofof Stroke Prevention Stroke Prevention in in

the the Setting Setting ofof Atrial Fibrillation (AF)Atrial Fibrillation (AF)

Achieving Balance Between Achieving Balance Between Thromboprophylaxis Thromboprophylaxis

and Bleeding Reductionand Bleeding ReductionGregory Y.H. Lip, MD FRCP FACC FESCGregory Y.H. Lip, MD FRCP FACC FESCProfessor of Cardiovascular Medicine, University of BirminghamProfessor of Cardiovascular Medicine, University of Birmingham

Visiting Professor of Haemostasis Thrombosis & Vascular Sciences, Visiting Professor of Haemostasis Thrombosis & Vascular Sciences, University of AstonUniversity of Aston

Centre for Cardiovascular SciencesCentre for Cardiovascular SciencesCity HospitalCity Hospital

Birmingham, England UKBirmingham, England UK

Independent Predictors of Stroke in AF: Independent Predictors of Stroke in AF: A Systematic ReviewA Systematic Review

Multivariately Multivariately significantsignificant

Adjusted relative risk Adjusted relative risk (95% CI)(95% CI)

Prior stroke or TIAPrior stroke or TIA 5 of 5 studies5 of 5 studies 2.5 (1.8–3.5)2.5 (1.8–3.5)

Increasing ageIncreasing age 6 of 6 studies6 of 6 studies 1.5/decade (1.3–1.7)1.5/decade (1.3–1.7)

History of hypertension or History of hypertension or systolic BP systolic BP >>160 mmHg160 mmHg 5 of 5 studies5 of 5 studies 2.0 (1.6–2.5)2.0 (1.6–2.5)

DiabetesDiabetes 4 of 4 studies4 of 4 studies 1.8 (1.5–22)1.8 (1.5–22)

Female genderFemale gender 3 of 6 studies3 of 6 studies 1.6 (1.4–1.9)1.6 (1.4–1.9)

Heart failureHeart failure 0 of 4 studies*0 of 4 studies* Not significantNot significant

Coronary artery diseaseCoronary artery disease 0 of 4 studies0 of 4 studies Not significantNot significant

*Significant in a subgroup of AFI pooled analysis participants who *Significant in a subgroup of AFI pooled analysis participants who underwent echocardiographyunderwent echocardiography

The Stroke Risk in AF Working Group. Neurology 2007;69:546–554The Stroke Risk in AF Working Group. Neurology 2007;69:546–554

Stroke Risk Stratification in AF Stroke Risk Stratification in AF Past and PresentPast and Present

Lip and Tse. Lancet 2007 August Lip and Tse. Lancet 2007 August 18;370(9587):604-1818;370(9587):604-18

EHS: Antithrombotic Drug Prescription EHS: Antithrombotic Drug Prescription per Risk Category per Risk Category

Eur Heart J 2006 27, 3018–3026Eur Heart J 2006 27, 3018–3026

ACC/AHA/ESC guidelines (A), ACCP (B), CHADS2 score (C), and Framingham ACC/AHA/ESC guidelines (A), ACCP (B), CHADS2 score (C), and Framingham score (D).score (D).

Potentially Preventable Strokes Potentially Preventable Strokes

Gladstone et al Stroke 2008Gladstone et al Stroke 2008

High-Risk Patients with AF Who Are Not Adequately High-Risk Patients with AF Who Are Not Adequately AnticoagulatedAnticoagulated

Preadmission medications in patients with known Preadmission medications in patients with known atrial fibrillation who were admitted with acute atrial fibrillation who were admitted with acute

ischemic stroke (high-risk cohort, n=597)ischemic stroke (high-risk cohort, n=597)

Preadmission medications in patients with known Preadmission medications in patients with known atrial fibrillation and a previous ischemic atrial fibrillation and a previous ischemic stroke/TIA who were admitted with acute stroke/TIA who were admitted with acute

ischemic stroke (very high-risk cohort, n=323)ischemic stroke (very high-risk cohort, n=323)

‘In high-risk patients with AF admitted with a stroke …. most were either not taking warfarin or were subtherapeutic at the time of ischemic stroke. …..’

Published Bleeding Risk ScoresPublished Bleeding Risk Scores

Tay, Lane & Lip Thromb Haemost 2008; 100: 955–957Tay, Lane & Lip Thromb Haemost 2008; 100: 955–957

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, ETOH HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low platelet count abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, uncontrolled HTN, or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 stroke, with 1 point for each risk factor present with 2 points for previous bleedpoints 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) + (0.32 abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for presence of x antiplatelet drug use) with 1 point for presence of each and 0 if absenteach and 0 if absent

Major Hemorrhage and Major Hemorrhage and Tolerability of WarfarinTolerability of Warfarin

Distribution of Major Hemorrhagic Events and Warfarin Terminations Distribution of Major Hemorrhagic Events and Warfarin Terminations Due to Perceived Safety Concerns by CHADS2 ScoreDue to Perceived Safety Concerns by CHADS2 Score

Hylek et al Circulation. 2007;115:2689-2696Hylek et al Circulation. 2007;115:2689-2696

First Year of Therapy Among Elderly Patients With AFFirst Year of Therapy Among Elderly Patients With AF

Major BleedMajor Bleed Taken Off TherapyTaken Off Therapy

CHADSCHADS22

ScoreScoreNN

Rate Rate (per 100 (per 100

person-years)person-years)95% CI95% CI NN

Rate Rate (per 100 (per 100

person-years)person-years)95% CI95% CI

00 11 3.123.12 0.08 to 17.380.08 to 17.38 55 15.5915.59 5.06-36.395.06-36.39

11 44 4.284.28 1.17 to 10.961.17 to 10.96 1616 17.1217.12 9.79 to 27.819.79 to 27.81

22 33 2.042.04 0.42 to 5.960.42 to 5.96 1919 12.9212.92 7.78 to 20.187.78 to 20.18

33 1212 19.5419.54 10.10 to 34.1310.10 to 34.13 2020 32.5632.56 19.89 to 50.2919.89 to 50.29

>>44 66 23.4223.42 8.59 to 50.978.59 to 50.97 99 35.1235.12 16.06 to 66.6816.06 to 66.68

TotalTotal 2626 6969

Risk Factors for Anticoagulation-Related Risk Factors for Anticoagulation-Related Bleeding Complications in Patients with Atrial Bleeding Complications in Patients with Atrial

FibrillationFibrillation

► Systematic review for NICE guideline [www.nice.org.uk] Systematic review for NICE guideline [www.nice.org.uk] 9 studies identified9 studies identified

► The following patient characteristics were identified as having The following patient characteristics were identified as having supporting evidence for being risk factors for anticoagulation-supporting evidence for being risk factors for anticoagulation-related bleeding complications: related bleeding complications:

● Advanced ageAdvanced age● Uncontrolled hypertensionUncontrolled hypertension● History of myocardial infarction or ischaemic heart diseaseHistory of myocardial infarction or ischaemic heart disease● Cerebrovascular diseaseCerebrovascular disease● Anaemia or a history of bleeding, and Anaemia or a history of bleeding, and ● The concomitant use of other drugs such as antiplatelet agentsThe concomitant use of other drugs such as antiplatelet agentsThe presence of diabetes mellitus, controlled hypertension and The presence of diabetes mellitus, controlled hypertension and

gender were not identified as significant risk factors. gender were not identified as significant risk factors.

► Some of the risk factors for anticoagulation-related bleeding are Some of the risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patients also indications for the use of anticoagulants in AF patients

Hughes and Lip QJM. 2007;100(10):599-607.Hughes and Lip QJM. 2007;100(10):599-607.

A Systematic ReviewA Systematic Review

Combining the CHADS2 and HEMORR2HAGES Combining the CHADS2 and HEMORR2HAGES Scores for Guiding Antithrombotic Prophylaxis in AFScores for Guiding Antithrombotic Prophylaxis in AF

‘ ‘The clinical usefulness of using the two scores seems poor since they The clinical usefulness of using the two scores seems poor since they indicated that two-thirds of the patients had a similar risk of hemorrhagic indicated that two-thirds of the patients had a similar risk of hemorrhagic

and ischemic events.’and ischemic events.’

One year stroke risk for 100 patients without anticoagulation according to CHADS2One year stroke risk for 100 patients without anticoagulation according to CHADS2Major hemorrhage risk for 100 patients with anticoagulation according to Major hemorrhage risk for 100 patients with anticoagulation according to HEMORRH2AGESHEMORRH2AGES

N=83

Mean age 89.2+/-4.9 years

Somme et al Aging Clin Exp Res. 2009 as DOI: 10.3275/6709Somme et al Aging Clin Exp Res. 2009 as DOI: 10.3275/6709

Clinical Usefulness in Geriatrics PatientsClinical Usefulness in Geriatrics Patients

ScoreScore

Eve

nts/

year

(%

)E

vent

s/ye

ar (

%)

00 1 2 3 4 5 1 2 3 4 5

2525

2020

1515

1010

55

00

Choosing Antithrombotic Therapy for Elderly Choosing Antithrombotic Therapy for Elderly Patients with AF Who are at Risk for Falls Patients with AF Who are at Risk for Falls

► A Markov decision analytic model A Markov decision analytic model

For patients with average risks of stroke and falling …For patients with average risks of stroke and falling …► Warfarin therapy associated with 12.90 quality-adjusted Warfarin therapy associated with 12.90 quality-adjusted

life-years per patient; life-years per patient; ► Aspirin therapy, 11.17 quality-adjusted life-years; and Aspirin therapy, 11.17 quality-adjusted life-years; and ► No antithrombotic therapy, 10.15 quality-adjusted life-No antithrombotic therapy, 10.15 quality-adjusted life-

years. years.

‘‘Elderly persons who fall have a mean of 1.81 falls per year. Elderly persons who fall have a mean of 1.81 falls per year.

… … Given that the risk of SDH must be 535-fold or greater Given that the risk of SDH must be 535-fold or greater for the risks of warfarin therapy to outweigh the benefits, for the risks of warfarin therapy to outweigh the benefits, persons taking warfarin must fall about 295 (535/1.81) persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin to not be the optimal therapy.’times in 1 year for warfarin to not be the optimal therapy.’

Man-Son-Hing et al Arch Intern Med. 1999;159(7):677-85Man-Son-Hing et al Arch Intern Med. 1999;159(7):677-85

TTR versus adverse events TTR versus adverse events (weighted by sample size) (weighted by sample size) for retrospective studies. for retrospective studies.

TTR versus major TTR versus major hemorrhage rate (n=9), hemorrhage rate (n=9), correlation: correlation: r= -0.78; r= -0.78; P=0.006; P=0.006;

TTR versus thromboembolic TTR versus thromboembolic rate (n=5), correlation: rate (n=5), correlation: r= -0.88; P=0.026r= -0.88; P=0.026

For retrospective studies, a 6.9% improvement in the TTR significantly reduced major For retrospective studies, a 6.9% improvement in the TTR significantly reduced major hemorrhage by 1 event per 100 patient-years of treatment (95% CI, 0.29 to 1.71 events)hemorrhage by 1 event per 100 patient-years of treatment (95% CI, 0.29 to 1.71 events)

Wan et al Wan et al Circ Cardiovasc Qual Outcomes. 2008;1:84-91Circ Cardiovasc Qual Outcomes. 2008;1:84-91

A Systematic ReviewA Systematic Review

Anticoagulation Control and Prediction of Anticoagulation Control and Prediction of Adverse Events in Patients With AFAdverse Events in Patients With AF

0 40 50 60 70 80 900 40 50 60 70 80 90

TTR (%)TTR (%)

Out

com

e ev

ents

rat

e (p

er 1

00 p

atie

nt/y

ears

, %)

Out

com

e ev

ents

rat

e (p

er 1

00 p

atie

nt/y

ears

, %)

Linear (major haemorrhageLinear (major haemorrhageLinear (Thromboembolic)Linear (Thromboembolic)

88

77

66

55

44

33

22

11

00

Risk FactorRisk Factor Net Clinical BenefitNet Clinical Benefit(95% CI)(95% CI)

Adjusted relative risk Adjusted relative risk (95% CI)(95% CI)

CHADSCHADS22

ScoreScoreICH Weight = 1.5 ICH Weight = 1.5

(Base Case)(Base Case)ICH Weight = 1ICH Weight = 1 ICH Weight = 2ICH Weight = 2

00 -0.11 (-0.44 to 0.20)-0.11 (-0.44 to 0.20) -0.07 (0.38 to 0.20)-0.07 (0.38 to 0.20) -0.14 (-0.53 to 0.21)-0.14 (-0.53 to 0.21)

11 0.19 (-0.27 to 0.45)0.19 (-0.27 to 0.45) 0.33 (-0.06 to 0.57)0.33 (-0.06 to 0.57) 0.06 (-0.50 to 0.34)0.06 (-0.50 to 0.34)

22 0.97 (0.43 to 1.41)0.97 (0.43 to 1.41) 1.07 (0.61 to 1.45)1.07 (0.61 to 1.45) 0.87 (0.26 to 1.35)0.87 (0.26 to 1.35)

33 2.07 (1.21 to 2.79)2.07 (1.21 to 2.79) 2.06 (1.26 to 2.72)2.06 (1.26 to 2.72) 2.09 (1.12 to 2.85)2.09 (1.12 to 2.85)

4-64-6 2.22 (0.58 to 3.75)2.22 (0.58 to 3.75) 2.51 (1.04 to 4.01)2.51 (1.04 to 4.01) 1.94 (0.19 to 3.52)1.94 (0.19 to 3.52)

Annual Net Clinical Benefit of Warfarin Annual Net Clinical Benefit of Warfarin Therapy Overall and by CHADSTherapy Overall and by CHADS22 Score Score

The net clinical benefit of warfarin increased from essentially zero in CHADS2 stroke risk The net clinical benefit of warfarin increased from essentially zero in CHADS2 stroke risk categories 0 and 1 to 2.22% per year (CI,0.58% to 3.75%) in CHADS2 categories 4 to 6. categories 0 and 1 to 2.22% per year (CI,0.58% to 3.75%) in CHADS2 categories 4 to 6.

The patterns of results were preserved when weighting factors for intracranial hemorrhage of The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used.1.0 and 2.0 were used.

Singer et al Ann Intern Med. 2009;151:297-305.Singer et al Ann Intern Med. 2009;151:297-305.

Using Different Weights for ICHUsing Different Weights for ICH

Warfarin vs Aspirin for Stroke Prevention in Warfarin vs Aspirin for Stroke Prevention in an Elderly Community Population with AF an Elderly Community Population with AF

Yearly risk 1.8% Yearly risk 1.8% vs vs 3.8%, RR 0·48, 95% CI 0·28–0·80, 3.8%, RR 0·48, 95% CI 0·28–0·80, p=0·003; p=0·003; Absolute yearly risk reduction 2%, 95% CI 0·7–3·2Absolute yearly risk reduction 2%, 95% CI 0·7–3·2

Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTABirmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA

Mant et al Lancet 2007; 370: 493–503Mant et al Lancet 2007; 370: 493–503

AspirinAspirinWarfarinWarfarin

00 11 22 33 44 55 66

Number at riskNumber at riskWarfarinWarfarin 488488 450450 383383 169169 7777 1919AspirinAspirin 485485 447447 378378 146146 7272 1414

100100

7575

5050

2525

00

Par

ticip

ants

with

out p

rimar

y ev

ent (

%)

Par

ticip

ants

with

out p

rimar

y ev

ent (

%)

Years since randomizationYears since randomization

RE-LY: Time to First Stroke / SSERE-LY: Time to First Stroke / SSE

Connolly SJ et al. N Engl J Med 2009;361:1139–51Connolly SJ et al. N Engl J Med 2009;361:1139–51

BID = twice daily; CI = confidence interval; NI = non-inferior; RR = relative risk; RRR = BID = twice daily; CI = confidence interval; NI = non-inferior; RR = relative risk; RRR = relative risk reduction; Sup = superiorrelative risk reduction; Sup = superior

YearsYears

0.0 0.5 1.0 1.5 2.0 2.5

0.01

0.02

0.03

0.05

0.04

Cum

ulat

ive

haza

rd r

ates

Cum

ulat

ive

haza

rd r

ates

0.00

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

RR 0.91(95% CI: 0.74–1.11)P<0.001 (NI)P=0.34 (Sup)

RR 0.66(95% CI: 0.53–0.82)P<0.001 (NI)P<0.001 (Sup)

RRRRRR34%34%

Antithrombotic Treatment and Risk of Stroke and Antithrombotic Treatment and Risk of Stroke and Death in Patients with AF and CHADSDeath in Patients with AF and CHADS22 Score=1 Score=1

Combined endpoint (death or stroke) in patients with a CHADS2 score of 1 according Combined endpoint (death or stroke) in patients with a CHADS2 score of 1 according to their antithrombotic treatment. A total of 1,012 patients, 949 ± 777 days FU, 124 to their antithrombotic treatment. A total of 1,012 patients, 949 ± 777 days FU, 124 events.events.

Gorin et al Thromb Haemostat 2010 MarchGorin et al Thromb Haemostat 2010 March

Issues with Current AF Stroke Risk Issues with Current AF Stroke Risk Assessment SchemaAssessment Schema

► All have modest predictive value for predicting high risk for All have modest predictive value for predicting high risk for thromboembolismthromboembolism

● Low risk category needs to be truly low riskLow risk category needs to be truly low risk● Needs to categorise low proportion in so-called ‘moderate/ Needs to categorise low proportion in so-called ‘moderate/

intermediate risk’ categoryintermediate risk’ category

► Recognise that risk factors are cumulativeRecognise that risk factors are cumulative► Simple and easy to remember, yet comprehensiveSimple and easy to remember, yet comprehensive

● Scoring system most popularScoring system most popular● AcronymAcronym

► Validated in multiple populations, ideally ‘real world’ cohorts rather Validated in multiple populations, ideally ‘real world’ cohorts rather than non-VKA arms of trial cohortsthan non-VKA arms of trial cohorts

Risk schema need to evolve with new therapeutic Risk schema need to evolve with new therapeutic information on thromboprophylaxis in AFinformation on thromboprophylaxis in AF

Lip and Halperin Am J Med 2009; 10.1016/j.amjmed.2009.12.013Lip and Halperin Am J Med 2009; 10.1016/j.amjmed.2009.12.013

Implications for the Implications for the FutureFuture

Comparison of Risk Comparison of Risk StratificationStratification

Schemes to Predict Schemes to Predict Thromboembolism Thromboembolism in Nonvalvular AFin Nonvalvular AF

Fang et al Fang et al J Am Coll Cardiol J Am Coll Cardiol

2008;51:810–52008;51:810–5

Risk for Thromboembolism (%)Risk for Thromboembolism (%) c-Statisticc-Statistic

LowLow IntermediateIntermediate HighHigh All patientsAll patients Subgroup*Subgroup*

AFIAFI 13.113.1 24.724.7 62.362.3 0.560.56 0.610.61

SPAFSPAF 27.727.7 28.528.5 43.843.8 0.600.60 0.650.65

CHADSCHADS22 18.818.8 61.261.2 20.120.1 0.580.58 0.670.67

FraminghFraminghamam 37.137.1 46.646.6 16.416.4 0.620.62 0.690.69

77thth ACCP ACCP 11.711.7 7.97.9 80.480.4 0.560.56 0.600.60

* Subgroup of 5,588 patients not on warfarin at baseline and with * Subgroup of 5,588 patients not on warfarin at baseline and with continuous follow-up off of warfarin for at least 12 monthscontinuous follow-up off of warfarin for at least 12 months

An

nu

al T

hro

mb

oe

mb

olis

m R

ate

(%

)A

nn

ua

l Th

rom

bo

em

bo

lism

Ra

te (

%)

Refining Clinical Risk Stratification for Predicting Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in AF Using A Novel Stroke and Thromboembolism in AF Using A Novel

Risk Factor-Based ApproachRisk Factor-Based Approach

Definitive risk Definitive risk factorsfactors Combination risk factorsCombination risk factors

Previous stroke, TIA Previous stroke, TIA

or embolismor embolismHeart failure or moderate-severe Heart failure or moderate-severe

LV dysfunction [eg. LV EF ≤40%]LV dysfunction [eg. LV EF ≤40%]Female genderFemale gender

Age ≥ 75 yAge ≥ 75 y HypertensionHypertension Age 65 to 74 yAge 65 to 74 y

Diabetes mellitusDiabetes mellitusVascular disease [previous MI, Vascular disease [previous MI,

aortic or peripheral artery disease]aortic or peripheral artery disease]

CHACHA22DSDS22-VASc -VASc ScoreScore

C C ongestive heart failure/ LV dysfunctionongestive heart failure/ LV dysfunction 11H H ypertensionypertension 11A A ge≥75ge≥75 22D D iabetes mellitusiabetes mellitus 11S S troke/TIA/TEtroke/TIA/TE 22V V ascular disease [prior MI, PAD, or aortic plaque]ascular disease [prior MI, PAD, or aortic plaque] 11A A ge 65-74ge 65-74 11S S ex ex ccategory [Female]ategory [Female] 11

The Euro Heart Survey on Atrial FibrillationThe Euro Heart Survey on Atrial Fibrillation

Lip et al Chest 2010 Feb;137(2):263-72. Epub 2009 Sep 17.

Risk Categorization, Incidence of Thromboembolism Risk Categorization, Incidence of Thromboembolism and Predictive Ability for Contemporary Risk and Predictive Ability for Contemporary Risk

Stratification Schema in the Euro Heart SurveyStratification Schema in the Euro Heart Survey

LowLow IntermediateIntermediate HighHigh c-statisticc-statistic(95% CI)(95% CI)

CHADSCHADS22 – classical – classical % in risk category% in risk category TE events, N (%)TE events, N (%)

20203 (1.4)3 (1.4)

61.961.916 (2.4)16 (2.4)

17.717.76 (3.2)6 (3.2)

0.5610.561(0.450-0.672)(0.450-0.672)

CHADSCHADS22 – revised – revised % in risk category% in risk category TE events, N (%)TE events, N (%)

20.43 (1.4)

34.97 (1.9)

44.744.715 (3.1)15 (3.1)

0.5860.586(0.477-0.695)(0.477-0.695)

FraminghamFramingham % in risk category% in risk category TE events, N (%)TE events, N (%)

48.348.36 (1.2)6 (1.2)

41.541.514 (3.2)14 (3.2)

10.210.25 (4.6)5 (4.6)

0.6380.638(0.532-0.744)(0.532-0.744)

NICE 2006NICE 2006 % in risk category% in risk category TE events, N (%)TE events, N (%)

13.113.10 (0.0)0 (0.0)

39.239.213 (3.1)13 (3.1)

47.747.712 (2.3)12 (2.3)

0.5980.598(0.498-0.698)(0.498-0.698)

ACC/AHA/ESC 2006 ACC/AHA/ESC 2006 % in risk category% in risk category TE events, N (%)TE events, N (%)

19.619.63 (.14)3 (.14)

32.632.67 (2.0)7 (2.0)

47.847.815 (2.9)15 (2.9)

0.5710.571(0.461-0.680)(0.461-0.680)

ACCP 2008ACCP 2008 % in risk category% in risk category TE events, N (%)TE events, N (%)

19.619.63 (.14)3 (.14)

33.433.47 (1.9)7 (1.9)

47.047.015 (3.0)15 (3.0)

0.5740.574(0.465-0.683)(0.465-0.683)

Birmingham 2009Birmingham 2009 % in risk category% in risk category TE events, N (%)TE events, N (%)

9.29.20 (0.0)0 (0.0)

15.115.11 (0.6)1 (0.6)

75.775.724 (3.0)24 (3.0)

0.6060.606(0.513-0.699)(0.513-0.699)CHACHA22DSDS22-VASc-VASc


Refining Clinical Risk Stratification for Predicting Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in AF Using a Novel Risk Stroke and Thromboembolism in AF Using a Novel Risk

Factor Based Approach Factor Based Approach

Risk categoryRisk categoryCHACHA22DSDS22VAScVASc

scorescoreRecommended antithrombotic Recommended antithrombotic

therapytherapy

One One definitive definitive risk risk factor factor or ≥2 or ≥2 combination combination risk factorsrisk factors

>1>1OAC OAC eg.VKA (INR 2-3, target 2.5), ?eg.VKA (INR 2-3, target 2.5), ?dabigatrandabigatran

One One combination combination risk risk factorfactor 11

Antithrombotic therapy, either as Antithrombotic therapy, either as OAC or aspirin 75-325mg daily OAC or aspirin 75-325mg daily We suggest OAC rather than aspirinWe suggest OAC rather than aspirin

No risk factors No risk factors 00

Aspirin 75-325mg daily or no Aspirin 75-325mg daily or no antithrombotic therapyantithrombotic therapyWe suggest no antithrombotic We suggest no antithrombotic therapytherapy

The Euro Heart Survey on Atrial Fibrillation


Challenges and Emerging Dimensions of Challenges and Emerging Dimensions of Stroke Prevention in the Setting of AFStroke Prevention in the Setting of AF

► AF increases the risk of stroke and thromboembolismAF increases the risk of stroke and thromboembolism► We need to balance stroke prevention against bleeding We need to balance stroke prevention against bleeding

riskrisk● New risk factors and data (eg. elderly, CHADS2=1, new New risk factors and data (eg. elderly, CHADS2=1, new

drugs etc) should be considereddrugs etc) should be considered● Aspirin (and antiplatelet Rx) less usefulAspirin (and antiplatelet Rx) less useful● Risk schema need to evolve with new therapeutic Risk schema need to evolve with new therapeutic

information on thromboprophylaxis in AFinformation on thromboprophylaxis in AF

► We need a paradigm shift in stroke risk assessment We need a paradigm shift in stroke risk assessment guidelinesguidelines

● All schema have modest value in predicting riskAll schema have modest value in predicting risk● We need to be better at identifying the low risk subjects, We need to be better at identifying the low risk subjects,

who do not need antithrombotic therapy; all others would who do not need antithrombotic therapy; all others would merit anticoagulationmerit anticoagulation

Achieving Balance Between Thromboprophylaxis Achieving Balance Between Thromboprophylaxis and Bleeding Reductionand Bleeding Reduction


The Evolving Paradigm of The Evolving Paradigm of Warfarin-Based Therapy: Still Warfarin-Based Therapy: Still Relevant? And for How Long?Relevant? And for How Long?

David A. Garcia, MDDavid A. Garcia, MDAssociate Professor, Division of General Internal Associate Professor, Division of General Internal

MedicineMedicineUniversity of New MexicoUniversity of New Mexico

Co-Director, University of New Mexico Anticoagulation Co-Director, University of New Mexico Anticoagulation Management ServiceManagement Service

President, Anticoagulation ForumPresident, Anticoagulation ForumAlbuquerque, New Mexico USAAlbuquerque, New Mexico USA

Long-Term Oral AnticoagulationLong-Term Oral AnticoagulationThe State of the ArtThe State of the Art

AFASAK I, 1989 (2); 1990 (3)AFASAK I, 1989 (2); 1990 (3)

SPAF I, 1991 (5)SPAF I, 1991 (5)

BAATAF, 1990 (4)BAATAF, 1990 (4)

CAFA,1991 (6)CAFA,1991 (6)

SPINAF, 1992 (7)SPINAF, 1992 (7)

EAFT. 1993 (8)EAFT. 1993 (8)

All trials (n=6)All trials (n=6)

Relative risk reduction (95% CI)Relative risk reduction (95% CI)

Favors warfarinFavors warfarin Favors placebo Favors placebo or controlor control

100 50 0 -50 -100

Warfarin Protects Against StrokeWarfarin Protects Against StrokeAdjusted-Dose Warfarin Compared With PlaceboAdjusted-Dose Warfarin Compared With Placebo

Hart, et al. Ann Intern Med. 2007 Jun 19;146(12):857-67.

Adjusted-dose warfarin compared with placeboAdjusted-dose warfarin compared with placebo

AC management clinics AC management clinics become increasingly prevalentbecome increasingly prevalent

19911950’s

Warfarin Warfarin first usedfirst used

1983

WHO endorses INRWHO endorses INR

Efficacy of VKA Efficacy of VKA to prevent AF-related stroketo prevent AF-related stroke

demonstrateddemonstrated

POC testing, PST, POC testing, PST, dosing algorithms,dosing algorithms,software programs,software programs,better understanding of better understanding of genetics and drug interactionsgenetics and drug interactions

1999

TimelineTimeline

Vitamin KVitamin K

WarfarinWarfarin

Synthesis of Synthesis of Dysfunctional Dysfunctional Coagulation Coagulation FactorsFactors

VIIVII

IXIX

XX

IIII

Vitamin K Utilization Impaired

WarfarinWarfarinMechanism of ActionMechanism of Action

CYP450

Slight genetic variation can produce significant

differences in dose-response

relationship

NADPHNADPH

WarfarinWarfarinMechanism of ActionMechanism of Action

Vitamin K epoxidereductase

Vitamin K epoxidereductase

Vitamin K reductase

Vitamin K reductase

Vitamin K EpoxideVitamin K EpoxideVitamin KH2Vitamin KH2

Vitamin KVitamin K

Carboxylated zymogenCarboxylated zymogenDecarboxylated zymogenDecarboxylated zymogen

XXSlight genetic variation can Slight genetic variation can produce significant differencesproduce significant differencesin dose-response relationshipin dose-response relationship

Coagulation PathwayCoagulation Pathway

InitiationInitiation Vlla/TFVlla/TF

PropagationPropagation

Fibrin FormationFibrin Formation

FibrinogenFibrinogen FibrinFibrin

IXIXXX

IXaIXa VllIaVllIa

XaXa

VaVa

IIa (Thrombin)

IIII

Limitations of Warfarin (VKA)Limitations of Warfarin (VKA)

NarrowNarrowTherapeuticTherapeutic

Index & Drug/DietIndex & Drug/DietInteractionsInteractions

LongLongHalf-LifeHalf-Life

SlowSlowOnset ofOnset ofActionAction

Anticoagulation Clinics Requires frequent monitoring

? Genotype testing

Heparin “overlap”often necessary

Periprocedural Anticoagulation Difficult

Complicates management of:• Bleeding patient• Patient with High INR

Is VKA (warfarin) therapy getting Is VKA (warfarin) therapy getting safer and more “user-friendly”?safer and more “user-friendly”?

► Wisespread use of the INRWisespread use of the INR

► Anticoagulation Management ServicesAnticoagulation Management Services

► Patient Self-testingPatient Self-testing

► PharmacogenomicsPharmacogenomics

► Reversal strategiesReversal strategies

Events per 100 Patient-Years According to Events per 100 Patient-Years According to International Normalized Ratio ControlInternational Normalized Ratio Control

Poor ControlPoor Control Moderate ControlModerate Control Good ControlGood Control

P Value P Value (Poor vs (Poor vs Good) Good)

P Value P Value (Moderate vs (Moderate vs

Poor) Poor)

P Value P Value (Good vs (Good vs

Moderate) Moderate) (n = (n = 1190) 1190) (n = 1207) (n = 1207) (n = 1190) (n = 1190)

Stroke or systemic Stroke or systemic embolism embolism 2.12.1 0.020.02 1.341.34 0.090.09 1.071.07 0.480.48

Death, all cause Death, all cause 4.24.2 < .01 < .01 1.841.84 < .01< .01 1.691.69 0.740.74

Death, stroke, or Death, stroke, or systemic embolism systemic embolism 5.985.98 < .01 < .01 3.013.01 < .01< .01 2.762.76 0.670.67

Major bleeding Major bleeding 3.853.85 < .01< .01 1.961.96 < .01 < .01 1.581.58 0.380.38

White H et al. Arch Intern Med. 2007.167:239-245White H et al. Arch Intern Med. 2007.167:239-245

Increased “Time-in-Range” Increased “Time-in-Range” = Better Outcomes= Better Outcomes

Witt et al. Blood 2009. 114: 952-956.Witt et al. Blood 2009. 114: 952-956.

““Stable” Stable” PatientsPatientsN=2504N=2504

Comparator Comparator GroupGroupN=3569N=3569

P valueP value

Deceased, %Deceased, % 0.40.4 1.61.6 <.001<.001

AC-related death, %AC-related death, % 0.040.04 0.10.1 .411.411

AC-related thrombosis, %AC-related thrombosis, % 0.40.4 0.70.7 0.10.1

AC-related bleeding, %AC-related bleeding, % 0.80.8 2.82.8 <.001<.001

AC-related bleeding or AC-related bleeding or thrombosis, %thrombosis, % 1.11.1 3.63.6 <.001<.001

Anticoagulation Management Anticoagulation Management Service Can Increase Time-in-RangeService Can Increase Time-in-Range

% time in range% time in range

%

of p

atie

nts

%

of p

atie

nts

Witt et al. Chest 2005.

Anticoagulation Management ServicesAnticoagulation Management Services

► Resource-intensiveResource-intensive

► Only available to a minority of Only available to a minority of patients in many countries patients in many countries (including the United States)(including the United States)

Patient Self-testing Reduces Risk of Patient Self-testing Reduces Risk of Thromboembolic EventsThromboembolic Events

Heneghan et al. Lancet. 2006 Feb 4;367(9508):404-11.Heneghan et al. Lancet. 2006 Feb 4;367(9508):404-11.

Patient Self-TestingPatient Self-Testing

► Not feasible for all warfarin-Not feasible for all warfarin-treated patientstreated patients

► Uptake in U.S. also limited by low Uptake in U.S. also limited by low CMS reimbursement for physician CMS reimbursement for physician oversightoversight

Knowledge of Genotype Allows Knowledge of Genotype Allows Better Dose PredictionBetter Dose Prediction

Gage B. Gage B. NEJMNEJM 2005. 2005.

A/A A/B B/BA/A A/B B/B A/A A/B B/BA/A A/B B/B A/A A/B B/BA/A A/B B/B

Mea

n W

arf

arin

Do

se (

mg

/da

y)M

ean

Wa

rfar

in D

ose

(m

g/d

ay)

Primary PopulationPrimary Population

**

*

††

Anderson et al RCT (n=200)Anderson et al RCT (n=200)

► Only published high-quality RCTOnly published high-quality RCT► Incorporated both CYP2C9 and VKORC1 genotypesIncorporated both CYP2C9 and VKORC1 genotypes

Anderson et al, Circulation, 2007; 116: 2563-70.Anderson et al, Circulation, 2007; 116: 2563-70.

PG (%)PG (%) Std (%)Std (%) pp

Out-of-range INROut-of-range INR 3131 3333 0.720.72

Therapeutic INR by Day 5Therapeutic INR by Day 5 7070 6868 0.850.85

Serious Adverse EventsSerious Adverse Events 44 55 0.710.71

Meta-analysis: % Time Meta-analysis: % Time TherapeuticTherapeutic

Kangelaris, JGIM, 2009; 24(5): 656-64.Kangelaris, JGIM, 2009; 24(5): 656-64.

Study IDStudy ID SMD 95% CISMD 95% CI

Hillman 2005Hillman 2005 0.01 (-0.3, 0.64)0.01 (-0.3, 0.64)

Caraco 2007Caraco 2007 0.57 (0.28, 0.86)0.57 (0.28, 0.86)

Anderson 2007Anderson 2007 0.05 (-0.23, 0.22)0.05 (-0.23, 0.22)

Overall (I-squared = 72.5%, p=0.026Overall (I-squared = 72.5%, p=0.026 0.24 (-0.16, 0.64)0.24 (-0.16, 0.64)

-1 -.5 0 .5 1-1 -.5 0 .5 1

Note: weights re from random effects analysisNote: weights re from random effects analysis

Standard dose favored Pharmacogenetics favoredStandard dose favored Pharmacogenetics favored

Pharmacogenetic TestingPharmacogenetic Testing

► Promising science but…Promising science but…

► Clinical benefit still unprovenClinical benefit still unproven

Reversal StrategiesReversal Strategies

Preston et al.Preston et al. British Journal of Haematology British Journal of Haematology 2002. 116: 619–6242002. 116: 619–624

BaselineBaseline 20 min 60 min 120 min13 20 min 60 min 120 min13

1313

1111

99

77

55

33

11

25 u/kg (m=20)25 u/kg (m=20)35 u/kg (n=12)35 u/kg (n=12)50 u/kg (n=10)50 u/kg (n=10)

4-factor prothrombin complex concentrate

administered

Warfarin ReversalWarfarin Reversal

► PO/IV vitamin KPO/IV vitamin K● Effective but INR decrease not immediateEffective but INR decrease not immediate

► Fresh Frozen PlasmaFresh Frozen Plasma● Each unit contains limited amount of vitamin-Each unit contains limited amount of vitamin-

K dependent clotting proteinsK dependent clotting proteins● Significant volume challengeSignificant volume challenge

► 4-factor4-factor PCC PCC● Not available in U.S.Not available in U.S.● ? Cost? Cost● ? Risk of thrombosis? Risk of thrombosis

ConclusionsConclusions

► Although warfarin treatment is safer and more Although warfarin treatment is safer and more practical than it was 10-15 years ago, there is practical than it was 10-15 years ago, there is certainly room for further improvement.certainly room for further improvement.

► The new agents in development mayThe new agents in development may● Eliminate some of the challenges unique to warfarinEliminate some of the challenges unique to warfarin● Allow patients for whom warfarin is not feasible to Allow patients for whom warfarin is not feasible to

receive highly effective anti-thrombotic therapyreceive highly effective anti-thrombotic therapy

Questions Regarding the New Oral Questions Regarding the New Oral AnticoagulantsAnticoagulants

► Do they represent a significant improvement for Do they represent a significant improvement for patients who have been taking warfarin with patients who have been taking warfarin with consistently therapeutic INR values for consistently therapeutic INR values for months/years?months/years?

► Will the lack of an evidence-based “reversal Will the lack of an evidence-based “reversal strategy” deter their use?strategy” deter their use?

► How long will it take clinicians and patients to How long will it take clinicians and patients to become comfortable with the lack of ability to become comfortable with the lack of ability to monitor?monitor?

► Will the elimination of regular INR measurement Will the elimination of regular INR measurement reduce compliance?reduce compliance?

► How will their cost compare to current costs How will their cost compare to current costs (including INR monitoring, dose adjustment, etc.)?(including INR monitoring, dose adjustment, etc.)?

► Which (if any) will be available to patients with Which (if any) will be available to patients with significantly impaired renal function?significantly impaired renal function?

Emerging Role of Direct Thrombin Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial and Factor Xa Inhibition in Atrial

FibrillationFibrillation

Mechanism and Applications for Mechanism and Applications for Thrombosis Mitigation Across the Thrombosis Mitigation Across the Cardiovascular Disease SpectrumCardiovascular Disease Spectrum

Richard C. Becker, MDRichard C. Becker, MDProfessor MedicineProfessor Medicine

Divisions of Cardiology and Hematology Divisions of Cardiology and Hematology Duke University Medical CenterDuke University Medical CenterDuke Clinical Research InstituteDuke Clinical Research Institute


Emerging Role of Direct Emerging Role of Direct Thrombin and Factor Xa AntagonistsThrombin and Factor Xa Antagonists

► Conditions, Dynamic Substrate and Conditions, Dynamic Substrate and Thrombus Survival in Atrial FibrillationThrombus Survival in Atrial Fibrillation

► Anticoagulants in DevelopmentAnticoagulants in Development

► Platelet-Thrombin Interface – A Roadmap Platelet-Thrombin Interface – A Roadmap for Future Pharmacotherapyfor Future Pharmacotherapy

► Redefining Atrial Fibrillation at the Redefining Atrial Fibrillation at the Molecular and Proteomic LevelMolecular and Proteomic Level

Increased Connective Tissue Growth Factor Increased Connective Tissue Growth Factor Expression and Fibrosis in LA of Patients with AFExpression and Fibrosis in LA of Patients with AF

Adam. JACC 2010;55:469-480.Adam. JACC 2010;55:469-480.

Rac1-induced CTGF Regulates Connexin Rac1-induced CTGF Regulates Connexin 43 and N-Cadherin Expression in AF43 and N-Cadherin Expression in AF

Adam. JACC 2010;55:469-480.Adam. JACC 2010;55:469-480.Adam. JACC 2010;55:469-480.Adam. JACC 2010;55:469-480.

Stabilization of Mast Cells Infiltrating the Stabilization of Mast Cells Infiltrating the Atrium of TAC-Operated Mice by CromolynAtrium of TAC-Operated Mice by Cromolyn

Liao. JCI 2010;120:242-253Liao. JCI 2010;120:242-253

Attenuation of AF and Atrial Fibrosis by Attenuation of AF and Atrial Fibrosis by Mast Cell Stabilization by CromolynMast Cell Stabilization by Cromolyn

Liao. JCI 2010;120:242-253Liao. JCI 2010;120:242-253Liao. JCI 2010;120:242-253Liao. JCI 2010;120:242-253

Attenuation of Atrial Fibrosis and AF by Attenuation of Atrial Fibrosis and AF by Reconsitution with BM Cells from W/WReconsitution with BM Cells from W/Wv v MiceMice

Liao. JCI 2010;120:242-253Liao. JCI 2010;120:242-253Liao. JCI 2010;120:242-253Liao. JCI 2010;120:242-253

Extracellular Matrix Degradation Extracellular Matrix Degradation and Fibrosis in Atrial Fibrillationand Fibrosis in Atrial Fibrillation

life.nctu.edu.tw/.../image006.jpg life.nctu.edu.tw/.../image006.jpg

Thrombin Generation According to Factor X Concentrations

Thrombin Generation According to Factor X Concentrations

Allen. J Thromb Haemost 2004;2:402-413Allen. J Thromb Haemost 2004;2:402-413Allen. J Thromb Haemost 2004;2:402-413Allen. J Thromb Haemost 2004;2:402-413

Thrombin Generation According to Thrombin Generation According to Prothrombin ConcentrationsProthrombin Concentrations

Allen. J Thromb Haemost 2004; 2:402-413Allen. J Thromb Haemost 2004; 2:402-413Allen. J Thromb Haemost 2004; 2:402-413Allen. J Thromb Haemost 2004; 2:402-413

ResupplyResupply of the Synthetic Coagulation of the Synthetic Coagulation ProteomeProteome

Orfeo T et al. J. Biol. Chem. 2008;283:9776-9786Orfeo T et al. J. Biol. Chem. 2008;283:9776-9786

Effect of Inhibitors Targeting fXa and fXa in the Prothrombinase ComplexEffect of Inhibitors Targeting fXa and fXa in the Prothrombinase Complex

Resupply of the Synthetic Resupply of the Synthetic Coagulation Proteome: Stability of Coagulation Proteome: Stability of

the Responsethe Response

Orfeo T et al. J. Biol. Chem. 2008;283:9776-9786Orfeo T et al. J. Biol. Chem. 2008;283:9776-9786

Traditional Paradigm of Traditional Paradigm of Factor Xa and ThrombinFactor Xa and Thrombin

Mackman. ATVB 2008;28:698-704Mackman. ATVB 2008;28:698-704

Thrombin-A Pluripotent Effector EnzymeThrombin-A Pluripotent Effector Enzyme

Coughlin. Nature 2000;407:258-264

Factor Xa - a Pluripotent Effector Factor Xa - a Pluripotent Effector EnzymeEnzyme

Trials of Antithrombotic Therapy for Trials of Antithrombotic Therapy for Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation

Warfarin-Control Phase IIIWarfarin-Control Phase III

Historical trials: 3,763Historical trials: 3,763

TrialTrial AgentAgent BlindBlind CHADSCHADS SizeSize StatusStatus

RE-LYRE-LY DabigatranDabigatran OLOL >>11 18,11318,113 CompleteComplete

ROCKETROCKET RivaroxabanRivaroxaban DBDB >>2-32-3 14,00014,000 CompleteComplete

ARISTOTLEARISTOTLE ApixabanApixaban DBDB >>11 15,00015,000 CompleteComplete

BOREALISBOREALISBiotinylatedBiotinylated

IdraparinuxIdraparinux

DBDB >>22 9,6009,600 EnrollingEnrolling

ENGAGEENGAGE EdoxabanEdoxaban DBDB ?? 15,00015,000 EnrollingEnrolling

TotalTotal 71,60071,600

Oral Direct Factor Xa Inhibitors Oral Direct Factor Xa Inhibitors Currently in DevelopmentCurrently in Development

DrugDrugHalf-Life Half-Life (hours)(hours)

BioavailabilityBioavailability Elimination (%) Elimination (%)

RenalRenal Hepatic HepaticDosingDosing

ApixabanApixaban 1212 5050 2525 7575 Twice dailyTwice daily

BetrixabanBetrixaban 1919 4747 00 100100 Once dailyOnce daily

EndoxabanEndoxaban 6-126-12 100%100% 6262 3535 Once dailyOnce daily

RivaroxabanRivaroxaban 5-95-9 8080 3333 6767 Once dailyOnce daily

YM150YM150 intestinalintestinal 18-2018-20 25-8225-82 NRNR NRNR Once/twiceOnce/twice

DCRI

This will need fine tweaking in order to add in the final column..i was unable to decide how to break this up...Phase II/III Evaluation

Factor Xa AF Trial Designs: ApixabanFactor Xa AF Trial Designs: Apixaban

RE-LYRE-LY

Non-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism

(at least one high risk factor)

RR

Warfarin1 mg, 3mg, 5 mg (INR 2.0-3.0)N=6000

Dabigatran Etexilate 110 mg b.i.d.N=6000

Dabigatran Etexilate 150 mg b.i.d.N=6000

Primary objective: Noninferiority to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up. Primary end point: Stroke + systemic embolism

Hazard Ratio Primary Outcome of Stroke Hazard Ratio Primary Outcome of Stroke or Systemic Embolismor Systemic Embolism

Connolly, et al. Connolly, et al. N Engl J Med N Engl J Med 2009;361:1139-512009;361:1139-51

0 6 12 18 24 300 6 12 18 24 30

WarfarinWarfarin

DabigatranDabigatran110 mg110 mg

DabigatranDabigatran150 mg150 mg

WarfarinWarfarin 60226022 58625862 57185718 45934593 28902890 13221322Dabigatran 110 mgDabigatran 110 mg 60156015 58625862 57105710 45934593 29452945 13851385Dabigatran 150 mgDabigatran 150 mg 60766076 59395939 57795779 46824682 30443044 14291429

0 6 12 18 24 300 6 12 18 24 30

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

0.050.05

0.040.04

0.030.03

0.020.02

0.010.01

0.000.00

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

D D

110mg110mg

D D

150mg150mgWarfarinWarfarin

D 110mg vs. D 110mg vs. WarfarinWarfarin

D 150mg vs. D 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

Connolly NEJM 2009;361:1139-1151.

RR 0.40 (95% CI: 0.27–0.60)RR 0.40 (95% CI: 0.27–0.60)

p<0.001 (sup)p<0.001 (sup)

RE-LY: Intracranial Bleeding RatesRE-LY: Intracranial Bleeding Rates

RR 0.31 (95% CI: 0.20–0.47)RR 0.31 (95% CI: 0.20–0.47)

p<0.001 (sup)p<0.001 (sup)

Num

ber

of e

vent

sN

umbe

r of

eve

nts

0,23 %0,23 %

0,74 %

0,30 %0,30 %

RRR69%

RRRRRR60%

Connolly. NEJM 2009:361:1139-1151.Connolly. NEJM 2009:361:1139-1151.

Lip, G. Y.H. et al. Eur Heart J 2009 30:2897-2907; doi:10.1093/eurheartj/ehp318Lip, G. Y.H. et al. Eur Heart J 2009 30:2897-2907; doi:10.1093/eurheartj/ehp318

Oral Direct Thrombin Inhibitor AZD0837 Oral Direct Thrombin Inhibitor AZD0837 PharmacokineticsPharmacokinetics

Lip, G. Y.H. et al. Eur Heart J 2009 30:2897-2907; doi:10.1093/eurheartj/ehp318Lip, G. Y.H. et al. Eur Heart J 2009 30:2897-2907; doi:10.1093/eurheartj/ehp318

Oral Direct Thrombin Inhibitor AZD0837 Oral Direct Thrombin Inhibitor AZD0837 DynamicsDynamics

Muller. Cell 2009;139:1143-1156Muller. Cell 2009;139:1143-1156Muller. Cell 2009;139:1143-1156Muller. Cell 2009;139:1143-1156

Platelet Polyphosphates and Platelet Polyphosphates and Factor XII ActivationFactor XII Activation

Platelet Polyphosphates and Platelet Polyphosphates and Factor XII ActivationFactor XII Activation

Muller. Cell 2009;139:1143-115614Muller. Cell 2009;139:1143-115614

00 20 40 60 20 40 60

TIME (MINUTES)TIME (MINUTES)

FX

IIa

[nM

]F

XII

a [n

M]

120120

100100

8080

6060

4040

2020

00

Adapted from Ginsburg et al. JACC 2005;46:1615Adapted from Ginsburg et al. JACC 2005;46:1615

Drug administered

Mechanistic Data Molecular basis of drug effect on clinical phenotype

Genome

Blood Transcriptome

Plasma Proteome

Integrated biosignatures that predict drug response

and clinical outcomes

Biological Phenotype(Anti-Factor Xa)

Clinical Phenotype(Ischemic stroke or bleeding)

Blood substudy program

► Atrial fibrillation is the end-result of conditions Atrial fibrillation is the end-result of conditions characterized by inflammation, fibrosis and tissue characterized by inflammation, fibrosis and tissue remodeling.remodeling.

► Thrombus formation represents a localized Thrombus formation represents a localized response to tissue injury and altered flow response to tissue injury and altered flow dynamics.dynamics.

► Thrombin and factor Xa inhibitors can attenuate Thrombin and factor Xa inhibitors can attenuate thrombus formation and possibly alter the natural thrombus formation and possibly alter the natural history of disease.history of disease.

► Never forget the platelet in thrombotic disorders.Never forget the platelet in thrombotic disorders.

► Defining atrial fibrillation at the molecular and Defining atrial fibrillation at the molecular and proteomic level may inform clinical data.proteomic level may inform clinical data.

Emerging Role of Direct Thrombin and Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Factor Xa Inhibition in Atrial Fibrillation

Emerging Role of Direct Thrombin and Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Factor Xa Inhibition in Atrial Fibrillation

► Studies using novel anticoagulants for stroke Studies using novel anticoagulants for stroke prevention in AF are likely to change the prevention in AF are likely to change the landscape of patient management in AF.landscape of patient management in AF.

► Additional trials, including those with Factor Xa Additional trials, including those with Factor Xa inhibitors will provide a robust foundation for inhibitors will provide a robust foundation for evaluating how the current therapeutic evaluating how the current therapeutic landscape for stroke prevention might change.landscape for stroke prevention might change.

► Studies evaluating safety and efficacy of Studies evaluating safety and efficacy of apixaban in patients who are not suitable apixaban in patients who are not suitable candidates for VKA have the potential to identify candidates for VKA have the potential to identify a non-ASA strategy for a unique subset of a non-ASA strategy for a unique subset of patients.patients.

The Emerging Role of Factor Xa and The Emerging Role of Factor Xa and Direct Thrombin Inhibition for the Direct Thrombin Inhibition for the

Setting of Post-ACS Secondary Setting of Post-ACS Secondary PreventionPrevention

Shamir R. Mehta MD, MSc, FRCPC, FACCShamir R. Mehta MD, MSc, FRCPC, FACCDirector, Interventional CardiologyDirector, Interventional Cardiology

Hamilton Health SciencesHamilton Health SciencesAssociate Professor of MedicineAssociate Professor of Medicine

McMaster UniversityMcMaster UniversityDirector, ACS Research ProgramDirector, ACS Research Program

Population Health Research InstitutePopulation Health Research Institute


Gaziano TA. Circ 2005.Gaziano TA. Circ 2005.

20022002

World pop.:World pop.: 6.12 billion6.12 billion

Deaths:Deaths: 56.6 million56.6 million

CVD deaths:CVD deaths: 16.6 million16.6 million

CVD: A Global EpidemicCVD: A Global Epidemic

OcclusiveOcclusivethrombosisthrombosis

Non-occlusiveNon-occlusivethrombosisthrombosis

CK - MB or Troponin CK - MB or Troponin ↑↑ Troponin elevated or notTroponin elevated or notCourtesy Dr. E FalkCourtesy Dr. E Falk

ThrombosisThrombosis

FibrinFibrin

Platelet Platelet AggregateAggregate

ThrombusThrombus

Atherosclerotic Atherosclerotic PlaquePlaque

Red Red Blood Blood CellsCells

Antiplatelets, Anticoagulants and their Antiplatelets, Anticoagulants and their Combination in ACS: Evidence from RCT’sCombination in ACS: Evidence from RCT’s

Short TermShort Term Long TermLong Term

Antiplatelet aloneAntiplatelet alone ASAASA ASA, clopidogrelASA, clopidogrel

Anticoagulant aloneAnticoagulant alone UFHUFH WarfarinWarfarin

CombinationCombinationUFH, LMWH, UFH, LMWH, fondaparinux, fondaparinux,

bivalirudinbivalirudinUnder studyUnder study

Randomized Trials of Aspirin in Unstable Randomized Trials of Aspirin in Unstable Angina: Short and Long Term BenefitAngina: Short and Long Term Benefit

*comparison versus placebo, *comparison versus placebo, ††comparison versus controlcomparison versus controlAdapted from Mehta SR, Adapted from Mehta SR, J Am Coll CardiolJ Am Coll Cardiol. 2003;41(suppl):79S. 2003;41(suppl):79S

TrialTrial ASA TreatmentASA Treatment Length of Length of Follow-upFollow-up RRRRRR PP value value

Veterans Affairs Veterans Affairs Study (1983)Study (1983) 325 mg/d*325 mg/d* 3 months3 months 41%41% 0.0040.004

Canadian Study Canadian Study (1985)(1985) 325 mg 4x daily325 mg 4x daily†† 18 months18 months 30%30% 0.0720.072

Montreal Heart Montreal Heart Study (1988)Study (1988)

650 mg first dose, 650 mg first dose, 325 mg/d*325 mg/d* 6 days6 days 63%63% 0.040.04

RISC (1990)RISC (1990) 75 mg for 3 mon*75 mg for 3 mon* 13 months13 months 64%64% 0.00010.0001

ATC meta-analysis ATC meta-analysis (2002)(2002) Various regimens*Various regimens* VariousVarious 46%46% <0.0001<0.0001

Benefit of Clopidogrel Therapy: Benefit of Clopidogrel Therapy: Day 0-30 and Day 30-1 yearDay 0-30 and Day 30-1 year

5965596559935993604860486159615963036303PlaceboPlacebo

5990599060266026607060706145614562596259ClopidogrelClopidogrel

No. at RiskNo. at Risk

23882388

24182418

Weeks

Pro

po

rtio

n E

ven

t-F

ree

0.9

00

.92

0.9

40

.96

0.9

81

.00

0 1 2 3 4

RRR 21%RRR 21%95% CI 0.67–0.92 P=0.003

Clopidogrel + ASA

Placebo + ASA

MI, stroke, CV Death: 0–30 days

Yusuf et al. Yusuf et al. CirculationCirculation. 2003;107:966. 2003;107:966

Pro

po

rtio

n E

ven

t-F

ree

31593159

31803180

39293929463946395390539059545954

40044004474247425481548159815981

Months

0.9

00

.92

0.9

40

.96

0.9

81

.00

1 4 6 8 10 12

MI, stroke, CV Death: 31 days - 1 year

RRR 18%RRR 18%95% CI 0.70–0.95 P=0.009

Clopidogrel + ASA

Placebo + ASA

0.150.15

0.100.10

0.050.05

0.00.0

0 100100 200200 300300 400400Days of follow-upDays of follow-up

P P = 0.002= 0.002N = 2658N = 2658

ClopidogrelClopidogrel+ ASA*+ ASA*

PlaceboPlacebo+ ASA*+ ASA*

Cu

mu

lati

ve H

azar

d R

ate

* In addition to other standard therapies.

Mehta et al for the CURE Investigators. Lancet. 2001;358:527

Composite of MI or cardiovascular death from Composite of MI or cardiovascular death from randomization to end of follow-uprandomization to end of follow-up

Early and Long Term Early and Long Term Clopidogrel in PCI PatientsClopidogrel in PCI Patients

12.6%12.6%

8.8%8.8%

31%31%Relative RiskRelative Risk

ReductionReduction

Initial Combination Therapy with an Initial Combination Therapy with an Anticoagulant + AntiplateletAnticoagulant + Antiplatelet

LMWH or UFH combined with ASA in ACS: Death or MI

Eikelboom J, et al. Lancet 2000Eikelboom J, et al. Lancet 2000

N=2,919

Reduces Death/MI in UA/ NSTEMIReduces Death/MI in UA/ NSTEMI

Combination Anticoagulant + Combination Anticoagulant + Antiplatelet Therapy AloneAntiplatelet Therapy Alone

N=16,842

LMWH combined with ASA in STEMI: Death

Eikelboom J, et al. Circulation 2006Eikelboom J, et al. Circulation 2006

LMWH combined with ASA in STEMI: MI

Reduce Mortality and MI in the Initial Management of STEMIReduce Mortality and MI in the Initial Management of STEMI

OASIS 6 Investigators. JAMA 2006OASIS 6 Investigators. JAMA 2006

Longer Term Longer Term Anticoagulant Therapy (8 days) + Anticoagulant Therapy (8 days) + Antiplatelet Therapy Alone Superior to Short Term Antiplatelet Therapy Alone Superior to Short Term

Therapy (48-72 hrs)Therapy (48-72 hrs)

Rothberg MD, et al. Ann Intern Med 2005Rothberg MD, et al. Ann Intern Med 2005

Study OR (95% CI)

n=5,938 Favors Combination Favors ASA

INR > 2.0

Long Term Anticoagulant Therapy + ASA Long Term Anticoagulant Therapy + ASA Reduces Death/MI/Stroke After ACSReduces Death/MI/Stroke After ACS

Rothberg MD, et al. Ann Intern Med 2005Rothberg MD, et al. Ann Intern Med 2005

INR > 2.0

n=5,938 Favors Combination Favors ASA

Study OR (95% CI)

Long Term Anticoagulant Therapy + ASA Long Term Anticoagulant Therapy + ASA May Increase Bleeding After ACSMay Increase Bleeding After ACS

Adapted from Turpie and Weitz & Bates,Adapted from Turpie and Weitz & Bates, J Thromb Haemost J Thromb Haemost 20072007

Novel AnticoagulantsNovel Anticoagulants

TFPI (tifacogin)TFPI (tifacogin) rNAPc2rNAPc2

FondaparinuxFondaparinux Idraparinux Idraparinux

RivaroxabanRivaroxabanApixabanApixabanLY517717LY517717

YM150YM150DU-176bDU-176b

BetrixabanBetrixabanTAK 442TAK 442813893813893

DabigatranDabigatran AZD0837AZD0837

OtamixabanOtamixaban DX-9065aDX-9065a

XaXa

IIaIIa

TF/VIIaTF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

IIII

FibrinFibrinFibrinogenFibrinogen

ATIIIATIII

APC (drotrecogin alfa)APC (drotrecogin alfa) sTM (ART-123)sTM (ART-123)

TTP889TTP889

ATI-5923ATI-5923

Aptamer/antidoteAptamer/antidote

Pure Factor Xa Inhibition with Fondaparinux Pure Factor Xa Inhibition with Fondaparinux Reduces Bleeding and Mortality vs EnoxaparinReduces Bleeding and Mortality vs Enoxaparin

OASIS 5 Investigators. N Engl J Med 2006;356:1464-76OASIS 5 Investigators. N Engl J Med 2006;356:1464-76

ApixabanApixaban

CharacteristicsCharacteristics Oral bioavailability: 58%Oral bioavailability: 58% No food effectNo food effect Low volume distributionLow volume distribution Half-life: THalf-life: T1/2 1/2 ≈ ≈ 12 h12 h Multiple elimination pathways: Multiple elimination pathways:

25% renal25% renal No CYP inhibition / inductionNo CYP inhibition / induction Highly selective for factor XaHighly selective for factor Xa No reactive intermediatesNo reactive intermediates No organ toxicity, LFT No organ toxicity, LFT

abnormalities, or QTc abnormalities, or QTc prolongationprolongationPinto DJ et al. Pinto DJ et al. J Med Chem.J Med Chem. 2007;50:5339-5356. 2007;50:5339-5356.

He K et al. Poster presented at: 48th Annual Meeting of the American Society of He K et al. Poster presented at: 48th Annual Meeting of the American Society of Hematology; December 2006; Orlando, FL. Poster 38-I.Hematology; December 2006; Orlando, FL. Poster 38-I.Frost C et al. Poster presented at: 21st Congress of the International Society of Frost C et al. Poster presented at: 21st Congress of the International Society of Thrombosis and Haemostasis; July 2007; Geneva, Switzerland.Thrombosis and Haemostasis; July 2007; Geneva, Switzerland.Lassen MR et al. Lassen MR et al. J Thromb Haem.J Thromb Haem. 2007;5:2368-2375. 2007;5:2368-2375.

N

N

O

H2N

O N

N O

OMe

APPRAISE Steering Committee and Investigators. APPRAISE Steering Committee and Investigators.

CirculationCirculation. 2009;119:2877-2885. 2009;119:2877-2885. .

Apixaban, an Oral, Direct, Selective Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Factor Xa Inhibitor, in Combination With

Antiplatelet Therapy After Acute Antiplatelet Therapy After Acute Coronary SyndromeCoronary Syndrome

Results of the Apixaban for Prevention of Acute Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) TrialIschemic and Safety Events (APPRAISE) Trial

Phase B = 1168

Study DesignStudy Design

Recent (7 days) Acute Coronary Syndromeplus at least one additional risk factor

Phase A = 547

Apixaban 10 mg QD

n=184

Apixaban 10 mg QD

n=184

Placebon=184

Phase A1:1:1

Phase A1:1:1

Apixaban2.5 mg BID

n=179

Apixaban2.5 mg BID

n=179

Interim analysis (DSMB review)Interim analysis (DSMB review)

Phase B3:1:1:2:2Phase B3:1:1:2:2

Placebon=427

Apixaban10 mg QD

n=134

Apixaban10 mg QD

n=134Total = 1715

Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH)Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic stroke

Discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapy

John H. Alexander, (John H. Alexander, (Circulation.Circulation. 2009;119:2877-2885.) 2009;119:2877-2885.)

Recent (7 days) Acute Coronary Syndromeplus at least one additional risk factor

Phase A1:1:1

Apixaban2.5 mg BID

n=179

Apixaban10 mg QD

n=184

•Randomized, double-blind. •Study drug for 6 months. •Aspirin 165 mg/d. •Clopidogrel per MD discretion (stratified randomization)

Phase B3:1:1:2:2

Apixaban2.5 mg BID

n=138

Apixaban10 mg QD

n=134

Apixaban10 mg BID

n=248

Apixaban20 mg QD

n=221

Ischemic OutcomesIschemic Outcomes


Ischemic Events by Clopidogrel Ischemic Events by Clopidogrel StatusStatus

N N 462462 232232 243243 149149 8585 7575


Bleeding Bleeding ISTH and TIMI ScalesISTH and TIMI Scales


Bleeding by Clopidogrel StatusBleeding by Clopidogrel Status

N N 453453 230230 241241 146146 8585 7474


Randomize 1:1Randomize 1:1Stratified by Antiplatelet RegimenStratified by Antiplatelet Regimen

Double blindDouble blind

Event DrivenEvent Driven

• AspirinAspirin• Other antiplatelet at MD Other antiplatelet at MD

discretiondiscretion

Start study drug ASAP after acute care stabilization / parenteral anticoagulation Start study drug ASAP after acute care stabilization / parenteral anticoagulation

N=10,800N=10,800

APPRAISE-2 TrialAPPRAISE-2 Trial

Recent Acute Coronary Syndrome(STEMI or NSTE-ACS)

Apixaban 5 mg BID Placebo

Primary: Death, MI, Ischemic Stroke

Secondary: Death, MI, Severe Recurrent Ischemia, Ischemic stroke

Safety: Major Bleeding

Study DesignStudy Design

MD Decision to Treat with ClopidogrelMD Decision to Treat with Clopidogrel

N = 3,491

Aspirin 75-100 mg

PLACEBON=253

5 mg (77)10 mg (98)20 mg (78)

RIVA QD N=254

5 mg (77)10 mg (99)20 mg (78)

RIVA BID N=254

2.5 mg (77)

5 mg (97)10 mg (80)

PLACEBON=907

5 mg (74)10 mg (428)15 mg (178)20 mg (227)

RIVA QDN=912

5 mg (78)10 mg (430)15 mg (178)20 mg (226)

Gibson CM, AHA 2008Gibson CM, AHA 2008

Recent ACS PatientsStabilized 1-7 Days Post-Index Event

MD Decision to Treat with Clopidogrel

NO YES

STRATUM 1ASA Alone

N=761

STRATUM 2ASA + Clop.

N=2,730

PLACEBON=253

5 mg (77)10 mg (98)20 mg (78)

RIVA QD N=254

5 mg (77)10 mg (99)20 mg (78)

RIVA BID N=254

2.5 mg (77)5 mg (97)

10 mg (80)

PLACEBON=907

5 mg (74)10 mg (428)15 mg (178)20 mg (227)

RIVA QDN=912

5 mg (78)10 mg (430)15 mg (178)20 mg (226)

RIVA BIDN=911

2.5 mg (76)5 mg (430)

7.5 mg (178)10 mg (227

Treat for 6 Months

Days After Start of TreatmentDays After Start of Treatment

Primary Safety EndpointPrimary Safety EndpointClinically Significant BleedingClinically Significant Bleeding

6.1%6.1%55

1010

1515

Clin

ical

ly S

igni

fican

t B

leed

ing

(%)

Clin

ical

ly S

igni

fican

t B

leed

ing

(%)

00

00 3030 6060 9090 120120 150150 180180

3.3%3.3%

10.9%10.9%

12.7%12.7%

15.3%15.3%Total Daily Dose:Total Daily Dose:

Rivaroxaban 20 mg ----Rivaroxaban 20 mg ----




Placebo ---Placebo ---

HR

2.22.2(1.25-3.91)

3.43.4(2.3-4.9)

3.63.6(2.3-5.6)

5.15.1(3.4-7.4)

*p<0.01 for *p<0.01 for placebo Vs Riva placebo Vs Riva 5mg. p<0.001 for 5mg. p<0.001 for Riva 10,15,20mg Riva 10,15,20mg

vs placebovs placebo

(= TIMI Major, TIMI Minor, Bleed Req. Med. Attn.)

Mega, Lancet 2009; DOI:10.1016/S0140-6736(09)Mega, Lancet 2009; DOI:10.1016/S0140-6736(09)Kaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio; Kaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio; CI=Confidence IntervalCI=Confidence Interval

Safety EndpointsSafety EndpointsTIMI Major, TIMI Minor and Bleeding Req. Med. TIMI Major, TIMI Minor and Bleeding Req. Med.

Attn.Attn.

Rat

e (%

)R

ate

(%)

Rat

e (%

)R

ate

(%)

TIMI MajorTIMI Major TIMI MinorTIMI Minor Med AttentionMed AttentionPlacPlac 55 1010 1515 2020 PlacPlac 55 1010 1515 2020 PlacPlac 55 1010 1515 2020

TIMI MajorTIMI Major TIMI MinorTIMI Minor Med AttentionMed AttentionPlac 55 1010 2020 Plac 55 1010 2020 Plac 55 1010 2020

P trend<0.001

P trend<0.0001

P trend=p value for dose response over actual dose values.Mega et. al, Lancet 2009; DOI:10.1016/S0140-6736(09)Mega et. al, Lancet 2009; DOI:10.1016/S0140-6736(09)

Secondary Efficacy EndpointSecondary Efficacy Endpoint: : Incidence of Death / MI / StrokeIncidence of Death / MI / Stroke

Dea

th /

MI /

Str

oke

(%

)D

eath

/ M

I / S

trok

e (

%)

Dea

th /

MI /

Str

oke

(%

)D

eath

/ M

I / S

trok

e (

%)

Stratum 1: ASA AloneStratum 1: ASA Alone Stratum 2: ASA + Clop.Stratum 2: ASA + Clop.

TDD

n=253 n=154 n=196 n=158 n=907 n=154 n=860 n=356 n=453

11.911.9

8.08.0

7.07.0

4.74.7

3.83.8

2.72.7 2.72.7

4.74.7

3.03.0

P trend = 0.01 P trend = 0.72

HR 0.67

HR 0.58

HR 0.37

HR 0.70

HR O.71

HR 1.24

HR 0.79

Mega et. al, Lancet 2009; DOI:10.1016/S0140-6736(09)Mega et. al, Lancet 2009; DOI:10.1016/S0140-6736(09)

Randomize 1:1Randomize 1:1Stratified by Antiplatelet RegimenStratified by Antiplatelet Regimen

Double blindDouble blind

Event DrivenEvent Driven

• AspirinAspirin• Other antiplatelet at MD Other antiplatelet at MD

discretiondiscretion

Start study drug ASAP after acute care stabilization / parenteral anticoagulation Start study drug ASAP after acute care stabilization / parenteral anticoagulation

N=10,800N=10,800

APPRAISE-2 TrialAPPRAISE-2 Trial

Recent Acute Coronary Syndrome(STEMI or NSTE-ACS)

Apixaban 5 mg BID Placebo

Primary: Death, MI, Ischemic Stroke

Secondary: Death, MI, Severe Recurrent Ischemia, Ischemic stroke

Safety: Major Bleeding

REDEEM: Outcomes by Dabigatran REDEEM: Outcomes by Dabigatran Randomization GroupRandomization Group

End pointEnd pointPlaceboPlacebo

(n=371)(n=371)

50 mg bid50 mg bid

(n=369)(n=369)

75 mg bid75 mg bid

(n=368)(n=368)

110 mg 110 mg bid bid

(n=406)(n=406)

150 150 mg bidmg bid(n=347)(n=347)

Primary end Primary end pointpoint 2.42.4 3.53.5 4.34.3 7.97.9 7.87.8

Major bleeding *Major bleeding * 0.50.5 0.80.8 0.30.3 2.02.0 1.21.2

CV death, CV death, nonfatal MI, or nonfatal MI, or strokestroke

3.83.8 4.64.6 4.94.9 3.03.0 3.53.5

* International Society of Thrombosis and Haemostasis criteria* International Society of Thrombosis and Haemostasis criteria

Oldgren J, American Heart Association 2009 Scientific Sessions; Nov. 18, 2009; Orlando, FLOldgren J, American Heart Association 2009 Scientific Sessions; Nov. 18, 2009; Orlando, FL

ConclusionsConclusions

1.1. Short and Long term antiplatelet alone and Short and Long term antiplatelet alone and anticoagulant therapy alone reduce major CV anticoagulant therapy alone reduce major CV events after ACSevents after ACS

2.2. Short term combination therapy reduces major Short term combination therapy reduces major CV events in ACSCV events in ACS

3.3. Long term combination therapy with new oral Long term combination therapy with new oral anticoagulants apixaban and rivaroxaban anticoagulants apixaban and rivaroxaban evaluated in the context of contemporary evaluated in the context of contemporary antiplatelet therapy demonstrate a reduction in antiplatelet therapy demonstrate a reduction in ischemic events with a dose dependent increase ischemic events with a dose dependent increase in bleedingin bleeding

4.4. The widespread use of these agents as routine The widespread use of these agents as routine therapy after ACS will depend on the balance of therapy after ACS will depend on the balance of ischemic event reduction vs bleeding currently ischemic event reduction vs bleeding currently being evaluated in large-scale phase III RCTsbeing evaluated in large-scale phase III RCTs

New Frontiers New Frontiers inin

Thrombosis Reduction Thrombosis Reduction forfor Heart Heart DiseaseDisease

Take Home Points and ConclusionsTake Home Points and Conclusions

Thrombosis Risk Reduction: SummaryThrombosis Risk Reduction: Summary

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIProgram ChairmanProgram Chairman

Chief of Cardiology, VA Boston Healthcare SystemChief of Cardiology, VA Boston Healthcare SystemDirector, Integrated Interventional Cardiovascular ProgramDirector, Integrated Interventional Cardiovascular Program

Brigham and Women’s Hospital and the VA Boston Healthcare SystemBrigham and Women’s Hospital and the VA Boston Healthcare SystemAssociate Professor of Medicine, Harvard Medical SchoolAssociate Professor of Medicine, Harvard Medical School

Senior Investigator, TIMI GroupSenior Investigator, TIMI Group

1.1. AF increases the risk of stroke and AF increases the risk of stroke and thromboembolismthromboembolism

2.2. Need to balance stroke prevention against Need to balance stroke prevention against bleeding risk: in search of the “ideal strategy”bleeding risk: in search of the “ideal strategy”

3.3. We need a paradigm shift in stroke risk We need a paradigm shift in stroke risk assessment guidelines: current schema have assessment guidelines: current schema have modest value in predicting risk and, therefore, modest value in predicting risk and, therefore, best prophylactic approachbest prophylactic approach

4.4. Defining AF at the molecular and proteomic level Defining AF at the molecular and proteomic level may helpmay help

5.5. Warfarin treatment has become safer and more Warfarin treatment has become safer and more practical, but limitations in achieving ideal TTR practical, but limitations in achieving ideal TTR persistpersist

6.6. Newer agents inhibiting Factor Xa or thrombin Newer agents inhibiting Factor Xa or thrombin offer unique opportunities in both efficacy and offer unique opportunities in both efficacy and safetysafety

Take Home Points: Take Home Points: AFAF

1.1. Following acute coronary syndrome patients Following acute coronary syndrome patients remain at high risk for: remain at high risk for: ● Recurrent ischemic events Recurrent ischemic events ● Bleeding (largely secondary to antithrombotic Bleeding (largely secondary to antithrombotic

therapy)therapy)

2.2. Inhibition of Factor Xa or thrombin with oral non-Inhibition of Factor Xa or thrombin with oral non-monitored agents has the potential to reduce monitored agents has the potential to reduce ischemic events but will probably also increase in ischemic events but will probably also increase in bleedingbleeding

3.3. Triple therapy with DAP plus oral, non-monitored Triple therapy with DAP plus oral, non-monitored anticoagulant may be attractive if bleeding risks anticoagulant may be attractive if bleeding risks can be mitigatedcan be mitigated

4.4. The ideal level of inhibition of Factor Xa or of The ideal level of inhibition of Factor Xa or of thrombin to improve ACS outcomes will require thrombin to improve ACS outcomes will require further studyfurther study

Take Home Points: Take Home Points: ACS ACS

1.1. Noninferiority may not suffice to alter Noninferiority may not suffice to alter VKA landscape, but superiority findings VKA landscape, but superiority findings and/or less bleeding observed in RE-LY and/or less bleeding observed in RE-LY are very encouragingare very encouraging

2.2. Many more trials will be forthcomingMany more trials will be forthcoming

3.3. Beware of off-label useBeware of off-label use

Take Home Points: Take Home Points: Novel AnticoagulantsNovel Anticoagulants

1.1. The RE-LY Trial represents the most compelling The RE-LY Trial represents the most compelling evidence to date for revising, reconsidering, and evidence to date for revising, reconsidering, and reshaping our current VKA-based paradigm for reshaping our current VKA-based paradigm for stroke prevention in atrial fibrillationstroke prevention in atrial fibrillation

2.2. Additional trials, including those with Factor Xa Additional trials, including those with Factor Xa inhibitors, will provide a more robust foundation inhibitors, will provide a more robust foundation for evaluating how the current therapeutic for evaluating how the current therapeutic landscape for stroke prevention might changelandscape for stroke prevention might change

3.3. Studies evaluating safety and efficacy Factor Xa Studies evaluating safety and efficacy Factor Xa inhibition in patients who inhibition in patients who are not suitable are not suitable candidates for VKAcandidates for VKA has the potential to identify a has the potential to identify a strategy for a unique subset of patientsstrategy for a unique subset of patients

Take Home Points: Take Home Points: Novel AnticoagulantsNovel Anticoagulants

1.1. Thrombosis is critical in multiple Thrombosis is critical in multiple cardiovascular syndromes, including ACS cardiovascular syndromes, including ACS and AFand AF

2.2. Thrombosis risk reduction presents a Thrombosis risk reduction presents a significant unmet need in patients with significant unmet need in patients with atherothrombosisatherothrombosis

3.3. Novel pathways to prevent thrombosis Novel pathways to prevent thrombosis likely to yield benefit based on number likely to yield benefit based on number and quality of trials in progress across the and quality of trials in progress across the arterial and venous risk spectrumarterial and venous risk spectrum

Take Home: Take Home: ConclusionsConclusions

please take this time to complete the pre-program performance

Documents

new opportunities

new challenges

new mexico usarichard

risk ratio

nonmonitored anticoagulation

mdassociate professor

acs prevention

novo patients