Stroke Prevention in Atrial Fibrillation An Expert Commentary With Paulus Kirchhof, MD A Clinical Context Report

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Stroke Prevention in Atrial Fibrillation An
Expert Commentary With Paulus Kirchhof, MDA
Clinical Context Report
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Stroke Prevention in Atrial FibrillationExpert
Commentary

• Jointly Sponsored by
• ?
• and

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Stroke Prevention in Atrial FibrillationExpert
Commentary

• Supported in part by an educational grant from
  Ortho-McNeil, Division of Ortho-McNeil-Janssen
  Pharmaceuticals, Inc., administered by
  Ortho-McNeil Janssen Scientific Affairs, LLC.

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Stroke Prevention in Atrial FibrillationClinical
Context Series
The goal of this series is to provide up-to-date
information and multiple perspectives on the
pathogenesis, symptoms, risk factors, and
complications of stroke prevention in atrial
fibrillation as well as current and emerging
treatments and best practices in the management
of stroke prevention in atrial fibrillation.
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Stroke Prevention in Atrial FibrillationClinical
Context SeriesTarget Audience
Electrophysiologists, cardiologists, primary care
physicians, nurses, nurse practitioners,
physician assistants, pharmacists, and other
healthcare professionals involved in the
management of stroke prevention in atrial
fibrillation.
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Activity Learning Objective

• Upon successful completion of this educational
  program, participants should be able to?

• Review the relevance and significance of the
  activity in the broader context of clinical care?

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CME Information Physicians

• Statement of Accreditation
• This activity has been planned and implemented
  in accordance with the Essential Areas and
  Policies of the Accreditation Council for
  Continuing Medical Education through the joint
  sponsorship of the University of Pennsylvania
  School of Medicine and MedPage Today. The
  University of Pennsylvania School of Medicine is
  accredited by the ACCME to provide continuing
  medical education for physicians.

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CME Information

• Credit Designation
• The University of Pennsylvania School of
  Medicine Office of CME designates this enduring
  material for a maximum of 1.0 AMA PRA Category 1
  Credits. Physicians should claim only the
  credit commensurate with the extent of their
  participation in the activity.

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CME Information Physicians

• Credit for Family Physicians
• MedPage Today "News-Based CME" has been reviewed
  and is acceptable for up to 2098 Elective credits
  by the American Academy of Family Physicians.
  AAFP accreditation begins January 1, 2011. Term
  of approval is for one year from this date. Each
  article is approved for 1 Elective credit. Credit
  may be claimed for one year from the date of each
  article.

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CE Information Nurses

• Statement of Accreditation
• Projects In Knowledge, Inc. (PIK) is accredited
  as a provider of continuing nursing education by
  the American Nurses Credentialing Centers
  Commission on Accreditation
• Projects In Knowledge is also an approved
  provider by the California Board of Registered
  Nursing, Provider Number CEP-15227
• This activity is approved for 0.75 nursing
  contact hours

DISCLAIMER Accreditation refers to educational
content only and does not imply ANCC, CBRN, or
PIK endorsement of any commercial product or
service.
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CE Information Pharmacists

• Projects In Knowledge is accredited by the
  Accreditation Council for Pharmacy Education
  (ACPE) as a provider of continuing pharmacy
  education. This program has been planned and
  implemented in accordance with the ACPE Criteria
  for Quality and Interpretive Guidelines. This
  activity is worth up to 0.75 contact hours (0.075
  CEUs). The ACPE Universal Activity Number
  assigned to this knowledge-type activity is
  0052-9999-11-2399-H04-P.

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Discussant

• Paulus Kirchhof, MD
• Chair in Cardiovascular Medicine
• University of Birmingham
• Birmingham, UK
• Professor, Cardiology and Angiology
• University of Müenster
• Müenster, Germany

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Disclosure Information

• Michael Mullen, MD, Clinical Instructor of
  Vascular Neurology, University of Pennsylvania
  Todd Neale and Dorothy Caputo, MA, RN, BC-ADM,
  CDE, Nurse Planner, have disclosed that they have
  no relevant financial relationships or conflicts
  of interest with commercial interests related
  directly or indirectly to this educational
  activity.
• The staff of The University of Pennsylvania
  School of Medicine Office of CME, MedPage Today,
  and Projects In Knowledge have no relevant
  financial relationships or conflicts of interest
  with commercial interests related directly or
  indirectly to this educational activity.

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Disclosure Information

• Paulus Kirchhof, MD,
• has disclosed the following relevant financial
  relationships?
• Served as an advisor or consultant for 3M
  Medica, AstraZeneca Pharmaceuticals LP, Bayer
  HealthCare Pharmaceuticals, Boehringer Ingelheim
  Pharmaceuticals, Inc, MEDA Pharmaceuticals, Inc,
  Medtronic, Inc, Merck Co.,Otsuka Pharma,
  Pfizer/BMS, sanofi-aventis, SERVIER, Siemens,
  Takeda Pharmaceuticals North America, Inc.
• Received grants for clinical research from 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 Research Foundation (DFG), St.
  Jude Medical, sanofi-aventis

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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.
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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

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Risk Factors for Stroke in Atrial Fibrillation

• Previous stroke or TIA
• Older age
• Hypertension
• Diabetes
• Heart failure
• Female gender
• Vascular disease

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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.
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CHA2DS2-VASc Stroke Risk Score

• 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

Source CHEST 2010 137(2) 263-272.
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ATHENA Trial

• 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

Source Circulation 2009, 120 1174-1180.
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Early treatment of Atrial fibrillation for Stroke
prevention

• 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 Enr
olment Patients with recent-onset AF at risk for
stroke or death
www.easttrial.org
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SPORTIF V Trial
3,922 patients with nonvalvular AF and risk
factors for stroke (previous stroke,
hypertension, or CHF)
Randomized Double-blind to

• Ximelagatran (36 mg bid)
• A novel, oral direct thrombin inhibitor
  ximelagatran
• (n 1,960)

• 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

AHA 2003 Late Breaking Trials
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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

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Primary Efficacy Outcome Stroke and non-CNS
Embolism
Warfarin
Rivaroxaban
Cumulative event rate ()
HR (95 CI) 0.79 (0.66, 0.96) P-value
Non-Inferiority lt0.001
Days from Randomization
No. at risk Rivaroxaban 6958 6211 5786
5468 4406 3407 2472 1496
634 Warfarin 7004 6327 5911
5542 4461 3478 2539 1538 655
Event Rates are per 100 patient-years Based on
Protocol Compliant on Treatment Population
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ROCKET AF Summary

• 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

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ARISTOTLE Data

• 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
  (p0.01)
• Reduces major bleeding by 31 (plt0.001)
• Reduces mortality by 11 (p0.047)
• with consistent effects across all major
  subgroups and with fewer study drug
  discontinuations on apixaban than on warfarin,
  consistent with good tolerability.

Source N Engl J Med 2011 365 981-992.
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Summary
At the end of this activity, participants should
understand

• 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

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Summary

• 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

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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