Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation

An Expert Commentary With An Expert Commentary With Michael D. Ezekowitz, MD, PhDMichael D. Ezekowitz, MD, PhD

A Clinical Context ReportA Clinical Context Report

Jointly Sponsored by:Jointly Sponsored by:

andand

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationExpert CommentaryExpert Commentary

Supported in part by an educational grant from Supported in part by an educational grant from Ortho-McNeilOrtho-McNeil, Division of Ortho-McNeil-, Division of Ortho-McNeil-

Janssen Pharmaceuticals, Inc., administered by Janssen Pharmaceuticals, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.Ortho-McNeil Janssen Scientific Affairs, LLC.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationExpert CommentaryExpert Commentary

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationClinical Context SeriesClinical Context Series

The goal of this series is to provide up-to-The goal of this series is to provide up-to-date information and multiple perspectives date information and multiple perspectives on the pathogenesis, symptoms, risk on the pathogenesis, symptoms, risk factors, and complications of stroke factors, and complications of stroke prevention in atrial fibrillation as well as prevention in atrial fibrillation as well as current and emerging treatments and best current and emerging treatments and best practices in the management of stroke practices in the management of stroke prevention in atrial fibrillation.prevention in atrial fibrillation.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationClinical Context SeriesClinical Context Series

Target AudienceTarget Audience

Electrophysiologists, cardiologists, Electrophysiologists, cardiologists, primary care physicians, nurses, nurse primary care physicians, nurses, nurse practitioners, physician assistants, practitioners, physician assistants, pharmacists, and other healthcare pharmacists, and other healthcare professionals involved in the management professionals involved in the management of stroke prevention in atrial fibrillation.of stroke prevention in atrial fibrillation.

Activity Activity Learning ObjectiveLearning Objective

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Michael D. Ezekowitz, MD, PhDProfessor of Medicine

Cardiovascular MedicineMainline Healthcare Interventional Cardiology

Wynnewood, Pennsylvania

DiscussantDiscussant

Disclosure InformationDisclosure InformationMichael D. Ezekowitz, MD, PhD,

has disclosed the following relevant financial relationships:has disclosed the following relevant financial relationships:

Served as a consultant for: Served as a consultant for: – ARYx Therapeutics– AstraZeneca Pharmaceuticals– Boehringer Ingelheim Pharmaceuticals, Inc.– Bristol-Myers Squibb– Daiichi-Sankyo– Eisai Inc.– Gilead Science, Inc.– Johnson & Johnson– Medtronic, Inc.– Merck & Co., Inc.– Pfizer Inc.– Portola Pharmaceuticals – Sanofi

Disclosure InformationDisclosure Information

Michael Mullen, MD, Clinical Instructor of Vascular Neurology, University of Pennsylvania; Todd Neale; andand Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner, have disclosed that they have no relevant financial have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity.related directly or indirectly to this educational activity.

The staff of The University of Pennsylvania School of Medicine Office of CME, MedPage Today, andand Projects In Knowledge have no relevant financial relationships or have no relevant financial relationships or conflicts of interest with commercial interests related directly conflicts of interest with commercial interests related directly or indirectly to this educational activity.or indirectly to this educational activity.

Risk Factors for Stroke in Atrial Fibrillation

• Previous stroke or TIA

• Older age

• Hypertension

• Diabetes

• Heart failure

• Female gender

• Vascular disease

Completed Studies: Warfarin vs. PlaceboCompleted Studies: Warfarin vs. Placebo

100% 50% 0% -50% -100%

Warfarin better Warfarin worse

Risk Reduction

AFASAK: Peterson, et al Lancet 1989; 1: 175

BAATAF: Investigators NEJM 1990; 323: 1505

SPAF: Investigators Stroke 1990; 21: 538

SPINAF: Ezekowitz, et al NEJM 1992; 327: 1406

27

15

23

29

811

922

508

972

# Events Pt-yrs

DOUBLE BLINDDOUBLE BLIND

OPEN LABELOPEN LABEL

Warfarin Era

1.81

25

1.87

5

1.93

75

ICH

Major Bleeding

Major GI Bleeding

Any Bleeding

Ischemic Stroke

Stroke

Hemorrhagic Stroke

Myocardial Infarction

Stroke / Systemic Embolism

DABIGATRAN WARFARIN

Hazard Ratio0 0.5 1 1.5 2

0.56

25

0.62

5

0.68

75

0.81

25

0.87

5

0.90

15

0.31

25

1.06

25

1.12

5

0.37

5

1.18

75

0.75

0.25

0.43

75

better better

0.56

25

0.62

5

0.68

75

0.31

25

1.12

5

0.37

5

0.75

0.25

0.43

75

better

0.12

5

0.18

75

1.06

25

1.18

75

1.56

25

1.56

25

1.68

75

1.75

All Cause Mortality

0.81

25

0.87

5

0.93

75

EfficacyOutcomes

SafetyOutcomes

Source: Connolly S, et al ”Dabigatran versus wafarin in patients with atrial fibrillation” N Engl J Med 2009: 361.c & N Engl J Med 2010: 363.

Modern Era: RE-LY 150 mg BID

ICH

Major Bleeding

Major GI Bleeding

Any Bleeding

Stroke

Ischemic Stroke

Hemorrhagic Stroke

EfficacyOutcomes

SafetyOutcomes

Stroke / Systemic Embolism

APIXABAN WARFARIN

Hazard Ratio0 0.5 1 1.5 2

0.56

25

0.62

5

0.68

75

0.81

25

0.87

5

0.90

15

0.31

25

1.06

25

1.12

5

0.37

5

1.18

75

0.75

0.25

0.43

75

better better

0.56

25

0.62

5

0.68

75

0.81

25

0.87

5

0.90

15

0.31

25

1.06

25

1.12

5

0.37

5

1.18

75

0.75

0.25

0.43

75

better

Myocardial Infarction

All Cause Mortality

Source: Connolly S, et al ”Dabigatran versus wafarin in patients with atrial fibrillation” N Engl J Med 2009: 361.c & N Engl J Med 2010: 363. Granger, et al N Engl J Med 2011

Modern Era: ARISTOTLE

Stroke/Systemic Embolism

Hemorrhagic Stroke

Myocardial Infarction

Safety Outcomes

ICH

Major Bleeding

Efficacy Outcomes

0 0.50 1.00 1.50 2.00

Rivaroxiban better Warfarin better

Rivaroxaban versus WARFARIN (ROCKET-AF)

Patient Populations Lacking Data With New Anticoagulants

• Patients with mechanical heart valves

• Patients with poor renal function

• Children

Reduction in Intracranial Hemorrhage Versus Placebo

• Dabigatran 150 mg BID – 0.30% versus 0.74% (RR 0.40, P<0.001)

• Apixaban 5 mg BID – 0.33% versus 0.80% (HR 0.42, P<0.001)

• Rivaroxaban 20 mg – 0.5% versus 0.7% (HR 0.67, P=0.02)

Sources: N Engl J Med 2009; 361: 1139-1151; N Engl J Med 2011; 365: 883-891; N Engl J Med 2011; 365: 981-992.

Mortality Reductions Versus Placebo

• Dabigatran 150 mg BID – 3.64% versus 4.13% (RR 0.88, P=0.051)

• Apixaban 5 mg BID – 3.52% versus 3.94% (HR 0.89, P=0.047)

• Rivaroxaban 20 mg – 4.5% versus 4.9% (HR 0.92, P=0.15)

Sources: N Engl J Med 2009; 361: 1139-1151; N Engl J Med 2011; 365: 883-891; N Engl J Med 2011; 365: 981-992.

Strokes associated with afib tend to be severe, killing about 20% of patients in a month

60% of survivors are severely disabled Afib-related strokes tend to become more

common as the population ages

Summary

At the end of this activity, participants should understand:

Dabigatran (Pradaxa) is a direct thrombin inhibitor, and apixaban and rivaroxaban (both not yet approved) are direct factor Xa inhibitors

All have been shown to as effective (rivaroxaban) or better (dabigatran and apixaban) than warfarin at preventing strokes

It is unclear whether the different mechanisms of action will be important in differentiating between the new anticoagulants

Summary

Warfarin will remain relevant, as some patient populations – including those with mechanical heart valves – have not been included in the trials of new anticoagulants

Patients who are well controlled on warfarin might want to keep taking it because it is inexpensive

Conversely, the reduction in intracranial bleeding with the newer anticoagulants might argue for switching patients who are well controlled on warfarin

Summary

Patients must be committed to taking the new anticoagulants and to the twice-daily regimen

Emphasis must be placed on minimizing temporary and permanent discontinuation of the novel anticoagulants

Much of the bleeding risk with the new anticoagulants comes from extracranial bleeds, which are more tolerable than intracranial hemorrhages

Summary