stroke prevention in atrial fibrillation an expert commentary with michael d. ezekowitz, md, phd a...
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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