N Engl J Med 2011

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Stroke Prevention in Atrial Fibrillation
An Expert Commentary With
Michael D. Ezekowitz, MD, PhD
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

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.
CME Information

Credit Designation
The University of Pennsylvania School of
Medicine Office of CME designates this
enduring material for a maximum of 0.5 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
approval is for one year from this date. Each
article is approved for 0.5 Elective credit.
Credit may be claimed for one year from the
date of each article.
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
Center’s 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 0.5 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.
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 0.5 contact hours
(0.05 CEUs). The ACPE Universal Activity
Number assigned to this knowledge-type activity
is 0052-9999-11-2353-H01-P.
Discussant
Michael D. Ezekowitz, MD, PhD
Professor of Medicine
Cardiovascular Medicine
Mainline Healthcare Interventional Cardiology
Wynnewood, Pennsylvania
Disclosure Information
Michael D. Ezekowitz, MD, PhD,
has disclosed the following relevant financial relationships:
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 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.
Risk Factors for Stroke in Atrial Fibrillation
• Previous stroke or TIA
• Older age
• Hypertension
• Diabetes
• Heart failure
• Female gender
• Vascular disease
Warfarin Era
Completed Studies: Warfarin vs. Placebo
OPEN LABEL
# Events
AFASAK: Peterson, et al
Pt-yrs
Lancet 1989; 1: 175
27
811
BAATAF: Investigators
15
922
23
508
29
972
NEJM 1990; 323: 1505
SPAF:
Investigators
Stroke 1990; 21: 538
DOUBLE BLIND
SPINAF: Ezekowitz, et al
NEJM 1992; 327: 1406
100%
50%
0%
Warfarin better
-50%
-100%
Warfarin worse
Risk Reduction
Modern Era: RE-LY
150 mg BID
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: ARISTOTLE
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
Rivaroxaban versus WARFARIN (ROCKET-AF)
Efficacy Outcomes
Stroke/Systemic Embolism
Hemorrhagic Stroke
Myocardial Infarction
Safety Outcomes
ICH
Major Bleeding
0
0.50
1.00
Rivaroxiban better
1.50
Warfarin better
2.00
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.
Summary
At the end of this activity, participants should understand:

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

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
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