Stroke Prevention in Atrial Fibrillation
An Expert Commentary With
Paulus Kirchhof, MD
A Clinical Context Report
Stroke Prevention in Atrial Fibrillation
Expert Commentary
Jointly Sponsored by:
and
Stroke Prevention in Atrial Fibrillation
Expert Commentary
Supported in part by an educational grant from
Ortho-McNeil, Division of Ortho-McNeilJanssen Pharmaceuticals, Inc., administered
by Ortho-McNeil Janssen Scientific Affairs,
LLC.
Stroke Prevention in Atrial Fibrillation
Clinical Context Series
The goal of this series is to provide up-todate 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.
Stroke Prevention in Atrial Fibrillation
Clinical Context Series
Target 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.
Activity Learning Objective
CME Information: Physicians

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CME Information

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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.
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
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Credit may be claimed for one year from the
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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
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.
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
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
• 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.
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.
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
Enrolment: Patients with recent-onset AF at risk for
stroke or death
www.easttrial.org
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
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
Primary Efficacy Outcome
Stroke and non-CNS Embolism
Cumulative event rate (%)
6
5
Event
Rate
Rivaroxaban
Warfarin
1.71
2.16
Warfarin
4
Rivaroxaban
3
HR (95% CI): 0.79 (0.66, 0.96)
2
P-value Non-Inferiority: <0.001
1
0
0
120
240
360
480
600
720
840
3407
3478
2472
2539
1496
1538
960
Days from Randomization
No. at risk:
Rivaroxaban 6958
Warfarin
7004
6211
6327
5786
5911
5468
5542
Event Rates are per 100 patient-years
Based on Protocol Compliant on Treatment Population
4406
4461
634
655
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
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% (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.
Source: N Engl J Med 2011; 365: 981-992.
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
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
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