spaf boston slidecast 181

Stroke Prevention Stroke Prevention in in Atrial FibrillationAtrial Fibrillation

Evidence- and Guideline-Based Strategies for Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Optimizing Clinical Outcomes and

Anticoagulation-Based Management for SPAFAnticoagulation-Based Management for SPAF

New Frontiers and Treatment New Frontiers and Treatment Paradigms forParadigms for

Program ChairmanProgram ChairmanSamuel 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-certified symposium CME-certified symposium jointly sponsored by the jointly sponsored by the University of Massachusetts University of Massachusetts Medical School and Medical School and CMEducation Resources, LLCCMEducation Resources, LLC

Commercial Support: Commercial Support: This This National Initiative is Sponsored National Initiative is Sponsored by an Independent by an Independent Educational Grant from the Educational Grant from the Bristol-Myers Squibb/Pfizer Bristol-Myers Squibb/Pfizer Cardiovascular Partnership. Cardiovascular Partnership.

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

Program FacultyProgram Faculty

PROGRAM CHAIRMANPROGRAM CHAIRMANSAMUEL Z. GOLDHABER, SAMUEL Z. GOLDHABER, MDMDCardiovascular DivisionCardiovascular DivisionBrigham and Women’s Brigham and Women’s HospitalHospitalProfessor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School

CHRISTIAN T. RUFF, MD, MPHTIMI Study GroupTIMI Study GroupBrigham and Women’s Brigham and Women’s HospitalHospitalHarvard Medical SchoolHarvard Medical SchoolBoston, MABoston, MA

ELAINE M. HYLEK, MD, ELAINE M. HYLEK, MD, MPHMPHProfessor of MedicineProfessor of MedicineDepartment of MedicineDepartment of MedicineBoston University Medical Boston University Medical CenterCenterBoston, MassachusettsBoston, Massachusetts

Conflict of Interest DisclosuresConflict of Interest Disclosures

Program ChairmanProgram ChairmanSAMUEL Z. GOLDHABER, MDSAMUEL Z. GOLDHABER, MDResearch SupportResearch Support: : Eisai, EKOS, Johnson & Johnson, sanofi-Eisai, EKOS, Johnson & Johnson, sanofi-aventisaventisConsultant: Consultant: Baxter, Boehringer-Ingelheim, Bristol-Myers Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventisaventis

CHRISTIAN T. RUFF, MD, MPHCHRISTIAN T. RUFF, MD, MPHResearch SupportResearch Support: : Daiichi Sankyo, AstraZeneca, Bristol-Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, sanofi-aventis Meyers Squibb, sanofi-aventis Consultant: Consultant: Alere and Beckman CoulterAlere and Beckman Coulter

ELAINE M. HYLEK, MD, MPHELAINE M. HYLEK, MD, MPHResearch Support: Research Support: Bristol-Myers Squibb, Ortho-McNeilBristol-Myers Squibb, Ortho-McNeilConsultant: Consultant: Bayer, Boehringer-Ingelheim, Bristol-Myers Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, PfizerSquibb, Daiichi Sankyo, Johnson & Johnson, Pfizer

Epidemiology and OverviewEpidemiology and OverviewRisk, Disease Burden, and Deciphering the Risk, Disease Burden, and Deciphering the Maze of Risk-Specific Interventions for AFMaze of Risk-Specific Interventions for AF

Focus on Non-Monitored Oral Anticoagulation and the Focus on Non-Monitored Oral Anticoagulation and the Unmet Need for Safer and More Effective Stroke Unmet Need for Safer and More Effective Stroke

Prevention in NVAFPrevention in NVAF

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDProgram ChairmanProgram Chairman

Director, VTE Research GroupDirector, VTE Research GroupCardiovascular DivisionCardiovascular Division

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

Harvard Medical SchoolHarvard Medical School

New Paradigms in the Science and Medicine New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillationof Stroke Prevention for Atrial Fibrillation

Faculty COI DisclosuresFaculty COI Disclosures

Research SupportResearch Support

Eisai, EKOS, Johnson & Johnson, sanofi-Eisai, EKOS, Johnson & Johnson, sanofi-aventisaventis

ConsultantConsultant

Baxter, Boehringer-Ingelheim, Bristol-Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventisMerck, Pfizer, Portola, sanofi-aventis

Formal Definition: Atrial FibrillationFormal Definition: Atrial Fibrillation

AF is an arrhythmia AF is an arrhythmia characterized by uncoordinated characterized by uncoordinated

atrial activation, with atrial activation, with consequent deterioration of consequent deterioration of atrial mechanical functionatrial mechanical function

Circulation 2011; 121: e269-e367Circulation 2011; 121: e269-e367

Normal sinus

rhythm

Atrial fibrillati

on

The ECG of Atrial FibrillationThe ECG of Atrial Fibrillation

ParoxysmalParoxysmalSelf-TerminatingSelf-Terminating

PersistentPersistentLasts > 7 DaysLasts > 7 Days

PermanentPermanentCardioversion Cardioversion Failed or Not Failed or Not

AttemptedAttempted

Normal Sinus RhythmNormal Sinus Rhythm

Atrial FibrillationAtrial Fibrillation

The The ““3 Ps3 Ps”” and Natural History and Natural History of Atrial Fibrillationof Atrial Fibrillation

Paroxysmal AF is as likely to cause stroke as

persistent or permanent AF

Atrial Fibrillation: EpidemiologyAtrial Fibrillation: Epidemiology

► The No. 1 preventable cause of stroke The No. 1 preventable cause of stroke

► In the United States, up to 16 million In the United States, up to 16 million individuals will be affected by the year individuals will be affected by the year 20502050

► Increasing survival from heart attack and Increasing survival from heart attack and increasing age (increasing age (““the the ‘‘grayinggraying’’ of America of America””) ) help explain rise in incidence of AFhelp explain rise in incidence of AF

Atrial Fibrillation Risk FactorsAtrial Fibrillation Risk Factors

Magnani JW et al. Circulation 2011; 124: 1982-1993

0

2

4

6

8

10

12

14

16

18

20002005

20102015

20202025

20302035

20402045

2050

YearYear

Pro

ject

ed N

um

ber

of

People

wit

h A

F Pro

ject

ed N

um

ber

of

People

wit

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F (m

illio

ns)

(mill

ions)

Miyakasa Y, et al. Circulation. 2006; 114:119-Miyakasa Y, et al. Circulation. 2006; 114:119-125.125.

Atrial Fibrillation: An EpidemicAtrial Fibrillation: An Epidemic

16 million16 millionUS Prevalence

1 in 4 lifetime risk in men and women 1 in 4 lifetime risk in men and women ≥ 40 years ≥ 40 years oldold

Age, years

Pre

vale

nce

, p

erc

ent

Relationship Between Relationship Between Atrial Fibrillation and AgeAtrial Fibrillation and Age

Go AS, et al. JAMA. 2001; 285:2370-2375.Go AS, et al. JAMA. 2001; 285:2370-2375.

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

Atrial Fibrillation Causes Stroke Atrial Fibrillation Causes Stroke Left Atrial Appendage ThrombusLeft Atrial Appendage Thrombus

Stroke and Atrial Fibrillation Burden Stroke and Atrial Fibrillation Burden

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

%%AF prevalence

Strokes attributable to AF

Age Range (years)Age Range (years)

0

10

20

30

50–59 60–69 70–79 80–89

Framingham

Approximately 5-fold increased risk of Approximately 5-fold increased risk of strokestroke

Quantify stroke risk: CHADSQuantify stroke risk: CHADS22/ CHA/ CHA22DSDS22--VAScVASc

AF strokes have worse outcomesAF strokes have worse outcomes

Costly health care ~ $16 billion/yearCostly health care ~ $16 billion/year

Ischemic Strokes in Atrial Fibrillation Ischemic Strokes in Atrial Fibrillation More Likely to be Severely DisablingMore Likely to be Severely Disabling

73

33

58

16

36

16

30

11

Framingham Heart Study

Lin HJ, et al. Stroke. 1996;27:1760-1764.

AF PIE:FUTURE

AF PIE:PAST

Fuster V. Circulation 2012; epubl April 18

ESC 2012 AF Update GuidelinesESC 2012 AF Update Guidelines

Anticoagulation in Atrial Fibrillation Anticoagulation in Atrial Fibrillation Effects on Stroke Risk ReductionEffects on Stroke Risk Reduction

Warfarin better Control better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Aggregate

RRR of stroke: 62%

RRR of stroke: 62%

RRR All-cause mortality:

26%

RRR All-cause mortality:

26%

RRR, relative risk reduction.

Hart RG, et al. Ann Intern Med. 1999;131:492-501.

ESC 2012 Update Guidelines ESC 2012 Update Guidelines HAS-BLEDHAS-BLED for Evaluation of Bleeding Risk for Evaluation of Bleeding Risk

Clinical CharacteristicClinical Characteristic PointsPoints

Hypertension (systolic BP > 160 mm Hg) 1

Abnormal renal or liver function 1 + 1

Stroke 1

Bleeding 1

Labile INRs 1

Elderly (age > 65 years) 1

Drugs or alcohol 1 + 1

Maximum score 9

Pisters R, et al. Chest. 2010;138:1093-1100.

Swedish AF Cohort; Circulation 2011; 125: 2298-2307

Known Problems With WarfarinKnown Problems With Warfarin

1)1) Delayed onset/offsetDelayed onset/offset

2)2) Unpredictable dose responseUnpredictable dose response

3)3) Narrow therapeutic indexNarrow therapeutic index

4)4) Drug-drug, drug-food interactionsDrug-drug, drug-food interactions

5)5) Problematic monitoringProblematic monitoring

6)6) High bleeding rateHigh bleeding rate

7)7) Slow reversibilitySlow reversibility

1)1) Established efficacy Established efficacy

2)2) Low cost ($4/month; $10/3 mos)Low cost ($4/month; $10/3 mos)

3)3) Long track record (1954)Long track record (1954)

4)4) Centralized anticoagulation clinics that Centralized anticoagulation clinics that maintain TTRs > 60%maintain TTRs > 60%

5)5) Rapid, turnaround genetic testingRapid, turnaround genetic testing

6)6) Point-of-care self-testingPoint-of-care self-testing

7)7) INR testing q 12 weeks if stableINR testing q 12 weeks if stable

Warfarin Will Likely Survive: Why?Warfarin Will Likely Survive: Why?

CoumaGen-II. Circ 2012; March 19CoumaGen-II. Circ 2012; March 19ACCP Chest Guidelines 2012ACCP Chest Guidelines 2012

COUMAGEN-IICOUMAGEN-IIPharmacogenetic Dosing Achieves TTR of Pharmacogenetic Dosing Achieves TTR of

71%71%

Circulation 2012; epub March 19

Comparison Overview of New Comparison Overview of New Anticoagulants with WarfarinAnticoagulants with Warfarin

FeaturesFeatures WarfarinWarfarin New AgentsNew Agents

Onset SlowSlow RapidRapid

Dosing VariableVariable FixedFixed

Food effect YesYes NoNo

Drug interactions ManyMany FewFew

Monitoring YesYes NoNo

Half-life LongLong ShortShort

Antidote YesYes NoNo

Sites of Action in Coagulation Sites of Action in Coagulation SystemSystem

Novel Factor Xa and DT InhibitorsNovel Factor Xa and DT Inhibitors

Hankey GJ and Eikelboom JW. Hankey GJ and Eikelboom JW. Circulation Circulation 2011;123:1436-14502011;123:1436-1450

RivaroxabanRivaroxabanApixabanApixabanEdoxabanEdoxabanBetrixabanBetrixaban

XaXa

IIaIIa

TF/VIIaTF/VIIa

XX IXIX

IXaIXaVIIIaVIIIa

VaVa

IIII

FibrinFibrinFibrinogenFibrinogen

Dabigatran Dabigatran

InitiationInitiation

PropagationPropagation

Fibrin formationFibrin formation

Steps in Coagulation Pathway Drugs

Novel Oral AnticoagulantsNovel Oral AnticoagulantsImportant Comparative FeaturesImportant Comparative Features

Circulation 2010;121:1523Circulation 2010;121:1523

Comparison of Phase 3 SPAF Trials Comparison of Phase 3 SPAF Trials for NOACs: A Robust Trial Basefor NOACs: A Robust Trial Base

Rivaroxaban Apixaban Edoxaban

Open Label

Two Doses

Twice Daily

RE-LY

Double Blind

Two Doses

Once Daily

ROCKET-AF

Double Blind

Two Doses

Twice Daily

ARISTOTLE

Double Blind

Two Doses

Once Daily

ENGAGE

Dabigatran

Novel Anticoagulants

FIIa Inhibitor Fxa Inhibitor

Despite continued use of warfarin, Despite continued use of warfarin, NOACs are considered by many NOACs are considered by many professional medical organizations to be professional medical organizations to be the the ““best optionbest option”” for anticoagulation of for anticoagulation of SPAF patients:SPAF patients:

► ESC 2012 AF Update GuidelinesESC 2012 AF Update Guidelines

► ACCP 2012 GuidelinesACCP 2012 Guidelines

► Canadian AF GuidelinesCanadian AF Guidelines

““Best OptionsBest Options”” for Anticoagulation for AnticoagulationThe Consensus is ShiftingThe Consensus is Shifting

ESC 2012UPDATE

GUIDELINESFor

ATRIALFIBRILLATION

Registries provide a Registries provide a ““real lifereal life”” perspective on perspective on patient populations, management patient populations, management ““in the field,in the field,”” and outcomes in settings that do not have the and outcomes in settings that do not have the special resources and monitoring capabilities of special resources and monitoring capabilities of pivotal randomized clinical trials. pivotal randomized clinical trials.

Information from registries complements Information from registries complements clinical trial data.clinical trial data.

Registries can highlight the disconnect between Registries can highlight the disconnect between

evidence/guidelines and clinical practice.evidence/guidelines and clinical practice.

The Rationale for AF RegistriesThe Rationale for AF Registries

The GARFIELD RegistryThe GARFIELD Registry

► Novel approach to outcomes researchNovel approach to outcomes research

► Planned to be conducted in 50 countriesPlanned to be conducted in 50 countries

► 50,000 prospective and 5000 retrospective 50,000 prospective and 5000 retrospective patientspatients

► Patients newly diagnosed with non-valvular Patients newly diagnosed with non-valvular AFAF

► Five sequential cohortsFive sequential cohorts

► Random site selectionRandom site selection

► Sites representative of national AF care Sites representative of national AF care settingssettings

► Consecutive patientsConsecutive patients

► Minimum follow-up period of 2 yearsMinimum follow-up period of 2 years

Summary of Garfield DataSummary of Garfield Data Cohort One: ESC 2012 Cohort One: ESC 2012

► 10,537 were available for this analysis10,537 were available for this analysis• 5075 retrospective and 5462 prospective5075 retrospective and 5462 prospective

► Newly diagnosed patients carry high risk for Newly diagnosed patients carry high risk for stroke stroke ● 57% with CHADS57% with CHADS22 score score >>22● 83% with CHA83% with CHA22DSDS22-VASc score -VASc score >>22

► VKAs not prescribed in:VKAs not prescribed in:● 38% of patients with CHADS38% of patients with CHADS22 score score >>2 2 ● 40% of patients with CHA40% of patients with CHA22DSDS22-VASc score -VASc score >>22

OAC, oral anticoagulant

Nieuwlaat et al. Eur Heart J 2006; Gage et al. JAMA 2001

CHADS2 score

OA

C t

hera

py (

%)

58 5964 61

0

20

40

60

80

100

1 2 3 4

5333 AF patients in 35 countries: 2003–2004

Modest Use of Vitamin K Antagonists Modest Use of Vitamin K Antagonists Even in High-Risk PatientsEven in High-Risk Patients

European Heart Survey

A “Failure to Prophylax” SyndromeA “Failure to Prophylax” Syndrome

Over the past decade, Over the past decade, about 40% of about 40% of patients with atrial fibrillation are patients with atrial fibrillation are unprotectedunprotected from stroke because of from stroke because of failure to prescribe anticoagulation. failure to prescribe anticoagulation.

Because criteria for anticoagulation have Because criteria for anticoagulation have expanded in 2012, expanded in 2012, the problem has the problem has intensified.intensified.

Heightened awareness of the disconnectHeightened awareness of the disconnect between guidelines/evidence and between guidelines/evidence and suboptimal intervention for SPAF. suboptimal intervention for SPAF. Anticoagulation is necessary as a first Anticoagulation is necessary as a first step. step.

The SPAF Landscape 2012: ConclusionsThe SPAF Landscape 2012: Conclusions

► The frequency of atrial fibrillation is The frequency of atrial fibrillation is increasing, so risk of devastating stroke increasing, so risk of devastating stroke is increasing as well.is increasing as well.

► Anticoagulants can effectively reduce Anticoagulants can effectively reduce stroke risk, but they are underutilized.stroke risk, but they are underutilized.

► NOACs have less ICH bleeding risk than NOACs have less ICH bleeding risk than warfarin and are superior—or at least warfarin and are superior—or at least noninferior—for stroke prevention.noninferior—for stroke prevention.

► We must overcome the failure-to-We must overcome the failure-to-prophylax syndrome.prophylax syndrome.

State-of-the-Art Risk State-of-the-Art Risk Stratification of Patients with Stratification of Patients with

Atrial FibrillationAtrial Fibrillation

Anticoagulation Strategies Based on Established Anticoagulation Strategies Based on Established and Evolving Atrial Fibrillation Scoring Systems and Evolving Atrial Fibrillation Scoring Systems

for Thrombosis and Hemorrhagic Riskfor Thrombosis and Hemorrhagic Risk

New Paradigms in the New Paradigms in the Science and Medicine of Heart DiseaseScience and Medicine of Heart Disease

Elaine M. Hylek, MD, MPHElaine M. Hylek, MD, MPHProfessor of MedicineProfessor of Medicine

Department of MedicineDepartment of MedicineBoston University Medical CenterBoston University Medical Center

Boston, MassachusettsBoston, Massachusetts

Independent Predictors of Stroke in AF Independent Predictors of Stroke in AF Systematic ReviewSystematic Review

Significant by Significant by Multivariate Multivariate

AnalysisAnalysis

Adjusted Relative Adjusted Relative Risk Risk

(95% CI)(95% CI)

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

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

History of hypertension or systolic BP > 160 mm Hg

5 of 5 studies5 of 5 studies 2.0 (1.6–2.5)2.0 (1.6–2.5)

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

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

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

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

** Significant in a subgroup of participants undergoing echocardiography in Significant in a subgroup of participants undergoing echocardiography in trials included AFI pooled analysistrials included AFI pooled analysis

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

Nonvalvular Atrial FibrillationNonvalvular Atrial Fibrillation

PriorPriorStroke/TIAStroke/TIA

AgeAge> 75 years> 75 years

HypertensionHypertension FemaleFemale DiabetesDiabetesHeart FailureHeart Failure LVEFLVEF

Str

oke

Rate

Str

oke

Rate

(%/y

ear)

(%/y

ear)

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

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

Risk Stratification in Atrial FibrillationRisk Stratification in Atrial FibrillationEstablished Stroke Risk FactorsEstablished Stroke 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. Chest 2004;126:429S.Fang MC, et al. Circulation 2005; 112: 1687.

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

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

The CHADSThe CHADS22 Score ScoreStroke Risk Threshold Favoring AnticoagulationStroke Risk Threshold Favoring Anticoagulation

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 18.2Van Walraven C, et al. Arch Intern Med 2003; 163:936.Go A, et al. JAMA 2003; 290: 2685.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 Score ScoreStroke 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. Arch Intern Med 2003; 163:936.* Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

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

Goto S, et al. Am Heart J 2008; 156: 855.

CV Event Rates in Patients with Atrial CV Event Rates in Patients with Atrial Fibrillation Related to CHADSFibrillation Related to CHADS22 Score Score

REACH RegistryREACH Registry

The CHAThe CHA22DSDS22-VASc Score-VASc ScoreStroke Risk Score for Atrial FibrillationStroke Risk Score for Atrial Fibrillation

CCongestive heart failure or LVEF ongestive heart failure or LVEF << 35% 35% 1 1

HHypertensionypertension 1 1

AAge > 75 yearsge > 75 years 22

DDiabetes mellitusiabetes mellitus 1 1

SStroke/TIA/systemic embolism troke/TIA/systemic embolism 22

VVascularascular Disease (MI/PAD/Aortic plaque)Disease (MI/PAD/Aortic plaque) 1 1

AAge 65-74 years ge 65-74 years 1 1

SSex ex ccategory (female)ategory (female) 1 1

Moderate-High riskModerate-High risk >> 2 2Low riskLow risk 0-1 0-1

Lip GYH, Halperin JL. Am J Med 2010; 123: 484.

Weight (points)Weight (points)

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 anticoagulation Availability of high-quality anticoagulation management programmanagement program

► Patient preferencesPatient preferences

Published Bleeding Risk ScoresPublished Bleeding Risk ScoresPatients on Oral Vitamin K Antagonist Anticoagulant Patients on Oral Vitamin K Antagonist Anticoagulant

TherapyTherapy

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

LowLow ModeratModeratee

HigHighh

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

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

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

00 1-21-2 ≥ ≥ 33

≥ ≥ 65 years old; GI bleed within 2 weeks; prior 65 years old; GI bleed within 2 weeks; prior stroke; comorbidities (recent MI, Hct < 30%, stroke; comorbidities (recent MI, Hct < 30%, diabetes, Cr > 1.5 mg/dL) ;1 point for each diabetes, Cr > 1.5 mg/dL) ;1 point for each condition; 0 if absentcondition; 0 if absent

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

< < 11 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; 1 point for each (CYP2C9) risk of fall or stroke; 1 point for each factor; 2 points for previous bleedingfactor; 2 points for previous bleeding

Shireman et al.Chest2006;130:1390.

≤ ≤ 1.071.07 1.07 - 2.191.07 - 2.19 > >

2.192.19

(0.49 x age > 70) + (0.32 x female) + (0.58 x (0.49 x age > 70) + (0.32 x female) + (0.58 x remote bleed) + 0.62 x recent bleed) + 0.71 x remote bleed) + 0.62 x recent bleed) + 0.71 x EtOH/drug abuse) + (0.27 x diabetes) + (0.86 x EtOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use); 1 point anemia) + (0.32 x antiplatelet drug use); 1 point for each; 0 if nonefor each; 0 if none

Advances in the Advances in the Science and Medicine of SPAFScience and Medicine of SPAF

Importance of the HAS-BLED ScoreImportance of the HAS-BLED Score

HHypertension (> 160 mm Hg systolic)ypertension (> 160 mm Hg systolic) 1 1 AAbnormal renal or hepatic function 1-bnormal renal or hepatic function 1-22 SStroketroke 11BBleeding history or anemialeeding history or anemia 1 1LLabile INR (TTR < 60%)abile INR (TTR < 60%) 1 1EElderly (age > 75 years)lderly (age > 75 years) 1 1DDrugs (antiplatelet, NSAID) or alcohol 1-2rugs (antiplatelet, NSAID) or alcohol 1-2

High risk High risk (> 4%/year)(> 4%/year) >> 4 4Moderate riskModerate risk (2-4%/year)(2-4%/year) 2-3 2-3Low riskLow risk (< 2%.year)(< 2%.year) 0-1 0-1

Pisters R, et al. Chest 2010; 138: 1093.Lip GYH, et al. J Am Coll Cardiol 2010; 57: 173.

Weight (points)Weight (points)

Risk Score for Predicting Bleeding inRisk Score for Predicting Bleeding inAnticoagulated Patients with Atrial FibrillationAnticoagulated Patients with Atrial Fibrillation

Canadian Cardiovascular SocietyCanadian Cardiovascular SocietyAF Guidelines 2012 UpdateAF Guidelines 2012 Update

Assess Thromboembolic Risk (CHADS2)

CHADSCHADS2 2 = 0= 0 CHADSCHADS2 2 = 1= 1 CHADSCHADS2 2 >> 2 2

No anti-No anti-thromboticthrombotic

ASAASA OAC*OAC* OAC*OAC* OACOAC

No additionalrisk factors of stroke

Either female sex or vascular

disease

Age > 65 y or

combination of female sex and vascular disease

*Aspirin is a reasonable alternative in some as

indicated by risk/benefit

Increasing stroke risk

All patients with atrial fibrillation or atrial flutter All patients with atrial fibrillation or atrial flutter (paroxysmal, persistent, or permanent), should be (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (eg, stratified using a predictive index for stroke (eg, CHADSCHADS22) and for the risk of bleeding (eg, HAS-) and for the risk of bleeding (eg, HAS-BLED), and that most patients should receive BLED), and that most patients should receive either an oral anticoagulant or aspirin. either an oral anticoagulant or aspirin. (Strong (Strong recommendation, high quality evidence)recommendation, high quality evidence)

When oral anticoagulation therapy is indicated, When oral anticoagulation therapy is indicated, most patients should receive dabigatran, most patients should receive dabigatran, rivaroxaban, or apixaban* in preference to rivaroxaban, or apixaban* in preference to warfarin.warfarin.

(Conditional recommendation. high-quality (Conditional recommendation. high-quality evidence). evidence).

**Once approved by Health CanadaOnce approved by Health Canada..

Canadian Cardiovascular SocietyCanadian Cardiovascular SocietyAF Guidelines 2012 UpdateAF Guidelines 2012 Update

2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace. 2012 Aug 24

ESC 2012 AF Update GuidelinesESC 2012 AF Update Guidelines


Thus, this guideline strongly recommends a practice shift toward greater focus on identification of ‘truly low-risk’ patients with AF (ie,‘age <65 and lone FL’ who do not need any antithrombotic therapy), instead of trying to focus on identifying ‘high-risk’ patients.

To achieve this, it is necessary to be more inclusive (rather than exclusive) of common stroke risk factors as part of any comprehensive stroke risk assessment. Indeed, patients with AF who have stroke risk factor(s) > 1 are recommended to receive effective stroke prevention therapy, which is essentially OAC with either well-controlled VKA therapy [INR 2-3, with a high percentage of time in the therapeutic range (TTR), for example, at least 70%] or one of the NOACs

ESC 2012 Guidelines: Identifying ESC 2012 Guidelines: Identifying ““Truly Low-RiskTruly Low-Risk”” Patients with AF Patients with AF

CHACHA22DSDS22-VASc vs. CHADS-VASc vs. CHADS22

Is More Information Better?Is More Information Better?

► The new scoring systems have been adopted The new scoring systems have been adopted in Europe but not in the United States, even in Europe but not in the United States, even in the latest practice guideline updates.in the latest practice guideline updates.

► The components of the CHAThe components of the CHA22DSDS22-VASc score -VASc score are less well validated than those of the are less well validated than those of the CHADSCHADS22 score. score.

► The C-statistic used to validate the CHAThe C-statistic used to validate the CHA22DSDS22--VASc score is only marginally superior to VASc score is only marginally superior to those of other schema.those of other schema.

► There is no consensus about how to combine There is no consensus about how to combine stroke risk and bleeding risk scores into a stroke risk and bleeding risk scores into a composite instrument. composite instrument.

Current AF Stroke Risk Stratification SchemesCurrent AF Stroke Risk Stratification SchemesLimitations, Challenges, and OpportunitiesLimitations, Challenges, and Opportunities

► All have modest predictive value for thromboembolismAll have modest predictive value for thromboembolism Patients classified as low risk must truly be at low risk to Patients classified as low risk must truly be at low risk to

safely avoid anticoagulationsafely avoid anticoagulation Should classify small proportion into the intermediate risk Should classify small proportion into the intermediate risk

category, for which optimum therapy is less clearcategory, for which optimum therapy is less clear

► Incorporate risk factors as cumulativeIncorporate risk factors as cumulative► Should be comprehensive yet easy to applyShould be comprehensive yet easy to apply

Scoring systems are the most popular methodScoring systems are the most popular method Acronym for easy recallAcronym for easy recall

► Should be validated in multiple populations, ideally clinical Should be validated in multiple populations, ideally clinical practice populations, rather than in the control arms of trial practice populations, rather than in the control arms of trial cohortscohorts

Lip GYH, Halperin JL. Am J Med 2010;123:484

Risk schemes must evolve to address thewider therapeutic margin offered by new oral anticoagulants

Atrial Fibrillation and ThromboembolismAtrial Fibrillation and ThromboembolismThe Next ChallengesThe Next Challenges

► Better risk-stratification that balances Better risk-stratification that balances stroke and bleeding and addresses new stroke and bleeding and addresses new anticoagulantsanticoagulants

► Noninvasive methods to better predict Noninvasive methods to better predict events and guide therapyevents and guide therapy

► Safer treatments for the highest risk Safer treatments for the highest risk patientspatients

► Achieving and confirming successful Achieving and confirming successful rhythm control over timerhythm control over time

► Targeted atrial fibrillation preventionTargeted atrial fibrillation prevention

Deciphering the Maze of Evidence Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-from Landmark Trials Evaluating Non-

Monitored, Oral Anticoagulants Monitored, Oral Anticoagulants (NOACs) for SPAF(NOACs) for SPAF

Christian T. Ruff, MD, MPHChristian T. Ruff, MD, MPHTIMI Study GroupTIMI Study Group

Brigham and Women’s HospitalBrigham and Women’s HospitalHarvard Medical SchoolHarvard Medical School

Boston, MABoston, MA



Daiichi Sankyo, AstraZeneca, Bristol-Meyers Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, sanofi-aventis Squibb, sanofi-aventis


Alere and Beckman CoulterAlere and Beckman Coulter


PropertiesProperties BenefitBenefit

Oral, once-daily dosing Ease of administrationEase of administration

Rapid onset of action No need for overlapping No need for overlapping parenteral anticoagulantparenteral anticoagulant

Minimal food or drug interactions Simplified dosingSimplified dosing

Predictable anticoagulant effect No coagulation monitoringNo coagulation monitoring

Extra renal clearance Safe in patients with renal Safe in patients with renal diseasedisease

Rapid offset in actionSimplifies management in Simplifies management in case of bleeding or case of bleeding or interventionintervention

Antidote For emergenciesFor emergencies

Properties of an Ideal Anticoagulant Properties of an Ideal Anticoagulant

Major Advances In Major Advances In Oral Anticoagulation for SPAFOral Anticoagulation for SPAF

6 Trials of Warfarin vs Placebo6 Trials of Warfarin vs Placebo1989-19931989-1993

RE-LYRE-LY((DabigatranDabigatran))

20092009

ROCKET AF ROCKET AF ((RivaroxabanRivaroxaban))

20102010

ARISTOTLEARISTOTLE ((ApixabanApixaban))

20112011

ENGAGE AFENGAGE AF ((EdoxabanEdoxaban))

20132013

Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14Ericksson BI, et al. Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22Clin Pharmacokinet 2009;48:1-22

DabigatranDabigatran ApixabanApixaban RivaroxabanRivaroxaban EdoxabanEdoxaban

Target IIa IIa (thrombin)(thrombin) XaXa XaXa XaXa

Hrs to Cmax 22 1-31-3 2-42-4 1-21-2

CYP metabolism NoneNone 15%15% 32%32% NRNR

Bioavailability 7%7% 66%66% 80%80% > 45%> 45%

Transporters P-gpP-gp P-gpP-gp P-gp/BCRPP-gp/BCRP P-gpP-gp

Protein binding 35%35% 87%87% >90%>90% 55%55%

Half-life 12-14h12-14h 8-15h8-15h 9-13h9-13h 8-10h8-10h

Renal elimination 80%80% 25%25% 33%33% 35%35%

Linear PK YesYes YesYes NoNo YesYes

BCRP = breast cancer resistance protein; CYP = cytochrome P450; NR = not reported; P-gp = P-glycoprotein

Comparative Pharmacokinetics/ Comparative Pharmacokinetics/ Pharmacodynamics of Novel Agents Pharmacodynamics of Novel Agents

The RE-LY Trial: DabigatranThe RE-LY Trial: Dabigatran

RE-LYRE-LY

Atrial fibrillation ≥1 Risk Factor

Absence of contra-indications

951 centers in 44 countries

R

Warfarin (INR 2.0-3.0)

N = 6022

Dabigatran Etexilate

110 mg bidN = 6015

Dabigatran Etexilate

150 mg bidN = 6076

PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events

10 efficacy outcome = stroke or systemic embolism10 safety outcome = major bleeding

Non-inferiority margin 1.46

open Blinded

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs Warfarin

Dabigatran 150 vs Warfarin

Non-inferiority

P-value

< 0.001

< 0.001

Superiority

P-value

0.34

< 0.001

Margin = 1.46

HR (95% CI)

RE-LY Efficacy (Dabigatran)RE-LY Efficacy (Dabigatran)Stroke/Systemic Embolic EventStroke/Systemic Embolic Event

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

0.1 0.3 0.5 1.0 2.0

Dabigatran 110 mg

Dabigatran 150 mg

Stroke/SEE

Ischemic Stroke

Hemorrhagic Stroke

0.91 (0.74-1.11)

0.66 (0.53-0.82)

1.11 (0.89-1.40)

0.76 (0.60-0.98)

0.31 (0.17-0.56)

0.26 (0.14-0.49)

Dabigatran Better Warfarin Better

RE-LY Efficacy (Dabigatran) RE-LY Efficacy (Dabigatran)

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

0.1 0.3 0.5 1.0 2.0

Major Bleed

ICH

GI Bleed

0.80 (0.69-0.93)

0.93 (0.81-1.07)

0.31 (0.20-0.47)

0.40 (0.27-0.60)

1.10 (0.86-1.41)

1.50 (1.19-1.89)

MI1.29 (0.96-

1.75)1.27 (0.94-1.71)

Dabigatran Better Warfarin Better

RE-LY Safety Results (Dabigatran) RE-LY Safety Results (Dabigatran)

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

Dabigatran 110 mg

Dabigatran 150 mg

0-10-1

22

3-63-6

D110D110

1.061.06

1.431.43

2.122.12

D150D150

0.650.65

0.840.84

1.881.88

WARFWARF

1.051.05

1.381.38

2.682.68

CHADSCHADS22

P = P = 0.440.44

0.500.50 1.001.00 1.501.50Dabigatran Dabigatran

betterbetterWarfarin Warfarin

betterbetter

Annualized Rate Stroke/SEE Annualized Rate Stroke/SEE (%)(%)

P = 0.82

0.50 1.00 1.50Dabigatran

betterWarfarin

better

RE-LY Efficacy Stratified by CHADSRE-LY Efficacy Stratified by CHADS22

Oldgren J, et al. ACC 2010Oldgren J, et al. ACC 2010

D110D110mgmg

D110D110mgmg

D15D150mg0mgD15D150mg0mg

RE-LY Efficacy Stratified by RE-LY Efficacy Stratified by Prior Vitamin K AnatagonistPrior Vitamin K Anatagonist

Ezekowitz MD, et al. Circulation 2010;122:2246-2253Ezekowitz MD, et al. Circulation 2010;122:2246-2253

0.8

0.3

0.6

1.7

0.6 0.6

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Dabi 110 mg Dabi 150 mg Warfarin

Stroke/SEE Major Bleeding

(N = 647)

RE-LY Cardioversion (Dabigatran)RE-LY Cardioversion (Dabigatran)

(N = 672) (N = 664)Nagarakanti R, et al. Circulation 2011;123:131-136Nagarakanti R, et al. Circulation 2011;123:131-136

Prevention of stroke in AFPrevention of stroke in AF

Available in 75 mg and 150 mg Available in 75 mg and 150 mg (twice daily)(twice daily)

Dose of 75 mg if CrCl 15-30 Dose of 75 mg if CrCl 15-30 mL/minmL/min

Data in favor of 110 mg were Data in favor of 110 mg were ““suggestive, but not entirely suggestive, but not entirely convincingconvincing””

Dabigatran ApprovalDabigatran Approval

ROCKET AF: RivaroxabanROCKET AF: Rivaroxaban

Rivaroxaban Warfarin

Primary End point: Stroke or non-CNS Systemic Embolism

Statistics: non-inferiority, > 95% power, 2.3% warfarin event rate

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49

Atrial Fibrillation

RandomizeDouble blind / Double Dummy

(n = 14,266)

Risk FactorsRisk Factors• CHF CHF • Hypertension Hypertension • Age Age 75 75 • Diabetes Diabetes OROR• Stroke, TIA or Systemic Stroke, TIA or Systemic

embolus embolus

At least 2 required

Monthly Monitoring and adherence to standard of care guidelines

RivaroxabanRivaroxaban WarfarinWarfarin

Event Event RateRate


HRHR(95% CI)(95% CI) PP-value-value

On On TreatmentTreatment

N = 14,143N = 14,143

1.701.70 2.152.15 0.79 0.79 (0.65, 0.95)(0.65, 0.95) 0.0150.015

ITTITTN = 14,171N = 14,171

2.122.12 2.422.42 0.88 0.88 (0.74, 1.03)(0.74, 1.03) 0.1170.117

RivaroxabanRivaroxabanbetterbetter

WarfarinWarfarinbetterbetter

Event Rates are per 100 patient-yearsEvent Rates are per 100 patient-yearsBased on Safety on Treatment or Intention-to-Treat throughBased on Safety on Treatment or Intention-to-Treat through

Site Notification populationsSite Notification populations

0.5 1 2

Patel, et al. Patel, et al. N Engl J Med N Engl J Med 2011;365(10);883-8912011;365(10);883-891

ROCKET AF EfficacyROCKET AF EfficacyStroke/Systemic Embolic EventStroke/Systemic Embolic Event

ROCKET AF Key Secondary EfficacyROCKET AF Key Secondary Efficacy

EventEvent RivaroxabanRivaroxaban(%/yr)(%/yr)

WarfarinWarfarin(%/yr)(%/yr)

Hazard RatioHazard Ratio(95% CI)(95% CI)

PP--valuevalue

Ischemic StrokeIschemic Stroke 1.341.34 1.421.42 0.94 (0.75-0.94 (0.75-1.17)1.17) 0.5810.581

Hemorrhagic StrokeHemorrhagic Stroke 0.260.26 0.440.44 0.59 (0.37-0.59 (0.37-0.93)0.93) 0.0240.024

MIMI 0.910.91 1.121.12 0.81 (0.63-0.81 (0.63-1.06)1.06) 0.1210.121

Total MortalityTotal Mortality 1.871.87 2.212.21 0.85 (0.70-0.85 (0.70-1.02)1.02) 0.0730.073

Vascular MortalityVascular Mortality 1.531.53 1.711.71 0.89 (0.73-0.89 (0.73-1.10)1.10) 0.2890.289

Patel, et al. Patel, et al. N Engl J Med 2011; N Engl J Med 2011; 365(10);883-891365(10);883-891

ROCKET AF Safety (Rivaroxaban)ROCKET AF Safety (Rivaroxaban)

EventEvent RivaroxabanRivaroxaban(%/yr)(%/yr)



PP--valuevalue

Major and Clinically Major and Clinically Relevant BleedRelevant Bleed

14.9 14.51.03 (0.96-

1.11)0.44

Major BleedMajor Bleed 3.6 3.41.04 (0.90-

1.20)0.58

Fatal BleedFatal Bleed 0.2 0.50.50 (0.31-

0.79)0.003

ICHICH 0.5 0.70.67 (0.47-

0.93)0.02

Patel, et al. Patel, et al. N Engl J Med 2011; N Engl J Med 2011; 365(10);883-891365(10);883-891

ROCKET AF Efficacy (Rivaroxaban)ROCKET AF Efficacy (Rivaroxaban)Moderate Renal ImpairmentModerate Renal Impairment

Fox KA, et al. Eur Heart J 2011;32(19):2387-94.Fox KA, et al. Eur Heart J 2011;32(19):2387-94.

ROCKET AF Safety ROCKET AF Safety Moderate Renal ImpairmentModerate Renal Impairment

Fox KA, et al. Eur Heart J 2011;32(19):2387-94.Fox KA, et al. Eur Heart J 2011;32(19):2387-94.

Prevention of stroke in AFPrevention of stroke in AF

Dose 20 mg if CrCl > 50 mL/minDose 20 mg if CrCl > 50 mL/min

Dose of 15 mg if CrCl 15-50 mL/minDose of 15 mg if CrCl 15-50 mL/min

Rivaroxaban ApprovalRivaroxaban Approval

AVERROESAVERROES

36 countries, 522 centers

Double-blind

Primary Outcome: Stroke or

Systemic Embolic Event (SEE)

AF and >1 risk factor, and AF and >1 risk factor, and demonstrated or unexpecteddemonstrated or unexpected

unsuitable of VKAunsuitable of VKA

Apixaban 5 mg bidApixaban 5 mg bid2 mg bid in selected patients2 mg bid in selected patients

ASA (81-324 mg/d)ASA (81-324 mg/d)

5600 patients5600 patientsR

AVERROES Trial Design: ApixabanAVERROES Trial Design: Apixaban

AVERROES: ApixabanAVERROES: Apixaban

Stroke or Systemic Embolic Event

Major Bleeding

HR 0.45 (0.32-0.62)HR 0.45 (0.32-0.62)HR 0.45 (0.32-0.62)HR 0.45 (0.32-0.62) HR 1.13 (0.74-1.75)HR 1.13 (0.74-1.75)HR 1.13 (0.74-1.75)HR 1.13 (0.74-1.75)

Connolly SJ, et al. N Engl J Med 2011 (epub)Connolly SJ, et al. N Engl J Med 2011 (epub)

AspirinAspirin

ApixabanApixaban

P < 0.001P < 0.001

0 30 3 6 9 12 186 9 12 18

0.050.05

0.040.04

0.030.03

0.020.02

0.010.01

0.000.00

AspirinAspirin

ApixabanApixaban

P < 0.001P < 0.001

0 30 3 6 9 12 186 9 12 18

0.0200.020

0.0150.015

0.0100.010

0.0050.005

0.0000.000

ARISTOTLE: ApixabanARISTOTLE: Apixaban

Warfarin (target INR 2-3)

Apixaban 5 mg oral twice daily(2.5 mg bid in selected patients)

Primary outcome: stroke or systemic embolism

Hierarchical testing: non-inferiority for primary outcome, superiority for Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death primary outcome, major bleeding, death

RandomizeRandomizedouble blind, double blind,

double dummydouble dummy(n = 18,201)(n = 18,201)

Inclusion risk factorsAge ≥ 75 years Prior stroke, TIA, or SEHF or LVEF ≤ 40%Diabetes mellitusHypertension

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device

ExclusionMechanical prosthetic valveSevere renal insufficiencyNeed for aspirin plus thienopyridine

ARISTOTLE Trial Design: ApixabanARISTOTLE Trial Design: Apixaban

ARISTOTLE Efficacy: ApixabanARISTOTLE Efficacy: Apixaban

Granger CB, et al. NEJM 2011; 365:981-992Granger CB, et al. NEJM 2011; 365:981-992

HR 0.79 (0.66–0.95)

P (non-inferiority) < 0.001

21% RRR

(1.27 %/yr )

(1.60 %/yr)

P (superiority) = 0.011

ARISTOTLE Efficacy OutcomesARISTOTLE Efficacy Outcomes


OutcomeOutcome

ApixabanApixaban(N = 9120)(N = 9120)

WarfarinWarfarin(N = (N = 9081)9081)

HR (95% CI)HR (95% CI) PP ValueValueEvent Event

RateRate(%/yr)(%/yr)


(%/yr)(%/yr)Stroke or systemic embolism* 1.271.27 1.601.60 0.79 (0.66, 0.79 (0.66,

0.95)0.95) 0.0110.011

Stroke 1.191.19 1.511.51 0.79 (0.65, 0.79 (0.65, 0.95)0.95) 0.0120.012

Ischemic or uncertain 0.970.97 1.051.05 0.92 (0.74, 0.92 (0.74, 1.13)1.13) 0.420.42

Hemorrhagic 0.240.24 0.470.47 0.51 (0.35, 0.51 (0.35, 0.75)0.75)

< < 0.0010.001

Systemic embolism (SE) 0.090.09 0.100.10 0.87 (0.44, 0.87 (0.44, 1.75)1.75) 0.700.70

All-cause death* 3.523.52 3.943.94 0.89 (0.80, 0.89 (0.80, 0.998)0.998) 0.0470.047

Stroke, SE, or all-cause death 4.494.49 5.045.04 0.89 (0.81, 0.89 (0.81,

0.98)0.98) 0.0190.019

Myocardial infarction 0.530.53 0.610.61 0.88 (0.66, 0.88 (0.66, 1.17)1.17) 0.370.37

ARISTOTLE Safety End PointsARISTOTLE Safety End Points

EventEvent ApixabanApixaban(%/yr)(%/yr)



PP--valuevalue

ISTH Major BleedingISTH Major Bleeding 2.132.13 3.093.09 0.69 (0.60-0.80)0.69 (0.60-0.80) < < 0.0010.001

ICHICH 0.330.33 0.800.80 0.42 (0.30-0.58)0.42 (0.30-0.58) < < 0.0010.001

GUSTO SevereGUSTO Severe 0.520.52 1.131.13 0.46 (0.35-0.60)0.46 (0.35-0.60) < < 0.0010.001

GastrointestinalGastrointestinal 0.760.76 0.860.86 0.89 (0.70-1.15)0.89 (0.70-1.15) 0.370.37


ARISTOTLE: ApixabanARISTOTLE: ApixabanRenal FunctionRenal Function

Hohnloser SH, et al. EHJ 2012 (epub August 29)Hohnloser SH, et al. EHJ 2012 (epub August 29)

Baseline Cockcroft-Gault eGFR mL/minBaseline Cockcroft-Gault eGFR mL/minBaseline Cockcroft-Gault eGFR mL/minBaseline Cockcroft-Gault eGFR mL/min

An

nu

aliz

ed

Even

t R

ate

An

nu

aliz

ed

Even

t R

ate

An

nu

aliz

ed

Even

t R

ate

An

nu

aliz

ed

Even

t R

ate

Stroke or SEE Major Bleeding

Low dose regimenEdoxaban 30 mg qd

(n ≈ 7000)

Active ControlWarfarin(n ≈ 7000)

High dose regimenEdoxaban 60 mg qd

(n ≈ 7000)

AF on Electrical Recording < 12 moIntended oral A/C

CHADS2 >2

N = 21,105

R

Randomization Stratified By 1. CHADS2 2-3 vs 4-62. Drug Clearance

Median Duration of Follow-up 24 Months

Primary ObjectiveEdoxaban: Therapeutically as Good as Warfarin

DOUBLE BLINDDOUBLE DUMMY

SEE = systemic embolic event

1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38)2º EP = Stroke or SEE or CV mortalitySafety EP’s = Major Bleeding, Hepatic Function

EVENT DRIVEN

Ruff CR et al. Am Heart J 2010; 160:635-41

Phase III: Protocol Schema

89

RE-LYRE-LY(Dabigatran)(Dabigatran)

ARISTOTLEARISTOTLE(Apixaban)(Apixaban)

ENGAGE AF-TIMI 48*ENGAGE AF-TIMI 48*(Edoxaban)(Edoxaban)

ROCKET-AFROCKET-AF(Rivaroxaban)(Rivaroxaban)

# Enrolled 18,11318,113 18,20118,201 21,10521,105 14,26414,264

Age (yrs) 72 ± 972 ± 9 70 [63-76]70 [63-76] 72 [64-77]72 [64-77] 73 [65-78]73 [65-78]

Female 36%36% 35%35% 38%38% 40%40%

CHADS2 score ≥3 32%32% 30%30% 52%52% 87%87%

VKA naive 50%50% 43%43% 41%41% 38%38%

Paroxysmal AF 33%33% 15%15% 25%25% 18%18%

Prior stroke/TIA 20%20% 19%19% 18% / 12%18% / 12% 55%**55%**

Diabetes 23%23% 25%25% 36%36% 40%40%

Prior CHF 32%32% 35%35% 56%56% 62%62%

Hypertension 79%79% 87%87% 90%90% 91%91%

*Preliminary data*Preliminary data**includes prior systemic embolism**includes prior systemic embolism

Connolly SJ et al. N Engl J Med 2009; 361:1139-51Connolly SJ et al. N Engl J Med 2009; 361:1139-51Patel MR et al. N Engl J Med 2011; 365:883-91Patel MR et al. N Engl J Med 2011; 365:883-91

Granger CB et al. N Engl J Med 2011; 365:981-92Granger CB et al. N Engl J Med 2011; 365:981-92Ruff CR et al. Am Heart J 2010;Ruff CR et al. Am Heart J 2010; 160:635-41 160:635-41

Pivotal Atrial Fibrillation Trials Pivotal Atrial Fibrillation Trials Baseline CharacteristicsBaseline Characteristics

90

Pivotal Atrial Fibrillation Trials Pivotal Atrial Fibrillation Trials Dose ComparisonDose Comparison

RE-LYRE-LY ROCKET-AFROCKET-AF ARISTOTLEARISTOTLEENGAGE ENGAGE AF-TIMI 48AF-TIMI 48

Drug DabigatranDabigatran RivaroxabanRivaroxaban ApixabanApixaban EdoxabanEdoxaban

N 18,11318,113 14,26614,266 18,20118,201 21,10521,105

Dose (mg)Frequency

150, 110150, 110bidbid

20 20 qdqd

55bidbid

60, 3060, 30qdqd

Initial Dose adj* NoNo 20 20 →→ 15 mg 15 mg 55 → → 2.5 mg2.5 mg60 60 → → 30 mg30 mg

3030 → → 15 mg15 mg

Dose adj (%) 00 2121 4.74.7 > 25> 25

Dose adj* after randomization NoNo NoNo NoNo YesYes

Design PROBEPROBE 2 x blind2 x blind 2 x blind2 x blind 2 x blind2 x blind

*Dose adjusted in patients with ↓drug clearance. *Dose adjusted in patients with ↓drug clearance. PROBE = prospective, randomized, PROBE = prospective, randomized,

open-label, blinded end point evaluation open-label, blinded end point evaluation

Connolly SJ et al. N Engl J Med 2009; 361:1139-51Connolly SJ et al. N Engl J Med 2009; 361:1139-51Patel MR et al. N Engl J Med 2011; 365:883-91Patel MR et al. N Engl J Med 2011; 365:883-91

Granger CB et al. N Engl J Med 2011; 365:981-92Granger CB et al. N Engl J Med 2011; 365:981-92Ruff CR et al. Am Heart J 2010;Ruff CR et al. Am Heart J 2010; 160:635-41 160:635-41

DrugDrugDose (mg)Dose (mg)

RE-LYRE-LY ROCKET-AFROCKET-AF ARISTOTLEARISTOTLE

DabigatranDabigatran110 bid 150 BID110 bid 150 BID

RivaroxabanRivaroxaban20 mg qd20 mg qd

ApixabanApixaban5 mg bid5 mg bid

Stroke + SEE non-infernon-infer Superior Superior ITT cohort: non-infer.ITT cohort: non-infer.On Rx cohort: SuperiorOn Rx cohort: Superior SuperiorSuperior

ICH SuperiorSuperior SuperiorSuperior SuperiorSuperior SuperiorSuperior

Bleeding LowerLower similarsimilar similarsimilar LowerLower

Mortality similarsimilar PP = 0.051 = 0.051 similarsimilar Superior: Superior: PP = 0.047 = 0.047

Ischemic stroke similarsimilar LowerLower similarsimilar similarsimilar

Mean TTR 64%64% 55%55% 62%62%

Stopped drug 21%21% 23%23% 23%23%

WD consent 2.3%2.3% 8.7%8.7% 1.1%1.1%

TTR = time in therapeutic rangeTTR = time in therapeutic rangeWD consent = withdrawal of consent, no further data availableWD consent = withdrawal of consent, no further data available

TTR = time in therapeutic rangeTTR = time in therapeutic rangeWD consent = withdrawal of consent, no further data availableWD consent = withdrawal of consent, no further data available

Pivotal Atrial Fibrillation Trials Pivotal Atrial Fibrillation Trials Results to DateResults to Date

92

Efficacy of New Oral AnticoagulantsEfficacy of New Oral Anticoagulants

Stroke & SEE

Ischemic & Unsp.

Stroke

Hemorraghic Stroke

Miller CS, et al. Am J Cardiol 2012;110(3):453-460.Miller CS, et al. Am J Cardiol 2012;110(3):453-460.

Favors NOACs Favors Warfarin

13%

55%

Safety of New Oral AnticoagulantsSafety of New Oral Anticoagulants

Major

ICH

GI

BleedingBleeding

Miller CS, et al. Am J Cardiol 2012;110(3):453-460.Miller CS, et al. Am J Cardiol 2012;110(3):453-460.

51%

Favors NOACs Favors Warfarin

Does INR Matter?Does INR Matter?

RE-LY (Dabigatran 150 mg)RE-LY (Dabigatran 150 mg) 0.20< 57.1% 1.1 1.9257.1–65.5% 1.04 2.0665.5–72.6% 1.04 1.51> 72.6% 1.27 1.34

Treatment GroupTreatment GroupEvent Rate / YearEvent Rate / Year

WarfarinWarfarinEvent Rate / YearEvent Rate / Year

PP-value-value(interaction)(interaction)

ROCKET AFROCKET AF 0.740.00-50.62% 1.77 2.53 50.71-58.54% 1.94 2.18 58.63-65.71% 1.90 2.14 65.74-100.0% 1.33 1.80

ARISTOTLEARISTOTLE 0.29< 58.0% 1.75 2.28 58.0–65.7% 1.30 1.61

65.7–72.2 % 1.21 1.55 > 72.2 % 0.83 1.02

0.2 21 5

Hazard Ratio (95% CI)Study Drug WarfarinFavors

www.fda.govwww.fda.govWallentin L, et al. Lancet 2010;376:975-983Wallentin L, et al. Lancet 2010;376:975-983Patel, et al. Patel, et al. NEJM NEJM 2011;365(10);883-8912011;365(10);883-891Granger CB, et al. NEJM 2011; 365:981-992Granger CB, et al. NEJM 2011; 365:981-992

Warfarin Treatment InterruptionWarfarin Treatment Interruption

Raunsø J, et al. Eur Heart J 2012; 33:1886-1892Raunsø J, et al. Eur Heart J 2012; 33:1886-1892

All-

Cau

se D

eath

&

Th

rom

boem

bolis

m

Novel Oral AnticoagulantNovel Oral AnticoagulantssMore Events More Events ““Off-DrugOff-Drug””

%/yr

P = 0.015 P = 0.117

25%

13%

Rivaroxaban

Warfarin

48.8

81.3

P = 0.008

Patel MR, et al. NEJM 2011; 365:883-891Patel MR, et al. NEJM 2011; 365:883-891Piccini JP, AHA Emerging Science Series, April 25, 2012 webinar. Abstract 114Piccini JP, AHA Emerging Science Series, April 25, 2012 webinar. Abstract 114

Safety/Days 3 to 30 after the last dose

ROCKET AFROCKET AFRivaroxaban Increased Events at End of TrialRivaroxaban Increased Events at End of Trial

Rivaroxaban Warfarin

Granger CB, et al. European Heart Journal 2012; 23 (Supplement):685-686Granger CB, et al. European Heart Journal 2012; 23 (Supplement):685-686

Days afterDays afterlast doselast dose

Apixaban to VKA groupApixaban to VKA group Warfarin to VKA groupWarfarin to VKA group

n/Nn/N %/year%/year n/Nn/N %/year%/year

Stroke or systemic embolismStroke or systemic embolism

1–30 21/679121/6791 4.024.02 5/65695/6569 0.990.99

1–2 1/67911/6791 2.692.69 1/65691/6569 2.782.78

3–7 4/67874/6787 4.314.31 0/65660/6566 00

8–14 5/67805/6780 3.853.85 1/65591/6559 0.800.80

15–30 11/677111/6771 4.184.18 3/65483/6548 1.181.18

Pattern mirrored the first 30 days of the trial where warfarin-naïve patients Pattern mirrored the first 30 days of the trial where warfarin-naïve patients starting warfarin had a higher rate of stroke or systemic embolism starting warfarin had a higher rate of stroke or systemic embolism

(5.41%/year) than (5.41%/year) than warfarin-experienced patients (1.41%/year).warfarin-experienced patients (1.41%/year).

ARISTOTLEARISTOTLEApixaban Increased Events at End of TrialApixaban Increased Events at End of Trial

““After the Deluge” of SPAF TrialsAfter the Deluge” of SPAF Trials

Translating Trials into Practice and Translating Trials into Practice and Guidelines: 2012 UpdateGuidelines: 2012 Update

Post-Trial, Real World Concerns, Post-Trial, Real World Concerns, Guidelines, and Actions—Where Have Guidelines, and Actions—Where Have

Landmark SPAF Trials Taken Us? Landmark SPAF Trials Taken Us? How Have Recent Guidelines Made How Have Recent Guidelines Made

Sense of These Data?Sense of These Data?

NOACs Elevated to "Favored" Status by ESC NOACs Elevated to "Favored" Status by ESC 2012 Update Guidelines for 2012 Update Guidelines for

Management of AFManagement of AF

The net clinical benefit of VKAs, balancing ischaemic stroke against ICH in patients with non-valvular AF, has been modeled on to stroke and bleeding rates from the Danish nationwide cohort study for dabigatran, rivaroxaban, and apixaban, on the basis of recent clinical trial outcome data for these NOACs. At a CHA2DS2-VASc score of 1, apixaban and both doses of dabigatran (110 mg bid and 150 mg bid) had a positive net clinical benefit while, in patients with CHA2DS2-VASc score ≥ 2, all three NOACs were superior to warfarin, with a positive net clinical benefit, irrespective of bleeding risk.


LINE SOLID = BEST OPTION

DASHED = ALTERNATIVE OPTION

NOAC VKA

Assess bleeding risk(HAS-BLED score)Consider patient

valuesand preferences


Bleeding Risk with DabigatranBleeding Risk with DabigatranFact vs FictionFact vs Fiction

Bleeding Risk with DabigatranBleeding Risk with DabigatranFact vs Fiction: What Do Regulators Fact vs Fiction: What Do Regulators

Conclude?Conclude?

EMA Report on Dabigatran: May 24, 2012EMA Report on Dabigatran: May 24, 2012 "What are the conclusions of the CHMP?"What are the conclusions of the CHMP? The CHMP concluded that the latest available data The CHMP concluded that the latest available data are consistent with the known risk of bleeding and are consistent with the known risk of bleeding and thatthat the risk profile of dabigatran was unchanged. the risk profile of dabigatran was unchanged. The Committee found that frequency of reported The Committee found that frequency of reported fatal bleedings with dabigatran was significantly fatal bleedings with dabigatran was significantly lower than what had been observed in clinical trialslower than what had been observed in clinical trials at the time of authorisation, but considered that the at the time of authorisation, but considered that the risks should nonetheless continue to be kept under risks should nonetheless continue to be kept under close review."close review."

Disconnect Between Clinical Trials and Post-MarketingSurveillance Bias: A Case Study

EMA Report on Dabigatran EMA Report on Dabigatran May 24, 2012May 24, 2012

Prescribers are reminded of the need to follow all the necessary precautions with regard to the risk of bleeding with dabigatran, including the assessment of kidney function before treatment in all patients and during treatment if a deterioration is suspected, as well as dose reductions in certain patients. Dabigatran must not be used in patients with a lesion or condition putting them at significant risk of major bleeding (see the revised product information for details).

Dabigatran must not be used in patients using any other anticoagulant, unless the patient is being switched to or from dabigatran (see the revised product information for details).

A European Commission decision on this opinion will be issued in due course.

What is the updated advice for prescribers?

Circulation, Healey et al., 2012Circulation, Healey et al., 2012

Dabigatran vs. Warfarin: Surgical Dabigatran vs. Warfarin: Surgical BleedingBleeding

Risk ProfileRisk Profile Class / LevelClass / Level

CHA2DS2-VASc = 0 No antithrombotic therapyI B

CHA2DS2-VASc = 1VKA (INR 2-3)

OrDabigatran / Rivaroxaban / Apixaban

IIa A (Favored)

CHA2DS2-VASc ≥ 2VKA (INR 2-3)

OrDabigatran / Rivaroxaban / Apixaban

I A (Favored)

ESC 2012 Atrial Fibrillation ESC 2012 Atrial Fibrillation Guidelines Update: Risk AssessmentGuidelines Update: Risk Assessment

► New therapies provide the promise of providing New therapies provide the promise of providing safer, more effective, and more convenient safer, more effective, and more convenient anticoagulation. Trials are consistent in reduction anticoagulation. Trials are consistent in reduction of intracranial hemorrhage and bleeding of intracranial hemorrhage and bleeding mortalitymortality..

► SPAF trials are consistent in demonstrating thatSPAF trials are consistent in demonstrating that NOACs are at least as good as, and in some cases, NOACs are at least as good as, and in some cases, superior to warfarinsuperior to warfarin in preventing stroke in in preventing stroke in patients with AF.patients with AF.

► There are important differences in the PK/PD of There are important differences in the PK/PD of these agents (half-life, metabolism, renal these agents (half-life, metabolism, renal elimination) that will alter the risk/benefit profile elimination) that will alter the risk/benefit profile in specific populations; in specific populations; in particular, careful in particular, careful monitoring of renal function is a precondition for monitoring of renal function is a precondition for optimizing safety and efficacy of these agents.optimizing safety and efficacy of these agents.

Conclusions: From Trials and Conclusions: From Trials and Evidence to Strategy and PracticeEvidence to Strategy and Practice

► No reversal agent is currently available but whether the lack of such agents lead to increased bleeding or mortality risk has not been substantiated.

► New ESC 2012 Update Guidelines for AF have refined and incorporated a new suite of risk prediction strategies (CHA2DS2-VASc, HAS-BLED) that will result in a greater proportion of patients being eligible for oral anticoagulation.

► New ESC 2012 Update Guidelines for AF have elevated NOACs to "favored" status over VKA for patients who meet risk stratification criteria for requiring oral anticoagulation for AF.

ConclusionsConclusions

Stroke Prevention in Stroke Prevention in Atrial FibrillationAtrial Fibrillation

Megatrends, Challenges, and Megatrends, Challenges, and Clinical DilemmasClinical Dilemmas

Samuel Z. Goldhaber, MD, Program ChairmanSamuel Z. Goldhaber, MD, Program ChairmanDirector, VTE Research GroupDirector, VTE Research Group

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

Professor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School




Eisai, EKOS, Johnson & Johnson, sanofi-Eisai, EKOS, Johnson & Johnson, sanofi-aventisaventis


Baxter, Boehringer-Ingelheim, Bristol-Myers Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventisPortola, sanofi-aventis

Risk Assessment MegatrendRisk Assessment Megatrend

► CHACHA22DSDS22-VASc has replaced CHADS-VASc has replaced CHADS22 as as the predominant assessment tool to the predominant assessment tool to predict stroke risk (ESC 2012 AF predict stroke risk (ESC 2012 AF Guidelines Update).Guidelines Update).

► HAS-BLED has gained dominanceHAS-BLED has gained dominance as the as the most predictive bleeding index. It is best most predictive bleeding index. It is best used as a cautionary used as a cautionary ““yellow flagyellow flag”” rather rather than as a reason to withhold than as a reason to withhold anticoagulation (ESC 2012).anticoagulation (ESC 2012).

Clinical Dilemma and Challenge—Clinical Dilemma and Challenge—Stroke Risk UnderestimatedStroke Risk Underestimated

► Paroxysmal AF is difficult to detect. Paroxysmal AF is difficult to detect.

► 24h Holter is often insufficient. Long-term 24h Holter is often insufficient. Long-term noninvasive or invasive monitoring may be noninvasive or invasive monitoring may be necessary.necessary.

► Many strokes are misclassified as Many strokes are misclassified as ““cryptogeniccryptogenic”” and are treated with aspirin or and are treated with aspirin or other antiplatelet agents, with questionable other antiplatelet agents, with questionable efficacy for AF. efficacy for AF.

► The misclassified strokes are really The misclassified strokes are really thromboembolic and warrant thromboembolic and warrant anticoagulants. anticoagulants.

Subclinical AF and Risk of StrokeSubclinical AF and Risk of Stroke

Healey JS, et al. NEJM 2012; 366:120-129Healey JS, et al. NEJM 2012; 366:120-129

Str

ok

e o

r S

yste

mic

Em

bo

lism

Years

Atrial tachyarrhythmia > 6 min ≤ 3 months after pacemaker or defibrillator implantation

ESC Guidelines: Eur Heart J . 2010;31:2369-2429.ESC Guidelines: Eur Heart J . 2010;31:2369-2429.

Redefining Risk vs Benefit for OACRedefining Risk vs Benefit for OACHAS-BLEDHAS-BLED

Lip GYH. Am J Med. 2011;124:111-114.Lip GYH. Am J Med. 2011;124:111-114.

LetterLetter Clinical Clinical CharacteristicCharacteristic PointsPoints

HH HypertensionHypertension 11

AAAbnormal Liver Abnormal Liver

or Renal or Renal FunctionFunction

1 or 21 or 2

SS StrokeStroke 11

BB BleedingBleeding 11

LL Labile INRLabile INR 11

EEElderly Elderly

(age > 65)(age > 65) 11

DDDrugs or Drugs or AlcoholAlcohol 1 or 21 or 2

Maximum Score 99

HAS-BLED HAS-BLED ScoreScore

StrokeStroke

(% / yr)(% / yr)0 1.1 %1.1 %

1 1.0 %1.0 %

2 1.9 %1.9 %

3 3.7 %3.7 %

4 8.7 %8.7 %

>5 ?? %?? %

Clinical Dilemma: Bleeding Risk Clinical Dilemma: Bleeding Risk Correlates With Stroke RiskCorrelates With Stroke Risk

► The higher the bleeding risk, as assessed The higher the bleeding risk, as assessed by the HAS-BLED Index, the higher the by the HAS-BLED Index, the higher the stroke risk—A “Catch 22” when considering stroke risk—A “Catch 22” when considering and/or deploying oral anticoagulation. and/or deploying oral anticoagulation.

► Based on observational and trial evidence, Based on observational and trial evidence, we must be especially vigilant to prescribe we must be especially vigilant to prescribe anticoagulation to AF patients at high risk anticoagulation to AF patients at high risk of bleeding, when the thrombosis risk of bleeding, when the thrombosis risk assessment justifies this course of action. assessment justifies this course of action.

Action Plan When OAC is Indicated Action Plan When OAC is Indicated and Patient Has High HAS-BLED and Patient Has High HAS-BLED

Index Index ► Modify bleeding risk factors.Modify bleeding risk factors.

► Intensify surveillance for bleeding and for Intensify surveillance for bleeding and for triggers that cause bleeding.triggers that cause bleeding.

► Consider Consider ““renal doserenal dose”” for NOAC, especially for NOAC, especially in the presence of some renal dysfunction in the presence of some renal dysfunction or frailty or age or frailty or age ≥ 80 years.≥ 80 years.

► Monitor renal function with vigilance.Monitor renal function with vigilance.

► Prescribe PPI when indicated. Prescribe PPI when indicated.

Stroke and Bleeding in Atrial Fibrillation Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Diseasewith Chronic Kidney Disease

Olesen JB. NEJM 2012; 367: 625-635

Danish Registry

13,879 were excluded

228 (6.4%) underwent renal-replacement

therapy during follow-up

127,884 (96.6%) did not have renal

disease

3587 (2.7%) received a diagnosis of non-end-stage chronic kidney

disease

901 (0.7%) underwent renal-

replacement therapy

4538 (3.5%) received a diagnosis of non-end-stage chronic kidney

disease

146,251 patients were discharged with nonvalvular atrial fibrillation (1997-

2008)

Stroke Risk and Renal DiseaseStroke Risk and Renal Disease

Olesen JB. NEJM 2012; 367:625-635

Aspirin does not prevent stroke

CharacteristicCharacteristic

Total Population Total Population (n = 132,372)(n = 132,372)

No Renal Disease No Renal Disease (n = 127,884)(n = 127,884)

Hazard Hazard Ratio (95% Ratio (95%

CI)CI)PP Value Value Hazard Ratio Hazard Ratio

(95% CI)(95% CI) PP Value Value

All participants 1.00

Antithrombotic Therapy

None 1.00 1.00

Warfarin0.59 (0.57-

0.62)< 0.001 1.10 (1.06-1.14) < 0.001

Aspirin1.11 (1.07-

1.15)< 0.001 1.10(1.06-1.14) < 0.001

Warfarin and aspirin

0.70(0.65-0.75)

< 0.001 0.69(0.64-0.74) < 0.001

Bleeding Risk and Renal DiseaseBleeding Risk and Renal Disease

Olesen JB. NEJM 2012; 367:625-635

Aspirin and warfarin/aspirin increase bleeding

CharacteristicCharacteristic

Total Population Total Population (n = 132,372)(n = 132,372)

No Renal Disease No Renal Disease (n = 127,884)(n = 127,884)

Hazard Hazard Ratio (95% Ratio (95%

CI)CI)PP Value Value Hazard Ratio Hazard Ratio

(95% CI)(95% CI) PP Value Value

All participants 1.00

Antithrombotic Therapy

None 1.00 1.00

Warfarin1.28(1.23-

1.33)< 0.001 1.28(1.23-1.33) < 0.001

Aspirin1.21(1.16-

1.26)< 0.001 1.21(1.16-1.26) < 0.001

Warfarin and aspirin

2.15(2.04-2.26)

< 0.001 2.18(2.07-2.30) < 0.001

Role of aspirin in the setting of Role of aspirin in the setting of SPAF is called into question.SPAF is called into question.

Aspirin is often prescribed for Aspirin is often prescribed for ““CAD prevention,CAD prevention,”” without a clear evidence-based rationale, thus without a clear evidence-based rationale, thus

increasing bleeding risk when combined with OACs increasing bleeding risk when combined with OACs used for SPAF. Evaluate necessity for ASA.used for SPAF. Evaluate necessity for ASA.

Megatrend: Megatrend: Recognizing Overuse of Aspirin Recognizing Overuse of Aspirin

Dosing Options for Renal DysfunctionDosing Options for Renal Dysfunction

► Dabigatran 75 mg bid (USA)Dabigatran 75 mg bid (USA) 50%50%

► Dabigatran 110 mg bid (non-USA)Dabigatran 110 mg bid (non-USA)

► Rivaroxaban 15 mg dailyRivaroxaban 15 mg daily 25%25%

► Apixaban 2.5 mg bidApixaban 2.5 mg bid 50%50%

ESC 2012

Consider also for age ≥80, weight ≤ 60 KG (frailty)

Dilemmas in “Under-Dilemmas in “Under-Anticoagulation”Anticoagulation”

► Anticoagulants clearly prevent stroke in Anticoagulants clearly prevent stroke in AF patients but are AF patients but are markedly underutilizedmarkedly underutilized

► Failure to prophylax in the setting of non-Failure to prophylax in the setting of non-valvular AF is characterized by fear of:valvular AF is characterized by fear of:

● BleedingBleeding● Older ageOlder age● Renal dysfunctionRenal dysfunction● Lack of medication adherenceLack of medication adherence

Dilemmas: NOACs vs WarfarinDilemmas: NOACs vs Warfarin

► By most metrics, NOACs are the By most metrics, NOACs are the ““best best optionoption”” for SPAF (ESC 2012 Update for AF) for SPAF (ESC 2012 Update for AF)

► Failure to prescribe NOACs is characterized Failure to prescribe NOACs is characterized by: by: ● Lack of familiarityLack of familiarity● Lack of reversal agentLack of reversal agent● Inability to measure NOAC levelInability to measure NOAC level● Inertia, fear of change, Inertia, fear of change, ““preapprovalspreapprovals””

NOACs vs Warfarin— NOACs vs Warfarin— A View From 30,000 FeetA View From 30,000 Feet

► NOACs generally more effective than NOACs generally more effective than warfarin for stroke preventionwarfarin for stroke prevention

► NOACs are generally safer (less bleeding, NOACs are generally safer (less bleeding, with some exceptions, with some exceptions, but NOACs but NOACs uniformly cause less intracranial uniformly cause less intracranial hemorrhage, most devastating and hemorrhage, most devastating and mortality-inducing bleeding complication mortality-inducing bleeding complication of OACof OAC))

► NOACs, overall, reduce mortality NOACs, overall, reduce mortality

► NOACs are more convenient for NOACs are more convenient for patient/clinicianpatient/clinician

New Anticoagulant Therapies New Anticoagulant Therapies Compared to Warfarin: Compared to Warfarin: All-cause All-cause

Mortality Mortality

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

Limitations of Novel Agents are Limitations of Novel Agents are ExaggeratedExaggerated

No antidote when bleeding

• Best treatment is prevention

• Warfarin has no great antidote

• Time is a great antidote

No antidote for urgent procedures

• RELY analysis 2012 shows no increase in bleeding in this setting

Lack standard measurement• Do not need one• Time since last dose is

helpful

Dependence on renal function• Rivaroxaban, apixaban

modest renal effect

Cost• Highly cost effective in

analyses

Deciphering the Pharmaco-economic Maze Deciphering the Pharmaco-economic Maze ““Cost-effectivenessCost-effectiveness””

Cost: Cost: Must take into account the costs Must take into account the costs of caring long-term for debilitated of caring long-term for debilitated thromboembolic stroke patients and the thromboembolic stroke patients and the costs of caring for intracranial costs of caring for intracranial hemorrhage when doing a hemorrhage when doing a ““cost-cost-effectivenesseffectiveness”” analysis of NOACs vs analysis of NOACs vs warfarin. warfarin.

However, we continue to have mostly However, we continue to have mostly ““silo budgeting.silo budgeting.””

► Dabigatran retail:Dabigatran retail: $240/month $240/month

► Warfarin discount retail:Warfarin discount retail: $4/month $4/month

► Will the high price of dabigatran cause poor Will the high price of dabigatran cause poor medication adherence?medication adherence?

““The cost of medical care looms as the single The cost of medical care looms as the single largest threat to the US economy.largest threat to the US economy.””

Avorn J. Circulation 2011: 123: 2519-2521Avorn J. Circulation 2011: 123: 2519-2521

Cost of Dabigatran vs WarfarinCost of Dabigatran vs Warfarin

Prevent > 50% AF Cases by Modifying Prevent > 50% AF Cases by Modifying Cardiovascular Risk FactorsCardiovascular Risk Factors

► N = 14,598 middle-aged subjectsN = 14,598 middle-aged subjects

► Over 17 years, 1520 incident cases of Over 17 years, 1520 incident cases of AF in the Atherosclerosis Risk in AF in the Atherosclerosis Risk in Communities (ARIC) StudyCommunities (ARIC) Study

► 56% of cases explained by elevated CV 56% of cases explained by elevated CV risk factors, especially hypertension, risk factors, especially hypertension, obesity, diabetes, and smokingobesity, diabetes, and smoking

Circulation 2011; 123: 1501-1508

Guidelines for Guidelines for ““BridgingBridging””with with Dabigatran (RE-LY)Dabigatran (RE-LY)

Healey JS. Circulation 2012; 126: 343-348

Renal Function Renal Function Impairment Impairment

(CrCL mL/min)(CrCL mL/min)

Estimated Estimated Half-life, h Half-life, h (Range)(Range)

Stopping Dabigatran Before Stopping Dabigatran Before Surgery/ProcedureSurgery/Procedure

High Risk for High Risk for BleedingBleeding

Standard Risk Standard Risk for Bleedingfor Bleeding

Mild: > 50 to 80

15 (12-18) 2-3d*24 h (2 doses)

Moderate: > 30 to < 50

18 (18-24) 4 dAt least 2 d

(48 h)

Severe: < 30 27 (> 24) > 5d 2-4 d

Interrupting Dabigatran and Interrupting Dabigatran and WarfarinWarfarin

RE-LYRE-LY► 1 of 4 patients underwent peri-1 of 4 patients underwent peri-

procedural anticoagulant interruptionprocedural anticoagulant interruption

► Stroke rate: 0.5%; major bleeding rate: Stroke rate: 0.5%; major bleeding rate: 4%, 7 days pre- to 30 days post 4%, 7 days pre- to 30 days post

► Dabigatran was withheld an average of Dabigatran was withheld an average of 2 days, whereas warfarin was withheld 2 days, whereas warfarin was withheld an average of 5 days preopan average of 5 days preop

Healey JS. Circulation 2012; 126: 343-348

Medication Adherence FailureMedication Adherence Failure

► Failing to fill or refill a prescriptionFailing to fill or refill a prescription

► Omitting dosesOmitting doses

► OverdosingOverdosing

► Prematurely discontinuing medicationPrematurely discontinuing medication

► Taking someone else’s medicationTaking someone else’s medication

► Taking a medication with prohibited foods Taking a medication with prohibited foods

► Taking outdated medicationsTaking outdated medications

Questions Regarding the New Questions Regarding the New Non-Monitored, Oral Non-Monitored, Oral

AnticoagulantsAnticoagulants► Do they represent a significant improvement Do they represent a significant improvement

for patients who have been taking warfarin for patients who have been taking warfarin with consistently therapeutic INR with consistently therapeutic INR values for months or years? values for months or years? They mayThey may..

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

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

Selecting Patients for Non-Monitored Selecting Patients for Non-Monitored Oral Anticoagulation (NOAC)Oral Anticoagulation (NOAC)

► Which patients are the best candidates for non-Which patients are the best candidates for non-monitored oral anticoagulation? Treatment-naive monitored oral anticoagulation? Treatment-naive and de novo patients? And/or patients on and de novo patients? And/or patients on warfarin?warfarin?

► Established patients on warfarin doing "well?" Established patients on warfarin doing "well?" Established on warfarin, doing well, but at high Established on warfarin, doing well, but at high risk for bleeding? High HAS-BLED? Previous risk for bleeding? High HAS-BLED? Previous stroke?stroke?

► On warfarin, and doing "reasonably" well, but On warfarin, and doing "reasonably" well, but requiring multiple interventions to keep INR/TTR requiring multiple interventions to keep INR/TTR controlled?controlled?

► Patients on warfarin who are doing well, but only Patients on warfarin who are doing well, but only with intensive monitoring?with intensive monitoring?

Clinical Dilemma #1Clinical Dilemma #1

Transitioning Patients from Warfarin to Transitioning Patients from Warfarin to a Non-Monitored Oral Anticoagulant a Non-Monitored Oral Anticoagulant

► How do we actually transition patients from How do we actually transition patients from warfarin to dabigatran, rivaroxaban, warfarin to dabigatran, rivaroxaban, apixaban, or other agents?apixaban, or other agents?

► What INR do we wait for?What INR do we wait for?

► What are the renal issues that need to be What are the renal issues that need to be considered for each agent?considered for each agent?


How do I Convert a Patient from How do I Convert a Patient from Warfarin to Dabigatran and Warfarin to Dabigatran and Vice Vice

VersaVersa??► Warfarin to dabigatran: Warfarin to dabigatran: Discontinue warfarin and Discontinue warfarin and

start dabigatran when the international start dabigatran when the international normalized ratio (INR) is below 2.0.normalized ratio (INR) is below 2.0.

► Dabigatran to warfarin:Dabigatran to warfarin:• CrCl > 50 mL/min, start warfarin 3 days before discontinuing CrCl > 50 mL/min, start warfarin 3 days before discontinuing

dabigatran.dabigatran.

• CrCl 31-50 mL/min, start warfarin 2 days before discontinuing CrCl 31-50 mL/min, start warfarin 2 days before discontinuing dabigatran.dabigatran.

• CrCl 15-30 mL/min, start warfarin 1 day before discontinuing CrCl 15-30 mL/min, start warfarin 1 day before discontinuing dabigatran.dabigatran.

• CrCl < 15 mL/min, no recommendations can be made.CrCl < 15 mL/min, no recommendations can be made.

Because dabigatran can contribute to an elevated INR, Because dabigatran can contribute to an elevated INR, the INR will better reflect warfarin’s effect after the INR will better reflect warfarin’s effect after

dabigatran has been stopped for at least 2 days.dabigatran has been stopped for at least 2 days.Dabigatran prescribing information 2010

Managing Patients Who Are on Non-Managing Patients Who Are on Non-Monitored Oral Anticoagulation and Have Had Monitored Oral Anticoagulation and Have Had

a Stroke a Stroke

► How do we approach a patient who has had an How do we approach a patient who has had an embolic stroke while on a non-monitored oral embolic stroke while on a non-monitored oral anticoagulant?anticoagulant?

► Should we switch? Why? Why not?Should we switch? Why? Why not?

► To what agent would we switch? From one To what agent would we switch? From one non-monitored oral anticoagulant to another? non-monitored oral anticoagulant to another? To warfarin?To warfarin?

► If we switch to warfarin, at what INR? What if If we switch to warfarin, at what INR? What if the patient is at risk for hemorrhage?the patient is at risk for hemorrhage?


What Should I Do if my Patient Has What Should I Do if my Patient Has an Ischemic Stroke on Dabigatran?an Ischemic Stroke on Dabigatran?

► Consider:Consider:● Is the patient compliant with dabigatran? Is the patient compliant with dabigatran?

Check aPTT or thrombin time– if dose taken Check aPTT or thrombin time– if dose taken within past 12 hours, these levels should within past 12 hours, these levels should be prolonged.be prolonged.

● If the stroke is cryptogenic, consider adding If the stroke is cryptogenic, consider adding antiplatelet therapy.antiplatelet therapy.

● Convert dabigatran to warfarin (target INR Convert dabigatran to warfarin (target INR 2-3 or higher?).2-3 or higher?).

● Switch to another NOAC?Switch to another NOAC?

Aligning Specific Patient and Risk Profiles with Aligning Specific Patient and Risk Profiles with Specific NOACS: Apixaban, Dabigatran, Specific NOACS: Apixaban, Dabigatran,

RivaroxabanRivaroxaban

► Based on AVERROES, RE-LY, ARISTOTLE, and Based on AVERROES, RE-LY, ARISTOTLE, and ROCKET-AF, should we be aligning specific, non-ROCKET-AF, should we be aligning specific, non-monitored oral anticoagulants with specific risk monitored oral anticoagulants with specific risk groups?groups?

► Should the warfarin-intolerant/ineligible patient be Should the warfarin-intolerant/ineligible patient be "steered" toward apixaban?"steered" toward apixaban?

► The "high-risk" patient be steered toward The "high-risk" patient be steered toward rivaroxaban?rivaroxaban?

► The intermediate-risk patient be "steered" toward The intermediate-risk patient be "steered" toward apixaban or dabigatran?apixaban or dabigatran?

► How do we know whether this kind of alignment is How do we know whether this kind of alignment is evidence-based, or if it is an artifact of the trial evidence-based, or if it is an artifact of the trial designs?designs?


What Should We Use For Hemorrhage on a What Should We Use For Hemorrhage on a Non-Monitored Oral Anticoagulant? Non-Monitored Oral Anticoagulant?

► What should be our clinical approach to a What should be our clinical approach to a patient who has had a hemorrhage on a patient who has had a hemorrhage on a non-monitored oral anticoagulant?non-monitored oral anticoagulant?

► Does it depend on the type of hemorrhage? Does it depend on the type of hemorrhage? Other factors?Other factors?

► Should we ever consider warfarin in these Should we ever consider warfarin in these patients?patients?


Guide to the Management ofGuide to the Management ofBleeding in Patients Taking NOACBleeding in Patients Taking NOAC

Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

Patients with bleeding on NOAC therapy

Mild bleedingModerate-Severe

bleedingLife-threatening

bleeding

• Delay next dose or discontinue treatment as appropriate

• Mechanical compression

• Surgical intervention• Fluid replacement and

hemodynamic support• Blood product

transfusion• Oral charcoal • Hemodialysis• ? Prothrombin Complex

Concentrate?(Circulation 2011; 2011: 124:

1573-9)

• Consideration of rFVIIa or PCC

• Charcoal filtration• ? Prothrombin

Complex Concentrate

(Circulation 2011; 2011: 124: 1573-9)

Antithrombotic AgentsAntithrombotic AgentsA New Era of A New Era of ““Alignment and Flexibility?Alignment and Flexibility?””

► Dabigatran: Dabigatran: Superior SPAF compared with Superior SPAF compared with warfarinwarfarin

► RivaroxabanRivaroxaban: Once-daily administration and less : Once-daily administration and less dependence on kidneys for metabolism; non-dependence on kidneys for metabolism; non-inferior in ITT analysis in very high-risk patient inferior in ITT analysis in very high-risk patient populationpopulation

► Apixaban: Apixaban: Safety equivalent to aspirin in Safety equivalent to aspirin in AVERROES, and superior stroke prevention in AVERROES, and superior stroke prevention in warfarin intolerant or ineligiblewarfarin intolerant or ineligible

► Apixaban:Apixaban: Superior SPAF, less major bleeding, Superior SPAF, less major bleeding, lower all-cause mortality.lower all-cause mortality.

SPAF Clinical Trial ProgramsSPAF Clinical Trial ProgramsTranslational Dilemmas and Cautionary Translational Dilemmas and Cautionary

NotesNotes

► Do clinical trial results apply to Do clinical trial results apply to ““real worldreal world”” medicine in busy clinical practices with brief medicine in busy clinical practices with brief office visits and minimal telephone follow-office visits and minimal telephone follow-up?up?

► Are patients who participate in clinical trials Are patients who participate in clinical trials healthier/more motivated than most? Does healthier/more motivated than most? Does this make favorable results more likely in this make favorable results more likely in both the new drug and the comparison both the new drug and the comparison groups?groups?

► Do the costs of a Do the costs of a ““copaycopay”” affect patient affect patient decisions to fill a prescription for a decisions to fill a prescription for a potentially more effective, safer drug vs a potentially more effective, safer drug vs a less expensive but less effective alternative?less expensive but less effective alternative?

Unresolved Issues with NOACsUnresolved Issues with NOACs

► No established methods of monitoring No established methods of monitoring

► No known therapeutic rangesNo known therapeutic ranges

► Lack of a proven antidoteLack of a proven antidote

► Uncertain management of bleedingUncertain management of bleeding

► Long term safety: to be determinedLong term safety: to be determined

► No head-to-head comparisons of new agentsNo head-to-head comparisons of new agents

Properties of Ideal AnticoagulantProperties of Ideal AnticoagulantDo NOACS Fit the Bill? Do NOACS Fit the Bill?

► Proven efficacy Proven efficacy √√

► Low bleeding risk Low bleeding risk √√

► Fixed dosing Fixed dosing √√

► Good oral bioavailability Good oral bioavailability √√

► No routine monitoring needed No routine monitoring needed √√

► Reversibility: ?PCC, FEIBA, rVIIaReversibility: ?PCC, FEIBA, rVIIa

► Rapid onset of action Rapid onset of action √√

► Few drug or food interactions Few drug or food interactions √√

NOACs: Advancing OpportunitiesNOACs: Advancing Opportunitiesto Connect Guidelines with Practiceto Connect Guidelines with Practice

► Lower stroke rates Lower stroke rates ► Fewer major and fatal bleeds, especially Fewer major and fatal bleeds, especially

ICHICH► Lower dose options for chronic kidney Lower dose options for chronic kidney

disease, elderly, and the disease, elderly, and the ““frailfrail”” or or ““underweightunderweight”” patient patient

► Use in conjunction with RF reduction: treat Use in conjunction with RF reduction: treat congestive heart failure, diabetes, congestive heart failure, diabetes, hypertension, obesityhypertension, obesity

► Facilitate periprocedural treatmentFacilitate periprocedural treatment► Should improve medication adherence—no Should improve medication adherence—no

injections/ no routine lab blood testinginjections/ no routine lab blood testing

So What Now? Trials in So What Now? Trials in Translation Translation

Applying Evidence-Driven Strategies to Applying Evidence-Driven Strategies to AF Patients at the Front Lines of Clinical AF Patients at the Front Lines of Clinical

PracticePractice

Audience Response System-Based InteractionsAudience Response System-Based Interactions

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDProgram ChairmanProgram Chairman

Director, VTE Research GroupDirector, VTE Research GroupCardiovascular DivisionCardiovascular Division

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

Harvard Medical SchoolHarvard Medical School

Advances in the Science and Medicine Advances in the Science and Medicine of Stroke Prevention in AFof Stroke Prevention in AF

Atrial Fibrillation Atrial Fibrillation Case Study #1Case Study #1

► A 71-year-old white female with a history of A 71-year-old white female with a history of chronic, non-valvular AF, controlled chronic, non-valvular AF, controlled hypertension, and a history of mild hypertension, and a history of mild congestive heart failure has been congestive heart failure has been evaluated by a cardiologist and found to be evaluated by a cardiologist and found to be a suitable candidate for warfarin therapy. a suitable candidate for warfarin therapy.

► Due to logistical barriers that make Due to logistical barriers that make monitoring difficult and dietary variations, monitoring difficult and dietary variations, the patient has had difficulty controlling her the patient has had difficulty controlling her INR. INR.

► Wide fluctuation in her INR has made her Wide fluctuation in her INR has made her question continued warfarin therapy.question continued warfarin therapy.

► Because of her high risk for embolic stroke, her Because of her high risk for embolic stroke, her cardiologist is considering alternative forms of cardiologist is considering alternative forms of thromboprophylaxis for SPAF. She has a HAS-thromboprophylaxis for SPAF. She has a HAS-BLED SCORE of 2.BLED SCORE of 2.

► Which of the following should we consider? Are Which of the following should we consider? Are any of these strategies optimal in this patient any of these strategies optimal in this patient type?type?

1)1) Keep patient on warfarinKeep patient on warfarin

2)2) Replace warfarin with aspirinReplace warfarin with aspirin

3)3) Replace warfarin with aspirin + clopidogrelReplace warfarin with aspirin + clopidogrel

4)4) Replace warfarin with a non-monitored oral Replace warfarin with a non-monitored oral anticoagulantanticoagulant

Audience Response System (ARS) Audience Response System (ARS) Question Question


► An 81-year-old white female with a history of An 81-year-old white female with a history of chronic, non-valvular AF, a history of a chronic, non-valvular AF, a history of a previous ischemic stroke, and a history of mild previous ischemic stroke, and a history of mild congestive heart failure has been on a congestive heart failure has been on a combination of clopidogrel and aspirin therapy combination of clopidogrel and aspirin therapy because she was found to be intolerant of because she was found to be intolerant of warfarin. warfarin.

► She is on a proton pump blocker, an ACE She is on a proton pump blocker, an ACE inhibitor, a diuretic, and digoxin.inhibitor, a diuretic, and digoxin.

► She is admitted to the hospital for a GI bleed, She is admitted to the hospital for a GI bleed, and is found to have a hematocrit of 29 and a and is found to have a hematocrit of 29 and a hemoglobin of 9.8. The aspirin and clopidogrel hemoglobin of 9.8. The aspirin and clopidogrel are discontinued.are discontinued.


The patient stabilizes, and the cardiologist is The patient stabilizes, and the cardiologist is consulted to determine the subsequent course consulted to determine the subsequent course of her antithrombotic treatment. She has a of her antithrombotic treatment. She has a HAS-BLED score of 3.HAS-BLED score of 3.

It is your opinion that:It is your opinion that: 1)1) Because of the documented GI bleed, the patient Because of the documented GI bleed, the patient

should not be treated with antithrombotic agents, should not be treated with antithrombotic agents, because the risk of bleeding outweighs the risk of because the risk of bleeding outweighs the risk of stroke and its complications.stroke and its complications.

2)2) Because of the patient's risk profile, there should Because of the patient's risk profile, there should be an attempt to provide thromboprophylaxis be an attempt to provide thromboprophylaxis against embolic stroke.against embolic stroke.


The cardiologist has determined that this The cardiologist has determined that this patient requires antithrombotic patient requires antithrombotic management for stroke prevention. management for stroke prevention.

At this point you would most likely:At this point you would most likely: 1)1) Try the patient on warfarin againTry the patient on warfarin again

2)2) Try to re-introduce clopidogrel and aspirinTry to re-introduce clopidogrel and aspirin

3)3) Treat the patient with aspirin aloneTreat the patient with aspirin alone

4)4) Introduce a non-monitored oral Introduce a non-monitored oral anticoagulant to the patient's regimen. anticoagulant to the patient's regimen.


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

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

► He has a CHADS-VASc score of 3, and a He has a CHADS-VASc score of 3, and a HAS—BLED score of 2.HAS—BLED score of 2.

► Which regimen would you prescribe for Which regimen would you prescribe for prophylaxis against thromboembolism?prophylaxis against thromboembolism?

Which regimen would you prescribe for Which regimen would you prescribe for prophylaxis against thromboembolism?prophylaxis against thromboembolism?

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

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

3.3. Aspirin 81 mg dailyAspirin 81 mg daily

4.4. Aspirin 81 mg + clopidogrel 75 mg dailyAspirin 81 mg + clopidogrel 75 mg daily

5.5. An oral Factor Xa or direct thrombin An oral Factor Xa or direct thrombin inhibitorinhibitor


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 (535/1.81) times in 1 year for warfarin

not to be the optimal therapy…”

A 71-year-old man with AF, heart failure, and a prior history of stroke presents with unstable angina and proceeds to cardiac catheterization where a culprit lesion is identified. Optimal management includes:

1) Placement of a drug-eluting stent with plan to continue anticoagulation in addition to 1 year of dual antiplatelet therapy

2) Placement of a drug-eluting stent with 1 year of dual antiplatelet therapy alone

3) Placement of a bare metal stent with plan to continue anticoagulation in addition to 1 month of dual antiplatelet therapy

4) Placement of a bare metal stent with 1 month of dual antiplatelet therapy alone


A 67-year-old female with a history of mitral stenosis with subsequent mechanical mitral valve replacement has AF.

Which of the following anticoagulants can be used for stroke prevention in this patient?

1) Warfarin

2) Dabigatran

3) Apixaban

4) Rivaroxaban

5) All of the above


The major potential benefits of the new The major potential benefits of the new non-monitored oral anticoagulants non-monitored oral anticoagulants include:include:

1)1) Rapid therapeutic anticoagulant effectRapid therapeutic anticoagulant effect

2)2) Greater safety with regards to intracranial Greater safety with regards to intracranial hemorrhagehemorrhage

3)3) Proven reversal agentProven reversal agent

4)4) All of the aboveAll of the above

5)5) Both 1 and 2Both 1 and 2

Atrial Fibrillation Atrial Fibrillation Knowledge Assessment Question Knowledge Assessment Question

An 82-year-old man with AF has had several An 82-year-old man with AF has had several admissions over the past 6 months for heart admissions over the past 6 months for heart failure complicated by worsening renal function. failure complicated by worsening renal function. His creatinine clearance is currently 20 mL/min His creatinine clearance is currently 20 mL/min but frequently fluctuates to 10-15 mL/min. He has but frequently fluctuates to 10-15 mL/min. He has a HAS-BLED score of 3.a HAS-BLED score of 3.

The best anticoagulant regimen for stroke The best anticoagulant regimen for stroke prevention is:prevention is:

1)1) Dabigatran 150 mg twice dailyDabigatran 150 mg twice daily

2)2) Dabigatran 75 mg twice dailyDabigatran 75 mg twice daily

3)3) Warfarin titrated to goal INR 2-3Warfarin titrated to goal INR 2-3

4)4) Rivaroxaban 20 mg once dailyRivaroxaban 20 mg once daily

5)5) Rivaroxaban 15 mg once dailyRivaroxaban 15 mg once daily


A 79-year-old woman with a CHADS-VASc score of 2 who has been on warfarin for the past 2 years returns to clinic for routine follow-up.

Her INR control has been excellent and she has never experienced a stroke or had significant bleeding. Her HAS-BLED score is 2.

Her complaints today are thinning hair, cold intolerance, and fatigue.

Her laboratory work is normal including a TSH.


Which of her symptoms could be due to warfarin?

1) Thinning hair

2) Cold intolerance

3) Fatigue

4) Both 1 and 2

5) All of the above


A 69-year-old woman with AF and CHADS2 score of 4 has a creatinine clearance that is stable at 40 mL/min.

Which of the following anticoagulation regimens are suitable for her?

1) Dabigatran 150 mg twice daily


3) Rivaroxaban 20 mg once daily


5) Both 1 and 4


What would her options be if her creatinine clearance was stable at 25 mL/min?



3) Only warfarin can be used in patients with creatinine clearance < 30 mL/min

4) Both 1 and 2


A 74-year-old man with AF on dabigatran is involved in a motor vehicle accident and needs emergency surgery.

It is unclear if he is taking this medication but the surgeon is concerned about operating on him if he is fully anticoagulated.


Which of the following lab tests, if normal, would reassure the team that the patient is not anticoagulated?

1) INR (international normalized ratio)

2) aPTT (activated partial thromboplastin time)

3) PT (prothrombin time)

4) Bleeding time


A 60-year-old man with AF has been on warfarin but it has been very difficult to control his INR. You have decided to switch to dabigatran. Which of the following is true regarding transitioning a patient from warfarin to dagibatran?

1) Start dabigatran when his INR < 3

2) Start dabigatran when his INR < 2

3) Start dabigatran 24 hours after his last dose of warfarin


What if you decided to switch the patient to rivaroxaban?

1) Start rivaroxaban when his INR < 3

2) Start rivaroxaban when his INR < 2

3) Start rivaroxaban 24 hours after his last dose of warfarin


A 78-year-old female with AF, systolic heart A 78-year-old female with AF, systolic heart failure, hypertension, diabetes, and a history of failure, hypertension, diabetes, and a history of significant GI bleeding has been on warfarin for significant GI bleeding has been on warfarin for many years but has had a difficult time many years but has had a difficult time controlling her INR with frequent controlling her INR with frequent supertherapeutic values despite intensive supertherapeutic values despite intensive monitoring and titration of her warfarin dose. monitoring and titration of her warfarin dose. Her HAS-BLED score is 3. The best treatment Her HAS-BLED score is 3. The best treatment option for her is:option for her is:

1)1) No antithrombotic therapyNo antithrombotic therapy

2)2) Discontinue warfarin and start aspirinDiscontinue warfarin and start aspirin

3)3) Discontinue warfarin and start dabigatran Discontinue warfarin and start dabigatran

4)4) Discontinue warfarin and start rivaroxaban Discontinue warfarin and start rivaroxaban

5)5) Discontinue warfarin and start apixabanDiscontinue warfarin and start apixaban


A 76-year-old woman with heart failure, hypertension, diabetes, and declining renal function (creatinine clearance 35 mL/min) has an embolic stroke due to newly diagnosed AF. She refuses to take warfarin.

What is the best validated antithrombotic regimen in this particular patient?

1)1) Aspirin Aspirin

2)2) Aspirin and clopidogrelAspirin and clopidogrel

3)3) Dabigatran Dabigatran

4)4) Apixaban Apixaban

5)5) RivaroxabanRivaroxaban


A 68-year-old man with a mechanical mitral A 68-year-old man with a mechanical mitral valve develops AF. valve develops AF.

The best anticoagulant option for him isThe best anticoagulant option for him is::

1)1) WarfarinWarfarin

2)2) DabigatranDabigatran

3)3) ApixabanApixaban


5)5) AspirinAspirin


A 76-year-old man with heart failure and A 76-year-old man with heart failure and hypertension undergoes successful catheter hypertension undergoes successful catheter ablation for symptomatic AF. ablation for symptomatic AF.

Which of the following is true regarding his Which of the following is true regarding his anticoagulation management?anticoagulation management?

1)1) He no longer requires anticoagulation now that he He no longer requires anticoagulation now that he is in sinus rhythmis in sinus rhythm

2)2) Patient should be on both aspirin and an Patient should be on both aspirin and an anticoagulantanticoagulant

3)3) Patient should be on an anticoagulant alonePatient should be on an anticoagulant alone

4)4) Aspirin and clopidogrel together is as effective as Aspirin and clopidogrel together is as effective as anticoagulation in these patientsanticoagulation in these patients


The cardiologist has determined that this The cardiologist has determined that this patient requires antithrombotic patient requires antithrombotic management for stroke prevention. At management for stroke prevention. At this point you would most likely:this point you would most likely:

1)1) Try the patient on warfarin againTry the patient on warfarin again

2)2) Treat the patient with aspirin aloneTreat the patient with aspirin alone

3)3) Introduce the non-monitored oral anticoagulant, Introduce the non-monitored oral anticoagulant, apixaban, into the patient's regimenapixaban, into the patient's regimen

4)4) Introduce dabigatran into the patient’s regimenIntroduce dabigatran into the patient’s regimen

5)5) Introduce rivaroxaban into the patient’s regimenIntroduce rivaroxaban into the patient’s regimen


► A 75-year-old male with a history of A 75-year-old male with a history of chronic, non-valvular AF, diabetic renal chronic, non-valvular AF, diabetic renal disease, previous history of ischemic disease, previous history of ischemic stroke, history of mild HF, and controlled stroke, history of mild HF, and controlled hypertension has been on warfarin hypertension has been on warfarin therapy. The HAS-BLED score is 4.therapy. The HAS-BLED score is 4.

► For the past 6 months, despite repeated For the past 6 months, despite repeated visits for monitoring and warfarin dose visits for monitoring and warfarin dose adjustment, his INR has varied between adjustment, his INR has varied between 1.5 and 4.3. 1.5 and 4.3.

► His estimated GFR is 30His estimated GFR is 30 mL/min mL/min..


At this point you would: 1)1) Continue to try to stabilize his INR on warfarinContinue to try to stabilize his INR on warfarin

2)2) Change to aspirin aloneChange to aspirin alone

3)3) Introduce the non-monitored oral anticoagulant Introduce the non-monitored oral anticoagulant rivaroxaban into the patient's regimenrivaroxaban into the patient's regimen

4)4) Introduce the non-monitored oral anticoagulant Introduce the non-monitored oral anticoagulant apixaban into the patient's regimenapixaban into the patient's regimen

5)5) Introduce the non-monitored oral anticoagulant Introduce the non-monitored oral anticoagulant dabigatran into the patient's regimendabigatran into the patient's regimen


► An 82-year-old man with hypertension, An 82-year-old man with hypertension, diabetes, mild congestive heart failure, diabetes, mild congestive heart failure, and previous ischemic stroke, is and previous ischemic stroke, is diagnosed with atrial fibrillation.diagnosed with atrial fibrillation.

► He has not been taking any He has not been taking any anticoagulants.anticoagulants.


Which regimen would you initiate for Which regimen would you initiate for prophylaxis against stroke?prophylaxis against stroke?

1)1) Warfarin (INR 2.0-3.0)Warfarin (INR 2.0-3.0)

2)2) Aspirin 81 mg + clopidogrel 75 mg dailyAspirin 81 mg + clopidogrel 75 mg daily





► An 82-year-old man with An 82-year-old man with hypertension, diabetes, mild CHF, hypertension, diabetes, mild CHF, and a previous ischemic stroke has and a previous ischemic stroke has permanent atrial fibrillation.permanent atrial fibrillation.

► He has been on warfarin for about 5 He has been on warfarin for about 5 years and his INR has remained years and his INR has remained constant between 2.3 and 2.7.constant between 2.3 and 2.7.

► He has a HAS-BLED score of 3.He has a HAS-BLED score of 3.


Which regimen would you continue or switch Which regimen would you continue or switch to for prophylaxis against stroke?to for prophylaxis against stroke?

1)1) Continue current therapy with warfarinContinue current therapy with warfarin

2)2) Aspirin 81 mg + clopidogrel 75 mg dailyAspirin 81 mg + clopidogrel 75 mg daily





A 75-year-old man with a CHADSA 75-year-old man with a CHADS2 2 of 3 has of 3 has been taking dabigatran 150 mg for SPAF. His been taking dabigatran 150 mg for SPAF. His estimated GFR was 55 estimated GFR was 55 mL/min 6 months ago 6 months ago and is now 40 and is now 40 mL/min. .

I would now:I would now:1)1) Continue to monitor patientContinue to monitor patient

2)2) Switch patient to 75 mg dabigatran twice Switch patient to 75 mg dabigatran twice per dayper day

3)3) Switch patient to warfarinSwitch patient to warfarin

4)4) Switch patient to rivaroxabanSwitch patient to rivaroxaban

5)5) Start ASA and clopidogrelStart ASA and clopidogrel


Interactive Question Interactive Question and Answer Sessionand Answer Session


spaf boston slidecast 181

Documents

prothrombin

bare metal

womens hospital

mph research

international

nonmonitored

revised product

systolic bp