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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
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
► 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
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
► 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
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
Hylek, EM Hylek, EM et alet al. . N Engl J MedN Engl J Med. 2003;349:1019-2614. 2003;349:1019-2614
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”
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
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
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
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
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
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
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
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
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
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
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
Stroke Risk in Atrial FibrillationStroke Risk in Atrial FibrillationUntreated Control Groups of Randomized TrialsUntreated Control Groups of Randomized Trials
Atrial Fibrillation Investigators. Atrial Fibrillation Investigators. Arch Intern MedArch Intern Med 1994;154:1449. 1994;154:1449.
Str
oke
Rat
e (%
per
yea
r)S
trok
e R
ate
(% p
er y
ear)
Age (years)Age (years)
Anticoagulation in Atrial FibrillationAnticoagulation in Atrial FibrillationStroke Risk ReductionsStroke Risk Reductions
Hart R, et al. Hart R, et al. Ann Intern MedAnn Intern Med 2007;146:857. 2007;146:857.
WarfarinWarfarinBetterBetter
ControlControlBetterBetter
AFASAKAFASAK
SPAFSPAF
BAATAFBAATAF
CAFACAFA
SPINAFSPINAF
EAFTEAFT
100%100% 50%50% 00 -50%-50% -100%-100%
AggregateAggregate
Anticoagulation in Atrial FibrillationAnticoagulation in Atrial FibrillationThe Standard of Care for Stroke PreventionThe Standard of Care for Stroke Prevention
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.
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.
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
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
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.
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.
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.
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.
The CHADSThe CHADS22 Index IndexStroke Risk Score for Atrial FibrillationStroke Risk Score for Atrial Fibrillation
CCongestive Heart failureongestive Heart failure 1 32 1 32HHypertensionypertension 1 65 1 65AAge >75 yearsge >75 years 1 28 1 28DDiabetes mellitusiabetes mellitus 1 18 1 18SStroke or TIAtroke or TIA 2 2 10 10
Moderate-High riskModerate-High risk >>2 50-602 50-60Low riskLow risk 0-1 40-500-1 40-50
VanWalraven C, et al. VanWalraven C, et al. Arch Intern MedArch Intern Med 2003; 163:936. 2003; 163:936.* Nieuwlaat R, et al. (EuroHeart survey) * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart JEur Heart J 2006 (E-published). 2006 (E-published).
Prevalence (%)*Prevalence (%)*Score (points)Score (points)
Nonvalvular Atrial FibrillationNonvalvular Atrial Fibrillation
PriorPriorStroke/TIAStroke/TIA
AgeAge> 75 years> 75 years
HypertensionHypertension FemaleFemale DiabetesDiabetes Heart FailureHeart Failure LVEFLVEF
Str
oke
Rat
eS
t rok
e R
ate
(%/ y
ear)
(%/y
e ar )
Hart RG et al. Hart RG et al. Neurology Neurology 2007; 69: 546.2007; 69: 546.
Stroke Rates Without AnticoagulationStroke Rates Without AnticoagulationAccording to Isolated Risk FactorsAccording to Isolated Risk Factors
00 1.91.9
1 1 2.82.8
22 4.04.0
33 5.95.9
44 8.58.5
55 12.5 12.5
66 18.2 18.2
Van Walraven C, et al. Van Walraven C, et al. Arch Intern MedArch Intern Med 2003; 163:936. 2003; 163:936.Go A, et al. JAMA 2003; 290: 2685.Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.Gage BF, et al. Circulation 2004; 110: 2287.
Risk of StrokeRisk of Stroke(%/year)(%/year)
ScoreScore(points)(points)
3%/year3%/yearApproximateApproximate
Risk threshold forRisk threshold forAnticoagulationAnticoagulation
The CHADSThe CHADS22 Index IndexStroke Risk Score for Atrial FibrillationStroke Risk Score for Atrial Fibrillation
Risk Stratification and AnticoagulationRisk Stratification and AnticoagulationStroke Reduction with Warfarin Instead of AspirinStroke Reduction with Warfarin Instead of Aspirin
Number of patients Number of patients Needed-to-treatNeeded-to-treatto preventto prevent1 stroke/year1 stroke/year
2502504242 8383
EAFT Study Group. EAFT Study Group. Lancet Lancet 1993; 324:1255. 1993; 324:1255. Zabalgoitia M, et al.Zabalgoitia M, et al. J Am Coll Cardiol J Am Coll Cardiol 1998; 31:1622.1998; 31:1622.
1313
CHADS2 Score ~ 3 2 1 0
Antithrombotic Therapy for Atrial FibrillationAntithrombotic Therapy for Atrial FibrillationACC/AHA/ESC Guidelines 2006ACC/AHA/ESC Guidelines 2006
Risk FactorRisk Factor Recommended Recommended TherapyTherapy
No risk factorsNo risk factors
CHADSCHADS22 = 0 = 0 Aspirin, 81-325 mg qdAspirin, 81-325 mg qd
One moderate risk factorOne moderate risk factor
CHADSCHADS22 = 1 = 1Aspirin, 81-325 mg/d orAspirin, 81-325 mg/d or
WarfarinWarfarin(INR 2.0-3.0, target 2.5)(INR 2.0-3.0, target 2.5)
Any high risk factor orAny high risk factor or>1 moderate risk factor>1 moderate risk factor
CHADSCHADS22 >>22
or Mitral stenosisor Mitral stenosis
WarfarinWarfarin(INR 2.0-3.0, target 2.5)(INR 2.0-3.0, target 2.5)
Prosthetic valveProsthetic valveWarfarinWarfarin
(INR 2.5-3.5, target 3.0)(INR 2.5-3.5, target 3.0)
"Actually, it's more of a 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.
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
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.
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
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
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
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.
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
Major Hemorrhage in Relation toMajor Hemorrhage in Relation toPrior Anticoagulant Therapy: Prior Anticoagulant Therapy: ACTIVE-WACTIVE-W
Interaction Interaction pp=0.028=0.028
YesYes
Anticoagulant Therapy at EntryAnticoagulant Therapy at Entry
NoNo
Connolly S, et al. Connolly S, et al. LancetLancet 2006; 367:1903. 2006; 367:1903.
Eve
nt R
ate
Eve
nt R
ate
(%/y
ear)
(%/y
ear)
““Starters”Starters” ““Switchers”Switchers”
The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirinClopidogrel + Aspirin
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.
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.
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.
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
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.
Warfarin Dosing and GenomicsWarfarin Dosing and GenomicsKeeping Ahead of the DataKeeping Ahead of the Data
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
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
DVT/VTEDVT/VTEProphylaxisProphylaxisOrthopaedicOrthopaedicSurgerySurgery
DVT/VTEDVT/VTETreatmentTreatment
AFib/StrokeAFib/StrokeProphylaxisProphylaxis
ArterialArterialDiseaseDisease
OtherOtherPotentialPotentialIndicationsIndications
New Anticoagulant DevelopmentNew Anticoagulant DevelopmentThe CThe Clinical Triallinical Trial Pathway Pathway
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
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.
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
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
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
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
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
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
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
Strokes after Conversion to NSRStrokes after Conversion to NSRRate vs. Rhythm Control TrialsRate vs. Rhythm Control Trials
nnRate Rate
controlcontrolRhythm Rhythm controlcontrol
RRRR(95% CI)(95% CI) pp
AFFIRMAFFIRM 4,9174,917 5.7%5.7% 7.3%7.3% 1.28 1.28 (0.95-1.72)(0.95-1.72) 0.120.12
RACERACE 522522 5.5%5.5% 7.9%7.9% 1.44 1.44 (0.75-2.78)(0.75-2.78) 0.440.44
STAFSTAF 266266 1.0%1.0% 3.0%3.0% 3.01 3.01 (0.35-25.3)(0.35-25.3) 0.520.52
PIAFPIAF 252252 0.8%0.8% 0.8%0.8% 1.02 1.02 (0.73-2.16)(0.73-2.16) 0.490.49
TotalTotal 5,9575,957 5.0%5.0% 6.5%6.5% 1.28 1.28 (0.98-1.66)(0.98-1.66) 0.080.08
Verheugt F, et al. Verheugt F, et al. J Am Coll CardiolJ Am Coll Cardiol 2003;41(suppl):130A. 2003;41(suppl):130A.
AFFIRM TrialAFFIRM TrialStroke RatesStroke Rates
► 74% of all strokes were proven 74% of all strokes were proven ischemicischemic 44% occurred after stopping 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.
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.
Percutaneous LAA OcclusionPercutaneous LAA OcclusionThe WATCHMANThe WATCHMAN®® DeviceDevice
Syed T, Halperin JL. Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med Nature Clin Prac Cardiovasc Med 2007; 4:4282007; 4:428Holmes DR, et al. Holmes DR, et al. Lancet 2009; 374: 534 Lancet 2009; 374: 534
Alternatives to AnticoagulationAlternatives to AnticoagulationAtrial FibrillationAtrial Fibrillation
Restoration and maintenance of sinus 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?
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
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.
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
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
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
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
**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
* 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
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
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
““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.
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
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
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
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
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
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
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%
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
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.
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
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
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
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
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
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.
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?
HemorrhageHemorrhage ThrombosisThrombosis
Optimizing Benefit and Reducing RiskOptimizing Benefit and Reducing Risk
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
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
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
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)
► 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
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
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:
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
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
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
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.
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
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
Limitations of WarfarinLimitations of Warfarin
LimitationLimitation ConsequenceConsequence
Slow onset of actionSlow onset of action Overlap with a parenteral Overlap with a parenteral anticoagulantanticoagulant
Genetic variation in metabolismGenetic variation in metabolism Variable dose requirementsVariable dose requirements
Multiple food and drug Multiple food and drug interactionsinteractions Frequent coagulation monitoringFrequent coagulation monitoring
Narrow therapeutic indexNarrow therapeutic index Frequent coagulation monitoringFrequent coagulation monitoring
New 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
Comparison of Features of New OralComparison of Features of New OralAnticoagulants in Advanced Stages of DevelopmentAnticoagulants in Advanced Stages of Development
FeaturesFeatures RivaroxabanRivaroxaban ApixabanApixaban Dabigatran Dabigatran EtexilateEtexilate
TargetTarget XaXa XaXa IIaIIa
Molecular WeightMolecular Weight 436436 460460 628628
ProdrugProdrug NoNo NoNo YesYes
Bioavailability (%)Bioavailability (%) 8080 5050 66
Time to peak (h)Time to peak (h) 33 33 22
Half-life (h)Half-life (h) 99 9-149-14 12-1712-17
Renal excretion Renal excretion (%)(%) 6565 2525 8080
AntidoteAntidote NoneNone NoneNone NoneNone
Comparison of Features of New Comparison of Features of New Anticoagulants With Those of WarfarinAnticoagulants With Those of Warfarin
FeaturesFeatures WarfarinWarfarin New AgentsNew Agents
OnsetOnset SlowSlow RapidRapid
DosingDosing VariableVariable FixedFixed
Food effectFood effect YesYes NoNo
Drug interactionsDrug interactions ManyMany FewFew
MonitoringMonitoring YesYes NoNo
Half-lifeHalf-life LongLong ShortShort
AntidoteAntidote YesYes NoNo
RE-LY: A Non-inferiority TrialRE-LY: A Non-inferiority Trial
R
Open
•Atrial Fibrillation with ≥ 1 Risk Factor• Absence of Contraindications• Conducted in 951 centers in 44
countries
WarfarinAdjusted
INR 2.0 – 3.0N=6000
Dabigatran etexilate 110 mg BID
N=6000
Dabigatran etexilate 150 mg BID
N=6000
Blinded Event Adjudication
OpenOpen BlindedBlinded
RR
RE-LY: Baseline CharacteristicsRE-LY: Baseline Characteristics
CharacteristicCharacteristic Dabigatran Dabigatran 110 mg110 mg
Dabigatran Dabigatran 150 mg150 mg WarfarinWarfarin
RandomizedRandomized 60156015 60766076 60226022
Mean age (years)Mean age (years) 71.471.4 71.571.5 71.671.6
Male (%)Male (%) 64.364.3 63.263.2 63.363.3
CHADS2 score CHADS2 score (mean)(mean) 0-1 (%)0-1 (%) 2 (%)2 (%) 3+ (%)3+ (%)
2.12.1
32.632.634.734.732.732.7
2.22.2
32.232.235.235.232.632.6
2.12.1
30.930.937.037.032.132.1
Prior stroke/TIA (%)Prior stroke/TIA (%) 19.919.9 20.320.3 19.819.8
Prior MI (%)Prior MI (%) 16.816.8 16.916.9 16.116.1
CHF (%)CHF (%) 32.232.2 31.831.8 31.931.9
Baseline ASA (%)Baseline ASA (%) 40.040.0 38.738.7 40.640.6
Warfarin Naïve (%)Warfarin Naïve (%) 49.949.9 49.849.8 51.451.4
Connolly et al., Connolly et al., NEJMNEJM, 2009, 2009
RE-LY: Stroke or Systemic EmbolismRE-LY: Stroke or Systemic Embolism
0.500.50 0.750.75 1.001.00 1.251.25 1.501.50
Dabigatran 110 vs. WarfarinDabigatran 110 vs. Warfarin
Dabigatran 150 vs. WarfarinDabigatran 150 vs. Warfarin
Non-inferiorityNon-inferiorityp-valuep-value<0.001<0.001
<0.001<0.001
SuperioritySuperiorityp-valuep-value
0.340.34
<0.001<0.001
Margin = 1.46Margin = 1.46
HR (95% CI)HR (95% CI)Warfarin betterWarfarin betterDabigatran betterDabigatran better
Connolly et al., Connolly et al., NEJMNEJM, 2009, 2009
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
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
► 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?
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%
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
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?
Camm J.: Oral presentation at ESC on Aug 30th 2009. Camm J.: Oral presentation at ESC on Aug 30th 2009.
Meta-analysis of Ischemic Stroke Meta-analysis of Ischemic Stroke or Systemic Embolismor Systemic Embolism
W vs placeboW vs placebo
W vs W low doseW vs W low dose
W vs ASAW vs ASA
W vs ASA + clopidogrelW vs ASA + clopidogrel
W vs dabigatran 150W vs dabigatran 150
0 0.3 0.6 0.9 1.2 1.5 1.8 2.0
FavoursFavours warfarinwarfarin Favours other treatmentFavours other treatment
What About Trials with What About Trials with Other New Oral Anticoagulants?Other New Oral Anticoagulants?
► ROCKET – RivaroxabanROCKET – Rivaroxaban
► ARISTOTLE – ApixabanARISTOTLE – Apixaban
► ENGAGE - EdoxabanENGAGE - Edoxaban
► ROCKET – RivaroxabanROCKET – Rivaroxaban
► ARISTOTLE – ApixabanARISTOTLE – Apixaban
► ENGAGE - EdoxabanENGAGE - Edoxaban
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
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
Time in Therapeutic Range (TTR) with Time in Therapeutic Range (TTR) with Warfarin in the RE-LY TrialWarfarin in the RE-LY Trial
GroupGroup Relative RiskRelative Risk
OverallOverall 64%64%
VKA ExperiencedVKA Experienced 61%61%
VKA NaVKA Naïveve 67%67%
All patientsLong-term VKA therapy
No
Yes
Region
North America
South America
Western Europe
Central Europe
South Asia
East Asia
Other
0.5 1.0 1.5 0.5 1.0 1.5
Dabigatran Better Dabigatran BetterWarfarin Better Warfarin Better
0.72
0.91
0.81
0.11
18,113 1.53 1.11 1.69
9,123 1.57 1.07 1.67
8,989 1.49 1.15 1.70
6,533 1.19 1.11 1.51
1,134 1.82 0.91 1.68
2,829 1.22 0.78 1.06
3,941 1.53 1.26 1.43
1,134 3.35 0.84 4.00
1,648 1.87 1.77 2.28
1,072 1.95 0.88 2.27
SubgroupPatientstotal no. 110 mg 150 mg
WarfarinDabigatranHazard Ratio withDabigatran, 100
mg (95% CI)
Hazard Ratio withDabigatran,
150 mg (95% CI)
P Valuefor
Interaction
P Valuefor
Interaction
Relative Risk of Stroke or Systemic Embolism 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
► 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?
► 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
► 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
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
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
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
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
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
► 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
Warfarin Clinical Dosing NomogramWarfarin Clinical Dosing Nomogram
NEJM 2009; 360: 753-764NEJM 2009; 360: 753-764
PHARMACO-PHARMACO-GENETIC GENETIC
NOMOGRAMNOMOGRAM
NEJM 2009; 360: 753-764NEJM 2009; 360: 753-764
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
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
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
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
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)
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?
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.
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
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
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
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)
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
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
► 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
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?
Discussion: Novel Oral AnticoagulantsDiscussion: Novel Oral Anticoagulants
Discussion, Questions, and CommentsDiscussion, Questions, and Comments
Discussion, Questions, and CommentsDiscussion, Questions, and Comments