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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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Paulus Kirchhof, MDChair in Cardiovascular Medicine

University of BirminghamBirmingham, UK

Professor, Cardiology and AngiologyUniversity of Müenster

Müenster, Germany

DiscussantDiscussant

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.

Disclosure InformationDisclosure InformationPaulus Kirchhof, MD,

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

Served as an advisor or consultant for: Served as an advisor or consultant for: 3M Medica, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim 3M Medica, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim

Pharmaceuticals, Inc, MEDA Pharmaceuticals, Inc, Medtronic, Inc, Merck & Co.,Otsuka Pharma, Pharmaceuticals, Inc, MEDA Pharmaceuticals, Inc, Medtronic, Inc, Merck & Co.,Otsuka Pharma, Pfizer/BMS, sanofi-aventis, SERVIER, Siemens, Takeda Pharmaceuticals North America, Inc.Pfizer/BMS, sanofi-aventis, SERVIER, Siemens, Takeda Pharmaceuticals North America, Inc.

Received grants for clinical research from: Received grants for clinical research from: 3M Medica/MEDA Pharmaceuticals, Inc, CV Therapeutics, Medtronic, Inc, Omron Healthcare, Inc, German 3M Medica/MEDA Pharmaceuticals, Inc, CV Therapeutics, Medtronic, Inc, Omron Healthcare, Inc, German

Federal Ministry of Education and Research (BMBF), European Union, Fondation LeDucq, German Federal Ministry of Education and Research (BMBF), European Union, Fondation LeDucq, German Research Foundation (DFG), St. Jude Medical, sanofi-aventis Research Foundation (DFG), St. Jude Medical, sanofi-aventis

KEY Points of AFNET/EHRA Report

• Diagnose atrial fibrillation early enough to start therapy and prevent complications such as stroke

• Identify both conventional and emerging risk factors for atrial fibrillation and stroke

• Identify needs to start using newer anticoagulants in clinical practice as they enter the market

• Educate patients, physicians, payers, and healthcare organizations on the use of the newer drugs

Source: Kirchhof P, et al “Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options -- a report from the 3rd Atrial Fibrillation Competence Network/European Heart Rhythm Association consensus conference” Europace 2011; DOI: 10.1093/europace/eur241.

Burden of Atrial Fibrillation

• In an unselected population of 40 year olds, 25% will develop atrial fibrillation in their lifetime

• Every fourth to fifth stroke is related to atrial fibrillation

• Emerging data show that a portion of cryptogenic strokes are related to silent, undiagnosed paroxysmal atrial fibrillation

Risk Factors for Stroke in Atrial Fibrillation

• Previous stroke or TIA

• Older age

• Hypertension

• Diabetes

• Heart failure

• Female gender

• Vascular disease

CHADS2 Stroke Risk Score

• Total possible score of 6

• Congestive heart failure – 1 point

• Hypertension – 1 point

• Age 75 or older – 1 point

• Diabetes – 1 point

• Previous stroke or transient ischemic attack – 2 points

Source: JAMA 2001; 285: 2864-2870.

CHA2DS2-VASc Stroke Risk Score

Source: CHEST 2010; 137(2): 263-272.

• Total possible score of 10

• Hypertension – 1 point

• Age 75 or older – 2 points

• Age 65 to 74 – 1 point

• Diabetes – 1 point

• Previous stroke, transient ischemic attack, or thromboembolism – 2 points

• Vascular disease – 1 point

• Female gender – 1 point

ATHENA Trial

Source: Circulation 2009, 120; 1174-1180.

• Main results showed that dronedarone 400 bid significantly reduced cardiovascular hospitalization or all-cause death in patients with atrial fibrillation

• A post hoc analysis showed that dronedarone reduced the risk of stroke from 1.8% to 1.2% per year (HR 0.66, 95% CI 0.46 to 0.96)

• The effect was greater in patients with higher baseline stroke risk

Hypothesis: Adequate and early comprehensive rhythm control therapy can prevent AF-related major complications (stroke, death, heart failure) compared to usual care

Primary outcome: composite of cardiovascular death, stroke, and heart failure or acute coronary syndrome measured as hospitalization

Enrolment: Patients with recent-onset AF at risk for stroke or death

www.easttrial.org

Early treatment of Atrial fibrillation for Stroke prevention

Ximelagatran (36 mg bid) A novel, oral direct thrombin

inhibitor ximelagatran(n = 1,960)

Ximelagatran (36 mg bid) A novel, oral direct thrombin

inhibitor ximelagatran(n = 1,960)

Warfarin Target INR 2.0-3.0

(n = 1,962)

Warfarin Target INR 2.0-3.0

(n = 1,962)

Endpoints (mean follow-up 20 months): Primary – All strokes (ischemic or hemorrhagic) and systemic embolic

events, based on an intention-to-treat analysis for non-inferiority Secondary – Composite of death, stroke, systemic embolism, and MI; and

safety variables, specifically bleeding and liver enzyme elevations

Endpoints (mean follow-up 20 months): Primary – All strokes (ischemic or hemorrhagic) and systemic embolic

events, based on an intention-to-treat analysis for non-inferiority Secondary – Composite of death, stroke, systemic embolism, and MI; and

safety variables, specifically bleeding and liver enzyme elevations

AHA 2003 Late Breaking TrialsAHA 2003 Late Breaking Trials

Randomized Double-blind to:Randomized Double-blind to:

3,922 patients with nonvalvular AF and risk factors for stroke (previous stroke, hypertension, or CHF)3,922 patients with nonvalvular AF and risk factors for stroke (previous stroke, hypertension, or CHF)

SPORTIF V Trial

RE-LY Study Overview

• In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke

• At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism

Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population

No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (

%)

Rivaroxaban

Rivaroxaban Warfarin

Event Rate

1.71 2.16

Primary Efficacy OutcomeStroke and non-CNS Embolism

Efficacy:– Rivaroxaban was non-inferior to warfarin for

prevention of stroke and non-CNS embolism

– Rivaroxaban was superior to warfarin while patients were taking study drug

– By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority

Safety:– Similar rates of bleeding and adverse events

– Less ICH and fatal bleeding with rivaroxaban

Conclusion:– Rivaroxaban is a proven alternative to warfarin

for moderate or high risk patients with AF

ROCKET AF Summary

Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke:

•Reduces stroke and systemic embolism by 21% (p=0.01)

•Reduces major bleeding by 31% (p<0.001)

•Reduces mortality by 11% (p=0.047)

with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability.

ARISTOTLE Data

Source: N Engl J Med 2011; 365: 981-992.

In an unselected population of 40 year olds, 25% will develop atrial fibrillation in their lifetime

Every fourth to fifth stroke is related to atrial fibrillation

Risk factors for atrial fibrillation overlap with those for stroke in atrial fibrillation and include older age, previous stroke or TIA, hypertension, diabetes, and heart failure

Summary

At the end of this activity, participants should understand:

Newer anticoagulants are challenging warfarin and other vitamin K antagonists for the prevention of stroke in atrial fibrillation

Dabigatran (Pradaxa), a direct thrombin inhibitor, has been approved for the prevention of stroke in this patient population

Investigational oral direct factor Xa inhibitors, including rivaroxaban and apixaban, have been shown to be at least as effective as warfarin at preventing strokes; apixaban was superior in the ARISTOTLE trial

Summary

The newer anticoagulants do not require regular testing of INR, as with the vitamin K antagonists

Patients who are difficult to maintain in the therapeutic INR range may be good candidates for one of the newer agents

The educational efforts surrounding vitamin K antagonists in past decades will need to be repeated for the newer agents

Summary