Stroke Prevention in Atrial Fibrillation

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

Anticoagulation-Based Management for SPAF

New Frontiers and Treatment Paradigms for

Program ChairmanSamuel Z. Goldhaber, MD

Cardiovascular DivisionBrigham and Women’s Hospital

Professor of MedicineHarvard Medical School

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

Commercial Support: This National Initiative is Sponsored by an Independent Educational Grant from Boehringer-Ingelheim

Welcome and Program Overview

Program FacultyPROGRAM CHAIRMANSAMUEL Z. GOLDHABER, MDCardiovascular DivisionBrigham and Women’s HospitalProfessor of MedicineHarvard Medical School

CHRISTIAN T. RUFF, MD, MPHTIMI Study GroupBrigham and Women’s HospitalHarvard Medical SchoolBoston, MA

CHRISTOPHER B. GRANGER, MD Professor of MedicineDuke University Medical CenterDirectory, Cardiac Care UnitDuke University Medical CenterDurham, NC

Conflict of Interest DisclosuresProgram ChairmanSAMUEL Z. GOLDHABER, MDResearch Support: Eisai; EKOS; Johnson and Johnson; sanofi-aventisConsultant: Baxter, Boehringer-Ingelheim; BMS; Daiichi; Eisai; Janssen; Merck; Pfizer; Portola, sanofi-aventis

CHRISTIAN T. RUFF, MD, MPHResearch Support: Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, Sanofi-Aventis Consultant: Alere and Beckman Coulter

CHRISTOPHER GRANGER, MDResearch Support: Boehring Ingelheim, Bristol Myers Squibb, GSK, Medtronic Foundation, Merck & Co., Pfizer, Sanofi-aventis, Takeda, The Medicines Company Consultant: Boehringer Ingelheim, Bristol Myers Squibb, GSK, Hoffmann-LaRoche, Lilly, Pfizer, Sanofi-aventis, Takeda, The Medicines Company, Astra Zeneca, Daiichi Sankyo, Ross Medical Corporation

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

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

Prevention in NVAF

Samuel Z. Goldhaber, MDProgram Chairman

Director, Thrombosis Research GroupCardiovascular Division

Brigham and Women’s HospitalProfessor of Medicine

Harvard Medical School

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

Faculty COI Disclosures

Research SupportBristol-Myers Squibb, Daiichi, EKOS, NHLBI, Thrombosis Research Institute

Consultant

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

Formal Definition: Atrial Fibrillation

AF is an arrhythmia characterized by uncoordinated

atrial activation, with consequent deterioration of atrial mechanical function

Circulation 2011; 121: e269-e367

Normal sinus

rhythm

Atrial fibrillati

The ECG of Atrial Fibrillation

ParoxysmalSelf-Terminating

PersistentLasts > 7 Days

PermanentCardioversion Failed or Not

Attempted

Normal Sinus Rhythm

Atrial Fibrillation

The “3 Ps” and Natural History of Atrial Fibrillation

Paroxysmal AF is as likely to cause stroke as

persistent or permanent AF

Atrial Fibrillation: Epidemiology

► The No. 1 preventable cause of stroke

► In the United States, up to 16 million individuals will be affected by the year 2050

► Increasing survival from heart attack and increasing age (“the ‘graying’ of America”) help explain rise in incidence of atrial fibrillation

20002005

20102015

20202025

20302035

20402045

2050Year

r of P

illion

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

Atrial Fibrillation: An Epidemic

16 millionUS Prevalence

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

Obesity

CVDDiabetes

Hypertension

AtrialFibrillation

Magnani J W et al. Circulation 2013;128:401-405

Atrial Fibrillation: An Epidemic

Age, years

ntRelationship Between

Atrial Fibrillation and Age

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

Atrial Fibrillation Causes Stroke Left Atrial Appendage Thrombus

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

Stroke and Atrial Fibrillation Burden

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

%AF prevalence Strokes attributable to AF

Age Range (years)0

50–59 60–69 70–79 80–89

Framingham

Approximately 5-fold increased risk of stroke

Quantify stroke risk: CHADS2/ CHA2DS2-VASc

AF strokes have worse outcomes Costly health care ~ $16 billion/year

Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling

Framingham Heart Study

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

More Patients are Vulnerable to Stroke than Previously Realized

Fuster V, Chinitz JS. Circulation 2012; 125:2285-2287

2012 Focused Update: ESC Guidelines

Assess stroke risk using CHA2DS2VASc, instead of CHADS2 Recommend anticoagulation for stroke prevention with CHA2DS2-VASc score ≥ 1

Favor novel, non-monitored anticoagulants (apixaban, rivaroxaban, and dabigatran)

Camm AJ, et al. European Heart Journal 2012; 33: 2719

Anticoagulation in Atrial Fibrillation Effects on Stroke Risk Reduction

Warfarin better Control better

AFASAKSPAF

BAATAFCAFA

SPINAF

100% 50% 0 -50% -100%

Aggregate

RRR of stroke: 62%

RRR All-cause mortality: 26%

RRR, relative risk reduction.

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

Known Problems With Warfarin

1) Delayed onset/offset

2) Unpredictable dose response

3) Narrow therapeutic index

4) Drug-drug, drug-food interactions

5) Problematic monitoring

6) High bleeding rate

7) Slow reversibility

1) Established efficacy 2) Low cost ($4/month; $10/3 mos)3) Long track record (1954)4) Centralized anticoagulation clinics that

maintain TTRs > 60%5) Rapid, turnaround genetic testing6) Point-of-care self-testing7) INR testing q 12 weeks if stable

Warfarin Will Likely Survive: Why?

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

Sites of Action in Coagulation System

Novel Factor Xa and DT Inhibitors

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

RivaroxabanApixabanEdoxabanBetrixaban

TF/VIIa

IXaVIIIaVa

FibrinFibrinogen

Dabigatran

Initiation

Propagation

Fibrin formation

Steps in Coagulation Pathway Drugs

Comparison Overview of New Anticoagulants with Warfarin

Features Warfarin New AgentsOnset Slow Rapid

Dosing Variable Fixed

Food effect Yes No

Drug interactions Many Few

Monitoring Yes No

Half-life Long Short

Antidote Yes No

Novel Oral AnticoagulantsImportant Comparative Features

• Oral direct thrombin inhibitor• Twice daily dosing• Renal clearance

Dabigatran

• Direct factor Xa inhibitor• Once daily (maintenance), twice daily (loading)• Renal clearance

Rivaroxaban

• Direct factor Xa inhibitor• Twice daily dosing• Hepatic clearance

Apixaban

• Direct factor Xa inhibitor• Once daily dosing• Hepatic clearance

Edoxaban

Circulation 2010;121:1523

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

Rivaroxaban Apixaban EdoxabanOpen LabelTwo DosesTwice Daily

Double BlindTwo DosesOnce Daily

ROCKET-AF

Double BlindTwo DosesTwice Daily

ARISTOTLE

Double BlindTwo DosesOnce Daily

ENGAGE

Dabigatran

Novel Anticoagulants

FIIa Inhibitor Fxa Inhibitor

A “Failure to Prophylax” Syndrome

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

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

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

Only 60% Use of Anticoagulation for SPAF: Euro Heart Survey

Nieuwlaat R, et al. Eur Heart J 2006; 27: 3018

CHADS2 Score

5,333 AF Patients; 35 Countries: 2003–2004

58 59 64 61

Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479

Only 60% Use of Anticoagulation: Minimal Variation by CHA2DS2-VASc

(n=10,607) (n=305) (n=1,345) (n=2,903) (n=2,471) (n=2,180) (n=1,311) (n=902)

Reasons Why VKAs Were Not Given: Patients with CHADS2 Score ≥ 2

Reasons for Failing to AnticoagulatePatients with CHADS2>2 [n=2,302] (n, %)

Alcohol misuse 11 (0.5)Already taking antiplatelet drug for another condition 117 (5.1)

Patient refusal 165 (7.2)Previous bleeding event 55 (2.4)Taking medication contraindicated/cautioned for use with vitamin K antagonists 16 (0.7)

Other 239 (10.4)Physicians choice 1,112 (48.3) Bleeding risk 170 (7.4) Concern over patient compliance 121 (5.3) Guideline recommendation 32 (1.4) Fall risk 150 (6.5) Low risk of stroke 95 (4.1) Other 544 (23.6)

Changing MD Behavior

► Guidelines alone do not suffice.► Physician champions► Individual hospital protocols► Registries (GARFIELD)► Coalitions (“Stop AF”)► Public awareness/ advocacy

(North American Thrombosis Forum) ► Litigation► Electronic alerts

Computerized Support:Tricks of the Trade

Piazza G, Goldhaber SZ. Circulation 2009;120:113

Integrate support into quality improvement. Link to an incentive system. Foster acceptance of computer guidance. Couple support with order entry software. Limit to key decisions to avoid alert fatigue. Use automatic, not user-initiated, systems. Measure outcomes and provider behavior.

The SPAF Landscape 2012: Conclusions

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

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

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

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

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

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

for Thrombosis and Hemorrhagic Risk

New Paradigms in the Science and Medicine of Heart Disease

CHRISTOPHER B. GRANGER, MD Professor of Medicine

Duke University Medical CenterDirectory, Cardiac Care Unit

Duke University Medical CenterDurham, NC

Stroke

Systemic Embolism

Embolic Hemodynamic

Fatigue

Shortness of Breath

Palpitations

Complications of AF

Antithrombotic Therapy

Rate ControlRhythm Control

Treatment of AF

Rate N:Rhythm N:

20272033

19251932

18251807

13281316

774780

236255

0 1 2 3 4 5

%RateRhythmp=0.078 unadjusted

Time (years)

p=0.068 adjusted

The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

AFFIRM: Rate vs. Rhythm Control

Nearly ¾ of all strokes were related to discontinuation or inadequate anticoagulation

Only 42% of strokes during documented AF

Al-Khatib SM, et al. EHJ 2013; 34: 2464-2471

Outcomes by AF Type - ARISTOTLE

Adjusted HR 0.70, 95% CI 0.51-0.93 P=0.015

Subclinical AF and Risk of Stroke

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

Atrial Tachyarrhythmia > 6 min ≤ 3 Months After Pacemaker or Defibrillator Implantation

Van Gelder IC et al. N Engl J Med. 2010;362:1363-1373.

RACE II: Lenient vs. Strict Rate Control

Noninferior

Strict control

Lenient control

Months

0 6 12 18 24 30 36

No. at RiskStrict control 303 282 273 262 246 212 131Lenient control 311 298 290 285 255 218 138

Balancing the Risks of Thrombosis and Bleeding

Adapted from Ferreiro JL et al. Thromb Haemost. 2010;103:1-8.

High risk of Thrombotic events

Potency of Antithrombotic Therapy

“Sweet spot”High risk of

bleeding events

– +Thrombotic risk Bleeding risk

Risk Factor Points

Congestive Heart Failure 1

Hypertension 1

Age ≥ 75 1

Diabetes Mellitus 1

Stroke or TIA 2

Maximum Score 6

CHADS2 Risk Score

Gage BF, et al. JAMA. 2001;285:2864-2870.VanWalraven C, et al. Arch Intern Med 2003; 163:936.Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.

CHADS2 Stroke (% / yr)0 1.91 2.8

5 12.5

6 18.2

3% / year

Risk Factor Recommended Therapy

No risk factorsCHADS2 = 0 Aspirin, 81-325 mg

One moderate risk factorCHADS2 = 1

Aspirin, 81-325 mg orWarfarin

(INR 2.0-3.0, target 2.5)

Any high risk factor or>1 moderate risk factorCHADS2 >2

Warfarin(INR 2.0-3.0, target 2.5)

Prosthetic valve Warfarin(INR 2.5-3.5, target 3.0)

Prior ACC/AHA/ESC Guidelines

Risk Factor PointsCHF / LV Dysfunction 1Hypertension 1

Age ≥ 75 2

Diabetes Mellitus 1

Stroke / TIA / Embolism 2

Vascular Disease 1

Age 64-74 1

Sex Category (female) 1

Maximum Score 9

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

CHA2DS2-VASc Score Stroke (% / yr)1 0 %2 1.3 %

3 2.2 %

4 4.0 %

5 6.7 %

6 9.8 %

7 9.6 %

8 6.7 %

9 15.2 %

Redefining Risk: CHA2DS2-VASc

CHA2DS2VASc Refines Stroke Risk Stratification in CHADS2=0

A nationwide Danish cohort study in 47,576 non-warfarin treated NVAF patients with a CHADS2 score = 0-1 at baseline (1997-2008)

CHADS2=0: n=17,327 person-yearsCHA2DS2VASc=0: n=6,919 person-yearsCHA2DS2VASc=1: n=6,811 person-yearsCHA2DS2VASc=2: n=3,347 person-yearsCHA2DS2VASc=3: n=250 person-years

Stroke / thromboembolism

rate (% person-years)

Days from discharge0 100 200 300

1.59%1.75%2.69%3.20%

Olesen et al. Thromb Haemost 2012; 107:1172-1179

Danish Hospital Registry Data 1997-200614,572 patients CHADS-VASc 0 or 1

Olesen J. BMJ 2011;342:d124

A nationwide Danish cohort study in 47,576 non-warfarin treated NVAF patients with a CHADS2 score = 0-1 at baseline (1997-2008)

CHADS2=1: n=22,945 person-yearsCHA2DS2VASc=1: n=2,069 person-

yearsCHA2DS2VASc=2: n=8,516 person-yearsCHA2DS2VASc=3: n=11,223 person-yearsCHA2DS2VASc=4: n=1,137 person-years

Days from discharge0 100 200 300

4.92%5.81%

Stroke / thromboembolism

rate (% person-years)

Olesen et al. Thromb Haemost 2012; 107:1172-1179

CHA2DS2VASc Refines Stroke Risk Stratification in CHADS2=1

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

Redefining Risk: HAS-BLED

Letter Clinical Characteristic Points

H Hypertension 1

A Abnormal Liver or Renal Function 1 or 2

S Stroke 1

B Bleeding 1

L Labile INR 1

E Elderly (age > 65) 1

D Drugs or Alcohol 1 or 2

Maximum Score 9 Pisters R, et al. Chest 2010; 138(5): 1093-1100

The Problem with Risk Scores (ARISTOTLE)

Lopes RD, et al. Lancet 2012; 380:1749-1758 Apixaban Better Warfarin Better

Stroke or SEE

Major Bleeding

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

HAS-BLED

Letter Clinical Characteristic Points

H Hypertension 1

A Abnormal Liver or Renal Function 1 or 2

S Stroke 1

B Bleeding 1

L Labile INR 1

E Elderly (age > 65) 1

D Drugs or Alcohol 1 or 2

Maximum Score 9 Pisters R, et al. Chest 2010; 138(5): 1093-1100

Reasons for Withholding OAC in Patients with AF and Stroke Risk

Patient Provider System

Appropriate: Refusal after complete understanding

Recent intracranial hemorrhage

Lack of access to INR monitoring and can not afford novel drug

Inappropriate: Desire to avoid monitoring (and can afford NOAC)

Old age; CHADS score = 1

Lack of time to address issues

Uncertain appropriateness:

Desire to avoid bruising

Substantial fall risk

Unable to afford cost of monitoring

Anticoagulation in Patients at Risk For Falls

“…persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin

not to be the optimal therapy…”

ACTIVE - Major Bleeding

The ACTIVE Writing Group. Lancet 2006;367:1903-1912

0.0 0.5 1.0 1.5

Clopidogrel+ASACum

# at RiskC+A 3335 3172 2403 914OAC 3371 3212 2423 901

2.4 %/year

2.2 %/year

RR = 1.06P = 0.67

Clopidogrel+ASA

Bleeding According to Antiplatelet Therapy in RE-LY Trial

Series of no, single, and dual antiplatelet therapy

HRs adjusted for age, gender, warfarin experience, SBP, CAD, HF, hypertension, diabetes, TIA, CrCl and statin use.

Circulation. published online December 27, 2012

ORBIT-AF Registry (N=7,347): 6-month Major Bleeding

Steinberg B et al. Circulation 2013;128:721-728

* Compared to control35 more minor bleeds occurred with warfarinPooled data from AFASAK, SPAF, and BAATAFIntention-to-treat analysis

For every 1000 patients with AF in clinical trials treated with warfarin for 1 year

Benefit Risk35 fewer thromboembolic

events*1 more intracranial or major bleed*

Adapted from Alberts et al. Ann Neurol 1991;30:511-518.

Anticoagulation in AFBenefit vs. Risk

Registry cohort study of all Danish pts surviving first-time hosp for AF between 1997 and 2006

82,854 of 118,606 pts had prescription filled for warfarin, ASA, or clopidogrel after discharge.

During follow-up of 3.3 yrs, 13,573 pts (11.4%) had nonfatal or fatal bleeding.

Arch Intern Med. 2010;170:1433-1441

Risk of Bleeding with Single, Dual, or Triple Therapy in Patients with AF

3 to 4 fold risk of bleeding with triple therapy

What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing

(WOEST)

N = 563

Bleeding Events

(OAC + clopidogrel)

Dewilde W, et al. Lancet 2013; 381:1107-1115

What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing

(WOEST)

Dewilde W, et al. Lancet 2013; 381:1107-1115

P = 0.027 0.38 0.88 0.13 0.17

Risk Profile Class / 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 AF Guidelines Update

Quartiles of NT-proBNP

Patton et al., Circulation 2009; 120:1768-74

Biomarkers and Risk PredictionNT-proBNP Predicts AF

Biomarkers & Risk Prediction – RE-LY

Hijazi Z, et al. Circulation 2012; 125:1605-1616

Troponin

NTproBNP

Troponin

NTproBNP

Stroke & SEE Vascular Death

Hijazi Z, et al. Circulation 2012; 125:1605-1616

Stroke, SEE, PE, MI, & Vascular Death

Trop NTproBNP

TropNTproBNP

Multimarker & Risk PredictionRE-LY

Enhanced Risk Prediction - ARISTOTLE

Hijazi Z, et al. JACC 2013;61:2274-2284

CHA2DS2VASc NTproBNP

CHA2DS2VASc

NTproBNP

Stroke or SEE

Cardiac Death

Summary

► Risk stratification is improving► Most patients with AF have at least one

risk factor for stroke and should be anticoagulated

► Now the focus is on identifying the low risk patient (who does not need anticoagulation)

► Biomarkers (BNP, hsTn) provide powerful prognostic information

► We need prospective studies of “multimarker” risk assessment tools

► Better understanding of how burden of AF relates to risk is needed

Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-

Monitored, Oral Anticoagulants (NOACs) for SPAF

Christian T. Ruff, MD, MPHTIMI Study Group

Brigham and Women’s HospitalHarvard Medical School

Boston, MA

New Paradigms in the Science and Medicine of Heart Disease

History of Warfarin

Limitations of Warfarin

Delayed onset/offset

Multiple food and drug interactions

Genetic variability in metabolism (VKORC1 and CYP2C9)

Requires frequent monitoring of INR due to limited therapeutic index

Subtherapeutic INR 29%

INR in range10%

No warfarin61%

Preventable Strokes

AF Patients with Stroke with no Known Contraindication to

Anticoagulation

Gladston, DJ, et al. Stroke 2009;40:235-40

Properties BenefitOral, once-daily dosing Ease of administration

Rapid onset of action No need for overlapping parenteral anticoagulant

Minimal food or drug interactions Simplified dosing

Predictable anticoagulant effect No coagulation monitoring

Extra renal clearance Safe in patients with renal disease

Rapid offset in action Simplifies management in case of bleeding or intervention

Antidote For emergencies

Properties of an Ideal Anticoagulant

Major Advances In Oral Anticoagulation for SPAF

6 Trial of Warfarin vs. Placebo1989-1993

RE-LY(Dabigatran)

ROCKET AF (Rivaroxaban)

ARISTOTLE (Apixaban)

ENGAGE AF (Edoxaban)

Dabigatran Rivaroxaban Apixaban Edoxaban

Target IIa (thrombin) Xa Xa Xa

Hrs to Cmax 2 2-4 1-3 1-2CYP metabolism None 32% 15% NRBioavailability 7% 80% 66% > 45%Transporters P-gp P-gp/BCRP P-gp P-gpProtein binding 35% >90% 87% 55%Half-life 12-14h 9-13h 8-15h 8-10hRenal elimination 80% 33% 25% 35%Linear PK Yes No Yes Yes

Comparative PK/PD of Novel Agents

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

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

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs Warfarin

Dabigatran 150 vs Warfarin

Non-inferiorityP-value< 0.001

< 0.001

SuperiorityP-value 0.34

< 0.001

Margin = 1.46

HR (95% CI)

RE-LY Efficacy - DabigatranStroke/Systemic Embolic Event

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

0.1 0.3 0.5 1.0 2.0

Dabigatran 110 mgDabigatran 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

0.1 0.3 0.5 1.0 2.0

Major Bleed

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)

MI 1.29 (0.96-1.75)1.27 (0.94-1.71)

Dabigatran Better Warfarin Better

RE-LY Safety Results

Dabigatran 110 mgDabigatran 150 mg

Rivaroxaban Warfarin

Event Rate

HR(95% CI) P-value

On Treatment

N = 14,1431.70 2.15 0.79

(0.65, 0.95) 0.015

ITTN = 14,171 2.12 2.42 0.88

(0.74, 1.03) 0.117

Rivaroxabanbetter

Warfarinbetter

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

Site Notification populations

0.5 1 2

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

ROCKET AF Efficacy - RivaroxabanStroke/Systemic Embolic Event

ROCKET AF Key Secondary Efficacy

Event Rivaroxaban(%/yr)

Warfarin(%/yr)

Hazard Ratio(95% CI)

P-value

Ischemic Stroke 1.34 1.42 0.94 (0.75-1.17) 0.581

Hemorrhagic Stroke 0.26 0.44 0.59 (0.37-0.93) 0.024

MI 0.91 1.12 0.81 (0.63-1.06) 0.121

Total Mortality 1.87 2.21 0.85 (0.70-1.02) 0.073

Vascular Mortality 1.53 1.71 0.89 (0.73-1.10) 0.289

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

ROCKET AF Safety

Event Rivaroxaban(%/yr)

Warfarin(%/yr)

P-value

Major and Clinically Relevant Bleed 14.9 14.5 1.03 (0.96-

1.11) 0.44

Major Bleed 3.6 3.4 1.04 (0.90-1.20) 0.58

Fatal Bleed 0.2 0.5 0.50 (0.31-0.79) 0.003

ICH 0.5 0.7 0.67 (0.47-0.93) 0.02

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

ARISTOTLE Efficacy - Apixaban

Granger 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 Outcomes

Outcome

Apixaban(N = 9120)

Warfarin(N = 9081)

HR (95% CI) P ValueEvent

Rate(%/yr)

Event Rate

(%/yr)Stroke or systemic embolism* 1.27 1.60 0.79 (0.66,

0.95) 0.011

Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012

Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42

Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75)

< 0.001

Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70

All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047

Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81,

0.98) 0.019

Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37

ARISTOTLE Safety End Points

Event Apixaban(%/yr)

Warfarin(%/yr)

P-value

ISTH Major Bleeding 2.13 3.09 0.69 (0.60-0.80) < 0.001

ICH 0.33 0.80 0.42 (0.30-0.58) < 0.001

GUSTO Severe 0.52 1.13 0.46 (0.35-0.60) < 0.001

Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) 0.37

AF Trials – Dose Comparison

RE-LY ROCKET-AF ARISTOTLEENGAGE

AF-TIMI 48Drug Dabigatran Rivaroxaban Apixaban Edoxaban

N 18,113 14,266 18,201 21,105Dose (mg)Frequency

150, 110BID

60, 30QD

Initial Dose adj* No 20 → 15 mg 5 → 2.5 mg 60 → 30 mg

30 → 15 mgDose adj (%) 0 21 4.7 >25Dose adj* after randomization No No No Yes

Design PROBE 2x blind 2x blind 2x blind

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

open-label, blinded end point evaluation

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

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

Baseline Characteristics in AF Trials

RE-LY(Dabigatran)

ARISTOTLE(Apixaban)

ENGAGE AF-TIMI 48*(Edoxaban)

ROCKET-AF(Rivaroxaban)

# Enrolled 18,113 18,201 21,105 14,264

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

Female 36% 35% 38% 40%

CHADS2 score ≥3 32% 30% 52% 87%

VKA naive 50% 43% 41% 38%

Paroxysmal AF 33% 15% 25% 18%

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

Diabetes 23% 25% 36% 40%

Prior CHF 32% 35% 56% 62%

Hypertension 79% 87% 90% 91%

*Preliminary data**includes prior systemic embolism

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

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

AF Trials: Results To Date

Outcomes vs. Warfarin Dabigatran 110 mg

Dabigatran150 mg Rivaroxaban Apixaban

Stroke or Systemic Embolism Non-inferiority Superiority Non-

inferiority Superiority

Stroke No Yes No Yes

Ischemic Stroke No Yes No No

Hemorrhagic Stroke Yes Yes Yes Yes

Fatal / Disabling Stroke No Yes No Yes

Vascular Death No Yes No No

All-Cause Death No No No Yes

Major Bleeding Yes No No Yes

ICH Yes Yes Yes Yes

GI Bleeding No Yes Yes No

Efficacy of New Oral Anticoagulants

Stroke & SEE

Ischemic & Unsp.

Stroke

Hemorraghic Stroke

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

Safety of New Oral Anticoagulants

Bleeding

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

Favors NOACs Favors Warfarin

Mortality Benefit ofNew Oral Anticoagulants

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

Apixaban 5 m b.i.d.

ivaroxaban 20 mg

abigatran 110 mg b.i.d.

bigatran 150 mg b.i.d.

0.5 1 2

Dabigatran 150 mg BID

Dabigatran 110 mg BID

Rivaroxaban 20 mg

Apixaban 5 mg BID

► 150 mg twice daily if CrCL > 30 mL/min

► 75 mg twice daily if CrCL 15-30 mL/min

Dabigatran

► 20 mg if CrCl > 50 mL/min

► 15 mg if CrCL 15-50 mL/min

Rivaroxaban

► 5 mg twice daily

► 2.5 mg twice daily if at least 2 of the following: Age ≥ 80 years Weight ≤ 60 kg Cr ≥ 1.5 mg/dL

Apixaban

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

RRandomization 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 mortality

Safety EP’s = Major Bleeding, Hepatic Function

EVENT DRIVEN

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

Phase III: Protocol Schema

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

Years Years

TTR < 65% TTR ≥ 65%RR=0.93 (0.70-1.24)

p=0.61RR=2.14 (1.61-2.85)

P=0.0001

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

ACTIVE-W: Risk of Stroke / SEE / MI / Vascular Death by cTTR

Does INR Matter?

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 GroupEvent Rate / Year

WarfarinEvent Rate / Year

p-value(interaction)

ROCKET 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

ARISTOTLE 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

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

Efficacy Stratified by Prior VKA (RE-LY)

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

Al-Khatib SM, et al. EHJ 2013 (published on-line April 17, 2013)

Outcomes by AF Type - ARISTOTLE

ARISTOTLE: Efficacy & SafetyAcross Baseline Risk

Lopes RD, et al. Lancet 2012; 380:1749-1758 Apixaban Better Warfarin Better

Stroke or SEE

Major Bleeding

ARISTOTLE: ApixabanRenal Function

Hohnloser SH, et al. EHJ 2012; 33:2821-2830

Baseline Cockcroft-Gault eGFR mL/min

Stroke or SEE Major Bleeding

(N=647)

Cardioversion

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

ROCKET AF

Cardioversion & Catheter Ablation

Piccini JP, et al. JACC 2013;61:1998-2006

Kim JS, et al. Heart Rhythm 2013; 10:483-489

Catheter Ablation with NOACs

Case-control: 763 consecutive patients undergoing AF ablationP=0.8

%P=0.81

Periprocedural Major Bleeding

Healey JS, et al. Circulation 2012; 126:343-348

Discontinuing NOACs Prior to Procedures

Heidbuchel H, et al. Eurospace 2013;15:625-651.

www.NOACfor AF.eu

Dabigatran Apixaban Edoxaban Rivaroxaban No important bleeding risk and/or adequate local haemostasis possible:

perform at trough level (i.e. ≥12h or 24h after last intake) Low risk High risk Low risk High risk Low risk High risk Low risk High risk

CrCl ≥80 ml/min ≥24h ≥48h ≥24h ≥48h no data no data ≥24h ≥48h

CrCl 50-80 ml/min ≥36h ≥72h ≥24h ≥48h no data no data ≥24h ≥48h

CrCl 30-50 ml/min ≥48h ≥96h ≥24h ≥48h no data no data ≥24h ≥48h

CrCl 15-30 ml/min

not indicate

not indicated ≥36h ≥48h no data no data ≥36h ≥48h

CrCl <15 ml/min no official indication for use

Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127

Dabigatran (FIIa) Monitoring

aPTT Hemoclot Test

Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127

Rivaroxaban (Fxa) Monitoring

Rivaroxaban (µg L-1)0 100 200 300 400 500 600

Rotachrom Anti-Xa

Managing Bleeding with NOACs

Heidbuchel H, et al. Eurospace 2013;15:625-651.

www.NOACfor AF.eu

Granger CB, et al. European Heart Journal 2012;33 (Supplement):685-686

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

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

1-2 3-7 8-14 15-300

Apixaban to VKA Group Warfarin to VKA Group Apixaban to VKA Total Events Warfarin to VKA Total Events

Days after last dose

ARISTOTLEApixaban: Increased Events at End of Trial

Rivaroxaban

Warfarin

ents P =

Patel MR, et al. NEJM 2011; 365:883-891Patel MR, et al. JACC 2013;61:651-658

Safety/Days 3 to 30 after the last dose

# Primary Events during first 30 days of transition

ROCKET AFRivaroxaban: Increased Events at End of Trial

Rivaroxaban Warfarin

Outcomes Following Discontinuation of Anticoagulation

P=0.35

Patel MR, et al. JACC 2013;61:651-658

P=0.62

P=0.66

P=0.004

P=0.03

Efficacy and Safety of NOACs in the“Real World”

Larsen TB, et al. JACC 2013;61:2264-2273

RELY-ABLE

Connolly SJ, et al. Circulation 2013;128:237-243

Stroke or SEE Major Bleeding

Dabigatran 150 mg: 3.74% / year Dabigatran 110 mg: 2.99% / year

HR 1.26 (1.04-1.53)

Dabigatran 150 mg: 1.46 % / year Dabigatran 110 mg: 1.60 % / year

HR 0.91 (0.69-1.20)

New therapies provide the promise of providing safer and more convenient anticoagulation.

There are important differences in the half-life, metabolism, & renal elimination across the NOACs that will alter the risk/benefit profile in specific populations.

Persistent concern with lack of ability to monitor the level of anticoagulation.

Further experience and guidance needed in managing anticoagulation peri-procedure.

Desire for reversal agent and strategies to manage serious bleeding.

Conclusions

Stroke Prevention In AF:Vision Statement

Director, Thrombosis Research GroupCardiovascular Division

Faculty COI Disclosures

Research SupportBristol-Myers Squibb, Daiichi, EKOS, NHLBI, Thrombosis Research Institute

Consultant

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

Themes

1. NOACs provide us with a potent pharmacological strategy to prevent stroke due to AF, and to treat PE/ DVT.

2. Appropriate uptake of NOACs will require sustained educational campaigns focusing on indication for therapy, appropriate patient profiles, and drug pharmacology.

Themes (Continued)

3. Electronic decision support can serve as an educational tool. More widespread availability of electronic medical records will facilitate decision support.

4. Anticoagulation therapy alone will not prevent stroke from AF. Our patients need intensified risk factor modification (e.g., quit cigarettes, treat hypertension) and transition to heart-healthy lifestyles re: exercise and nutrition.

NOACS vs. Warfarin: Cochrane Database

Efficacy and Safety Meta-Analysis

Bruins Slot KM, Berge E. Cochrane Database Syst Rev. 2013 Aug 8;8:CD008980.

Factor Xa Inhibitors Compared with Vitamin K Antagonists for the Prevention of Stroke and other Systemic Embolic Events in Patients with Atrial Fibrillation

Clinical OutcomesIllustrative Comparative Risks* (95%

CI)Assumed Risk Corresponding Risk

Warfarin Factor Xa InhibitorsStroke and other systemic embolic events (Follow-up: 12 weeks to 1.9 years)

32 per 1000 25 per 1000(0 to 38)

All strokes(Follow-up: 12 weeks to 1.9 years) 27 per 1000 20 per 1000

(0 to 26)Major bleeding(Follow-up: 12 weeks to 1.9 years) 46 per 1000 39 per 1000

(0 to 55)Intracranial hemorrhages(Follow-up: 12 weeks to 1.9 years) 11 per 1000 6 per 1000

(0 to 8)All-cause deaths(Follow-up: 12 weeks to 1.9 years) 51 per 1000 45 per 1000

(0 to 66)

Emergence of a New Safety and Efficacy

Paradigm

“Drugs don’t work in patients who don’t take them.”

C. Everett Koop, M.D.

Surgeon General 1981-1989

Failure To Anticoagulate Patients At High Risk For Stroke:

Scope Of Problem,

Strategic Tips

ONLY 60% USE of Anticoagulation: Minimal Variation by CHA2DS2-VASc Score

(n=10,607) (n=305) (n=1,345) (n=2,903) (n=2,471) (n=2,180) (n=1,311) (n=902)

Changing MD Behavior

► Guidelines alone do not suffice.► Physician champions► Individual hospital protocols► Registries (GARFIELD)► Coalitions (“Stop AF”)► Public awareness/ Advocacy

(North American Thrombosis Forum) ► Litigation► Electronic alerts

Unresolved Issues

► No established methods of monitoring ► No known therapeutic ranges► Lack of an established antidote► Uncertain management of bleeding► Long term safety► No head to head comparisons of new agents

Novel Anticoagulants: New Opportunities

Immediate onset of actionFixed dosing, with “low-dose” optionNo laboratory coagulation monitoringMinimal drug-food interactionsShort half-life; therefore, no “bridging” Improved efficacy, fewer catastrophic head

bleeds, trend toward lower all-cause mortality

1. NOACs for SPAF show: superiority or at least noninferiority to warfarin, reduction in ICH, more convenience for patients and clinicians.

2. Lower stroke and bleeding complication rates: not anticipated.

3. Many AF patients remain at risk and receive no anticoagulation.

Take Home Points

Take Home Points4. The rapid expansion of anticoagulation

options places clinician education at a premium. Focus must be on correct selection of patients, drugs, and doses.

5. Combining optimal anticoagulation with intensive lifestyle modification provide the best strategy for lowering cardiovascular disease burden.

So What Now? Trials in Translation

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

Practice

Director, VTE Research GroupCardiovascular Division

Advances in the Science and Medicine of Stroke Prevention in AF

Atrial Fibrillation Case Study #1

A patient with AF has a CHA2DS2-VASc score of 3 and and a HAS-BLED score of 4. What would you do for stroke prevention?

1) Anticoagulate the patient because risk of stroke outweighs risk of bleeding

2) Prescribe aspirin as the risk of bleeding with anticoagulation outweighs the risk of stroke

Please Enter Your Response On Your Keypad

Atrial Fibrillation Case Study #2 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) Warfarin2) Dabigatran 3) Rivaroxaban 4) Apixaban 5) All of the above

Atrial Fibrillation Case Study #3Question #1

A 78-year-old woman with symptomatic AF, heart failure, and hypertension undergoes successful cardioversion and is now in sinus rhythm. She has been treated with warfarin. What would you do regarding her antithrombotic regimen?

1) She does not need any now that she is in sinus rhythm

2) Switch to aspirin3) Continue anticoagulation

Our patient has recurrent AF and is continued on warfarin. She has had very labile INRs despite careful management. The best step in her management is?

1) Switch to aspirin and clopidogrel 2) Switch to a factor Xa or IIa inhibitor3) Continue warfarin

What about if her INR has been stable 2.0-3.0 on warfarin. Is there any benefit from to switching to a novel anticoagulant?

1) Yes

She wants to start a NOAC. Her weight is 70 kg (154 lbs) and her creatinine clearance (CrCl) is currently 20 mL/min but frequently fluctuates to 10-15 mL/min. What are her options?

1) Dabigatran 150 mg twice daily2) Dabigatran 75 mg twice daily3) Rivaroxaban 20 mg once daily4) Rivaroxaban 15 mg once daily5) Apixaban 5 mg twice daily6) Apixaban 2.5 mg twice daily7) She should continue on warfarin

What NOAC would be dose adjusted if her CrCl was stable at 40 mL/min (Cr 1.3)?

1) Dabigatran 2) Rivaroxaban 3) Apixaban

You decide to start dabigatran. Which of the following is true regarding transitioning a patient from warfarin to dabigatran?

1) Start dabigatran when INR < 32) Start dabigatran when INR < 23) Start dabigatran 24 hours after last dose of

warfarin

What about if you decide to start rivaroxaban instead?

1) Start rivaroxaban when INR < 32) Start rivaroxaban when INR < 23) Start rivaroxaban 24 hours after last dose of

warfarin

A man taking dabigatran for AF is in a motor vehicle accident and needs emergency surgery. It is unclear when he last took his dabigatran. Which of the following tests, if normal, would reassure surgeon that he is not anticoagulated?

1) INR (international normalized ratio)2) aPTT (activated partial thromboplastin time)3) PT (prothrombin time)4) Bleeding time

What if he had been on rivaroxaban or apixaban?

1) INR (international normalized ratio)2) aPTT (activated partial thromboplastin time)3) PT (prothrombin time)4) Bleeding time

Atrial Fibrillation Case Study #5 A patient on a NOAC is having life-threatening

bleeding. What reversal agent(s) can be considered?

1) Protamine sulfate2) Vitamin K3) Fresh frozen plasma (FFP)4) Activated prothrombin complex concentrate

(aPCC)5) Factor VIIa 6) All of the above7) 1, 2, and 38) 4 and 5Please Enter Your Response On Your Keypad

Atrial Fibrillation Case Study #6 A patient with atrial fibrillation on anticoagulation is

admitted to the hospital with NSTEMI and is found to have a lesion amenable to PCI. What is the best management option?

1) Placement of a DES with 1 year of aspirin, clopidogrel, and an anticoagulant and then anticoagulant and aspirin alone.

2) Placement of BMS with 1 month of aspirin, clopidogrel, and an anticoagulant and then anticoagulant and aspirin alone.

3) Placement of DES with 1 year of aspirin, prasugrel/ticagrelor, and an anticoagulant and then anticoagulant and aspirin alone.

4) Placement of a BMS with 1 month of aspirin, prasugrel/ticagrelor, and an anticoagulant and then anticoagulant and aspirin alone.

5) Placement of either a BMS/DES with initial treatment of clopidogrel and an anticoagulant.

Atrial Fibrillation Case Study #7 A patient on a NOAC is having an elective

surgical procedure. When should he stop his NOAC prior to surgery?

1) 24 hours before2) 36 hours before3) 48 hours before4) Depends on renal function

Stroke Prevention in Atrial Fibrillation

atrial fibrillationaf

atrial fibrillation

boehringer ingelheim

bristol myers squibb

sanofiaventis christian

daiichi sankyo

ross medical corporation

boehring ingelheim

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