Mar 26, 2015
New Paradigms New Paradigms andand Landscape Changes Landscape Changes in in
Atrial FibrillationAtrial Fibrillation
Emerging Perspectives in Thrombosis Mitigation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular Specialist—Applying for the Cardiovascular Specialist—Applying
Landmark Trials to the Front Lines of Cardiology Landmark Trials to the Front Lines of Cardiology PracticePractice
National Experts National Experts inin Cardiovascular Medicine Cardiovascular Medicine Illuminate Illuminate andand Debate Debate
Program Chairman and ModeratorProgram Chairman and ModeratorPeter Libby, MD, FACCPeter Libby, MD, FACCChief, Cardiovascular MedicineChief, Cardiovascular MedicineBrigham and Women’s HospitalBrigham and Women’s Hospital
Mallinckrodt Professor of MedicineMallinckrodt Professor of MedicineHarvard Medical SchoolHarvard Medical SchoolBoston, MassachusettsBoston, Massachusetts
CME-certified symposium CME-certified symposium jointly jointly sponsored by the University of sponsored by the University of Massachusetts Medical School Massachusetts Medical School and CMEducation Resources, and CMEducation Resources, LLCLLC
Commercial Support: Commercial Support: Sponsored Sponsored by an independent educational by an independent educational grant from Boehringer-grant from Boehringer-IngelheimIngelheim
Faculty disclosures: Faculty disclosures: Listed in Listed in program syllabusprogram syllabus
Welcome and Program Overview Welcome and Program Overview
Program FacultyProgram Faculty
Peter Libby, MD, FACCPeter Libby, MD, FACCProgram Chairman and Program Chairman and Moderator Moderator Chief, Cardiovascular MedicineChief, Cardiovascular MedicineBrigham and Women’s HospitalBrigham and Women’s HospitalMallinckrodt Professor of MedicineMallinckrodt Professor of MedicineHarvard Medical SchoolHarvard Medical SchoolBoston, MassachusettsBoston, Massachusetts
Jonathan L. Halperin, MDJonathan L. Halperin, MDMount Sinai School of MedicineMount Sinai School of MedicineDirector, Clinical Cardiology ServiceDirector, Clinical Cardiology ServiceThe Zena and Michael A. Wiener The Zena and Michael A. Wiener Cardiovascular InstituteCardiovascular InstituteThe Marie-Josée and Henry R. Kravis The Marie-Josée and Henry R. Kravis Center for Cardiovascular HealthCenter for Cardiovascular HealthNew York, New YorkNew York, New York
Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHAssociate Professor of MedicineAssociate Professor of MedicineDepartment of MedicineDepartment of MedicineBoston University Medical CenterBoston University Medical CenterBoston, MassachusettsBoston, Massachusetts
Jeffrey I. Weitz, MD, FRCP, FACPJeffrey I. Weitz, MD, FRCP, FACPProfessor of Medicine and BiochemistryProfessor of Medicine and BiochemistryMcMaster UniversityMcMaster UniversityDirector, Henderson Research CenterDirector, Henderson Research CenterCanada Research Chair in ThrombosisCanada Research Chair in ThrombosisHeart and Stroke FoundationHeart and Stroke FoundationJ.F. Mustard Chair in Cardiovascular J.F. Mustard Chair in Cardiovascular ResearchResearchOntario, CanadaOntario, Canada
Challenges in Stroke PreventionChallenges in Stroke Preventionfor Patients with Atrial Fibrillationfor Patients with Atrial Fibrillation
Achieving Balance BetweenAchieving Balance BetweenPrevention of Thromboembolism Prevention of Thromboembolism
and Risk of Bleedingand Risk of BleedingRisk Stratification, Current Guidelines and Therapeutic Risk Stratification, Current Guidelines and Therapeutic
ChoicesChoices
New Frontiers in Atrial FibrillationNew Frontiers in Atrial Fibrillation
Jonathan L. Halperin, MDJonathan L. Halperin, MDProfessor of Medicine (Cardiology) Professor of Medicine (Cardiology)
Mount Sinai School of MedicineMount Sinai School of MedicineDirector, Clinical Cardiology ServicesDirector, Clinical Cardiology Services
The Zena and Michael A. Wiener Cardiovascular InstituteThe Zena and Michael A. Wiener Cardiovascular InstituteThe Marie-Josée and Henry R. KravisThe Marie-Josée and Henry R. Kravis
Center for Cardiovascular HealthCenter for Cardiovascular Health
Atrial FibrillationAtrial FibrillationA Substantial Threat to the BrainA Substantial Threat to the Brain
► Affects Affects
~~4% of people aged 4% of people aged >>60 years60 years
~9% of those aged ~9% of those aged >>80 years80 years► 5%/year stroke rate5%/year stroke rate► 12%/year for those with prior stroke12%/year for those with prior stroke► $ billions annual cost for stroke care$ billions annual cost for stroke care► AF-related strokes have worse AF-related strokes have worse
outcomesoutcomesAF identifies millions of people
with afive-fold increased risk of
stroke
Natural History of “Lone” Atrial Natural History of “Lone” Atrial FibrillationFibrillation
No Cardiopulmonary Disease; <60 Years OldNo Cardiopulmonary Disease; <60 Years Old
Kopecky S, et al. Kopecky S, et al. N Engl J MedN Engl J Med 1987; 317:669. 1987; 317:669.
97 PatientsMean Age = 44
14.8 yearsFollow-up
0.35%/yr Stroke0.40%/yr Mortality
Stroke Risk in Atrial FibrillationStroke Risk in Atrial FibrillationUntreated Control Groups of Randomized TrialsUntreated Control Groups of Randomized Trials
Atrial Fibrillation Investigators. Atrial Fibrillation Investigators. Arch Intern MedArch Intern Med 1994;154:1449. 1994;154:1449.
Str
oke
Rat
e (%
per
yea
r)S
trok
e R
ate
(% p
er y
ear)
Age (years)Age (years)
Anticoagulation in Atrial FibrillationAnticoagulation in Atrial FibrillationStroke Risk ReductionsStroke Risk Reductions
Hart R, et al. Hart R, et al. Ann Intern MedAnn Intern Med 2007;146:857. 2007;146:857.
WarfarinWarfarinBetterBetter
ControlControlBetterBetter
AFASAKAFASAK
SPAFSPAF
BAATAFBAATAF
CAFACAFA
SPINAFSPINAF
EAFTEAFT
100%100% 50%50% 00 -50%-50% -100%-100%
AggregateAggregate
Anticoagulation in Atrial FibrillationAnticoagulation in Atrial FibrillationThe Standard of Care for Stroke PreventionThe Standard of Care for Stroke Prevention
WarfarinWarfarinBetterBetter
ControlControlBetterBetter
AFASAKAFASAK
SPAFSPAF
BAATAFBAATAF
CAFACAFA
SPINAFSPINAF
EAFTEAFT
100%100% 50%50% 00 -50%-50% -100%-100%
AggregateAggregate
Terminated earlyTerminated early
Double-blind; Men onlyDouble-blind; Men only
UnblindedUnblinded
UnblindedUnblinded
UnblindedUnblinded
22oo prevention; Unblinded prevention; Unblinded
Hart R, et al. Hart R, et al. Ann Intern MedAnn Intern Med 2007;146:857. 2007;146:857.
Antithrombotic Therapy for Atrial FibrillationAntithrombotic Therapy for Atrial FibrillationStroke Risk ReductionStroke Risk Reduction
Antiplatelet drugsAntiplatelet drugsvs. Placebovs. Placebo
Warfarin vs.Warfarin vs.Placebo/ControlPlacebo/Control
100%100% 50%50% 00 -50%-50%
6 Trials6 Trialsn = 2,900n = 2,900
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 >10% of intracerebral hemorrhages (ICH) occur in patients on (ICH) occur in patients on antithrombotic therapyantithrombotic therapy
► Aspirin increases the risk by ~ 40%Aspirin increases the risk by ~ 40%
► Warfarin (INR 2–3) Warfarin (INR 2–3) doublesdoubles the risk to the risk to 0.3–0.6%/year0.3–0.6%/year
► ICH during anticoagulation is ICH during anticoagulation is catastrophiccatastrophic
Hart RG, et al. Hart RG, et al. StrokeStroke 2005;36:1588 2005;36:1588
The Most Feared Complication of Antithrombotic TherapyThe Most Feared Complication of Antithrombotic Therapy
Risk Stratification in AFRisk Stratification in AFStroke Risk FactorsStroke Risk Factors
High-Risk FactorsHigh-Risk Factors
► Mitral stenosisMitral stenosis
► Prosthetic heart valveProsthetic heart valve
► History of stroke or TIAHistory of stroke or TIA
Singer DE, et al. Singer DE, et al. ChestChest 2004;126:429S. 2004;126:429S.Fang MC, et al. Fang MC, et al. CirculationCirculation 2005; 112: 1687. 2005; 112: 1687.
High-Risk FactorsHigh-Risk Factors
► Mitral stenosisMitral stenosis
► Prosthetic heart valveProsthetic heart valve
► History of stroke or History of stroke or TIATIA
Moderate-Risk FactorsModerate-Risk Factors
►Age >75 yearsAge >75 years
►HypertensionHypertension
►Diabetes mellitusDiabetes mellitus
►Heart failure or Heart failure or ↓↓ LV function LV function
Risk Stratification in AFRisk Stratification in AFStroke Risk FactorStroke Risk Factorss
Singer DE, et al. Singer DE, et al. ChestChest 2004;126:429S. 2004;126:429S.Fang MC, et al. Fang MC, et al. CirculationCirculation 2005; 112: 1687. 2005; 112: 1687.
High-Risk FactorsHigh-Risk Factors► Mitral stenosisMitral stenosis► Prosthetic heart valveProsthetic heart valve► History of stroke or History of stroke or
TIATIA
Moderate-Risk FactorsModerate-Risk Factors► Age >75 yearsAge >75 years► HypertensionHypertension► Diabetes mellitusDiabetes mellitus► Heart failure or Heart failure or ↓↓ LV function LV function
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 History of stroke or
TIATIA
Moderate-Risk FactorsModerate-Risk Factors► Age >75 yearsAge >75 years► HypertensionHypertension► Diabetes mellitusDiabetes mellitus► Heart failure or Heart failure or ↓↓ LV function LV function
Less Validated Risk FactorsLess Validated Risk Factors► Age 65–75 yearsAge 65–75 years► Coronary artery diseaseCoronary artery disease► Female genderFemale gender► ThyrotoxicosisThyrotoxicosis
Dubious FactorsDubious Factors► Duration of AFDuration of AF► Pattern of AFPattern of AF
(persistent vs. paroxysmal)(persistent vs. paroxysmal)► Left atrial diameterLeft atrial diameter
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 Actually, it's more of a guideline than a rule.”guideline than a rule.”
Bill Murray in GhostbustersBill Murray in Ghostbusters Ⓒ Ⓒ (1984)(1984),,relaxing his rule "never to get involved relaxing his rule "never to get involved with possessed people" in response to with possessed people" in response to Sigourney Weaver's seductive advances.Sigourney Weaver's seductive advances.
Patient Selection for AnticoagulationPatient Selection for AnticoagulationAdditional ConsiderationsAdditional Considerations
► Risk of bleedingRisk of bleeding
► Newly anticoagulated vs. Newly anticoagulated vs. established therapyestablished therapy
► Availability of high-quality Availability of high-quality anticoagulation management anticoagulation management programprogram
► Patient preferencesPatient preferences
The ACTIVE TrialThe ACTIVE TrialClopidogrel + AspirClopidogrel + Aspirinin
Atrial Fibrillation + Risk Factors
VKA(INR 2-3)
Clopidogrel+ Aspirin
Aspirin+ Placebo
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.
Risk factor for bleeding*Risk factor for bleeding* 23%23%
Physician judgment against Physician judgment against anticoagulation for patientanticoagulation for patient
50%50%
Patient preference onlyPatient preference only 26%26%
* Inability to comply with INR monitoringInability to comply with INR monitoring* Predisposition to falling or head traumaPredisposition to falling or head trauma* Persistent hypertension >160/100 mmHgPersistent hypertension >160/100 mmHg* Previous serious bleeding on VKAPrevious serious bleeding on VKA
* Severe alcohol abuse within 2 yearsSevere alcohol abuse within 2 years* Peptic ulcer diseasePeptic ulcer disease* ThrombocytopeniaThrombocytopenia* Chronic need for NSAIDChronic need for NSAID
* Severe alcohol abuse within 2 yearsSevere alcohol abuse within 2 years* Peptic ulcer diseasePeptic ulcer disease* ThrombocytopeniaThrombocytopenia* Chronic need for NSAIDChronic need for NSAID
Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066. Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066.
The ACTIVE TrialThe ACTIVE TrialReasons for Exclusion from AnticoagulationReasons for Exclusion from Anticoagulation
ACTIVE-AACTIVE-ATotal Stroke RateTotal Stroke Ratess
Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066. Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066.
296 (2.4%/year)296 (2.4%/year)
408 (3.3%/year)408 (3.3%/year)
Cum
ulat
ive
Inci
denc
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
The ACTIVE TrialsThe ACTIVE TrialsStroke Rates and Risk ReductionsStroke Rates and Risk Reductions
Connolly SJ, et al. Connolly SJ, et al. LancetLancet 2006; 367:1903. 2006; 367:1903.Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066. Connolly SJ, et al. Connolly SJ, et al. LancetLancet 2006; 367:1903. 2006; 367:1903.Connolly SJ, et al. Connolly SJ, et al. N Engl J MedN Engl J Med 2009; 360:2066. 2009; 360:2066.
TreatmentTreatment VKAVKA C+AC+A AspirinAspirin
ACTIVE WACTIVE W(Annual Rate)(Annual Rate)
1.41.4 2.42.4 ~~
ACTIVE AACTIVE A(Annual Rate)(Annual Rate)
~~ 2.42.4 3.33.3
RRRRRRversus Aspirinversus Aspirin
-58%-58% -28%-28% ~~
RRRRRRversus C+Aversus C+A
-42%-42% ~ ~ ~~
VKA VKA = oral anticoagulant= oral anticoagulantC+A C+A = clopidogrel + aspirin= clopidogrel + aspirinVKA VKA = oral anticoagulant= oral anticoagulantC+A C+A = clopidogrel + aspirin= clopidogrel + aspirin
Investigational Anticoagulant TargetsInvestigational Anticoagulant Targets
TFPI (tifacogin)
Idraparinux
RivaroxabanRivaroxabanApixabanApixabanEdoxabanEdoxabanLY517717LY517717YM150YM150BetrixabanBetrixabanTAK 42TAK 42
Dabigatran
ORALORAL PARENTERALPARENTERAL
DX-9065aOtamixaban
Xa Xa
IIa IIa
TF/VIIaTF/VIIa
XX IXIX
IXaIXaVIIIaVIIIa
VaVa
II (thrombin)II (thrombin)
FibrinFibrinFibrinogenFibrinogen
ATAT
APC (drotrecogin alfa)sTM (ART-123)
Adapted from Weitz JI.Adapted from Weitz JI. Thromb Haemost Thromb Haemost 2007; 5 Suppl 1:65-7.2007; 5 Suppl 1:65-7.
TTP889
APC activated protein CAPC activated protein CAT antithrombinAT antithrombinsTM soluble thrombomodulinsTM soluble thrombomodulinTF tissue factorTF tissue factorFPI tissue factor pathway FPI tissue factor pathway inhibitorinhibitor
Dose, Concentration, or Intensity of Dose, Concentration, or Intensity of AnticoagulationAnticoagulation
Th
rom
bosi
sT
hro
mbo
sis B
leed
ing
Blee
din
g
Safe TherapeuticSafe TherapeuticRangeRange
ThrombosisThrombosis BleedingBleeding
The Ideal AnticoagulantThe Ideal AnticoagulantWide Therapeutic MarginWide Therapeutic Margin
Emerging AnticoagulantsEmerging AnticoagulantsRegulatory IssuesRegulatory Issues
► Open-label vs. blinded trial designOpen-label vs. blinded trial design
► Issues related to active-control trial Issues related to active-control trial designdesign
► How many trials are needed?How many trials are needed?
► Preventing use for unapproved Preventing use for unapproved indicationsindications
► Assessing patient-oriented outcomesAssessing patient-oriented outcomes
Alternatives to AnticoagulationAlternatives to AnticoagulationAtrial FibrillationAtrial Fibrillation
Restoration and maintenance of sinus rhythmRestoration and maintenance of sinus rhythm• Antiarrhythmic drug therapyAntiarrhythmic drug therapy• Catheter ablationCatheter ablation• Maze operationMaze operation
Current approachesCurrent approaches
Emerging (investigational) approachesEmerging (investigational) approaches
Obliteration of the left atrial Obliteration of the left atrial appendageappendage• Trans-catheter occluding devicesTrans-catheter occluding devices• Thoracoscopic epicardial plicationThoracoscopic epicardial plication• Amputation Amputation
Strokes after Conversion to NSRStrokes after Conversion to NSRRate vs. Rhythm Control TrialsRate vs. Rhythm Control Trials
nnRate Rate
controlcontrolRhythm Rhythm controlcontrol
RRRR(95% CI)(95% CI) pp
AFFIRMAFFIRM 4,9174,917 5.7%5.7% 7.3%7.3% 1.28 1.28 (0.95-1.72)(0.95-1.72) 0.120.12
RACERACE 522522 5.5%5.5% 7.9%7.9% 1.44 1.44 (0.75-2.78)(0.75-2.78) 0.440.44
STAFSTAF 266266 1.0%1.0% 3.0%3.0% 3.01 3.01 (0.35-25.3)(0.35-25.3) 0.520.52
PIAFPIAF 252252 0.8%0.8% 0.8%0.8% 1.02 1.02 (0.73-2.16)(0.73-2.16) 0.490.49
TotalTotal 5,9575,957 5.0%5.0% 6.5%6.5% 1.28 1.28 (0.98-1.66)(0.98-1.66) 0.080.08
Verheugt F, et al. Verheugt F, et al. J Am Coll CardiolJ Am Coll Cardiol 2003;41(suppl):130A. 2003;41(suppl):130A.
AFFIRM TrialAFFIRM TrialStroke RatesStroke Rates
► 74% of all strokes were proven 74% of all strokes were proven ischemicischemic 44% occurred after stopping warfarin44% occurred after stopping warfarin 28% in patients taking warfarin with INR 28% in patients taking warfarin with INR
<2.0<2.0 42% occurred during documented AF42% occurred during documented AF
Wyse AG, et al. Wyse AG, et al. N Engl J MedN Engl J Med 2002; 347: 1825 2002; 347: 1825.
ATHENA TrialATHENA TrialDronedarone vs. Placebo in Patients with AFDronedarone vs. Placebo in Patients with AF
Hohnloser SH, et al. Hohnloser SH, et al. N Engl J MedN Engl J Med 2009; 360: 668-78. 2009; 360: 668-78.
EventEvent Placebo Placebo (%/y)(%/y)
Dronedarone Dronedarone (%/y)(%/y)
HR HR (95% CI)(95% CI)
PP
StrokeStroke 1.791.79 1.191.19 0.660.66 0.0270.027
Stroke or Stroke or TIATIA 2.052.05 1.371.37 0.670.67 0.0200.020
Fatal strokeFatal stroke 0.540.54 0.360.36 0.670.67 0.2470.247
Stroke Rates Stroke Rates (Secondary Analysis(Secondary Analysis))
Percutaneous LAA OcclusionPercutaneous LAA OcclusionThe WATCHMANThe WATCHMAN®® DeviceDevice
Syed T, Halperin JL. Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med Nature Clin Prac Cardiovasc Med 2007; 4:4282007; 4:428Holmes DR, et al. Holmes DR, et al. Lancet 2009; 374: 534 Lancet 2009; 374: 534
Alternatives to AnticoagulationAlternatives to AnticoagulationAtrial FibrillationAtrial Fibrillation
Restoration and maintenance of sinus Restoration and maintenance of sinus rhythmrhythm• Antiarrhythmic drug therapyAntiarrhythmic drug therapy• Catheter ablationCatheter ablation• Maze operationMaze operation
Current approachesCurrent approaches
Emerging (investigational) approachesEmerging (investigational) approaches
Obliteration of the left atrial Obliteration of the left atrial appendageappendage• Trans-catheter occluding devicesTrans-catheter occluding devices• Thoracoscopic epicardial plicationThoracoscopic epicardial plication• Amputation Amputation
Is atrial fibrillation the cause of strokeor a marker of a population at risk?
Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismThe Next ChallengesThe Next Challenges
► Better tools to stratify bleeding riskBetter tools to stratify bleeding risk
► Noninvasive imaging and biomarkers of Noninvasive imaging and biomarkers of inflammation and thrombosis to predict inflammation and thrombosis to predict clinical events and guide therapyclinical events and guide therapy
► Confirming successful rhythm control over Confirming successful rhythm control over timetime
► Targeted therapy to prevent AF in patients Targeted therapy to prevent AF in patients at riskat risk
► Defining role and risk stratification Defining role and risk stratification strategies for non-monitored, oral strategies for non-monitored, oral anticoagulants anticoagulants
From Fermented Sweet CloverFrom Fermented Sweet Cloverto Molecular Targeting of Coagulationto Molecular Targeting of Coagulation
The Promise of New ApproachesThe Promise of New Approaches
The Goal:The Goal:To bring effective therapy to many more patients To bring effective therapy to many more patients
and prevent thousands of strokes.and prevent thousands of strokes.
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
► An 82-year-old man with An 82-year-old man with hypertension and diabetes has hypertension and diabetes has permanent atrial fibrillationpermanent atrial fibrillation
► He has a history of spinal He has a history of spinal stenosis and walks with a walkerstenosis and walks with a walker
Question 1: Question 1: Which regimen would you Which regimen would you prescribe for prophylaxis against prescribe for prophylaxis against thromboembolism?thromboembolism?
a.a. Warfarin (INR 2.0-3.0)Warfarin (INR 2.0-3.0)
b.b. Warfarin (INR 1.5-2.0)Warfarin (INR 1.5-2.0)
c.c. Aspirin, 81 mg dailyAspirin, 81 mg daily
d.d. Aspirin, 81 mg + clopidogrel, 75 mg Aspirin, 81 mg + clopidogrel, 75 mg dailydaily
e.e. No antithrombotic therapyNo antithrombotic therapy
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyAssessment of Thromboembolic RiskAssessment of Thromboembolic Risk
00 1.91.9
1 1 2.82.8
22 4.04.0
33 5.95.9
44 8.58.5
55 12.5 12.5
66 18.2 18.2
Van Walraven C, et al. Van Walraven C, et al. Arch Intern MedArch Intern Med 2003; 163: 936. 2003; 163: 936.Go A, et al. JAMA 2003; 290: 2685.Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.Gage BF, et al. Circulation 2004; 110: 2287.
Risk of StrokeRisk of Stroke(%/year)(%/year)
ScoreScore(points)(points)
Question 2: Question 2: What if you learn that he has What if you learn that he has tripped and fallen twice in the past two tripped and fallen twice in the past two years?years?
a.a. Warfarin (INR 2.0-3.0)Warfarin (INR 2.0-3.0)
b.b. Warfarin (INR 1.5-2.0)Warfarin (INR 1.5-2.0)
c.c. Aspirin, 81 mg dailyAspirin, 81 mg daily
d.d. Aspirin, 81 mg + clopidogrel, 75 mg Aspirin, 81 mg + clopidogrel, 75 mg dailydaily
e.e. No antithrombotic therapyNo antithrombotic therapy
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Question 3: Question 3: If the oral direct thrombin inhibitor If the oral direct thrombin inhibitor dabigatran were available and FDA-approved for dabigatran were available and FDA-approved for stroke prevention in AF, in this patient with a stroke prevention in AF, in this patient with a history of tripping you would treat with:history of tripping you would treat with:
a.a. Warfarin (INR 2.0-3.0)Warfarin (INR 2.0-3.0)
b.b. Warfarin (INR 1.5-2.0)Warfarin (INR 1.5-2.0)
c.c. Dabigatran 110 mg P.O. B.I.DDabigatran 110 mg P.O. B.I.D
d.d. Dabigatran 150 mg P.O. B.I.D.Dabigatran 150 mg P.O. B.I.D.
e.e. Aspirin, 81 mg + clopidogrel, 75 mg Aspirin, 81 mg + clopidogrel, 75 mg dailydaily
f.f. No antithrombotic therapyNo antithrombotic therapy
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyAnticoagulation in Patients at Risk of FallsAnticoagulation in Patients at Risk of Falls
Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyAnticoagulation in Patients at Risk of FallsAnticoagulation in Patients at Risk of Falls
“…“…persons taking warfarin must fall about 295 persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin (535/1.81) times in 1 year for warfarin notnot to be the to be the optimal therapy…”optimal therapy…”
Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyICH in Patients with AF Prone to FallsICH in Patients with AF Prone to Falls
Gage BF, et al. Gage BF, et al. Am J MedAm J Med 2005; 118:612. 2005; 118:612.
► The risk of ICH was 2.8%/year in The risk of ICH was 2.8%/year in patients at patients at high risk of falls and high risk of falls and 1.1 in other patients.1.1 in other patients.
► Warfarin was associated with an Warfarin was associated with an increased increased risk of mortality risk of mortality among those with ICH (30 day among those with ICH (30 day mortality = 52 vs. 34%, mortality = 52 vs. 34%, p p = = 0.007).0.007).
FactorFactor Hazard ratio Hazard ratio (95% CI)(95% CI) P valueP value
High-risk for fallsHigh-risk for falls 1.9 (1.03-2.9)1.9 (1.03-2.9) 0.0020.002
Prior strokePrior stroke 2.2 (1.7-2.8)2.2 (1.7-2.8) <0.0001<0.0001
Prior bleedPrior bleed 1.8 (1.4-2.4)1.8 (1.4-2.4) <0.0001<0.0001
Neuropsychiatric Neuropsychiatric impairmentimpairment 1.4 (1.0-1.9)1.4 (1.0-1.9) 0.0550.055
Hazard ratios of independent predictors Hazard ratios of independent predictors of intracranial hemorrhageof intracranial hemorrhage
Atrial Fibrillation Case StudyAtrial Fibrillation Case StudyOutcomes in Patients with AF Prone to FalOutcomes in Patients with AF Prone to Fallsls
Gage BF, et al. Gage BF, et al. Am J MedAm J Med 2005; 118:612. 2005; 118:612.
CHADS CHADS 22
scorescoreHazard ratio Hazard ratio
(95% CI)(95% CI) P valueP valueRecommended Recommended antithrombotic antithrombotic
therapytherapy
0-10-1 0.98 (0.56, 1.72)0.98 (0.56, 1.72) 0.940.94 Aspirin or nilAspirin or nil
2-62-6 0.75 (0.61, 0.91)0.75 (0.61, 0.91) 0.0040.004 AnticoagulantAnticoagulant
Hazard ratio of warfarin for composite outcome—out-of-Hazard ratio of warfarin for composite outcome—out-of-hospital death or hospitalization for stroke, MI, or hemorrhagehospital death or hospitalization for stroke, MI, or hemorrhage
—in 1245 patients at high risk for falls—in 1245 patients at high risk for falls
Summary of Case StudySummary of Case Study
► The risk of intracranial hemorrhage is The risk of intracranial hemorrhage is increased in patients who fall.increased in patients who fall.
► The use of oral anticoagulation does not The use of oral anticoagulation does not predict ICH, but mortality is higher among predict ICH, but mortality is higher among patients on anticoagulants who develop patients on anticoagulants who develop ICH.ICH.
► The risk of mortality due to ICH is offset by The risk of mortality due to ICH is offset by the reduction in ischemic events achieved the reduction in ischemic events achieved with anticoagulation in elderly patients with anticoagulation in elderly patients with AF at high risk of thromboembolism.with AF at high risk of thromboembolism.
► Better risk-stratification instruments are Better risk-stratification instruments are needed.needed.
Stroke Prevention in Stroke Prevention in High Risk PopulationsHigh Risk Populations
Optimizing Warfarin Therapy in Optimizing Warfarin Therapy in Challenging Patient PopulationsChallenging Patient Populations
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
Prevalence of AF by AgePrevalence of AF by Age
Feinberg WM. Arch Intern Med. 1995;155(5):469–473Feinberg WM. Arch Intern Med. 1995;155(5):469–473
Framingham StudyFramingham Study
Cardiovascular Health StudyCardiovascular Health Study
Mayo Clinic StudyMayo Clinic Study
Western Australia StudyWestern Australia Study
Pre
vale
nce
(%)
Pre
vale
nce
(%)
Age (years)Age (years)4040 50 50 60 60 70 70 80 80 90 90
2020
1818
1616
1414
1212
1010
88
66
44
22
00
Atrial FibrillationAtrial FibrillationMorbidity and MortalityMorbidity and Mortality
►4- to 5-fold increased risk of stroke4- to 5-fold increased risk of stroke►Doubling of the risk for dementiaDoubling of the risk for dementia►Tripling of risk for heart failureTripling of risk for heart failure►40 to 90% increased risk for overall 40 to 90% increased risk for overall
mortalitymortality►Risk of stroke in AF patients by age Risk of stroke in AF patients by age
groupgroup– 1.5% in 50 to 59 year age group1.5% in 50 to 59 year age group– 23.5% in 80 to 89 year age group23.5% in 80 to 89 year age group
Benjamin EJ, et al. Circulation 2009;119:606-618Benjamin EJ, et al. Circulation 2009;119:606-618
““The graying population will slowly, The graying population will slowly, radically transform society.” radically transform society.” Richard Suzman, Richard Suzman,
NIA NIA
► More than 37 million people are ≥ age More than 37 million people are ≥ age 65.65.
► By 2030, this number will exceed 70 By 2030, this number will exceed 70 million. million.
► By 2040, those aged ≥75 years will By 2040, those aged ≥75 years will exceed the exceed the
population 65 to 74 years old.population 65 to 74 years old.► By 2050, 12%, or 1 in 8 Americans, will By 2050, 12%, or 1 in 8 Americans, will
be be
age 75 or older.age 75 or older.
**Coronary heart disease, heart failure, stroke and hypertensionCoronary heart disease, heart failure, stroke and hypertension
15.9
37.9
73.379.3
7.8
38.5
72.6
85.9
0102030405060708090
100
20-39 40-59 60-79 80+
Per
cen
t of P
op
ula
tion
Men Women
Prevalence of CVD* in Adults by Age and Prevalence of CVD* in Adults by Age and Sex (NHANES: 2005-2006)Sex (NHANES: 2005-2006)
Source: NCHS and NHLBI
AgeAge
Pharmacokinetic and Pharmacodynamic Pharmacokinetic and Pharmacodynamic Changes with AgingChanges with Aging
► MetabolismMetabolism Generally, lower drug doses are required to Generally, lower drug doses are required to
achieve the same effectachieve the same effect Receptor numbers, affinity, or post-receptor Receptor numbers, affinity, or post-receptor
cellular effects may changecellular effects may change Overall decline in metabolic capacityOverall decline in metabolic capacity Decreased liver mass Decreased liver mass Decreased oxidative metabolism Decreased oxidative metabolism
through P450 system through P450 system decreased decreased clearance of drugsclearance of drugs
Kidney Function and AgeKidney Function and Age
Andres and Tobin, 1976Andres and Tobin, 1976
Age (years)Age (years)
Sta
ndar
d C
reat
ine
Cle
aran
ceS
tand
ard
Cre
atin
e C
lear
ance
ml/m
in/1
.73
ml/m
in/1
.73
30 40 50 60 70 8030 40 50 60 70 80
140140
130130
120120
110110
100100
Prevalence of Dementia Prevalence of Dementia
North America: 6.9% prevalence; 63% increase 2010-North America: 6.9% prevalence; 63% increase 2010-2030; 151% increase 2010-2050 2030; 151% increase 2010-2050
Polypharmacy in the ElderlyPolypharmacy in the Elderly
► Elderly = 12% of population; Elderly = 12% of population;
32% of prescriptions32% of prescriptions
► Average of 6 prescription medications;Average of 6 prescription medications;
1 to 3.5 over-the-counter drugs 1 to 3.5 over-the-counter drugs
► Average nursing home patientAverage nursing home patient
takes 7 medicationstakes 7 medications
► Average American senior spends Average American senior spends
$670/year for pharmaceuticals$670/year for pharmaceuticals
Adverse Drug ReactionsAdverse Drug Reactions
► About 15% of hospitalizations in the About 15% of hospitalizations in the elderly are related to adverse drug elderly are related to adverse drug reactionsreactions
► The risk of adverse drug reactions The risk of adverse drug reactions increases with the number of increases with the number of prescription medications prescription medications
Polypharmacy and Non-adherencePolypharmacy and Non-adherence
► Strongest predictor of non-adherence is Strongest predictor of non-adherence is
the number of medicationsthe number of medications► Non-adherence rates estimated 25-50%Non-adherence rates estimated 25-50%► Intentional about 75% of the timeIntentional about 75% of the time
Changes in regimen made by Changes in regimen made by patients to: patients to: - Increase convenience - Increase convenience - Reduce adverse effects or - Reduce adverse effects or - Decrease refill expense- Decrease refill expense
Hazards of Anticoagulant MedicationsHazards of Anticoagulant Medications
► #1 in 2003 and 2004 in the number of #1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse mentions of “deaths for drugs causing adverse effects in therapeutic use”effects in therapeutic use”11
► Warfarin-6% of 702,000 ADEs treated in ED per Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalizationyear; 17% require hospitalization11
► 21 million warfarin prescriptions in 1998>>>31 21 million warfarin prescriptions in 1998>>>31 million in 2004million in 200422
► The incidence AC-related intracranial The incidence AC-related intracranial hemorrhage quintupled during this time periodhemorrhage quintupled during this time period33
11 Wysowski DK, et al. Wysowski DK, et al. Arch Intern Med.Arch Intern Med. 2007;167:1414-1419. 2007;167:1414-1419. 22 Budnitz DS, et al. Budnitz DS, et al. JAMAJAMA. 2006;296:1858-1866. . 2006;296:1858-1866. 33 Flaherty ML, et al. Flaherty ML, et al. Neurology.Neurology. 2007;68:116-121. 2007;68:116-121.
Od
ds
Rat
io
005.05.0 6.06.0 8.08.0
INR1.01.0 2.02.0 3.03.0 4.04.0 7.07.0
5.05.0
15.015.0
10.010.0StrokeStroke Intracranial BleedIntracranial Bleed
1.01.0
Fuster et al. Fuster et al. J Am Coll CardiolJ Am Coll Cardiol. 2001;38:1231-1266.. 2001;38:1231-1266.
Ischemic Stroke and Ischemic Stroke and Intracranial BleedingIntracranial Bleeding
Adjusted Odds in Relation to Intensity of AnticoagulationAdjusted Odds in Relation to Intensity of Anticoagulation
Warfarin Dosing is ComplexWarfarin Dosing is ComplexFactors that Correlate w/ Warfarin DoseFactors that Correlate w/ Warfarin Dose
• AgeAge• Body surface area Body surface area
(BSA) or weight(BSA) or weight• Amiodarone Amiodarone • Other drugs (e.g. Other drugs (e.g.
acetaminophen)acetaminophen)• RaceRace• SexSex• Plasma vitamin K levelPlasma vitamin K level• Decompensated CHFDecompensated CHF• ChemotherapyChemotherapy• Genetic status Genetic status
Other Factors (up to 40%)
Age, Sex, Age, Sex, Weight Weight (10-20%)(10-20%)
CYP2C9 CYP2C9 (up to (up to 15%)15%)
VKORC1 VKORC1 (up to 25%)(up to 25%)
ACTIVE W TrialACTIVE W TrialVKA vs dualVKA vs dual
antiplatelet Rxantiplatelet Rx
Circulation 2008;118. Connolly SJ for Active W InvestigatorsCirculation 2008;118. Connolly SJ for Active W Investigators
Minimum thresholdMinimum threshold TTR TTR necessary to necessary to
realize benefit of warfarin:realize benefit of warfarin:
≥ ≥ 58%58%
Comparison of Outcomes Among Patients Comparison of Outcomes Among Patients Randomized to Warfarin According to Anticoagulant Randomized to Warfarin According to Anticoagulant
Control Control Results From SPORTIF III and VResults From SPORTIF III and V
TTR <60%TTR <60% TTR 60-75%TTR 60-75% TTR TTR >75%>75%
OutcomeOutcome TTR < 60%TTR < 60% TTR 60-75%TTR 60-75% TTR>75%TTR>75%
Mortality, %Mortality, % 4.24.2 1.841.84 1.691.69
Major Bleed, %Major Bleed, % 3.853.85 1.961.96 1.581.58
Stroke/SEE,%Stroke/SEE,% 2.102.10 1.341.34 1.071.07
Arch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers GArch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G
Major Hemorrhage RatesMajor Hemorrhage Rates
Randomized TrialsRandomized Trials INR TargetINR Target ICHICH MajorMajor AgeAge
AFIAFI 1.5-4.51.5-4.5 0.30.3 1.01.0 6969
SPAF IISPAF II 2.0-4.52.0-4.5 0.90.9 1.41.4 7070
AFFIRMAFFIRM 2.0-3.02.0-3.0 -------- 2.02.0 7070
RE-LYRE-LY 2.0-3.02.0-3.0 0.70.7 3.43.4 7272
ObservationalObservational INR TargetINR Target ICHICH MajorMajor AgeAge
Van der Meer, et al. Van der Meer, et al. (1993)(1993) 2.8-4.82.8-4.8 0.60.6 2.02.0 6666
Palareti, et al (1996)Palareti, et al (1996) 2.0-4.52.0-4.5 0.50.5 0.90.9 6262
Go, et al (2003)Go, et al (2003) 2.0-3.02.0-3.0 0.50.5 1.01.0 7171
Historical Historical trialstrials
SPORTIF SPORTIF III/VIII/V
ACTIVE ACTIVE WW
RE-LYRE-LY
Year publishedYear published 1989-19931989-1993 2003-20052003-2005 20062006 20092009
NN 3,7633,763 7,3277,327 6,7066,706 18,11318,113
Age, yrsAge, yrs 6969 7171 7070 7272
FemaleFemale 29%29% 31%31% 33%33% 37%37%
Prior strokePrior stroke 5%5% 21%21% 15%15% 20%20%
HypertensionHypertension 45%45% 77%77% 83%83% 79%79%
CHRCHR 26%26% 18%18% 21%21% 32%32%
DiabetesDiabetes 13%13% 18%18% 21%21% 23%23%
CHADSCHADS22 score score NANA NANA 2.02.0 2.12.1
Baseline Characteristics AF TrialsBaseline Characteristics AF Trials
Cumulative Incidence of Major BleedingCumulative Incidence of Major Bleeding
Hylek EM et al, Hylek EM et al, CirculationCirculation 2007;115(21) 2007;115(21)::2689-2696.2689-2696.
Days of WarfarinDays of Warfarin00 100 200 300 400 100 200 300 400
Age < 80Age < 80 Age >=80 Age >=80
Cum
ulat
ive
Pro
port
ion
Cum
ulat
ive
Pro
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
First Year Among Patients Newly Starting Warfarin by AgeFirst Year Among Patients Newly Starting Warfarin by Age
Risk of Stopping Therapy in the First Year Risk of Stopping Therapy in the First Year Among Among
Patients Newly Starting Warfarin by AgePatients Newly Starting Warfarin by Age
Hylek EM et al, Hylek EM et al, CirculationCirculation 2007;115(21) 2007;115(21)::2689-2696.2689-2696.
Days of WarfarinDays of Warfarin
Ris
k of
Sto
ppin
g W
arfa
rinR
isk
of S
topp
ing
War
farin
00 100 200 300 400 100 200 300 400
0
.000
5
.
001
.001
5
.
002
0
.000
5
.
001
.001
5
.
002
Age < 80Age < 80 Age >=80 Age >=80
HemorrhageHemorrhage ThrombosisThrombosis
Optimizing Benefit and Reducing RiskOptimizing Benefit and Reducing Risk
Strategies To Minimize Strategies To Minimize Risk Of HemorrhageRisk Of Hemorrhage
Incidence of UGIB and LGIB increases with Incidence of UGIB and LGIB increases with age.age.
70% of acute UGIB occur > 60 years of 70% of acute UGIB occur > 60 years of age.age.
Differential mucosal effect of ASA by ageDifferential mucosal effect of ASA by age
Incidence of LGIB increases 200-fold from Incidence of LGIB increases 200-fold from the the 33rdrd to 9 to 9thth decade of life: d decade of life: diverticulosis, iverticulosis, angiodysplasias, ischemic colitis, malignancyangiodysplasias, ischemic colitis, malignancy
THE FACTS:THE FACTS:
Bleeding Risk Scores for Warfarin Bleeding Risk Scores for Warfarin TherapyTherapy
LowLow ModerateModerate HighHigh
Kuijer et al. Kuijer et al. Arch Intern Med Arch Intern Med 1999;159:457-601999;159:457-60
00 1-31-3 >3>3 1.6 x age + 1.3 x sex +2.2 x cancer with 1 point for 1.6 x age + 1.3 x sex +2.2 x cancer with 1 point for ≥60, female or malignancy and 0 if none≥60, female or malignancy and 0 if none
Beyth et al.Beyth et al.Am J Med Am J Med 1998;105:91-91998;105:91-9
00 1-21-2 ≥≥33
≥≥65 years old; GI bleed in last 2 weeks; previous 65 years old; GI bleed in last 2 weeks; previous stroke; comorbidities (recent MI, Hct < 30%, stroke; comorbidities (recent MI, Hct < 30%, diabetes, Creat > 1.5) with 1 point for presence of diabetes, Creat > 1.5) with 1 point for presence of each condition and 0 if absenteach condition and 0 if absent
Gage et al.Gage et al.Am Heart J Am Heart J 2006;151:713-92006;151:713-9
0-10-1 2-32-3 ≥≥44
HEMORR2HAGES score: liver/renal disease, HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low ETOH abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, platelet count or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 points for previous bleedrisk factor present with 2 points for previous bleed
Shireman et al.Shireman et al.ChestChest2006;130:1390-62006;130:1390-6
≤≤1.071.07 >1.07 - >1.07 - <2.19<2.19 >2.19>2.19
(0.49 x age >70) + (0.32 x female) + (0.58 x remote (0.49 x age >70) + (0.32 x female) + (0.58 x remote bleed) + 0.62 x recent bleed) + 0.71 x ETOH/drug bleed) + 0.62 x recent bleed) + 0.71 x ETOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for (0.32 x antiplatelet drug use) with 1 point for presence of each and 0 if absentpresence of each and 0 if absent
Warfarin Dose by Age Warfarin Dose by Age
Derived from two independent Derived from two independent ambulatory populationsambulatory populations
Garcia D, et al. Chest 2005 2005;127:2049-2056Garcia D, et al. Chest 2005 2005;127:2049-2056
Female MaleFemale Male Female MaleFemale MaleAgeAgeAgeAge
War
farin
Wee
kly
Dos
e, m
gW
arfa
rin W
eekl
y D
ose,
mg
War
farin
Wee
kly
Dos
e, m
gW
arfa
rin W
eekl
y D
ose,
mg
<50 50-59 60-69 70-79 80-89 >=90<50 50-59 60-69 70-79 80-89 >=90 <50 50-59 60-69 70-79 80-89 >=90<50 50-59 60-69 70-79 80-89 >=90
5050
4545
4040
3535
3030
2525
2020
5050
4545
4040
3535
3030
2525
2020
0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00
Interval (days)
1
2
3
4
6
10
INR
1b
Index INR 7 - 9 (n = 235)Median INR half life = 2.3 daysInterquartile Range = (1.7,3.8)
Median days to INR < 4: 1.5 daysInterquartile Range = (1.1,2.5)
Hylek et al, Ann Intern Med. 2001;135:393-400
Delay in INR Normalization with Delay in INR Normalization with Increasing AgeIncreasing Age
Risk Factors for INR > 4.0 After Risk Factors for INR > 4.0 After Holding Two Doses of WarfarinHolding Two Doses of Warfarin
Adjusted Odds Ratio
Warfarin dose, weekly per 10 mgWarfarin dose, weekly per 10 mg 0.87 (0.79 - 0.97)0.87 (0.79 - 0.97)
Age, per decadeAge, per decade 1.18 (1.01 – 1.38)1.18 (1.01 – 1.38)
Decompensated heart failureDecompensated heart failure 2.79 (1.30 – 5.98)2.79 (1.30 – 5.98)
Active malignancyActive malignancy 2.48 (1.11 – 5.57)2.48 (1.11 – 5.57)
Index INR, per unitIndex INR, per unit 1.25 (1.14 – 1.37)1.25 (1.14 – 1.37)
Risk of UGIB with Different Combinations Risk of UGIB with Different Combinations of Antithrombotic Agentsof Antithrombotic Agents
Hallas J, et al. BMJ doi:10.1136/bmj.38947.697558.AEHallas J, et al. BMJ doi:10.1136/bmj.38947.697558.AE
Mean age=72 yearsMean age=72 years
Evolving Role for AspirinEvolving Role for Aspirin
► Meta-analysis of 10 trials that compared oral Meta-analysis of 10 trials that compared oral anticoagulant (OAC) therapy to ASA+OAC. anticoagulant (OAC) therapy to ASA+OAC.
► 4,180 patients with either heart valve, AF, or CAD4,180 patients with either heart valve, AF, or CAD
► Combination therapy:Combination therapy:● Lower incidence of thromboembolism (OR 0.66), but Lower incidence of thromboembolism (OR 0.66), but
the benefits were limited to patients with valves (OR the benefits were limited to patients with valves (OR 0.27). 0.27).
● Did notDid not benefit patients with AF (OR 0.99) or CAD (OR benefit patients with AF (OR 0.99) or CAD (OR 0.69) nor did it influence all cause mortality. 0.69) nor did it influence all cause mortality.
● DidDid increase the risk of major bleeding (OR 1.43). increase the risk of major bleeding (OR 1.43).
Dentali F, Douketis JD, Lim W, Crowther M.Dentali F, Douketis JD, Lim W, Crowther M.Arch Intern Med 2007; 167:117-124.Arch Intern Med 2007; 167:117-124.
Strategies to Improve Quality of Strategies to Improve Quality of VKA-Based Anticoagulant TherapyVKA-Based Anticoagulant Therapy
► Vigilant monitoring around all transitions Vigilant monitoring around all transitions in carein care
► Initiate lower doses in most susceptible Initiate lower doses in most susceptible patient subsetspatient subsets
► Increase monitoring with medication Increase monitoring with medication changes changes
► Reinforce safety points with patients and Reinforce safety points with patients and caregiverscaregivers
► Justify use of concomitant antiplatelet Justify use of concomitant antiplatelet therapytherapy
Summary Points and ConclusionsSummary Points and Conclusions
► Elderly patients with AF are at the highest risk of Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage.stroke and the highest risk of hemorrhage.
► Rates of ischemic stroke significantly exceed Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage rates of ICH and major extracranial hemorrhage on OAC.on OAC.
► Intensive efforts to optimize OAC will help to Intensive efforts to optimize OAC will help to decrease major bleeding.decrease major bleeding.
► Novel anticoagulants Novel anticoagulants maymay be safer in the elderly be safer in the elderly population due to their wider therapeutic index, population due to their wider therapeutic index, shorter tshorter t1/21/2, lack of dietary interference, and fewer , lack of dietary interference, and fewer drug interactions.drug interactions.
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
► 85-year-old female with AF, HTN, HF, prior TIA, 85-year-old female with AF, HTN, HF, prior TIA, osteoarthritis and prior diverticular GIB six osteoarthritis and prior diverticular GIB six months ago, on warfarin, who presents to the months ago, on warfarin, who presents to the ED with complaints of SOB for several days and ED with complaints of SOB for several days and black stools.black stools.
► Medications: atenolol, lisinopril, lasix, warfarin, Medications: atenolol, lisinopril, lasix, warfarin, ASA ASA
► Most recent INR 3 weeks ago = 3.1Most recent INR 3 weeks ago = 3.1
Atrial Fibrillation Patient Case StudyAtrial Fibrillation Patient Case Study
Question 1: Question 1: This patient’s estimated This patient’s estimated stroke risk per year without warfarin is:stroke risk per year without warfarin is:
a)a)5%5%
b)b)12%12%
c)c)20%20%
d)d)None of the aboveNone of the above
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Exam:Exam: afebrile, HR 110-130, BP 154/90 afebrile, HR 110-130, BP 154/90 lungs-bibasilar raleslungs-bibasilar ralesCOR-irreg irregCOR-irreg irregABD-nontenderABD-nontenderguaiac + guaiac +
ECG:ECG: AF with rapid VRAF with rapid VR
CXR:CXR: mild pulmonary edemamild pulmonary edema
Labs:Labs: Hct=21, INR=8.0, Troponin - Hct=21, INR=8.0, Troponin -
Physical Exam and Pertinent DataPhysical Exam and Pertinent Data
Question 2: Question 2: The most appropriate The most appropriate management strategy for this patient management strategy for this patient would be to:would be to:
a)a)Stop both aspirin and warfarin – Resume Stop both aspirin and warfarin – Resume aspirinaspirin only in one weekonly in one week
b)b)Stop both aspirin and warfarin – Resume Stop both aspirin and warfarin – Resume warfainwarfain
c)c)Stop both aspirin and warfarin – Resume Stop both aspirin and warfarin – Resume bothboth warfarin and aspirin in one weekwarfarin and aspirin in one week
d)d)Stop both aspirin and warfarin permanentlyStop both aspirin and warfarin permanently
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Question 3: Question 3: The patient’s bleeding episode The patient’s bleeding episode resolves, she is started back on warfarin, and resolves, she is started back on warfarin, and she returns six months later with an hematocrit she returns six months later with an hematocrit of 35 (her baseline). Her INR is 3.7. If of 35 (her baseline). Her INR is 3.7. If dabigatran were approved by the FDA for SPAF, dabigatran were approved by the FDA for SPAF, at this point you would:at this point you would:
a)a)Stop warfarin and put the patient on clopidogrel and Stop warfarin and put the patient on clopidogrel and aspirinaspirinb)b)Adjust the warfarin to achieve an INR of 2.0 - 3.0Adjust the warfarin to achieve an INR of 2.0 - 3.0c)c)Transition patient to dabigatran 110mg PO BIDTransition patient to dabigatran 110mg PO BIDd)d)Transition patient to dabigatran 150 mg PO BidTransition patient to dabigatran 150 mg PO Bide)e)Start aspirin onlyStart aspirin onlyf)f)Stop all anticoagulationStop all anticoagulation
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
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
LimitationLimitation ConsequenceConsequence
Slow onset of actionSlow onset of action Overlap with a parenteral Overlap with a parenteral anticoagulantanticoagulant
Genetic variation in metabolismGenetic variation in metabolism Variable dose requirementsVariable dose requirements
Multiple food and drug Multiple food and drug interactionsinteractions Frequent coagulation monitoringFrequent coagulation monitoring
Narrow therapeutic indexNarrow therapeutic index Frequent coagulation monitoringFrequent coagulation monitoring
New New Oral Anticoagulants for Stroke Oral Anticoagulants for Stroke Prevention in AFPrevention in AF
Direct Inhibitors of Factor Xa Direct Inhibitors of Factor Xa or Thrombinor Thrombin
Comparison of Features of New OralComparison of Features of New OralAnticoagulants in Advanced Stages of DevelopmentAnticoagulants in Advanced Stages of Development
FeaturesFeatures RivaroxabanRivaroxaban ApixabanApixaban Dabigatran Dabigatran EtexilateEtexilate
TargetTarget XaXa XaXa IIaIIa
Molecular WeightMolecular Weight 436436 460460 628628
ProdrugProdrug NoNo NoNo YesYes
Bioavailability (%)Bioavailability (%) 8080 5050 66
Time to peak (h)Time to peak (h) 33 33 22
Half-life (h)Half-life (h) 99 9-149-14 12-1712-17
Renal excretion Renal excretion (%)(%) 6565 2525 8080
AntidoteAntidote NoneNone NoneNone NoneNone
Comparison of Features of New Comparison of Features of New Anticoagulants With Those of WarfarinAnticoagulants With Those of Warfarin
FeaturesFeatures WarfarinWarfarin New AgentsNew Agents
OnsetOnset SlowSlow RapidRapid
DosingDosing VariableVariable FixedFixed
Food effectFood effect YesYes NoNo
Drug interactionsDrug interactions ManyMany FewFew
MonitoringMonitoring YesYes NoNo
Half-lifeHalf-life LongLong ShortShort
AntidoteAntidote YesYes NoNo
1.1. Oral factor Xa inhibitors have a better safety profile Oral factor Xa inhibitors have a better safety profile than oral thrombin inhibitorsthan oral thrombin inhibitors
2.2. Of the new oral anticoagulants, dabigatran etexilate Of the new oral anticoagulants, dabigatran etexilate is most advanced in developmentis most advanced in development
3.3. Oral factor Xa inhibitors can be safely given to Oral factor Xa inhibitors can be safely given to patients with a creatinine clearance < 30 ml/minpatients with a creatinine clearance < 30 ml/min
4.4. The prothrombin time can be used to monitor all The prothrombin time can be used to monitor all of the new oral anticoagulantsof the new oral anticoagulants
5.5. Fresh frozen plasma will reverse the anticoagulantFresh frozen plasma will reverse the anticoagulant effects of the new oral anticoagulantseffects of the new oral anticoagulants
Which of the Following Which of the Following Statements is trueStatements is true??
RE-LY: A Non-inferiority TrialRE-LY: A Non-inferiority Trial
R
Open
•Atrial Fibrillation with ≥ 1 Risk Factor• Absence of Contraindications• Conducted in 951 centers in 44
countries
WarfarinAdjusted
INR 2.0 – 3.0N=6000
Dabigatran etexilate 110 mg BID
N=6000
Dabigatran etexilate 150 mg BID
N=6000
Blinded Event Adjudication
OpenOpen BlindedBlinded
RR
RE-LY: Baseline CharacteristicsRE-LY: Baseline Characteristics
CharacteristicCharacteristic Dabigatran Dabigatran 110 mg110 mg
Dabigatran Dabigatran 150 mg150 mg WarfarinWarfarin
RandomizedRandomized 60156015 60766076 60226022
Mean age (years)Mean age (years) 71.471.4 71.571.5 71.671.6
Male (%)Male (%) 64.364.3 63.263.2 63.363.3
CHADS2 score CHADS2 score (mean)(mean) 0-1 (%)0-1 (%) 2 (%)2 (%) 3+ (%)3+ (%)
2.12.1
32.632.634.734.732.732.7
2.22.2
32.232.235.235.232.632.6
2.12.1
30.930.937.037.032.132.1
Prior stroke/TIA (%)Prior stroke/TIA (%) 19.919.9 20.320.3 19.819.8
Prior MI (%)Prior MI (%) 16.816.8 16.916.9 16.116.1
CHF (%)CHF (%) 32.232.2 31.831.8 31.931.9
Baseline ASA (%)Baseline ASA (%) 40.040.0 38.738.7 40.640.6
Warfarin Naïve (%)Warfarin Naïve (%) 49.949.9 49.849.8 51.451.4
Connolly et al., Connolly et al., NEJMNEJM, 2009, 2009
RE-LY: Stroke or Systemic EmbolismRE-LY: Stroke or Systemic Embolism
0.500.50 0.750.75 1.001.00 1.251.25 1.501.50
Dabigatran 110 vs. WarfarinDabigatran 110 vs. Warfarin
Dabigatran 150 vs. WarfarinDabigatran 150 vs. Warfarin
Non-inferiorityNon-inferiorityp-valuep-value<0.001<0.001
<0.001<0.001
SuperioritySuperiorityp-valuep-value
0.340.34
<0.001<0.001
Margin = 1.46Margin = 1.46
HR (95% CI)HR (95% CI)Warfarin betterWarfarin betterDabigatran betterDabigatran better
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
How can dabigatran be more effective How can dabigatran be more effective than warfarin yet cause less bleeding?than warfarin yet cause less bleeding?
RE-LY: Secondary Efficacy Outcomes RE-LY: Secondary Efficacy Outcomes According to Treatment GroupAccording to Treatment Group
Connolly, et al. N Engl J Med N Engl J Med 2009;361:1139-51
EventEvent Dabigatran Dabigatran 110 mg110 mg
Dabigatran Dabigatran 150 mg150 mg WarfarinWarfarin
Myocardial Myocardial infarctioninfarction 0.7%0.7% 0.7%0.7% 0.5%0.5%
Vascular deathVascular death 2.4%2.4% 2.3%2.3% 2.7%2.7%
All-cause All-cause mortalitymortality 3.8%3.8% 3.6%3.6% 4.1%4.1%
► Chance finding?Chance finding?
► Warfarin superior to dabigatran for Warfarin superior to dabigatran for inhibitionof clotting at sites of plaque inhibitionof clotting at sites of plaque disruption?disruption?
► Other factors?Other factors?
Why is There More MI with Dabigatran?Why is There More MI with Dabigatran?
End pointEnd point Warfarin Warfarin Dabigatran Dabigatran
110 mg 110 mg twice dailytwice daily
RR (95% CI) RR (95% CI) vs warfarinvs warfarin pp
Dabigatran Dabigatran 150 mg150 mg
twice dailytwice daily
RR (95% CI) RR (95% CI) vs warfarinvs warfarin pp
Stroke/ systemic Stroke/ systemic embolism embolism (%/year)(%/year)
2.742.74 2.322.32 0.850.85(0.59–1.22)(0.59–1.22) 0.370.37 2.07 2.07 0.760.76
(0.53–1.10) (0.53–1.10) 0.140.14
Hemorrhagic Hemorrhagic stroke (n)stroke (n) 1818 22
0.110.11(0.03–0.47)(0.03–0.47) 0.0030.003 55
0.270.27(0.10–0.72) (0.10–0.72) 0.0090.009
ICH (n)ICH (n) 3030 660.200.20
(0.08–0.47)(0.08–0.47) 0.0010.001 1313 0.410.41(0.21–0.79) (0.21–0.79) 0.0070.007
RE-LY: Outcomes in Secondary-Prevention RE-LY: Outcomes in Secondary-Prevention Patients with AF by Treatment AssignmentPatients with AF by Treatment Assignment
Diener HC et al. American Stroke Association International Stroke Conference Diener HC et al. American Stroke Association International Stroke Conference 2010; February 26, 2010; San Antonio, TX. 2010; February 26, 2010; San Antonio, TX.
RE-LY: Cumulative Risk of ALT or AST RE-LY: Cumulative Risk of ALT or AST >3x ULN After Randomization>3x ULN After Randomization
Years of follow-up
DabigatranDabigatran 110 mg110 mg
Cu
mu
lati
ve r
isk
0.0
0.01
0.02
0.03
0.04
0 0.5 1.0 1.5 2.0 2.5
Dabigatran 150 mg
Warfarin
Connolly, et al. N Engl J Med N Engl J Med 2009;361:1139-51
Lower-dose regimenLower-dose regimen
► ElderlyElderly
► Renal insufficiencyRenal insufficiency
► Lower stroke risk (CHADSLower stroke risk (CHADS22 score of 1) score of 1)
Higher-dose regimenHigher-dose regimen
► Higher stroke risk (CHADSHigher stroke risk (CHADS22 score ≥ 2) score ≥ 2)
Which Dose for Which Patient?Which Dose for Which Patient?
Camm J.: Oral presentation at ESC on Aug 30th 2009. Camm J.: Oral presentation at ESC on Aug 30th 2009.
Meta-analysis of Ischemic Stroke Meta-analysis of Ischemic Stroke or Systemic Embolismor Systemic Embolism
W vs placeboW vs placebo
W vs W low doseW vs W low dose
W vs ASAW vs ASA
W vs ASA + clopidogrelW vs ASA + clopidogrel
W vs dabigatran 150W vs dabigatran 150
0 0.3 0.6 0.9 1.2 1.5 1.8 2.0
FavoursFavours warfarinwarfarin Favours other treatmentFavours other treatment
What About Trials with What About Trials with Other New Oral AnticoagulantsOther New Oral Anticoagulants??
► ROCKETROCKET – Rivaroxaban – Rivaroxaban
► ARISTOTLEARISTOTLE – Apixaban – Apixaban
► ENGAGEENGAGE - Edoxaban - Edoxaban
What about other What about other indications?indications?
RE-COVERRE-COVERTM TM Trial DesignTrial Design
ObjectiveObjectiveconfirmationconfirmation
of VTEof VTE
EE RR
30 days30 daysfollow up follow up
Initial parenteraltherapy
Single-dummyperiod Double-dummy period
7272 hh
6 months6 monthsEnd of treatmentEnd of treatment
Until INR Until INR 2.0 on2.0 ontwo consecutivetwo consecutivemeasurementsmeasurements
(8-11 days)(8-11 days)
WarfarinWarfarin WarfarinWarfarin(INR 2.0–3.0)(INR 2.0–3.0)
Dabigatran etexilate placebo bidDabigatran etexilate placebo bid
Warfarin placeboWarfarin placebo
Dabigatran etexilate 150 mg bidDabigatran etexilate 150 mg bidWarfarinWarfarinplaceboplacebo
E= enrolmentE= enrolmentR= randomizationR= randomization
Efficacy and Safety OutcomesEfficacy and Safety Outcomes
Schulman et al., N Engl J Med, 2009Schulman et al., N Engl J Med, 2009
OutcomeOutcome DabigatranDabigatran DabigatranDabigatran HR (95% CI)HR (95% CI)
Recurrent VTE Recurrent VTE and VTE-related and VTE-related deathdeath
2.4%2.4% 2.1%2.1% 1.10 (0.65-1.84)1.10 (0.65-1.84)
Major bleedingMajor bleeding 1.6%1.6% 1.9%1.9% 0.82 (0.45-1.48)0.82 (0.45-1.48)
Is Warfarin Obsolete?Is Warfarin Obsolete?
► New oral anticoagulants are more New oral anticoagulants are more convenientconvenient
► But, warfarin effective when time But, warfarin effective when time in therapeutic range is highin therapeutic range is high
Cumulative Risk of Stroke, MI, Cumulative Risk of Stroke, MI, Systemic Embolism, or Vascular DeathSystemic Embolism, or Vascular Death
Connolly, S. J. et al. Circulation 2008;118:2029-2037Connolly, S. J. et al. Circulation 2008;118:2029-2037
OACOAC
OACOAC
C+AC+A
C+AC+A
YearsYears YearsYears
Eve
nt R
ate
(%)
Eve
nt R
ate
(%)
Eve
nt R
ate
(%)
Eve
nt R
ate
(%)
TTR < 65%TTR < 65% TTR >= 65%TTR >= 65%
RR=0.93 (0.70-1.24)RR=0.93 (0.70-1.24)p=0.61p=0.61
RR=2.14 (1.61-2.85)RR=2.14 (1.61-2.85)P=0.0001P=0.0001
0.0 0.5 1.0 1.50.0 0.5 1.0 1.5 0.0 0.5 1.0 1.50.0 0.5 1.0 1.5
1212
1010
88
66
44
22
00
1212
1010
88
66
44
22
00
Patients treated at centers with a TTR below or above the study median (65%)Patients treated at centers with a TTR below or above the study median (65%)
Time in Therapeutic Range (TTR) with Time in Therapeutic Range (TTR) with Warfarin in the RE-LY TrialWarfarin in the RE-LY Trial
GroupGroup Relative RiskRelative Risk
OverallOverall 64%64%
VKA ExperiencedVKA Experienced 61%61%
VKA NaVKA Naïveve 67%67%
All patientsLong-term VKA therapy
No
Yes
Region
North America
South America
Western Europe
Central Europe
South Asia
East Asia
Other
0.5 1.0 1.5 0.5 1.0 1.5
Dabigatran Better Dabigatran BetterWarfarin Better Warfarin Better
0.72
0.91
0.81
0.11
18,113 1.53 1.11 1.69
9,123 1.57 1.07 1.67
8,989 1.49 1.15 1.70
6,533 1.19 1.11 1.51
1,134 1.82 0.91 1.68
2,829 1.22 0.78 1.06
3,941 1.53 1.26 1.43
1,134 3.35 0.84 4.00
1,648 1.87 1.77 2.28
1,072 1.95 0.88 2.27
SubgroupPatientstotal no. 110 mg 150 mg
WarfarinDabigatranHazard Ratio withDabigatran, 100
mg (95% CI)
Hazard Ratio withDabigatran,
150 mg (95% CI)
P Valuefor
Interaction
P Valuefor
Interaction
Relative Risk of Stroke or Systemic Embolism Relative Risk of Stroke or Systemic Embolism with According to Geographical Regionwith According to Geographical Region
Connolly et al., Connolly et al., NEJM NEJM 20092009
Dabigatran Versus WarfarinDabigatran Versus Warfarin
► Stable on warfarinStable on warfarin
► Renal impairmentRenal impairment
► Severe hepatic diseaseSevere hepatic disease
► Poor compliance Poor compliance
Who is Not a Candidate for Who is Not a Candidate for Dabigatran?Dabigatran?
► Management of patients with severe Management of patients with severe coronary artery disease or recent GI coronary artery disease or recent GI bleeding?bleeding?
► Will short half-life obviate need for Will short half-life obviate need for antidotes?antidotes?
► Will elimination of monitoring Will elimination of monitoring adversely impact patient care?adversely impact patient care?
Unanswered QuestionsUnanswered Questions
► Dabigatran etexilate is superior to Dabigatran etexilate is superior to warfarin for stroke prevention and warfarin for stroke prevention and non-inferior for VTE treatmentnon-inferior for VTE treatment
► Dosing of new oral anticoagulants is Dosing of new oral anticoagulants is critical; are the doses of factor Xa critical; are the doses of factor Xa inhibitors optimal?inhibitors optimal?
► New oral anticoagulants will replace New oral anticoagulants will replace warfarin, but transition likely to be warfarin, but transition likely to be slowslow
Conclusions: RE-LY and New, Oral Non-Conclusions: RE-LY and New, Oral Non-Monitored AnticoagulationMonitored Anticoagulation
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
► Mrs. A. is a 78-year-old woman who is Mrs. A. is a 78-year-old woman who is taking warfarin for stroke prevention on the taking warfarin for stroke prevention on the background of atrial fibrillation. She also background of atrial fibrillation. She also takes ASA 81 mg daily. takes ASA 81 mg daily.
► Her risk factors for stroke include Her risk factors for stroke include hypertension and type II diabetes mellitus. hypertension and type II diabetes mellitus. Her INR control has been erratic with values Her INR control has been erratic with values ranging from 1.5 to 6.8. ranging from 1.5 to 6.8.
► For the past two weeks, she has had For the past two weeks, she has had intermittent nosebleeds lasting 5 to 20 intermittent nosebleeds lasting 5 to 20 minutes. She is anxious to stop warfarin. minutes. She is anxious to stop warfarin.
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Question 1: Question 1: What is the best approach for What is the best approach for this patient?this patient?
(a)(a)Stop the warfarin and the ASAStop the warfarin and the ASA
(b)(b)Stop the ASA, but continue warfarinStop the ASA, but continue warfarin
(c)(c)Perform CYP2C9 and VKORC1 genotyping to Perform CYP2C9 and VKORC1 genotyping to better identify an appropriate warfarin dosebetter identify an appropriate warfarin dose
(d)(d)Stop the warfarin and add clopidogrel 75 mg Stop the warfarin and add clopidogrel 75 mg dailydaily
(e)(e)Continue warfarin and ASA, but monitor the Continue warfarin and ASA, but monitor the INR more frequentlyINR more frequently
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
The ASA was stopped, but Mrs. A. still The ASA was stopped, but Mrs. A. still complains of nosebleeds. Despite complains of nosebleeds. Despite weekly monitoring, her INR continues weekly monitoring, her INR continues to range from 1.8 to 4.8. A calculated to range from 1.8 to 4.8. A calculated creatinine clearance is 45 ml/min.creatinine clearance is 45 ml/min.
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Question 2Question 2: If dabigatran were approved for : If dabigatran were approved for stroke prevention in patients with atrial stroke prevention in patients with atrial fibrillation, what would you likely do at this fibrillation, what would you likely do at this point?point?
(a)(a)Continue on warfarinContinue on warfarin
(b)(b)Continue on warfarin, but add low-dose Continue on warfarin, but add low-dose vitamin Kvitamin K
(c)(c)Switch from warfarin to dabigatran etexilate Switch from warfarin to dabigatran etexilate 110 mg b.i.d.110 mg b.i.d.
(d)(d)Switch from warfarin to dabigatran etexilate Switch from warfarin to dabigatran etexilate 150 mg b.i.d.150 mg b.i.d.
(e)(e)Switch from warfarin to ASA and clopidogrelSwitch from warfarin to ASA and clopidogrel
Atrial Fibrillation Case StudyAtrial Fibrillation Case Study
Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismCurrent State of the Art and ScienceCurrent State of the Art and Science
► There is a new, quickening rhythm to the pace of There is a new, quickening rhythm to the pace of research and clinical advances in atrial fibrillationresearch and clinical advances in atrial fibrillation
► Etiology of AF is multifactorial and we are just Etiology of AF is multifactorial and we are just beginning to understand the inter-relationship beginning to understand the inter-relationship among myriad factorsamong myriad factors
► Noninvasive imaging and biomarkers of Noninvasive imaging and biomarkers of inflammation and thrombosis can predict clinical inflammation and thrombosis can predict clinical events in AF and may help guide therapyevents in AF and may help guide therapy
► Risk stratification strategies for AF are useful but Risk stratification strategies for AF are useful but imperfect: advances and refinements are required imperfect: advances and refinements are required to help define role for non-monitored, oral to help define role for non-monitored, oral anticoagulants anticoagulants
Atrial Fibrillation and ThromboembolismAtrial Fibrillation and Thromboembolism Current State of the Art and ScienceCurrent State of the Art and Science
► Strategies are being developed to improve the Strategies are being developed to improve the safety and efficacy of vitamin K antagonists safety and efficacy of vitamin K antagonists (VKAs), but achieving acceptable TTRs remains a (VKAs), but achieving acceptable TTRs remains a challengechallenge
► Elderly patients with AF are at the highest risk of Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage, and stroke and the highest risk of hemorrhage, and therefore demand special attentiontherefore demand special attention
► Novel anticoagulants Novel anticoagulants appearappear to be safer in the to be safer in the elderly population due to their wider therapeutic elderly population due to their wider therapeutic index, shorter tindex, shorter t1/21/2, lack of dietary interference, , lack of dietary interference, and fewer drug interactions.and fewer drug interactions.
Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismCurrent State of the Art and ScienceCurrent State of the Art and Science
► Dabigatran etexilate is superior to warfarin for Dabigatran etexilate is superior to warfarin for stroke stroke prevention and non-inferior for VTE treatmentprevention and non-inferior for VTE treatment
► Dosing strategy for new oral anticoagulants is Dosing strategy for new oral anticoagulants is critical:critical: selecting the appropriate dose in the individual selecting the appropriate dose in the individual patient to patient to achieve ideal balance of stroke prevention and achieve ideal balance of stroke prevention and bleeding bleeding minimization is a work in progressminimization is a work in progress
► New oral anticoagulants will replace warfarin, and New oral anticoagulants will replace warfarin, and the the transition will impact the landscape of transition will impact the landscape of anticoagulation anticoagulation managementmanagement
The RE-LY Trial represents the most compelling The RE-LY Trial represents the most compelling evidence evidence to date for revising, reconsidering, and reshaping to date for revising, reconsidering, and reshaping our our current VKA-based paradigm for stroke prevention current VKA-based paradigm for stroke prevention in AFin AF
► Dabigatran etexilate is superior to warfarin for Dabigatran etexilate is superior to warfarin for stroke stroke prevention and non-inferior for VTE treatmentprevention and non-inferior for VTE treatment
► Dosing strategy for new oral anticoagulants is Dosing strategy for new oral anticoagulants is critical:critical: selecting the appropriate dose in the individual selecting the appropriate dose in the individual patient to patient to achieve ideal balance of stroke prevention and achieve ideal balance of stroke prevention and bleeding bleeding minimization is a work in progressminimization is a work in progress
► New oral anticoagulants will replace warfarin, and New oral anticoagulants will replace warfarin, and the the transition will impact the landscape of transition will impact the landscape of anticoagulation anticoagulation managementmanagement
The RE-LY Trial represents the most compelling The RE-LY Trial represents the most compelling evidence evidence to date for revising, reconsidering, and reshaping to date for revising, reconsidering, and reshaping our our current VKA-based paradigm for stroke prevention current VKA-based paradigm for stroke prevention in AFin AF
► At least four trials evaluating the safety and At least four trials evaluating the safety and efficacy of oral, non-monitored anticoagulants efficacy of oral, non-monitored anticoagulants
for SPAF are in progress: stay tunedfor SPAF are in progress: stay tuned
Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismCurrent State of the Art and ScienceCurrent State of the Art and Science
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