+ All Categories
Home > Documents > National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New...

National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New...

Date post: 26-Mar-2015
Category:
Upload: amber-munoz
View: 212 times
Download: 0 times
Share this document with a friend
Popular Tags:
168
Transcript
Page 1: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.
Page 2: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

National Experts in Cardiovascular Medicine National Experts in Cardiovascular Medicine Illuminate and DebateIlluminate and Debate

New Frontiers New Frontiers inin Atrial Fibrillation Atrial Fibrillation

Emerging Perspectives in Thrombosis Mitigation for the Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular Specialist—Cardiovascular Specialist—TranslatingTranslating Evidence into ActionEvidence into Action

New Dimensions and New Dimensions and Landmark Practice AdvancesLandmark Practice Advances

Program ModeratorProgram ModeratorSamuel Z. Goldhaber, MDSamuel Z. Goldhaber, MD

Cardiovascular DivisionCardiovascular DivisionBrigham and Women’s HospitalBrigham and Women’s Hospital

Professor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School

Page 3: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

CME-accredited symposium CME-accredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC

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

Mission statement: Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes: Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI: COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

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

Page 4: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Program Educational ObjectivesProgram Educational Objectives

As a result of this educational activity, participants will learn about:As a result of this educational activity, participants will learn about:

► Advances in oral anticoagulation based on new mechanisms involving inhibition of the coagulation cascade and possible implications for prophylaxis of arterial thromboembolism in the setting of atrial fibrillation.

► The mechanisms involved in thromboembolic prevention and the rationale for identifying agents with predictable anticoagulation, in the absence of clinical monitoring.

► Current ACCP, ACC, AHA, and AAN guidelines for stroke prevention in the setting of AF.

► Novel approaches for residual risk reduction and secondary prevention of adverse thromboembolic events (stroke) in the setting of atrial fibrillation, and related conditions.

As a result of this educational activity, participants will learn about:As a result of this educational activity, participants will learn about:

► Advances in oral anticoagulation based on new mechanisms involving inhibition of the coagulation cascade and possible implications for prophylaxis of arterial thromboembolism in the setting of atrial fibrillation.

► The mechanisms involved in thromboembolic prevention and the rationale for identifying agents with predictable anticoagulation, in the absence of clinical monitoring.

► Current ACCP, ACC, AHA, and AAN guidelines for stroke prevention in the setting of AF.

► Novel approaches for residual risk reduction and secondary prevention of adverse thromboembolic events (stroke) in the setting of atrial fibrillation, and related conditions.

Page 5: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Program FacultyProgram Faculty

Program ModeratorProgram ModeratorSamuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular DivisionBrigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School  Jonathan L. Halperin, MDJonathan L. Halperin, MDProfessor of Medicine (Cardiology) Professor of Medicine (Cardiology) Mount Sinai School of MedicineMount Sinai School of MedicineDirector, Clinical Cardiology ServicesDirector, Clinical Cardiology ServicesThe Zena and Michael A. Wiener The Zena and Michael A. Wiener Cardiovascular InstituteCardiovascular InstituteThe Marie-Josée and Henry R. KravisThe Marie-Josée and Henry R. Kravis Center for Cardiovascular HealthCenter for Cardiovascular Health  

  Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of MedicineDepartment of MedicineDepartment of MedicineDirector, Thrombosis Clinic and Director, Thrombosis Clinic and Anticoagulation ServiceAnticoagulation ServiceBoston University Medical CenterBoston University Medical CenterBoston, MassachusettsBoston, Massachusetts  Jeffrey I. Weitz, MD, FRCP, FACPJeffrey I. Weitz, MD, FRCP, FACPProfessor of Medicine and BiochemistryProfessor of Medicine and BiochemistryMcMaster UniversityMcMaster UniversityDirector, Henderson Research CenterDirector, Henderson Research CenterCanada Research Chair in ThrombosisCanada Research Chair in ThrombosisHeart and Stroke FoundationHeart and Stroke FoundationJ.F. Mustard Chair in Cardiovascular J.F. Mustard Chair in Cardiovascular ResearchResearch

Page 6: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Faculty COI DisclosuresFaculty COI Disclosures

  Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDResearch SupportResearch Support: BMS, Boehringer-Ingelheim, Eisai, Johnson and Johnson, sanofi-: BMS, Boehringer-Ingelheim, Eisai, Johnson and Johnson, sanofi-aventis aventis Consultant: Consultant: BMS, Boehringer-Ingelheim, Eisai, Medscape, Merck, sanofi-aventis, BMS, Boehringer-Ingelheim, Eisai, Medscape, Merck, sanofi-aventis, VortexVortex  Jonathan L. Halperin, MDJonathan L. Halperin, MDConsulting Consulting fees from the following companies involved in development of fees from the following companies involved in development of investigational drugs or devices: Astellas Pharma, U.S., Bayer HealthCare, Biotronik, investigational drugs or devices: Astellas Pharma, U.S., Bayer HealthCare, Biotronik, Inc., Boehringer Ingelheim, Daiichi Sankyo Pharma, Johnson & Johnson, Portola Inc., Boehringer Ingelheim, Daiichi Sankyo Pharma, Johnson & Johnson, Portola Pharmaceuticals, and sanofi-aventisPharmaceuticals, and sanofi-aventis  Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHSteering Committee: Steering Committee: Bristol-Myers SquibbBristol-Myers SquibbAdvisory Board: Advisory Board: Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, sanofi-Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, sanofi-aventisaventis  Jeffrey I. Weitz, MD, FRCP, FACPJeffrey I. Weitz, MD, FRCP, FACPGrants/Research Support:Grants/Research Support:  CIHR, HSFO, CFI, ORF  CIHR, HSFO, CFI, ORFSpeakers Bureau: Speakers Bureau:  Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, Daiichi- Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, Daiichi-Sankyo, Bayer, Pfizer, The Medicines Company, Eisai, TakedaSankyo, Bayer, Pfizer, The Medicines Company, Eisai, Takeda    

Page 7: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

ATRIAL FIBRILLATION ATRIAL FIBRILLATION Current Challenges Current Challenges

in Thrombosis Medicine for the in Thrombosis Medicine for the Cardiovascular SpecialistCardiovascular Specialist

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of Medicine

Harvard Medical SchoolHarvard Medical School

New Frontiers in Atrial FibrillationNew Frontiers in Atrial Fibrillation

Page 8: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Atrial Fibrillation: Twice as Common Atrial Fibrillation: Twice as Common as Previously Suspectedas Previously Suspected

► Incidence increased 13% over past Incidence increased 13% over past 20 years 20 years

► In USA, 12-16 million will be affected In USA, 12-16 million will be affected by 2050by 2050

► Increasing obesity and increasing Increasing obesity and increasing age are risk factors that help explain age are risk factors that help explain rise in incidencerise in incidence

► Incidence increased 13% over past Incidence increased 13% over past 20 years 20 years

► In USA, 12-16 million will be affected In USA, 12-16 million will be affected by 2050by 2050

► Increasing obesity and increasing Increasing obesity and increasing age are risk factors that help explain age are risk factors that help explain rise in incidencerise in incidence

Miyasaka Y. Circulation 2006; 114: 119-125Miyasaka Y. Circulation 2006; 114: 119-125

Page 9: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

AF Prevalence: Age and GenderAF Prevalence: Age and Gender

JAMA 2001; 285: 2370JAMA 2001; 285: 2370

Prevalence of atrial fibrillation with age Prevalence of atrial fibrillation with age

Age, yearsAge, years

Pre

vale

nce,

per

cent

Pre

vale

nce,

per

cent

Page 10: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Mortality Rates in AFMortality Rates in AF

► Double the overall age and gender Double the overall age and gender matched populationmatched population

► No reduction in past two decadesNo reduction in past two decades

► Mortality 9-fold higher during 1Mortality 9-fold higher during 1stst 4 4 months after diagnosismonths after diagnosis

► Double the overall age and gender Double the overall age and gender matched populationmatched population

► No reduction in past two decadesNo reduction in past two decades

► Mortality 9-fold higher during 1Mortality 9-fold higher during 1stst 4 4 months after diagnosismonths after diagnosis

Miyasaka Y, et al. JACC 2007; 49: 986-992Miyasaka Y, et al. JACC 2007; 49: 986-992

Page 11: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Risk Factors for StrokeRisk Factors for Stroke

Risk FactorRisk Factor Relative RiskRelative RiskOld Stroke/TIAOld Stroke/TIA 2.52.5

HypertensionHypertension 1.61.6

CHFCHF 1.41.4

Increased age Increased age 1.4/10 years1.4/10 years

DMDM 1.71.7

CADCAD 1.51.5

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

Page 12: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Atrial Fibrillation: A Risk Factor Atrial Fibrillation: A Risk Factor for Vascular Events for Vascular Events

Atherosclerosis/Atherothrombosis

MI AF CHF

Wolf PA Wolf PA et al. Arch Intern Medet al. Arch Intern Med 1987; 147: 1561-1564 1987; 147: 1561-1564Leckey R Leckey R et al. Can J Cardiolet al. Can J Cardiol 2000; 16: 481-485 2000; 16: 481-485

RISK FACTORS for THROMBOSISRISK FACTORS for THROMBOSIS•• HypertensionHypertension•• HyperlipidemiaHyperlipidemia•• AgeAge•• Diabetes MellitusDiabetes Mellitus•• SmokingSmoking

Atherosclerosis/Atherothrombosis

Stroke, MI, Vascular Death

MI AF CHF

Page 13: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Thrombus in left Thrombus in left atrial appendage is atrial appendage is

correlated with correlated with increased increased

thromboembolic risk thromboembolic risk in AFin AF

ThrombusThrombus Left Atrial Left Atrial AppendageAppendage

Chimowitz. Chimowitz. Stroke Stroke 1993; 24: 10151993; 24: 1015Zabalgoitia. Zabalgoitia. J Am Coll CardiolJ Am Coll Cardiol 1998; 31: 1622 1998; 31: 1622

Thrombus in Left Atrial Appendage Thrombus in Left Atrial Appendage Associated with StrokeAssociated with Stroke

Page 14: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Wolf Wolf et al. Strokeet al. Stroke 1991; 22: 983-988 1991; 22: 983-988

One Sixth of all Strokes One Sixth of all Strokes Attributable to AFAttributable to AF

%

AF prevalence

Strokes attributable to AF

Age Range (years)Age Range (years)

Framingham StudyFramingham Study

0

10

20

30

50–59 60–69 70–79 80–89

Page 15: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Problems with Established Problems with Established Therapy: WarfarinTherapy: Warfarin

► Delayed onset/offsetDelayed onset/offset

► Unpredictable dose responseUnpredictable dose response

► Narrow therapeutic rangeNarrow therapeutic range

► Drug–drug, drug–food interactionsDrug–drug, drug–food interactions

► Problematic monitoringProblematic monitoring

► High bleeding rateHigh bleeding rate

► Slow reversibilitySlow reversibility

► Delayed onset/offsetDelayed onset/offset

► Unpredictable dose responseUnpredictable dose response

► Narrow therapeutic rangeNarrow therapeutic range

► Drug–drug, drug–food interactionsDrug–drug, drug–food interactions

► Problematic monitoringProblematic monitoring

► High bleeding rateHigh bleeding rate

► Slow reversibilitySlow reversibility

Page 16: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

First First Month of Warfarin Therapy has Month of Warfarin Therapy has High Bleeding RateHigh Bleeding Rate

Bleeding TypeBleeding Type Head BleedHead Bleed Major Non-Major Non-Head BleedHead Bleed

11stst Month Month WarfarinWarfarin 0.92%0.92% (annualized) (annualized) 1.2%1.2% (annualized)(annualized)

Subsequent Subsequent WarfarinWarfarin 0.46% per year0.46% per year 0.61% per year0.61% per year

Fang MC. J Am Geriatr Soc 2006; 54: 1231-1236Fang MC. J Am Geriatr Soc 2006; 54: 1231-1236

Page 17: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

FDA Adds “Black Box” FDA Adds “Black Box” Warning/Precaution for WarfarinWarning/Precaution for Warfarin

October 6, 2006October 6, 2006

August 16, 2007August 16, 2007Precaution:Precaution: “Consider a “Consider a lower initial lower initial warfarin dosewarfarin dose for patients with for patients with certain certain genetic variationsgenetic variations.”.”

Warning: Bleeding RiskWarning: Bleeding Risk

Page 18: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► Warfarin dosing and geneticsWarfarin dosing and genetics

► FDA warfarin labeling vs. NHLBI Randomized FDA warfarin labeling vs. NHLBI Randomized Clinical Trial Clinical Trial

► Warfarin dosing and geneticsWarfarin dosing and genetics

► FDA warfarin labeling vs. NHLBI Randomized FDA warfarin labeling vs. NHLBI Randomized Clinical Trial Clinical Trial

Learning ObjectivesLearning Objectives

Page 19: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Warfarin: AdvantagesWarfarin: Advantages

1.1. INR assesses anticoagulant levelINR assesses anticoagulant level

2.2. Multiple antidotes availableMultiple antidotes available

3.3. Omitting one or two doses usually is not clinically Omitting one or two doses usually is not clinically problematicproblematic

4.4. Introduced in 1954. Has “stood the test of time.” Introduced in 1954. Has “stood the test of time.” No liver toxicityNo liver toxicity

5.5. Ability to maintain target INR is improving Ability to maintain target INR is improving (Now > 60% in top facilities)(Now > 60% in top facilities)

6.6. No anticoagulant has demonstrated superior No anticoagulant has demonstrated superior efficacy or safetyefficacy or safety

7.7. InexpensiveInexpensive

1.1. INR assesses anticoagulant levelINR assesses anticoagulant level

2.2. Multiple antidotes availableMultiple antidotes available

3.3. Omitting one or two doses usually is not clinically Omitting one or two doses usually is not clinically problematicproblematic

4.4. Introduced in 1954. Has “stood the test of time.” Introduced in 1954. Has “stood the test of time.” No liver toxicityNo liver toxicity

5.5. Ability to maintain target INR is improving Ability to maintain target INR is improving (Now > 60% in top facilities)(Now > 60% in top facilities)

6.6. No anticoagulant has demonstrated superior No anticoagulant has demonstrated superior efficacy or safetyefficacy or safety

7.7. InexpensiveInexpensive

Page 20: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► Excessive dose precipitates Excessive dose precipitates hemorrhagehemorrhage

► Inadequate dose predisposes to stroke Inadequate dose predisposes to stroke and pulmonary embolismand pulmonary embolism

► Dosing nomograms are awkward, Dosing nomograms are awkward, cumbersomecumbersome

► Dosing by trial and error predominatesDosing by trial and error predominates

► Excessive dose precipitates Excessive dose precipitates hemorrhagehemorrhage

► Inadequate dose predisposes to stroke Inadequate dose predisposes to stroke and pulmonary embolismand pulmonary embolism

► Dosing nomograms are awkward, Dosing nomograms are awkward, cumbersomecumbersome

► Dosing by trial and error predominatesDosing by trial and error predominates

Warfarin: Walking a TightropeWarfarin: Walking a Tightrope

Page 21: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Therapeutic Range for WarfarinTherapeutic Range for WarfarinINR Values at Stroke or ICHINR Values at Stroke or ICHO

dds

Rat

ioO

dds

Rat

io

005.05.0 6.06.0 8.08.0

INRINR1.01.0 2.02.0 3.03.0 4.04.0 7.07.0

5.05.0

15.015.0

10.010.0

StrokeStroke

1.01.0

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

Intracranial Intracranial HemorrhageHemorrhage

Page 22: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Hylek, EM Hylek, EM et alet al. . N Engl J MedN Engl J Med. 2003;349:1019-2614. 2003;349:1019-2614

Page 23: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

““Most intracranial hemorrhages (62%) Most intracranial hemorrhages (62%) occur at INRs < 3.0”occur at INRs < 3.0”

Page 24: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Reduction of Stroke in AF – Warfarin Reduction of Stroke in AF – Warfarin Compared with PlaceboCompared with Placebo

Hart Hart et alet al. . Ann Intern MedAnn Intern Med 1999; 131: 492 1999; 131: 492--501501

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

AFASAK I

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trials (n=6)

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

Warfarin betterWarfarin better Warfarin worseWarfarin worse

62% (48% to 72%)

100 50 0 -50 -100

Page 25: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

ACTIVE W TrialACTIVE W Trial

OACOAC• Standard Care (INR 2.0 – 3.0)Standard Care (INR 2.0 – 3.0)

• INR at least monthlyINR at least monthly

Clopidogrel plus ASAClopidogrel plus ASA• Clopidogrel 75 mg once dailyClopidogrel 75 mg once daily

• ASA 75-100 mg once dailyASA 75-100 mg once daily

Page 26: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

ACTIVE W: Outcome EventsACTIVE W: Outcome Events

Primary OutcomePrimary Outcome• Stroke, Non-CNS Systemic Stroke, Non-CNS Systemic

Embolism, MI, Vascular DeathEmbolism, MI, Vascular Death

Safety OutcomeSafety Outcome• Major BleedingMajor Bleeding

Page 27: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

0.0

0.02

0.04

0.06

0.08

0.10

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASA

ACTIVE W: Stroke, Non-CNS Embolism, ACTIVE W: Stroke, Non-CNS Embolism, MI and Vascular DeathMI and Vascular Death

Cum

ulat

ive

Cum

ulat

ive

Ha

zard

Ha

zard

Rat

es

Rat

es

YearsYears# at Risk# at RiskC+AC+A 3335 3335 3149 3149 2387 2387 916 916OACOAC 3371 3371 3220 3220 2453 2453 911 911

3.93 %/year

5.64 %/yearRR = 1.45

P = 0.0002

Page 28: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

0.0

0.01

0.02

0.03

0.04

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASA

ACTIVE W: Major BleedingACTIVE W: Major BleedingC

umul

ativ

e C

umul

ativ

e H

aza

rdH

aza

rd R

ates

R

ates

YearsYears# at Risk# at RiskC+AC+A 3335 3335 3172 3172 2403 2403 914 914OACOAC 3371 3371 3212 3212 2423 2423 901 901

2.4 %/year

2.2 %/year

LancetLancet. 2006;367:1903-1912, 1877-1878. 2006;367:1903-1912, 1877-1878

RR = 1.06

P = 0.67

Page 29: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

New oral anticoagulants, given in fixed dose New oral anticoagulants, given in fixed dose without laboratory coagulation monitoring, without laboratory coagulation monitoring,

may improve and expand on existing may improve and expand on existing anticoagulation options. We will hear about anticoagulation options. We will hear about

thesethese exciting development tonight. exciting development tonight.

The Frontiers of Thrombosis: The Frontiers of Thrombosis: Mitigation (Stroke Reduction) in Mitigation (Stroke Reduction) in

Atrial FibrillationAtrial Fibrillation

The Frontiers of Thrombosis: The Frontiers of Thrombosis: Mitigation (Stroke Reduction) in Mitigation (Stroke Reduction) in

Atrial FibrillationAtrial Fibrillation

Page 30: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Achieving Balance BetweenAchieving Balance BetweenPrevention of Thromboembolism Prevention of Thromboembolism

and Risk of Bleedingand Risk of Bleeding

New Frontiers in Atrial FibrillationNew Frontiers in Atrial Fibrillation

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

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

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

Center for Cardiovascular HealthCenter for Cardiovascular Health

Page 31: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Projected U.S. Prevalence of AFProjected U.S. Prevalence of AFAn Expanding EpidemicAn Expanding Epidemic

Miyakasa Y, et al. Miyakasa Y, et al. CirculationCirculation 2006; 114: 119. 2006; 114: 119.

0

2

4

6

8

10

12

14

16

18

20002005

20102015

20202025

20302035

20402045

2050

YearYear

Pro

ject

ed N

umbe

r of

Peo

ple

with

AF

P

roje

cted

Num

ber

of P

eopl

e w

ith A

F

(mill

ions

)(m

illio

ns)

Based on Projected Incidence

Based on Current Incidence

Page 32: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

► Affects Affects

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

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

► Affects Affects

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

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

AF identifies millions of people with afive-fold increased risk of stroke

Page 33: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Priorities in the Management of AFPriorities in the Management of AFThe Patient Care PathwayThe Patient Care Pathway

Rhythm ControlRhythm Control

Prevention of Prevention of ThromboembolismThromboembolism

Rate ControlRate Control

Page 34: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Natural History of “Lone” Atrial FibrillationNatural History of “Lone” Atrial Fibrillation

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

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

97 PatientsMean Age = 44

14.8 yearsFollow-up

0.35%/yr Stroke0.40%/yr Mortality

Page 35: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

Str

oke

Rat

e (%

per

yea

r)S

trok

e R

ate

(% p

er y

ear)

Age (years)Age (years)

Page 36: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Anticoagulation in Atrial FibrillationAnticoagulation in Atrial FibrillationStroke Risk ReductionsStroke Risk Reductions

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

WarfarinWarfarinBetterBetter

ControlControlBetterBetter

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

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

AggregateAggregate

Page 37: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

WarfarinWarfarinBetterBetter

ControlControlBetterBetter

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

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

AggregateAggregate

Terminated early

Double-blind; Men only

Unblinded

Unblinded

Unblinded

2o prevention; Unblinded

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

Page 38: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Antiplatelet drugsAntiplatelet drugsvs. Placebovs. Placebo

Warfarin vs.Warfarin vs.Placebo/ControlPlacebo/Control

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

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

8 Trials8 Trialsn = 4,876n = 4,876

TreatmentTreatmentBetterBetter

TreatmentTreatmentWorseWorse

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

Page 39: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Warfarin vs.Warfarin vs.No anticoagulationNo anticoagulation

Warfarin vs.Warfarin vs.Placebo/ControlPlacebo/Control

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

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

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

TreatmentTreatmentBetterBetter

TreatmentTreatmentWorseWorse

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

Page 40: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Intracerebral HemorrhageIntracerebral Hemorrhage

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

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

► Warfarin (INR 2–3) Warfarin (INR 2–3) doublesdoubles the risk to 0.3– the risk to 0.3–0.6%/year0.6%/year

► ICH during anticoagulation is catastrophicICH during anticoagulation is catastrophic

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

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

► Warfarin (INR 2–3) Warfarin (INR 2–3) doublesdoubles the risk to 0.3– the risk to 0.3–0.6%/year0.6%/year

► ICH during anticoagulation is catastrophicICH during anticoagulation is catastrophic

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

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

Page 41: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Risk Stratification in AFRisk Stratification in AFStroke Risk FactorsStroke Risk Factors

High-Risk FactorsHigh-Risk Factors

► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

High-Risk FactorsHigh-Risk Factors

► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

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

Page 42: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

High-Risk FactorsHigh-Risk Factors

► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

High-Risk FactorsHigh-Risk Factors

► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

Moderate-Risk FactorsModerate-Risk Factors

►Age >75 yearsAge >75 years

►HypertensionHypertension

►Diabetes mellitusDiabetes mellitus

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

Risk Stratification in AFRisk Stratification in AFStroke Risk FactorsStroke Risk Factors

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

Page 43: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

High-Risk FactorsHigh-Risk Factors► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

High-Risk FactorsHigh-Risk Factors► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

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

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

Risk Stratification in AFRisk Stratification in AFStroke Risk FactorsStroke Risk Factors

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

Page 44: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

High-Risk FactorsHigh-Risk Factors► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

High-Risk FactorsHigh-Risk Factors► Mitral stenosisMitral stenosis

► Prosthetic heart valveProsthetic heart valve

► History of stroke or TIAHistory of stroke or TIA

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

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

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

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

Risk Stratification in AFRisk Stratification in AFStroke Risk FactorsStroke Risk Factors

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

Page 45: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

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

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

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

Page 46: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Nonvalvular Atrial FibrillationNonvalvular Atrial Fibrillation

PriorPriorStroke/TIAStroke/TIA

AgeAge> 75 years> 75 years

HypertensionHypertension FemaleFemale DiabetesDiabetes Heart FailureHeart Failure LVEFLVEF

Str

oke

Rat

eS

t rok

e R

ate

(%/ y

ear)

(%/y

e ar )

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

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

Page 47: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

00 1.91.9

1 1 2.82.8

22 4.04.0

33 5.95.9

44 8.58.5

55 12.5 12.5

66 18.2 18.2

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

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

ScoreScore(points)(points)

3%/year3%/yearApproximateApproximate

Risk threshold forRisk threshold forAnticoagulationAnticoagulation

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

Page 48: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

2502504242 8383

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

1313

CHADS2 Score ~ 3 2 1 0

Page 49: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Risk FactorRisk Factor Recommended Recommended TherapyTherapy

No risk factorsNo risk factors

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

One moderate risk factorOne moderate risk factor

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

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

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

CHADSCHADS22 >>22

or Mitral stenosisor Mitral stenosis

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

Prosthetic valveProsthetic valveWarfarinWarfarin

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

Page 50: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

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

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

Page 51: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Patient Selection for AnticoagulationPatient Selection for AnticoagulationAdditional ConsiderationsAdditional Considerations

► Risk of bleedingRisk of bleeding

► Newly anticoagulated vs. established Newly anticoagulated vs. established therapytherapy

► Availability of high-quality Availability of high-quality anticoagulation management programanticoagulation management program

► Patient preferencesPatient preferences

Page 52: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

INR at the Time of Stroke or BleedingINR at the Time of Stroke or BleedingEfficacy and Safety of WarfarinEfficacy and Safety of Warfarin

5.0 6.0 8.01.0 2.0 3.0 4.0 7.0

5

15

10

Ischemic StrokeIschemic Stroke Intracranial bleedingIntracranial bleeding

1

20

Odd

s R

atio

Odd

s R

atio

International Normalized RatioInternational Normalized Ratio

Fang MC, et al. Ann Intern Med 2004; 141:745. Hylek EM, et al. N Engl J Med 1996; 335:540.

Page 53: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

INR above INR above targettarget

6%6%

Subtherapeutic INR Subtherapeutic INR 13%13%

INR inINR intarget rangetarget range

15%15%

No warfarinNo warfarin65%65%

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

Page 54: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirinClopidogrel + Aspirin

Atrial Fibrillation + Risk Factors

VKA(INR 2-3)

Clopidogrel+ Aspirin

Aspirin+ Placebo

Clopidogrel+ Aspirin

Double-blindSuperiorityn = 7,554

Open-labelNon-inferiorityn = 6,706

Anticoagulation-eligible OAC Contraindications or Unwilling

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

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

ACTIVE - WACTIVE - W ACTIVE - AACTIVE - A

ACTIVE - IACTIVE - I

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

Page 55: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirinClopidogrel + Aspirin

Atrial Fibrillation + Risk Factors

ACTIVE – W ACTIVE – W

VKA(INR 2-3)

Clopidogrel+ Aspirin

Aspirin+ Placebo

Clopidogrel+ Aspirin

Double-blindSuperiorityn = 7,554

Open-labelNon-inferiorityn = 6,706

Anticoagulation-eligible OAC Contraindications or Unwilling

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

ACTIVE - AACTIVE - A

ACTIVE - IACTIVE - I

Page 56: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

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

Anticoagulation vs.Anticoagulation vs.Antiplatelet drugsAntiplatelet drugs

7 Trials7 Trialsn = 4,232n = 4,232

n = 6,706n = 6,706

WarfarinWarfarinBetterBetter

Antiplatelet RxAntiplatelet RxBetterBetter

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

Page 57: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

Warfarin vs.Warfarin vs.Aspirin + ClopidogrelAspirin + Clopidogrel

WarfarinWarfarinBetterBetter

Antiplatelet RxAntiplatelet RxBetterBetter

Prior OACPrior OAC

VKA-naVKA-naïïveve

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

All patientsAll patients

Page 58: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Interaction Interaction pp=0.028=0.028

YesYes

Anticoagulant Therapy at EntryAnticoagulant Therapy at Entry

NoNo

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

Eve

nt R

ate

Eve

nt R

ate

(%/y

ear)

(%/y

ear)

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

Page 59: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirinClopidogrel + Aspirin

Atrial Fibrillation + Risk Factors

ACTIVE – W ACTIVE – W

VKA(INR 2-3)

Clopidogrel+ Aspirin

Aspirin+ Placebo

Clopidogrel+ Aspirin

Double-blindSuperiorityn = 7,554

Open-labelNon-inferiorityn = 6,706

Anticoagulation-eligible OAC Contraindications or Unwilling

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

ACTIVE - ACTIVE - AA

ACTIVE - IACTIVE - I

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

Page 60: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

ACTIVE-AACTIVE-A Reasons for Exclusion from AnticoagulationReasons for Exclusion from Anticoagulation

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

Physician judgment against Physician judgment against anticoagulation for patientanticoagulation for patient

50%50%

Patient preference onlyPatient preference only 26%26%

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

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

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

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

Page 61: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

ACTIVE-AACTIVE-ATotal Stroke RatesTotal Stroke Rates

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

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

Cum

ulat

ive

Inci

denc

eC

umul

ativ

e In

cide

nce

Cum

ulat

ive

Inci

denc

eC

umul

ativ

e In

cide

nce

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

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

0.00.0

0.050.05

0.100.10

0.150.15

00 11 22 33 44

AspirinAspirin

Clopidogrel + AspirinClopidogrel + Aspirin

YearsYears

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

Page 62: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

TreatmentTreatment VKAVKA C+AC+A AspirinAspirin

ACTIVE WACTIVE W(Annual Rate)(Annual Rate)

1.41.4 2.42.4 ~~

ACTIVE AACTIVE A(Annual Rate)(Annual Rate)

~~ 2.42.4 3.33.3

RRRRRRversus Aspirinversus Aspirin

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

RRRRRRversus C+Aversus C+A

-42%-42% ~ ~ ~~

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

Page 63: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Warfarin Dosing and GenomicsWarfarin Dosing and Genomics

CYP2C9CYP2C9 – Gene encoding cytochrome P450 – Gene encoding cytochrome P450 hepatic enzyme responsible for primary hepatic enzyme responsible for primary clearance of S-warfarin, the active enantiomer;clearance of S-warfarin, the active enantiomer;

variant alleles are associated with sensitivity to variant alleles are associated with sensitivity to warfarin.warfarin.

VKORC1 VKORC1 – Gene encoding vitamin K epoxide – Gene encoding vitamin K epoxide reductase complex 1; variant alleles are reductase complex 1; variant alleles are associated with warfarin resistance.associated with warfarin resistance.

CYP2C9CYP2C9 – Gene encoding cytochrome P450 – Gene encoding cytochrome P450 hepatic enzyme responsible for primary hepatic enzyme responsible for primary clearance of S-warfarin, the active enantiomer;clearance of S-warfarin, the active enantiomer;

variant alleles are associated with sensitivity to variant alleles are associated with sensitivity to warfarin.warfarin.

VKORC1 VKORC1 – Gene encoding vitamin K epoxide – Gene encoding vitamin K epoxide reductase complex 1; variant alleles are reductase complex 1; variant alleles are associated with warfarin resistance.associated with warfarin resistance.

Page 64: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Warfarin Dosing and GenomicsWarfarin Dosing and GenomicsKeeping Ahead of the DataKeeping Ahead of the Data

Page 65: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Dose InitiationDose Initiation Dose TitrationDose Titration

11 22 33 4, 4, 55

66 77 88 ……

Intervention Period:Intervention Period:Informed by genetic/clinical Informed by genetic/clinical informationinformation

ObjectiveObjective: : To compare the effect of pharmacogenetic &To compare the effect of pharmacogenetic & clinical warfarin dosing algorithms on initial proportion of clinical warfarin dosing algorithms on initial proportion of time in therapeutic range of anticoagulation intensitytime in therapeutic range of anticoagulation intensity

Page 66: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Thr

ombo

sis

Thr

ombo

sis

Bleeding

Bleeding

Safe TherapeuticSafe TherapeuticRangeRange

ThrombosisThrombosis BleedingBleeding

The Ideal AnticoagulantThe Ideal AnticoagulantWide Therapeutic MarginWide Therapeutic Margin

Page 67: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

DVT/VTEDVT/VTEProphylaxisProphylaxisOrthopaedicOrthopaedicSurgerySurgery

DVT/VTEDVT/VTETreatmentTreatment

AFib/StrokeAFib/StrokeProphylaxisProphylaxis

ArterialArterialDiseaseDisease

OtherOtherPotentialPotentialIndicationsIndications

New Anticoagulant DevelopmentNew Anticoagulant DevelopmentThe CThe Clinical Triallinical Trial Pathway Pathway

Page 68: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Investigational Anticoagulant TargetsInvestigational Anticoagulant Targets

TFPI (tifacogin)TFPI (tifacogin)

IdraparinuxIdraparinux

RivaroxabanRivaroxabanApixabanApixabanLY517717LY517717YM150YM150DU-176bDU-176bBetrixabanBetrixabanTAK 42TAK 42

DabigatranDabigatran

ORALORAL PARENTERALPARENTERAL

DX-9065aDX-9065aOtamixabanOtamixaban

XaXaXaXa

IIaIIaIIaIIa

TF/VIIaTF/VIIaTF/VIIaTF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

II (thrombin)II (thrombin)

FibrinFibrinFibrinogenFibrinogen

ATAT

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

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

TTP889TTP889

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

Page 69: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

SPORTIF III and VSPORTIF III and VStroke and Systemic EmbolismStroke and Systemic Embolism

Difference in Absolute Event RatesDifference in Absolute Event Rates(Ximelagatran – Warfarin)(Ximelagatran – Warfarin)

Ximelagatran BetterXimelagatran Better Warfarin BetterWarfarin Better

-1-1 00 11 22

SPORTIF IIISPORTIF IIISPORTIF IIISPORTIF III

SPORTIF VSPORTIF VSPORTIF VSPORTIF V

-0.66-0.66

+0.45+0.45

pp=0.10=0.10

pp=0.13=0.13

PooledPooledPooledPooled-0.03-0.03

pp=0.94=0.94

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

SPORTIF-V Investigators. SPORTIF-V Investigators. JAMAJAMA 2005; 293: 690-8. 2005; 293: 690-8.

Page 70: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

SPORTIF III and VSPORTIF III and VSecondary Stroke PreventionSecondary Stroke Prevention

Eve

nt R

ate

(%/y

ear)

Eve

nt R

ate

(%/y

ear)

pp=NS=NS

ΔΔ = = –0.44%/year –0.44%/year95% CI –1.86, 0.98; 95% CI –1.86, 0.98; pp=0.625=0.625

Diener H-C, et al. Diener H-C, et al. Cerebrovasc DisCerebrovasc Dis 2006; 21: 279 2006; 21: 279

Page 71: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Major Bleeding ComplicationsMajor Bleeding ComplicationsSPORTIF III and VSPORTIF III and V

Eve

nt R

ate

(%/y

ear)

Eve

nt R

ate

(%/y

ear)

SPORTIF VSPORTIF V PooledPooledSPORTIF IIISPORTIF III

pp=0.054=0.054

Diener H-C, et al. Diener H-C, et al. Cerebrovasc DisCerebrovasc Dis 2006; 21: 279 2006; 21: 279

On-treatment AnalysisOn-treatment Analysis

Page 72: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

SPORTIF III and VSPORTIF III and VLiver Enzyme ElevationsLiver Enzyme Elevations

00

2020

4040

6060

8080

100100

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1515 1616 1818 2121 2727

XimelagatranXimelagatranWarfarinWarfarin

MonthsMonths

Num

ber

of p

atie

nts

Num

ber

of p

atie

nts

Inci

denc

e (%

)In

cide

nce

(%)

ALT >3x ULNALT >3x ULN

Diener H-C, et al. Diener H-C, et al. Cerebrovasc DisCerebrovasc Dis 2006; 21: 279 2006; 21: 279

ALT >3 x ULNALT >3 x ULN

Page 73: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Emerging AnticoagulantsEmerging AnticoagulantsPotential Alternatives to WarfarinPotential Alternatives to Warfarin

Thrombin inhibitorsThrombin inhibitorsDirect, oralDirect, oral

XimelagatranXimelagatran

DabigatranDabigatran (RE-LY Trial)(RE-LY Trial)

Thrombin inhibitorsThrombin inhibitorsDirect, oralDirect, oral

XimelagatranXimelagatran

DabigatranDabigatran (RE-LY Trial)(RE-LY Trial)

Factor Xa Factor Xa inhibitorsinhibitors Indirect, Indirect, parenteralparenteral

IdraparinuxIdraparinux

Direct, oralDirect, oral

RivaroxabanRivaroxaban

ApixabanApixaban

EdoxabanEdoxaban

othersothers

Page 74: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Oral Factor Xa InhibitorsOral Factor Xa Inhibitors

TrialAcronym

Drug Dose Comparator NRisk

factors

ROCKET-AFROCKET-AF RivaroxabanRivaroxaban20 mg*20 mg*

qdqd

WarfarinWarfarin

(INR 2-3)(INR 2-3)14,00014,000 ≥ ≥ 22

ARISTOTLEARISTOTLE ApixabanApixaban5 mg5 mg

bidbid

WarfarinWarfarin

(INR 2-3)(INR 2-3)15,00015,000 ≥ ≥ 11

ENGAGE-AFENGAGE-AF EdoxabanEdoxaban30 mg bid30 mg bid

60 mg* qd60 mg* qd

WarfarinWarfarin

(INR 2-3)(INR 2-3)16,50016,500 ≥ ≥ 22

** Adjusted based on renal functionAdjusted based on renal function

Ongoing Phase III Trials for Prevention of Stroke and Systemic Ongoing Phase III Trials for Prevention of Stroke and Systemic Embolism in Patients with AFEmbolism in Patients with AF

Page 75: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Emerging AnticoagulantsEmerging AnticoagulantsRegulatory IssuesRegulatory Issues

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

• Issues related to active-control trial designIssues related to active-control trial design

• How many trials are needed?How many trials are needed?

• Preventing use for unapproved indicationsPreventing use for unapproved indications

• Assessing patient-oriented outcomesAssessing patient-oriented outcomes

Page 76: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Alternatives to AnticoagulationAlternatives to AnticoagulationAtrial FibrillationAtrial Fibrillation

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

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

Current approachesCurrent approaches

Emerging (investigational) approachesEmerging (investigational) approaches

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

Page 77: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

nnRate Rate

controlcontrolRhythm Rhythm controlcontrol

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

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

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

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

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

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

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

Page 78: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

AFFIRM TrialAFFIRM TrialStroke RatesStroke Rates

► 74% of all strokes were proven 74% of all strokes were proven ischemicischemic 44% occurred after stopping 44% occurred after stopping

warfarinwarfarin 28% in patients taking warfarin with 28% in patients taking warfarin with

INR <2.0INR <2.0 42% occurred during documented 42% occurred during documented

AFAF

► 74% of all strokes were proven 74% of all strokes were proven ischemicischemic 44% occurred after stopping 44% occurred after stopping

warfarinwarfarin 28% in patients taking warfarin with 28% in patients taking warfarin with

INR <2.0INR <2.0 42% occurred during documented 42% occurred during documented

AFAF

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

Page 79: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

EventEventPlacebo Placebo

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

(%/y)(%/y)HRHR

(95% CI)(95% CI)pp

StrokeStroke1.791.79 1.191.19 0.660.66 0.0270.027

Stroke or TIAStroke or TIA 2.052.05 1.371.37 0.670.67 0.0200.020

Fatal stroke Fatal stroke 0.540.54 0.360.36 0.670.67 0.2470.247

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

Page 80: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Percutaneous LAA OcclusionPercutaneous LAA OcclusionThe WATCHMANThe WATCHMAN®® DeviceDevice

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

Page 81: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Alternatives to AnticoagulationAlternatives to AnticoagulationAtrial FibrillationAtrial Fibrillation

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

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

Current approachesCurrent approaches

Emerging (investigational) approachesEmerging (investigational) approaches

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

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

Page 82: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismThe Next ChallengesThe Next Challenges

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

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

► Confirming successful rhythm control over timeConfirming successful rhythm control over time

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

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

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

► Confirming successful rhythm control over timeConfirming successful rhythm control over time

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

Page 83: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

The Promise of New ApproachesThe Promise of New Approaches

The Goal:The Goal:To bring effective therapy to many more patients and prevent thousands To bring effective therapy to many more patients and prevent thousands of strokes.of strokes.

Page 84: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Stroke Prevention Stroke Prevention in High Risk Populationsin High Risk Populations

The Journey from Warfarin to The Journey from Warfarin to New Options and StrategiesNew Options and Strategies

New Frontiers in Atrial FibrillationNew Frontiers in Atrial Fibrillation

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

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

Boston University Medical CenterBoston University Medical CenterBoston, MassachusettsBoston, Massachusetts

Page 85: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Miyasaka, Y. et al. Circulation 2006;114:119-125Miyasaka, Y. et al. Circulation 2006;114:119-125

Projected Number of Persons with AF in Projected Number of Persons with AF in the U.S. Between 2000 and 2050the U.S. Between 2000 and 2050

Assumes no further increase in age-adjusted AF incidence (Assumes no further increase in age-adjusted AF incidence (blue curveblue curve) and assumes a ) and assumes a continued increase in incidence rate as evident in 1980 to 2000 (continued increase in incidence rate as evident in 1980 to 2000 (yellow curveyellow curve))

15.915.915.215.2

11.711.7

13.113.115.915.9

10.210.2

8.98.9

6.76.77.77.7

5.95.95.15.1

11.711.712.112.1

11.111.110.310.3

9.49.48.48.4

7.57.56.86.86.16.1

5.65.65.15.1

YearYear

Pro

ject

ed N

umbe

r of

Per

sons

Pro

ject

ed N

umbe

r of

Per

sons

with

AF

(M

illio

ns)

with

AF

(M

illio

ns)

2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 20502000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

1616

1414

1212

1010

88

66

44

22

00

Page 86: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Atrial FibrillationAtrial FibrillationMorbidity and MortalityMorbidity and Mortality

►4- to 5-fold increased risk of stroke4- to 5-fold increased risk of stroke

►Doubling of the risk for dementiaDoubling of the risk for dementia

►Tripling of risk for heart failureTripling of risk for heart failure

►40 to 90% increased risk for overall mortality40 to 90% increased risk for overall mortality

►Risk of stroke in AF patients by age groupRisk of stroke in AF patients by age group

– 1.5% in 50 to 59 year age group1.5% in 50 to 59 year age group

– 23.5% in 80 to 89 year age group23.5% in 80 to 89 year age group

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

Page 87: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Prevalence of AF by AgePrevalence of AF by Age

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

Framingham StudyFramingham Study

Cardiovascular Health StudyCardiovascular Health Study

Mayo Clinic StudyMayo Clinic Study

Western Australia StudyWestern Australia Study

Pre

vale

nce

(%)

Pre

vale

nce

(%)

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

2020

1818

1616

1414

1212

1010

88

66

44

22

00

Page 88: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

15.9

37.9

73.379.3

7.8

38.5

72.6

85.9

0102030405060708090

100

20-39 40-59 60-79 80+

Per

cent

of P

opu

lati

on

Men Women

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

Source: NCHS and NHLBI

AgeAge

Page 89: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

* MD * MD review of medical records using strict diagnostic criteriareview of medical records using strict diagnostic criteria

9.2

22.3

41.9

4.7

14.8

32.7

05

1015202530354045

65-74 75-84 85+

Pe

r 1

,00

0 P

ers

on

Ye

ars

AgeMen Women

Incidence of Heart Failure* by Age and Sex Incidence of Heart Failure* by Age and Sex (Framingham Heart Study: 1980-2003)(Framingham Heart Study: 1980-2003)

Source: NHLBI

Page 90: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Source: NCHS and NHLBISource: NCHS and NHLBI

0.1

2.2

9.3

13.8

0.21.2

4.8

12.2

0

2

4

6

8

10

12

14

16

20-39 40-59 60-79 80+

Per

cent

of

Pop

ulat

ion

Men Women

Prevalence of Heart Failure by Age and Sex Prevalence of Heart Failure by Age and Sex (NHANES: 2005-2006)(NHANES: 2005-2006)

AgeAge

Page 91: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Prevalence of DementiaPrevalence of Dementia

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

Page 92: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

► More than 37 million people are ≥ age 65.More than 37 million people are ≥ age 65.

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

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

population 65 to 74 years old.population 65 to 74 years old.

► By 2050, 12%, or 1 in 8 Americans, will be By 2050, 12%, or 1 in 8 Americans, will be

age 75 or older.age 75 or older.

► More than 37 million people are ≥ age 65.More than 37 million people are ≥ age 65.

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

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

population 65 to 74 years old.population 65 to 74 years old.

► By 2050, 12%, or 1 in 8 Americans, will be By 2050, 12%, or 1 in 8 Americans, will be

age 75 or older.age 75 or older.

Page 93: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Polypharmacy in the ElderlyPolypharmacy in the Elderly

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

32% of prescriptions32% of prescriptions

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

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

► Average nursing home patientAverage nursing home patient

takes 7 medicationstakes 7 medications

► Average American senior spends Average American senior spends

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

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

32% of prescriptions32% of prescriptions

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

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

► Average nursing home patientAverage nursing home patient

takes 7 medicationstakes 7 medications

► Average American senior spends Average American senior spends

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

Page 94: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Pharmacokinetic and Pharmacodynamic Pharmacokinetic and Pharmacodynamic Changes with AgingChanges with Aging

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

the same effectthe same effect Receptor numbers, affinity, or post-receptor cellular Receptor numbers, affinity, or post-receptor cellular

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

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

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

the same effectthe same effect Receptor numbers, affinity, or post-receptor cellular Receptor numbers, affinity, or post-receptor cellular

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

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

Page 95: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Kidney Function and AgeKidney Function and Age

Andres and Tobin, 1976Andres and Tobin, 1976

Age (years)Age (years)

Sta

ndar

d C

reat

ine

Cle

aran

ceS

tand

ard

Cre

atin

e C

lear

ance

ml/m

in/1

.73

ml/m

in/1

.73

30 40 50 60 70 8030 40 50 60 70 80

140140

130130

120120

110110

100100

Page 96: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Adverse Drug ReactionsAdverse Drug Reactions

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

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

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

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

Page 97: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Od

ds

Rat

io

005.05.0 6.06.0 8.08.0

INR1.01.0 2.02.0 3.03.0 4.04.0 7.07.0

5.05.0

15.015.0

10.010.0 StrokeStroke Intracranial BleedIntracranial Bleed

1.01.0

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

Adjusted Odds Ratios for Ischemic Stroke and Intracranial Adjusted Odds Ratios for Ischemic Stroke and Intracranial Bleeding in Relation to Intensity of AnticoagulationBleeding in Relation to Intensity of Anticoagulation

Page 98: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Polypharmacy and Non-adherencePolypharmacy and Non-adherence

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

the number of medicationsthe number of medications

► Non-adherence rates estimated 25-50%Non-adherence rates estimated 25-50%

► Intentional about 75% of the timeIntentional about 75% of the timeChanges in regimen made by patients to: Changes in regimen made by patients to:

- Increase convenience - Increase convenience - Reduce adverse effects or - Reduce adverse effects or - Decrease refill expense- Decrease refill expense

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

the number of medicationsthe number of medications

► Non-adherence rates estimated 25-50%Non-adherence rates estimated 25-50%

► Intentional about 75% of the timeIntentional about 75% of the timeChanges in regimen made by patients to: Changes in regimen made by patients to:

- Increase convenience - Increase convenience - Reduce adverse effects or - Reduce adverse effects or - Decrease refill expense- Decrease refill expense

Page 99: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

ACTIVE W TrialACTIVE W TrialVKA vs dualVKA vs dual

antiplatelet Rxantiplatelet Rx

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

Minimum thresholdMinimum threshold TTR necessary to TTR necessary to realize benefit of warfarin:realize benefit of warfarin:

≥ ≥ 58%58%

Page 100: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Results From SPORTIF III and VResults From SPORTIF III and V

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

Mortality, %Mortality, % 4.24.2 1.841.84 1.691.69

Major Bleed, %Major Bleed, % 3.853.85 1.961.96 1.581.58

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

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

Page 101: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Hazards of Anticoagulant MedicationsHazards of Anticoagulant Medications

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

► Warfarin-6% of 702,000 ADEs treated in ED per year; Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization17% require hospitalization11

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

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

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

► Warfarin-6% of 702,000 ADEs treated in ED per year; Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization17% require hospitalization11

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

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

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

Page 102: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Major Hemorrhage RatesMajor Hemorrhage Rates

Randomized TrialsRandomized Trials INR TargetINR Target ICHICH MajorMajor AgeAge

AFIAFI 1.5-4.51.5-4.5 0.30.3 1.01.0 6969

SPAF IISPAF II 2.0-4.52.0-4.5 0.90.9 1.41.4 7070

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

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

ObservationalObservational INR TargetINR Target ICHICH MajorMajor AgeAge

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

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

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

Page 103: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Caveats Relating to Published Caveats Relating to Published Data on HemorrhageData on Hemorrhage

Randomized trialsRandomized trials- Enrolled few patients - Enrolled few patients ≥≥ 80 years 80 years- Highly selected, closely monitored- Highly selected, closely monitored- Vitamin K antagonist at entry- Vitamin K antagonist at entry

Prospective cohort studiesProspective cohort studies- Predominantly non-inception cohort studies of - Predominantly non-inception cohort studies of prevalent warfarin use (survivor bias)prevalent warfarin use (survivor bias)- Enrolled few patients - Enrolled few patients ≥ ≥ 80 years80 years- Varying definitions of bleeding- Varying definitions of bleeding- Most conducted within anticoagulation clinic setting- Most conducted within anticoagulation clinic setting

Page 104: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Baseline Characteristics AF TrialsBaseline Characteristics AF Trials

Historical trialsHistorical trials SPORTIF III/V SPORTIF III/V ACTIVE W RE-LY ACTIVE W RE-LY

Year publishedYear published 1989-19931989-1993 2003-2005 2003-2005 2006 2006 2009 2009

NN 3,7633,763 7,327 7,327 6,706 6,706 18,113 18,113

Age, yrsAge, yrs 6969 71 71 70 72 70 72

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

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

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

CHFCHF 26%26% 18% 18% 21% 21% 32% 32%

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

CHADSCHADS22 score score NANA NA NA 2.0 2.12.0 2.1

Historical trialsHistorical trials SPORTIF III/V SPORTIF III/V ACTIVE W RE-LY ACTIVE W RE-LY

Year publishedYear published 1989-19931989-1993 2003-2005 2003-2005 2006 2006 2009 2009

NN 3,7633,763 7,327 7,327 6,706 6,706 18,113 18,113

Age, yrsAge, yrs 6969 71 71 70 72 70 72

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

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

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

CHFCHF 26%26% 18% 18% 21% 21% 32% 32%

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

CHADSCHADS22 score score NANA NA NA 2.0 2.12.0 2.1

Page 105: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Cumulative Incidence of Major Bleeding in the First Cumulative Incidence of Major Bleeding in the First Year Among Patients Newly Starting Warfarin by AgeYear Among Patients Newly Starting Warfarin by Age

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

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

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

Cum

ulat

ive

Pro

port

ion

Cum

ulat

ive

Pro

port

ion

with

Maj

or H

emor

rhag

ew

ith M

ajor

Hem

orrh

age

0.00

0

.02

0.

04

0.06

0.

08

0.10

0.00

0

.02

0.

04

0.06

0.

08

0.10

Page 106: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Risk of Stopping Therapy in the First Year Among Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by AgePatients Newly Starting Warfarin by Age

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

Days of WarfarinDays of Warfarin

Ris

k of

Sto

ppin

g W

arfa

rinR

isk

of S

topp

ing

War

farin

00 100 200 300 400 100 200 300 400

0

.000

5

.

001

.001

5

.

002

0

.000

5

.

001

.001

5

.

002

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

Page 107: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

CHADSCHADS22

ScoreScoreNN

Major Major Bleed Bleed

(N)(N)

Bleeding Bleeding RatesRates

%%

Taken Off Taken Off Therapy (N)Therapy (N)

Taken Off Taken Off RatesRates

%%

00 4242 11 3.173.17 55 15.8415.84

11 121121 44 4.354.35 1616 17.3917.39

22 181181 33 2.082.08 1919 13.1613.16

33 9494 1212 19.719.7 2020 32.8432.84

≥≥44 3434 66 23.6323.63 99 35.4435.44

TotalTotal 472472 2626 6969

Major Hemorrhagic Events and Warfarin Major Hemorrhagic Events and Warfarin Terminations by CHADSTerminations by CHADS22 Score Score

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

Page 108: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

How Do We Reconcile How Do We Reconcile These Disparate Rates?These Disparate Rates?

► Inception versus prevalent?Inception versus prevalent?

► Burden of hemorrhagic risk factors?Burden of hemorrhagic risk factors?

► Post-discharge versus outpatient?Post-discharge versus outpatient?

► Prevalence of combination therapy?Prevalence of combination therapy?

► Degree of initial selection bias? Degree of initial selection bias?

► Observation period?Observation period?

Page 109: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

HemorrhageHemorrhage ThrombosisThrombosis

Optimizing Benefit and Reducing RiskOptimizing Benefit and Reducing Risk

Page 110: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Bleeding Risk Scores Bleeding Risk Scores for Warfarin Therapyfor Warfarin Therapy

LowLow ModerateModerate HighHigh

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

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

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

00 1-21-2 ≥≥33

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

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

0-10-1 2-32-3 ≥≥44

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

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

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

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

Page 111: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Maintenance Warfarin Dose by Age Maintenance Warfarin Dose by Age INR Target 2-3INR Target 2-3

Derived from two independent Derived from two independent ambulatory populationsambulatory populations

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

Female MaleFemale Male Female MaleFemale MaleAgeAgeAgeAge

War

farin

Wee

kly

Dos

e, m

gW

arfa

rin W

eekl

y D

ose,

mg

War

farin

Wee

kly

Dos

e, m

gW

arfa

rin W

eekl

y D

ose,

mg

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

5050

4545

4040

3535

3030

2525

2020

5050

4545

4040

3535

3030

2525

2020

Page 112: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00

Interval (days)

1

2

3

4

6

10

INR

1b

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

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

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

Page 113: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Adjusted Odds Ratio

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

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

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

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

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

Page 114: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► InitiationInitiation

► Decreased vitamin K intakeDecreased vitamin K intake

► Potentiating MedicationsPotentiating Medications

► Decompensated heart failureDecompensated heart failure

► ChemotherapyChemotherapy

► Warfarin dosing errorWarfarin dosing error

► Binge alcohol consumptionBinge alcohol consumption

Causes of Elevated INRsCauses of Elevated INRs

Page 115: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

Mean age=72 yearsMean age=72 years

Page 116: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Strategies To Minimize Strategies To Minimize Risk Of HemorrhageRisk Of Hemorrhage

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

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

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

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

THE FACTS:THE FACTS:

Page 117: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

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

► Increase monitoring with medication changes Increase monitoring with medication changes

► Reinforce safety points with patients and caregiversReinforce safety points with patients and caregivers

► Justify use of concomitant antiplatelet therapyJustify use of concomitant antiplatelet therapy

► Promise of novel anticoagulants Promise of novel anticoagulants

Page 118: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Incidence of Intracranial HemorrhageIncidence of Intracranial HemorrhageDabigatran vs Warfarin (RE-LY)Dabigatran vs Warfarin (RE-LY)

Anticoagulant/Dose Anticoagulant/Dose ICH RR P

Dabigatran 110 mg BIDDabigatran 110 mg BID 0.23%0.23% 0.290.29 <0.001<0.001

Dabigatran 150 mg BIDDabigatran 150 mg BID 0.30%0.30% 0.410.41 <0.001<0.001

Warfarin (open label)Warfarin (open label) 0.74%0.74% REFREF REFREF

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

Page 119: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Risk Factors for Intracranial HemorrhageRisk Factors for Intracranial Hemorrhage

► INR intensityINR intensity

► AgeAge

► Aspirin therapyAspirin therapy

► Ischemic cerebrovascular diseaseIschemic cerebrovascular disease

► HypertensionHypertension

► TraumaTrauma

► Vasculopathy-Leukoaraiosis, amyloid angiopathyVasculopathy-Leukoaraiosis, amyloid angiopathy

Page 120: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Summary Points and ConclusionsSummary Points and Conclusions

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

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

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

► Novel anticoagulants Novel anticoagulants maymay be safer in the elderly be safer in the elderly population due to their wider therapeutic index, shorter population due to their wider therapeutic index, shorter tt1/21/2, lack of dietary interference, and fewer drug , lack of dietary interference, and fewer drug

interactions.interactions.

Page 121: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

New Frontiers in Atrial FibrillationNew Frontiers in Atrial Fibrillation

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

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

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

Page 122: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Overview of PresentationOverview of Presentation

► Limitations of warfarinLimitations of warfarin

► New oral anticoagulantsNew oral anticoagulants

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

► Limitations of warfarinLimitations of warfarin

► New oral anticoagulantsNew oral anticoagulants

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

Page 123: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Limitations of WarfarinLimitations of Warfarin

LimitationLimitation ConsequenceConsequence

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

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

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

Narrow therapeutic indexNarrow therapeutic index Frequent coagulation monitoringFrequent coagulation monitoring

Page 124: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

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

Page 125: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

FeaturesFeatures RivaroxabanRivaroxaban ApixabanApixaban Dabigatran Dabigatran EtexilateEtexilate

TargetTarget XaXa XaXa IIaIIa

Molecular WeightMolecular Weight 436436 460460 628628

ProdrugProdrug NoNo NoNo YesYes

Bioavailability (%)Bioavailability (%) 8080 5050 66

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

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

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

AntidoteAntidote NoneNone NoneNone NoneNone

Page 126: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

FeaturesFeatures WarfarinWarfarin New AgentsNew Agents

OnsetOnset SlowSlow RapidRapid

DosingDosing VariableVariable FixedFixed

Food effectFood effect YesYes NoNo

Drug interactionsDrug interactions ManyMany FewFew

MonitoringMonitoring YesYes NoNo

Half-lifeHalf-life LongLong ShortShort

AntidoteAntidote YesYes NoNo

Page 127: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

R

Open

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

countries

WarfarinAdjusted

INR 2.0 – 3.0N=6000

Dabigatran etexilate 110 mg BID

N=6000

Dabigatran etexilate 150 mg BID

N=6000

Blinded Event Adjudication

OpenOpen BlindedBlinded

RR

Page 128: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

RE-LY: Baseline CharacteristicsRE-LY: Baseline Characteristics

CharacteristicCharacteristic Dabigatran Dabigatran 110 mg110 mg

Dabigatran Dabigatran 150 mg150 mg WarfarinWarfarin

RandomizedRandomized 60156015 60766076 60226022

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

Male (%)Male (%) 64.364.3 63.263.2 63.363.3

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

2.12.1

32.632.634.734.732.732.7

2.22.2

32.232.235.235.232.632.6

2.12.1

30.930.937.037.032.132.1

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

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

CHF (%)CHF (%) 32.232.2 31.831.8 31.931.9

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

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

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

Page 129: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

0.500.50 0.750.75 1.001.00 1.251.25 1.501.50

Dabigatran 110 vs. WarfarinDabigatran 110 vs. Warfarin

Dabigatran 150 vs. WarfarinDabigatran 150 vs. Warfarin

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

<0.001<0.001

SuperioritySuperiorityp-valuep-value

0.340.34

<0.001<0.001

Margin = 1.46Margin = 1.46

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

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

Page 130: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

DabigatranDabigatran

110mg110mg

DabigatranDabigatran

150mg150mgWarfarinWarfarin

Dabigatran Dabigatran 110mg vs. 110mg vs. WarfarinWarfarin

Dabigatran Dabigatran 150mg vs. 150mg vs. WarfarinWarfarin

nn 60156015 60786078 60226022RRRR

95% CI95% CIpp

RRRR

95% CI95% CIpp

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

0.74-0.830.74-0.83<0.001<0.001

0.910.91

0.86-0.970.86-0.970.0020.002

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

0.69-0.930.69-0.930.0030.003

0.930.93

0.81-1.070.81-1.070.310.31

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

0.680.68

0.55-0.830.55-0.83<0.001<0.001

0.810.81

0.66-0.990.66-0.990.040.04

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

1.101.10

0.86-1.410.86-1.410.430.43

1.501.50

1.19-1.891.19-1.89<0.001<0.001

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

Page 131: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

RR 0.40 (95% CI: 0.27–0.60)

p<0.001 (sup)

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

RR 0.31 (95% CI: 0.20–0.47)

p<0.001 (sup)

Nu

mb

er o

f ev

ents

Nu

mb

er o

f ev

ents

0,23 %0,23 %

0,74 %0,74 %

0,30 %0,30 %

RRRRRR69%69%

RRRRRR60%60%

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

Page 132: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► Targeted inhibition of thrombinTargeted inhibition of thrombin

► Consistent and predictable Consistent and predictable anticoagulant effectanticoagulant effect

► Targeted inhibition of thrombinTargeted inhibition of thrombin

► Consistent and predictable Consistent and predictable anticoagulant effectanticoagulant effect

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

Page 133: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

EventEvent Dabigatran Dabigatran 110 mg110 mg

Dabigatran Dabigatran 150 mg150 mg WarfarinWarfarin

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

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

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

Page 134: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

RE-LY: Cumulative risk of ALT or AST RE-LY: Cumulative risk of ALT or AST >3x ULN after randomization>3x ULN after randomization

Years of follow-up

Dabigatran 110 mg

Cu

mu

lati

ve r

isk

0.0

0.01

0.02

0.03

0.04

0 0.5 1.0 1.5 2.0 2.5

Dabigatran 150 mg

Warfarin

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

Page 135: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Lower-dose regimenLower-dose regimen

► ElderlyElderly

► Renal insufficiencyRenal insufficiency

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

Higher-dose regimenHigher-dose regimen

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

Lower-dose regimenLower-dose regimen

► ElderlyElderly

► Renal insufficiencyRenal insufficiency

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

Higher-dose regimenHigher-dose regimen

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

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

Page 136: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

W vs placeboW vs placebo

W vs W low doseW vs W low dose

W vs ASAW vs ASA

W vs ASA + clopidogrelW vs ASA + clopidogrel

W vs dabigatran 150W vs dabigatran 150

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

FavoursFavours warfarinwarfarin Favours other treatmentFavours other treatment

Page 137: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

► ROCKET – RivaroxabanROCKET – Rivaroxaban

► ARISTOTLE – ApixabanARISTOTLE – Apixaban

► ENGAGE - EdoxabanENGAGE - Edoxaban

► ROCKET – RivaroxabanROCKET – Rivaroxaban

► ARISTOTLE – ApixabanARISTOTLE – Apixaban

► ENGAGE - EdoxabanENGAGE - Edoxaban

Page 138: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Is Warfarin Obsolete?Is Warfarin Obsolete?

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

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

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

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

Page 139: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Cumulative risk of stroke, myocardial infarction, systemic embolism, or Cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death for patients treated at centers with a TTR below or above vascular death for patients treated at centers with a TTR below or above

the study median (65%)the study median (65%)

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

OACOAC

OACOAC

C+AC+A

C+AC+A

YearsYears YearsYears

Eve

nt R

ate

(%)

Eve

nt R

ate

(%)

Eve

nt R

ate

(%)

Eve

nt R

ate

(%)

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

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

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

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

1212

1010

88

66

44

22

00

1212

1010

88

66

44

22

00

Page 140: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

GroupGroup Relative RiskRelative Risk

OverallOverall 64%64%

VKA ExperiencedVKA Experienced 61%61%

VKA NaVKA Naïveve 67%67%

Page 141: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

All patientsLong-term VKA therapy

No

Yes

Region

North America

South America

Western Europe

Central Europe

South Asia

East Asia

Other

0.5 1.0 1.5 0.5 1.0 1.5

Dabigatran Better Dabigatran BetterWarfarin Better Warfarin Better

0.72

0.91

0.81

0.11

18,113 1.53 1.11 1.69

9,123 1.57 1.07 1.67

8,989 1.49 1.15 1.70

6,533 1.19 1.11 1.51

1,134 1.82 0.91 1.68

2,829 1.22 0.78 1.06

3,941 1.53 1.26 1.43

1,134 3.35 0.84 4.00

1,648 1.87 1.77 2.28

1,072 1.95 0.88 2.27

SubgroupPatientstotal no. 110 mg 150 mg

WarfarinDabigatranHazard Ratio withDabigatran, 100

mg (95% CI)

Hazard Ratio withDabigatran,

150 mg (95% CI)

P Valuefor

Interaction

P Valuefor

Interaction

Relative Risk of Stroke or Systemic Embolism with Dabigatran Relative Risk of Stroke or Systemic Embolism with Dabigatran Versus Warfarin According to Geographical RegionVersus Warfarin According to Geographical Region

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

Page 142: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► Stable on warfarinStable on warfarin

► Renal impairmentRenal impairment

► Severe hepatic diseaseSevere hepatic disease

► Poor compliance Poor compliance

► Stable on warfarinStable on warfarin

► Renal impairmentRenal impairment

► Severe hepatic diseaseSevere hepatic disease

► Poor compliance Poor compliance

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

Page 143: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

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

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

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

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

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

Unanswered QuestionsUnanswered Questions

Page 144: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► Dabigatran etexilate is superior to Dabigatran etexilate is superior to warfarin for stroke preventionwarfarin for stroke prevention

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

► New oral anticoagulants will replace New oral anticoagulants will replace warfarin, but transition may be slowwarfarin, but transition may be slow

► Dabigatran etexilate is superior to Dabigatran etexilate is superior to warfarin for stroke preventionwarfarin for stroke prevention

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

► New oral anticoagulants will replace New oral anticoagulants will replace warfarin, but transition may be slowwarfarin, but transition may be slow

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

Page 145: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Atrial FibrillationAtrial FibrillationCurrent Challenges in Thrombosis MedicineCurrent Challenges in Thrombosis Medicine

for the Cardiovascular Specialistfor the Cardiovascular Specialist

Discussion, Comments, and The Way ForwardDiscussion, Comments, and The Way Forward

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of Medicine

Harvard Medical SchoolHarvard Medical School

New Frontiers in Atrial FibrillationNew Frontiers in Atrial Fibrillation

Page 146: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

It is fighting back with:It is fighting back with:

1)1) Excellent efficacy (ACTIVE)Excellent efficacy (ACTIVE)

2)2) Pharmacogenetics analysisPharmacogenetics analysis

3)3) Point-of-care testingPoint-of-care testing

4)4) Low costLow cost

5)5) Track Record (approved in 1954)Track Record (approved in 1954)

Warfarin is Not Just Sitting AroundWarfarin is Not Just Sitting Around

Page 147: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Can rapid turnaround genetic testing Can rapid turnaround genetic testing reduce the “Educated Guessing reduce the “Educated Guessing Game” and “Play of Chance” in Game” and “Play of Chance” in

warfarin dosing?warfarin dosing?

The “Red Line” in the SandThe “Red Line” in the SandThe “Red Line” in the SandThe “Red Line” in the Sand

Page 148: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Warfarin PharmacogenomicsWarfarin Pharmacogenomics

1.1. Cytochrome P450 2C9 genotyping Cytochrome P450 2C9 genotyping identifies mutations associated with identifies mutations associated with impaired warfarin metabolism.impaired warfarin metabolism.

2.2. Vitamin K receptor polymorphism testing Vitamin K receptor polymorphism testing can identify whether patients require low, can identify whether patients require low, intermediate, or high doses of warfarinintermediate, or high doses of warfarin..

1.1. Cytochrome P450 2C9 genotyping Cytochrome P450 2C9 genotyping identifies mutations associated with identifies mutations associated with impaired warfarin metabolism.impaired warfarin metabolism.

2.2. Vitamin K receptor polymorphism testing Vitamin K receptor polymorphism testing can identify whether patients require low, can identify whether patients require low, intermediate, or high doses of warfarinintermediate, or high doses of warfarin..

Schwartz UI. NEJM 2008; 358: 999Schwartz UI. NEJM 2008; 358: 999

Page 149: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Warfarin Pharmacogenetics Consortium. NEJM 2009;360:753-764Warfarin Pharmacogenetics Consortium. NEJM 2009;360:753-764

Percent with Dose Estimates within 20% of Actual DosePercent with Dose Estimates within 20% of Actual Dose Pharmacogenetic Algorithm versus Clinical Algorithm Pharmacogenetic Algorithm versus Clinical Algorithm

versus Fixed-Dose Approachversus Fixed-Dose Approach

Page 150: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► Rapid turnaround CYP2C9 and VKORC1 Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”testing vs. “empiric”

► Primary endpoint: TTR Primary endpoint: TTR

► Smaller and fewer dosing changes with Smaller and fewer dosing changes with genetic testing genetic testing

► No difference in TTRNo difference in TTR

► Rapid turnaround CYP2C9 and VKORC1 Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”testing vs. “empiric”

► Primary endpoint: TTR Primary endpoint: TTR

► Smaller and fewer dosing changes with Smaller and fewer dosing changes with genetic testing genetic testing

► No difference in TTRNo difference in TTR

Genotype vs Standard Warfarin Genotype vs Standard Warfarin Dosing (N=206) Couma-Gen TrialDosing (N=206) Couma-Gen Trial

Circulation 2007; 116: 2563-2570Circulation 2007; 116: 2563-2570

Page 151: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Warfarin Clinical Dosing NomogramWarfarin Clinical Dosing Nomogram

NEJM 2009; 360: 753-764NEJM 2009; 360: 753-764

Page 152: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

PHARMACO-PHARMACO-GENETIC GENETIC

NOMOGRAMNOMOGRAM

NEJM 2009; 360: 753-764NEJM 2009; 360: 753-764

Page 153: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Warfarin PharmacogeneticsWarfarin Pharmacogenetics

Routine use of CYP2C9 andRoutine use of CYP2C9 andVKORC1 genotyping in patientsVKORC1 genotyping in patientswho begin warfarin therapywho begin warfarin therapyis is notnot supported by evidence supported by evidencecurrently available. currently available.

Pharmacotherapy 2008; 28: 1084-1087Pharmacotherapy 2008; 28: 1084-1087

Page 154: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Genetic Testing for Warfarin Remains Genetic Testing for Warfarin Remains Unproven: NHLBI TrialUnproven: NHLBI Trial

About 1,200 Patients will be randomized to:About 1,200 Patients will be randomized to:

1.1.Genetic plus clinical guided nomogram, Genetic plus clinical guided nomogram, versusversus

1.1.Clinically-guided nomogramClinically-guided nomogram

Results will be available in 2012Results will be available in 2012

Page 155: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

NHLBI Trial: 2009-2012NHLBI Trial: 2009-2012

Primary Endpoint:Primary Endpoint:

% Time in Therapeutic Range (TTR)% Time in Therapeutic Range (TTR)

Hypothesis:Hypothesis:

60% TTR in Clinical arm versus60% TTR in Clinical arm versus

>> 72% TTR in Genetics Plus Clinical Nomogram 72% TTR in Genetics Plus Clinical Nomogram armarm

Primary Endpoint:Primary Endpoint:

% Time in Therapeutic Range (TTR)% Time in Therapeutic Range (TTR)

Hypothesis:Hypothesis:

60% TTR in Clinical arm versus60% TTR in Clinical arm versus

>> 72% TTR in Genetics Plus Clinical Nomogram 72% TTR in Genetics Plus Clinical Nomogram armarm

Clinical Trials # NCT00839657Clinical Trials # NCT00839657

Page 156: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Self-Monitoring INRSelf-Monitoring INR Meta-analysis of 14 RCTSMeta-analysis of 14 RCTS

► Reduced TE events (55% fewer)Reduced TE events (55% fewer)► Reduced all-cause mortality (39% less)Reduced all-cause mortality (39% less)► Reduced major bleeds (35% fewer)Reduced major bleeds (35% fewer)

Benefits increase further with self-dosingBenefits increase further with self-dosing► 73% fewer TE events73% fewer TE events► 63% lower all-cause mortality63% lower all-cause mortality

► Reduced TE events (55% fewer)Reduced TE events (55% fewer)► Reduced all-cause mortality (39% less)Reduced all-cause mortality (39% less)► Reduced major bleeds (35% fewer)Reduced major bleeds (35% fewer)

Benefits increase further with self-dosingBenefits increase further with self-dosing► 73% fewer TE events73% fewer TE events► 63% lower all-cause mortality63% lower all-cause mortality

Heneghan C. Lancet 2006; 367: 404-411Heneghan C. Lancet 2006; 367: 404-411

Page 157: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

March 19, 2008: Medicare Expanded March 19, 2008: Medicare Expanded Reimbursement for Home INR MonitoringReimbursement for Home INR Monitoring

► Medicare used to cover only mechanical Medicare used to cover only mechanical heart valvesheart valves

► Now will reimburse VTE (after 3 months of Now will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillationwarfarin) and permanent atrial fibrillation

► Aetna follows new Medicare guidelines Aetna follows new Medicare guidelines (and surely others will, too) (and surely others will, too)

► Medicare used to cover only mechanical Medicare used to cover only mechanical heart valvesheart valves

► Now will reimburse VTE (after 3 months of Now will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillationwarfarin) and permanent atrial fibrillation

► Aetna follows new Medicare guidelines Aetna follows new Medicare guidelines (and surely others will, too) (and surely others will, too)

Page 158: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Will Novel Anticoagulants Warrant Will Novel Anticoagulants Warrant Additional Costs?Additional Costs?

1.1. Does this require deconstruction, Does this require deconstruction, demobilization, and/or reconstruction of demobilization, and/or reconstruction of anticoagulation management services?anticoagulation management services?

2.2. Will patients require monitoring of renal/ Will patients require monitoring of renal/ hepatic function?hepatic function?

1.1. Does this require deconstruction, Does this require deconstruction, demobilization, and/or reconstruction of demobilization, and/or reconstruction of anticoagulation management services?anticoagulation management services?

2.2. Will patients require monitoring of renal/ Will patients require monitoring of renal/ hepatic function?hepatic function?

Page 159: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Novel Oral AnticoagulantsNovel Oral Anticoagulants

1.1. Noninferiority may not suffice, but superiority Noninferiority may not suffice, but superiority findings (150 mg dose) in RE-LY are findings (150 mg dose) in RE-LY are encouraging.encouraging.

2.2. Superiority may be necessary to alter Superiority may be necessary to alter prescribing behavior.prescribing behavior.

3.3. More trials will be forthcoming.More trials will be forthcoming.

4.4. Beware of off-label use.Beware of off-label use.

1.1. Noninferiority may not suffice, but superiority Noninferiority may not suffice, but superiority findings (150 mg dose) in RE-LY are findings (150 mg dose) in RE-LY are encouraging.encouraging.

2.2. Superiority may be necessary to alter Superiority may be necessary to alter prescribing behavior.prescribing behavior.

3.3. More trials will be forthcoming.More trials will be forthcoming.

4.4. Beware of off-label use.Beware of off-label use.

Page 160: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

0.500.50 0.750.75 1.001.00 1.251.25 1.501.50

Dabigatran 110 vs. WarfarinDabigatran 110 vs. Warfarin

Dabigatran 150 vs. WarfarinDabigatran 150 vs. Warfarin

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

<0.001<0.001

SuperioritySuperiorityp-valuep-value

0.340.34

<0.001<0.001

Margin = 1.46Margin = 1.46

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

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

Page 161: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

RE-LY: Cumulative Hazard Rates for the Primary RE-LY: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic EmbolismOutcome of Stroke or 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

Page 162: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Relative Risk of Stroke or Systemic Embolism Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LYwith Dabigatran versus Warfarin: RE-LY

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

Hazard Ratio with Hazard Ratio with Dabigatran, 110 mg(95% CIDabigatran, 110 mg(95% CI)) Hazard Ratio with Hazard Ratio with Dabigatran, 110 mg(95% CIDabigatran, 110 mg(95% CI))

Hazard Ratio with Dabigatran, 150 mg(95% CI) Hazard Ratio with Dabigatran, 150 mg(95% CI)

Dabigatran Better Warfarin BetterDabigatran Better Warfarin Better Dabigatran Better Warfarin BetterDabigatran Better Warfarin Better Dabigatran Better Warfarin BetterDabigatran Better Warfarin Better Dabigatran Better Warfarin BetterDabigatran Better Warfarin Better

Page 163: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

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

Relative Risk of Stroke or Systemic Embolism Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LYwith Dabigatran versus Warfarin: RE-LY

Hazard Ratio with Hazard Ratio with Dabigatran, 110 mg(95% CIDabigatran, 110 mg(95% CI)) Hazard Ratio with Hazard Ratio with Dabigatran, 110 mg(95% CIDabigatran, 110 mg(95% CI))

Hazard Ratio with Dabigatran, 150 mg(95% CI) Hazard Ratio with Dabigatran, 150 mg(95% CI)

Page 164: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Gage, B N Engl J Med 361;12 nejm.org September 17, 2009 Connolly SJ, Pogue J, Eikelboom J, et al.  Circulation 2008;118:2029 37. 

► RE-LY participants  who were randomly assigned RE-LY participants  who were randomly assigned to receive warfarin would have needed to have an to receive warfarin would have needed to have an INR time within the therapeutic range (TTR) INR time within the therapeutic range (TTR) approximately approximately 79% of the time79% of the time to have a stroke rate  to have a stroke rate as low as that in the group  receiving 150 mg of as low as that in the group  receiving 150 mg of dabigatran.dabigatran.

► Even with diligent, patient self-monitoring or Even with diligent, patient self-monitoring or pharmacogenetic dosing, such tight control is pharmacogenetic dosing, such tight control is unlikely in real world practice.unlikely in real world practice.

RE-LY: Analysis and CommentsRE-LY: Analysis and Comments

Page 165: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Rose, AJ Thromb Haemost. 2008 Oct;6(10):1647-54.Rose, AJ Thromb Haemost. 2008 Oct;6(10):1647-54.Baker WL et al, J Manag Care Pharm. 2009 Apr;15(3):244-5Baker WL et al, J Manag Care Pharm. 2009 Apr;15(3):244-5

    

101 Community-Based Practices in 38 States (1)101 Community-Based Practices in 38 States (1)  ► Mean TTR was 66.5%, but varies widely, with 37% having TTR Mean TTR was 66.5%, but varies widely, with 37% having TTR above 75%, and 34% with TTR below 60%above 75%, and 34% with TTR below 60%

► Mean TTR for new warfarin users (57.5%) lower than prevalent Mean TTR for new warfarin users (57.5%) lower than prevalent users for first six monthsusers for first six months

► TTR of patients with warfarin interruptions had TTR of 61.6%TTR of patients with warfarin interruptions had TTR of 61.6%

►TTR rates vary widely and are affected by new warfarin use, TTR rates vary widely and are affected by new warfarin use, procedural interruptions and INR target rangeprocedural interruptions and INR target range

  Meta-Analysis (2)Meta-Analysis (2)

► TTR was 55%TTR was 55%    

        Time in Therapeutic Range (TTR) in Time in Therapeutic Range (TTR) in Community-Based Practice: RangesCommunity-Based Practice: Ranges

Page 166: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

► To prevent one To prevent one nonhemorrhagic strokenonhemorrhagic stroke, the , the number of patients who would  need to be number of patients who would  need to be treated with dabigatran at a dose of 150 mg treated with dabigatran at a dose of 150 mg twice daily, rather than warfarin, is twice daily, rather than warfarin, is approximately 357.approximately 357.

► The number of patients who would need to be The number of patients who would need to be treated with dabigatran (rather than warfarin) to treated with dabigatran (rather than warfarin) to prevent one prevent one hemorrhagichemorrhagic stroke stroke is approximately 370.is approximately 370.

 

RE-LY: Analysis and CommentsRE-LY: Analysis and Comments

Page 167: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Discussion: Novel Oral AnticoagulantsDiscussion: Novel Oral Anticoagulants

1. “In summary although there are qualifications, we 1. “In summary although there are qualifications, we can rely on RE-LY.”can rely on RE-LY.”

Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial)Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial)

2. The RE-LY Trial represents the most compelling 2. 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 AF.stroke prevention in AF.

1. “In summary although there are qualifications, we 1. “In summary although there are qualifications, we can rely on RE-LY.”can rely on RE-LY.”

Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial)Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial)

2. The RE-LY Trial represents the most compelling 2. 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 AF.stroke prevention in AF.

Where Do We Stand, November 12, 2009?Where Do We Stand, November 12, 2009?Where Do We Stand, November 12, 2009?Where Do We Stand, November 12, 2009?

Page 168: National Experts in Cardiovascular Medicine Illuminate and Debate Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in.

Discussion: Novel Oral AnticoagulantsDiscussion: Novel Oral Anticoagulants

Discussion, Questions, and CommentsDiscussion, Questions, and Comments

Discussion, Questions, and CommentsDiscussion, Questions, and Comments


Recommended