Transcript Slide 1

National Experts in Cardiovascular Medicine
Illuminate and Debate
New Paradigms and Landscape Changes in
Atrial Fibrillation
Emerging Perspectives in Thrombosis Mitigation for the
Cardiovascular Specialist—Applying Landmark Trials to the
Front Lines of Cardiology Practice
Program Chairman and Moderator
Peter Libby, MD, FACC
Chief, Cardiovascular Medicine
Brigham and Women’s Hospital
Mallinckrodt Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Welcome and Program Overview
CME-certified symposium jointly
sponsored by the University of
Massachusetts Medical School and
CMEducation Resources, LLC
Commercial Support: Sponsored by
an independent educational grant
from Boehringer-Ingelheim
Faculty disclosures: Listed in
program syllabus
Program Faculty
Peter Libby, MD, FACC
Elaine M. Hylek, MD, MPH
Program Chairman and Moderator Associate Professor of Medicine
Chief, Cardiovascular Medicine
Brigham and Women’s Hospital
Mallinckrodt Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Jonathan L. Halperin, MD
Mount Sinai School of Medicine
Director, Clinical Cardiology Service
The Zena and Michael A. Wiener
Cardiovascular Institute
The Marie-Josée and Henry R. Kravis
Center for Cardiovascular Health
New York, New York
Department of Medicine
Boston University Medical Center
Boston, Massachusetts
Jeffrey I. Weitz, MD, FRCP, FACP
Professor of Medicine and Biochemistry
McMaster University
Director, Henderson Research Center
Canada Research Chair in Thrombosis
Heart and Stroke Foundation
J.F. Mustard Chair in Cardiovascular
Research
Ontario, Canada
New Frontiers in Atrial Fibrillation
Challenges in Stroke Prevention
for Patients with Atrial Fibrillation
Achieving Balance Between
Prevention of Thromboembolism
and Risk of Bleeding
Risk Stratification, Current Guidelines and Therapeutic Choices
Jonathan L. Halperin, MD
Professor of Medicine (Cardiology)
Mount Sinai School of Medicine
Director, Clinical Cardiology Services
The Zena and Michael A. Wiener Cardiovascular Institute
The Marie-Josée and Henry R. Kravis
Center for Cardiovascular Health
Atrial Fibrillation
A Substantial Threat to the Brain
►Affects
~4% of people aged >60 years
~9% of those aged >80 years
►
5%/year stroke rate
►
12%/year for those with prior stroke
►
$ billions annual cost for stroke care
►
AF-related strokes have worse outcomes
AF identifies millions of people with a
five-fold increased risk of stroke
Natural History of “Lone” Atrial Fibrillation
No Cardiopulmonary Disease; <60 Years Old
97 Patients
Mean Age = 44
14.8 years
Follow-up
0.35%/yr Stroke
0.40%/yr Mortality
Kopecky S, et al. N Engl J Med 1987; 317:669.
Stroke Risk in Atrial Fibrillation
Stroke Rate (% per year)
Untreated Control Groups of Randomized Trials
Age (years)
Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449.
Anticoagulation in Atrial Fibrillation
Stroke Risk Reductions
Warfarin
Better
Control
Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
Aggregate
100%
Hart R, et al. Ann Intern Med 2007;146:857.
50%
0
-50%
-100%
Anticoagulation in Atrial Fibrillation
The Standard of Care for Stroke Prevention
Warfarin
Better
Control
Better
Unblinded
AFASAK
SPAF
Unblinded
BAATAF
Unblinded
Terminated early
CAFA
SPINAF
Double-blind; Men only
2o prevention; Unblinded
EAFT
Aggregate
100%
50%
Hart R, et al. Ann Intern Med 2007;146:857.
0
-50%
-100%
Antithrombotic Therapy for Atrial Fibrillation
Stroke Risk Reduction
Treatment
Better
Treatment
Worse
Warfarin vs.
Placebo/Control
6 Trials
n = 2,900
Antiplatelet drugs
vs. Placebo
8 Trials
n = 4,876
100%
Hart R, et al. Ann Intern Med 2007;146:857.
50%
0
-50%
Efficacy of Warfarin in Trials vs. Practice
Stroke Risk Reductions
Treatment
Better
Treatment
Worse
Warfarin vs.
Placebo/Control
6 Trials
n = 2,900
Warfarin vs.
No anticoagulation
Medicare cohort
n = 23,657
100%
Hart R, et al. Ann Intern Med 2007;146:857
Birman-Deych E. Stroke 2006; 37: 1070–1074
50%
0
-50%
Intracerebral Hemorrhage
The Most Feared Complication of Antithrombotic Therapy
► >10% of intracerebral hemorrhages (ICH)
occur in patients on antithrombotic therapy
► Aspirin increases the risk by ~ 40%
► Warfarin (INR 2–3) doubles the risk to 0.3–
0.6%/year
► ICH during anticoagulation is catastrophic
Hart RG, et al. Stroke 2005;36:1588
Risk Stratification in AF
Stroke Risk Factors
High-Risk Factors
►Mitral stenosis
►Prosthetic heart valve
►History of stroke or TIA
Singer DE, et al. Chest 2004;126:429S.
Fang MC, et al. Circulation 2005; 112: 1687.
Risk Stratification in AF
Stroke Risk Factors
High-Risk Factors
Moderate-Risk Factors
► Mitral stenosis
►Age >75 years
► Prosthetic heart valve
►Hypertension
► History of stroke or TIA
Singer DE, et al. Chest 2004;126:429S.
Fang MC, et al. Circulation 2005; 112: 1687.
►Diabetes mellitus
►Heart failure or ↓ LV function
Risk Stratification in AF
Stroke Risk Factors
High-Risk Factors
Moderate-Risk Factors
► Mitral stenosis
►
►
►
►
► Prosthetic heart valve
► History of stroke or TIA
Age >75 years
Hypertension
Diabetes mellitus
Heart failure or ↓ LV function
Less Validated Risk Factors
►
►
►
►
Age 65–75 years
Coronary artery disease
Female gender
Thyrotoxicosis
Singer DE, et al. Chest 2004;126:429S.
Fang MC, et al. Circulation 2005; 112: 1687.
Risk Stratification in AF
Stroke Risk Factors
High-Risk Factors
Moderate-Risk Factors
► Mitral stenosis
►
►
►
►
► Prosthetic heart valve
► History of stroke or TIA
Age >75 years
Hypertension
Diabetes mellitus
Heart failure or ↓ LV function
Less Validated Risk Factors Dubious Factors
►
►
►
►
Age 65–75 years
Coronary artery disease
Female gender
Thyrotoxicosis
Singer DE, et al. Chest 2004;126:429S.
Fang MC, et al. Circulation 2005; 112: 1687.
► Duration of AF
► Pattern of AF
(persistent vs. paroxysmal)
► Left atrial diameter
The CHADS2 Index
Stroke Risk Score for Atrial Fibrillation
Score (points)
Prevalence (%)*
Congestive Heart failure
Hypertension
Age >75 years
Diabetes mellitus
Stroke or TIA
1
1
1
1
2
32
65
28
18
10
Moderate-High risk
Low risk
>2
0-1
50-60
40-50
VanWalraven C, et al. Arch Intern Med 2003; 163:936.
* Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).
Nonvalvular Atrial Fibrillation
Stroke Rates Without Anticoagulation
According to Isolated Risk Factors
Prior
Age Hypertension Female
Stroke/TIA > 75 years
Hart RG et al. Neurology 2007; 69: 546.
Diabetes Heart Failure
 LVEF
The CHADS2 Index
Stroke Risk Score for Atrial Fibrillation
Approximate
Risk threshold for
Anticoagulation
Score
(points)
Risk of Stroke
(%/year)
0
1
1.9
2.8
3%/year
2
3
4
5
6
Van Walraven C, et al. Arch Intern Med 2003; 163:936.
Go A, et al. JAMA 2003; 290: 2685.
Gage BF, et al. Circulation 2004; 110: 2287.
4.0
5.9
8.5
12.5
18.2
Risk Stratification and Anticoagulation
Stroke Reduction with Warfarin Instead of Aspirin
CHADS2 Score ~
3
2
1
0
13
42
83
250
EAFT Study Group. Lancet 1993; 324:1255.
Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.
Number of patients
Needed-to-treat
to prevent
1 stroke/year
Antithrombotic Therapy for Atrial Fibrillation
ACC/AHA/ESC Guidelines 2006
Risk Factor
No risk factors
CHADS2 = 0
One moderate risk factor
CHADS2 = 1
Any high risk factor or
>1 moderate risk factor
CHADS2 >2
or Mitral stenosis
Prosthetic valve
Recommended
Therapy
Aspirin, 81-325 mg qd
Aspirin, 81-325 mg/d or
Warfarin
(INR 2.0-3.0, target 2.5)
Warfarin
(INR 2.0-3.0, target 2.5)
Warfarin
(INR 2.5-3.5, target 3.0)
"Actually,
it's more of a
guideline than a rule.”
Bill Murray in GhostbustersⒸ (1984),
relaxing his rule "never to get involved with
possessed people" in response to Sigourney
Weaver's seductive advances.
Patient Selection for Anticoagulation
Additional Considerations
► Risk of bleeding
► Newly anticoagulated vs. established
therapy
► Availability of high-quality
anticoagulation management program
► Patient preferences
The ACTIVE Trial
Clopidogrel + Aspirin
Atrial Fibrillation + Risk Factors
ACTIVE - W
Anticoagulation-eligible
VKA
(INR 2-3)
Clopidogrel
+ Aspirin
Open-label
Non-inferiority
n = 6,706
ACTIVE - A
OAC Contraindications or Unwilling
Aspirin
+ Placebo
Double-blind
Superiority
n = 7,554
Irbesartan, 300 mg/d vs. Placebo
n = 9,016
Risk Factors:
Age 75, hypertension, prior
stroke/TIA, LVEF<45%, PAD, age
55-74 + CAD or diabetes
Clopidogrel
+ Aspirin
ACTIVE - I
Primary outcome: Stroke, systemic
embolism, MI or cardiovascular
death
The ACTIVE Trial
Clopidogrel + Aspirin
Atrial Fibrillation + Risk Factors
ACTIVE – W
ACTIVE - A
Anticoagulation-eligible
OAC Contraindications or Unwilling
VKA
(INR 2-3)
Clopidogrel
+ Aspirin
Open-label
Non-inferiority
n = 6,706
Aspirin
+ Placebo
Clopidogrel
+ Aspirin
Double-blind
Superiority
n = 7,554
Irbesartan, 300 mg/d vs. Placebo
n = 9,016
ACTIVE - I
Antithrombotic Therapy for Atrial Fibrillation
Stroke Risk Reductions
Warfarin
Better
Antiplatelet Rx
Better
ACTIVE-W
Anticoagulation vs.
Aspirin + Clopidogrel
n = 6,706
Anticoagulation vs.
Antiplatelet drugs
7 Trials
n = 4,232
100%
Connolly S, et al. Lancet 2006; 367:1903.
Hart R, et al. Ann Intern Med 2007;146:857.
50%
0
-50%
Antithrombotic Therapy for Atrial Fibrillation
Stroke Risk Reductions
Warfarin
Better
Antiplatelet Rx
Better
All patients
Warfarin vs.
Aspirin + Clopidogrel
Prior OAC
VKA-naïve
100%
Connolly S, et al. Lancet 2006; 367:1903.
50%
0
-50%
Major Hemorrhage in Relation to
Prior Anticoagulant Therapy: ACTIVE-W
Event Rate
(%/year)
“Starters”
“Switchers”
Interaction p=0.028
No
Yes
Anticoagulant Therapy at Entry
Connolly S, et al. Lancet 2006; 367:1903.
The ACTIVE Trial
Clopidogrel + Aspirin
Atrial Fibrillation + Risk Factors
ACTIVE – W
ACTIVE - A
Anticoagulation-eligible
OAC Contraindications or Unwilling
VKA
(INR 2-3)
Clopidogrel
+ Aspirin
Open-label
Non-inferiority
n = 6,706
Aspirin
+ Placebo
Double-blind
Superiority
n = 7,554
Irbesartan, 300 mg/d vs. Placebo
n = 9,016
Connolly SJ, et al. N Engl J Med 2009; 360:2066.
Clopidogrel
+ Aspirin
ACTIVE - I
The ACTIVE Trial
Reasons for Exclusion from Anticoagulation
*
*
*
*
Risk factor for bleeding*
23%
Physician judgment against
anticoagulation for patient
50%
Patient preference only
26%
Inability to comply with INR monitoring * Severe alcohol abuse within 2 years
Predisposition to falling or head trauma * Peptic ulcer disease
Persistent hypertension >160/100 mmHg * Thrombocytopenia
* Chronic need for NSAID
Previous serious bleeding on VKA
Connolly SJ, et al. N Engl J Med 2009; 360:2066.
ACTIVE-A
Total Stroke Rates
28% RRR
0.15
HR 0.72
(95% CI, 0.62–0.83)
p <0.001
408 (3.3%/year)
Cumulative Incidence
Aspirin
0.10
296 (2.4%/year)
Clopidogrel + Aspirin
0.05
0.0
0
1
2
Years
Connolly SJ, et al. N Engl J Med 2009; 360:2066.
3
4
The ACTIVE Trials
Stroke Rates and Risk Reductions
Treatment
VKA
C+A
Aspirin
ACTIVE W
(Annual Rate)
1.4
2.4
~
ACTIVE A
(Annual Rate)
~
2.4
3.3
RRR
versus Aspirin
-58%
-28%
~
RRR
versus C+A
-42%
~
~
VKA = oral anticoagulant
C+A = clopidogrel + aspirin
Connolly SJ, et al. Lancet 2006; 367:1903.
Connolly SJ, et al. N Engl J Med 2009; 360:2066.
Investigational Anticoagulant Targets
ORAL
PARENTERAL
TF/VIIa
TFPI (tifacogin)
TTP889
X
IX
VIIIa
Rivaroxaban
Apixaban
Edoxaban
LY517717
YM150
Betrixaban
TAK 42
APC (drotrecogin alfa)
sTM (ART-123)
IXa
Va
AT
Xa
II (thrombin)
Dabigatran
Idraparinux
DX-9065a
Otamixaban
IIa
Fibrinogen
Fibrin
Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.
APC activated protein C
AT
antithrombin
sTM soluble thrombomodulin
TF
tissue factor
FPI
tissue factor pathway
inhibitor
The Ideal Anticoagulant
Wide Therapeutic Margin
Safe Therapeutic
Range
Bleeding
Thrombosis
Thrombosis
Dose, Concentration, or Intensity of
Anticoagulation
Emerging Anticoagulants
Regulatory Issues
► Open-label vs. blinded trial design
► Issues related to active-control trial design
► How many trials are needed?
► Preventing use for unapproved indications
► Assessing patient-oriented outcomes
Alternatives to Anticoagulation
Atrial Fibrillation
Current approaches
Restoration and maintenance of sinus rhythm
• Antiarrhythmic drug therapy
• Catheter ablation
• Maze operation
Emerging (investigational) approaches
Obliteration of the left atrial appendage
• Trans-catheter occluding devices
• Thoracoscopic epicardial plication
• Amputation
Strokes after Conversion to NSR
Rate vs. Rhythm Control Trials
n
AFFIRM
Rate Rhythm
control control
RR
(95% CI)
p
4,917
5.7%
7.3%
1.28 (0.95-1.72)
0.12
RACE
522
5.5%
7.9%
1.44 (0.75-2.78)
0.44
STAF
266
1.0%
3.0%
3.01 (0.35-25.3)
0.52
PIAF
252
0.8%
0.8%
1.02 (0.73-2.16)
0.49
Total
5,957
5.0%
6.5%
1.28 (0.98-1.66)
0.08
Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A.
AFFIRM Trial
Stroke Rates
► 74% of all strokes were proven ischemic



44% occurred after stopping warfarin
28% in patients taking warfarin with INR <2.0
42% occurred during documented AF
Wyse AG, et al. N Engl J Med 2002; 347: 1825.
ATHENA Trial
Dronedarone vs. Placebo in Patients with AF
Stroke Rates (Secondary Analysis)
Placebo
Dronedarone
HR
(%/y)
(%/y)
(95% CI)
Stroke
1.79
1.19
0.66
0.027
Stroke or
TIA
2.05
1.37
0.67
0.020
Fatal stroke
0.54
0.36
0.67
0.247
Event
Hohnloser SH, et al. N Engl J Med 2009; 360: 668-78.
P
Percutaneous LAA Occlusion
The WATCHMAN® Device
Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med 2007; 4:428
Holmes DR, et al. Lancet 2009; 374: 534
Alternatives to Anticoagulation
Atrial Fibrillation
Current approaches
Restoration and maintenance of sinus rhythm
• Antiarrhythmic drug therapy
• Catheter ablation
• Maze operation
Emerging (investigational) approaches
Obliteration of the left atrial appendage
• Trans-catheter occluding devices
• Thoracoscopic epicardial plication
• Amputation
Is atrial fibrillation the cause of stroke
or a marker of a population at risk?
Atrial Fibrillation and Thromboembolism
The Next Challenges
►
Better tools to stratify bleeding risk
►
Noninvasive imaging and biomarkers of
inflammation and thrombosis to predict clinical
events and guide therapy
►
Confirming successful rhythm control over time
►
Targeted therapy to prevent AF in patients at
risk
►
Defining role and risk stratification strategies for
non-monitored, oral anticoagulants
From Fermented Sweet Clover
to Molecular Targeting of Coagulation
The Promise of New Approaches
The Goal:
To bring effective therapy to many more patients
and prevent thousands of strokes.
Atrial Fibrillation Case Study
Atrial Fibrillation Case Study
► An 82-year-old man with
hypertension and diabetes has
permanent atrial fibrillation
► He has a history of spinal stenosis
and walks with a walker
Atrial Fibrillation Case Study
Question 1: Which regimen would you
prescribe for prophylaxis against
thromboembolism?
a. Warfarin (INR 2.0-3.0)
b. Warfarin (INR 1.5-2.0)
c. Aspirin, 81 mg daily
d. Aspirin, 81 mg + clopidogrel, 75 mg daily
e. No antithrombotic therapy
Atrial Fibrillation Case Study
Assessment of Thromboembolic Risk
Score
(points)
Risk of Stroke
(%/year)
0
1.9
1
2.8
2
3
4
5
6
4.0
5.9
8.5
12.5
18.2
Van Walraven C, et al. Arch Intern Med 2003; 163: 936.
Go A, et al. JAMA 2003; 290: 2685.
Gage BF, et al. Circulation 2004; 110: 2287.
Atrial Fibrillation Case Study
Question 2: What if you learn that he has tripped
and fallen twice in the past two years?
a. Warfarin (INR 2.0-3.0)
b. Warfarin (INR 1.5-2.0)
c. Aspirin, 81 mg daily
d. Aspirin, 81 mg + clopidogrel, 75 mg daily
e. No antithrombotic therapy
Atrial Fibrillation Case Study
Question 3: If the oral direct thrombin inhibitor
dabigatran were available and FDA-approved for stroke
prevention in AF, in this patient with a history of
tripping you would treat with:
a. Warfarin (INR 2.0-3.0)
b. Warfarin (INR 1.5-2.0)
c. Dabigatran 110 mg P.O. B.I.D
d. Dabigatran 150 mg P.O. B.I.D.
e. Aspirin, 81 mg + clopidogrel, 75 mg daily
f. No antithrombotic therapy
Atrial Fibrillation Case Study
Anticoagulation in Patients at Risk of Falls
Atrial Fibrillation Case Study
Anticoagulation in Patients at Risk of Falls
“…persons taking warfarin must fall about 295
(535/1.81) times in 1 year for warfarin not to be the
optimal therapy…”
Atrial Fibrillation Case Study
ICH in Patients with AF Prone to Falls
Hazard ratios of independent predictors
of intracranial hemorrhage
Hazard ratio
(95% CI)
P value
High-risk for falls
1.9 (1.03-2.9)
0.002
Prior stroke
2.2 (1.7-2.8)
<0.0001
Prior bleed
1.8 (1.4-2.4)
<0.0001
Neuropsychiatric
impairment
1.4 (1.0-1.9)
0.055
Factor
► The risk of ICH was 2.8%/year in
patients at high risk of falls and 1.1 in
other patients.
► Warfarin was associated with an
increased risk of mortality among
those with ICH (30 day mortality = 52
vs. 34%, p = 0.007).
Gage BF, et al. Am J Med 2005; 118:612.
Atrial Fibrillation Case Study
Outcomes in Patients with AF Prone to Falls
Hazard ratio of warfarin for composite outcome—out-of-hospital death
or hospitalization for stroke, MI, or hemorrhage—in 1245 patients at
high risk for falls
CHADS 2
score
Hazard ratio
(95% CI)
P value
Recommended
antithrombotic
therapy
0-1
0.98 (0.56, 1.72)
0.94
Aspirin or nil
2-6
0.75 (0.61, 0.91)
0.004
Anticoagulant
Gage BF, et al. Am J Med 2005; 118:612.
Summary of Case Study
► The risk of intracranial hemorrhage is increased
in patients who fall.
► The use of oral anticoagulation does not predict
ICH, but mortality is higher among patients on
anticoagulants who develop ICH.
► The risk of mortality due to ICH is offset by the
reduction in ischemic events achieved with
anticoagulation in elderly patients with AF at
high risk of thromboembolism.
► Better risk-stratification instruments are needed.
New Frontiers in Atrial Fibrillation
Stroke Prevention in
High Risk Populations
Optimizing Warfarin Therapy in
Challenging Patient Populations
Elaine M. Hylek, MD, MPH
Associate Professor of Medicine
Department of Medicine
Director, Thrombosis Clinic and Anticoagulation Service
Boston University Medical Center
Boston, Massachusetts
Prevalence of AF by Age
Prevalence (%)
20
18
Framingham Study
16
Cardiovascular Health Study
14
Mayo Clinic Study
12
Western Australia Study
10
8
6
4
2
0
40
50
60
Age (years)
Feinberg WM. Arch Intern Med. 1995;155(5):469–473
70
80
90
Atrial Fibrillation
Morbidity and Mortality
►4- to 5-fold increased risk of stroke
►Doubling of the risk for dementia
►Tripling of risk for heart failure
►40 to 90% increased risk for overall mortality
►Risk of stroke in AF patients by age group
– 1.5% in 50 to 59 year age group
– 23.5% in 80 to 89 year age group
Benjamin EJ, et al. Circulation 2009;119:606-618
“The graying population will slowly, radically
transform society.” Richard Suzman, NIA
►
More than 37 million people are ≥ age 65.
►
By 2030, this number will exceed 70 million.
►
By 2040, those aged ≥75 years will exceed the
population 65 to 74 years old.
►
By 2050, 12%, or 1 in 8 Americans, will be
age 75 or older.
Percent of Population
Prevalence of CVD* in Adults by Age and
Sex (NHANES: 2005-2006)
100
90
80
70
60
50
40
30
20
10
0
73.3 72.6
37.9 38.5
15.9
7.8
20-39
40-59
60-79
Age
Men
Women
*Coronary heart disease, heart failure, stroke and hypertension
Source: NCHS and NHLBI
79.3
85.9
80+
Pharmacokinetic and Pharmacodynamic
Changes with Aging
►
Metabolism
 Generally, lower drug doses are required to achieve




the same effect
Receptor numbers, affinity, or post-receptor cellular
effects may change
Overall decline in metabolic capacity
Decreased liver mass
Decreased oxidative metabolism
through P450 system  decreased
clearance of drugs
Standard Creatine Clearance
ml/min/1.73
Kidney Function and Age
140
130
120
110
100
30
40
50
60
Age (years)
Andres and Tobin, 1976
70
80
Prevalence of Dementia
North America: 6.9% prevalence; 63% increase 20102030; 151% increase 2010-2050
Polypharmacy in the Elderly
►
Elderly = 12% of population;
32% of prescriptions
►
Average of 6 prescription medications;
1 to 3.5 over-the-counter drugs
►
Average nursing home patient
takes 7 medications
►
Average American senior spends
$670/year for pharmaceuticals
Adverse Drug Reactions
►
About 15% of hospitalizations in the elderly
are related to adverse drug reactions
►
The risk of adverse drug reactions increases
with the number of prescription medications
Polypharmacy and Non-adherence
►
Strongest predictor of non-adherence is
the number of medications
►
Non-adherence rates estimated 25-50%
►
Intentional about 75% of the time
Changes in regimen made by patients to:
- Increase convenience
- Reduce adverse effects or
- Decrease refill expense
Hazards of Anticoagulant Medications
►
#1 in 2003 and 2004 in the number of mentions of
“deaths for drugs causing adverse effects in
therapeutic use”1
►
Warfarin-6% of 702,000 ADEs treated in ED per year;
17% require hospitalization1
►
21 million warfarin prescriptions in 1998>>>31 million
in 20042
►
The incidence AC-related intracranial hemorrhage
quintupled during this time period3
1
Wysowski DK, et al. Arch Intern Med. 2007;167:1414-1419. 2 Budnitz DS, et al. JAMA.
2006;296:1858-1866. 3 Flaherty ML, et al. Neurology. 2007;68:116-121.
Ischemic Stroke and
Intracranial Bleeding
Adjusted Odds in Relation to Intensity of Anticoagulation
Odds Ratio
15.0
10.0
Stroke
Intracranial Bleed
5.0
1.0
0
1.0
2.0
3.0
4.0
5.0
INR
Fuster et al. J Am Coll Cardiol. 2001;38:1231-1266.
6.0
7.0
8.0
Warfarin Dosing is Complex
Factors that Correlate w/ Warfarin Dose
• Age
• Body surface area (BSA) or
•
•
•
•
•
•
•
•
weight
Amiodarone
Other drugs (e.g.
acetaminophen)
Race
Sex
Plasma vitamin K level
Decompensated CHF
Chemotherapy
Genetic status
Other Factors
(up to 40%)
Age, Sex,
Weight (10-20%)
VKORC1
(up to 25%)
CYP2C9
(up to 15%)
ACTIVE W Trial
VKA vs dual
antiplatelet Rx
Minimum threshold TTR
necessary to
realize benefit of warfarin:
≥ 58%
Circulation 2008;118. Connolly SJ for Active W Investigators
Comparison of Outcomes Among Patients Randomized to
Warfarin According to Anticoagulant Control
Results From SPORTIF III and V
TTR <60%
TTR 60-75%
TTR >75%
Outcome
TTR < 60%
TTR 60-75%
TTR>75%
Mortality, %
4.2
1.84
1.69
Major Bleed, %
3.85
1.96
1.58
Stroke/SEE,%
2.10
1.34
1.07
Arch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G
Major Hemorrhage Rates
Randomized Trials
INR Target
ICH
Major
Age
AFI
1.5-4.5
0.3
1.0
69
SPAF II
2.0-4.5
0.9
1.4
70
AFFIRM
2.0-3.0
----
2.0
70
RE-LY
2.0-3.0
0.7
3.4
72
INR Target
ICH
Major
Age
Van der Meer, et al.
(1993)
2.8-4.8
0.6
2.0
66
Palareti, et al (1996)
2.0-4.5
0.5
0.9
62
Go, et al (2003)
2.0-3.0
0.5
1.0
71
Observational
Baseline Characteristics AF Trials
Historical
trials
SPORTIF
III/V
ACTIVE
W
RE-LY
1989-1993
2003-2005
2006
2009
3,763
7,327
6,706
18,113
Age, yrs
69
71
70
72
Female
29%
31%
33%
37%
Prior stroke
5%
21%
15%
20%
Hypertension
45%
77%
83%
79%
CHR
26%
18%
21%
32%
Diabetes
13%
18%
21%
23%
NA
NA
2.0
2.1
Year published
N
CHADS2 score
Cumulative Incidence of Major Bleeding
0.04 0.06 0.08 0.10
0.02
0.00
Cumulative Proportion
with Major Hemorrhage
First Year Among Patients Newly Starting Warfarin by Age
0
100
200
Days of Warfarin
Age < 80
Hylek EM et al, Circulation 2007;115(21):2689-2696.
300
Age >=80
400
.0015
.001
.0005
0
Risk of Stopping Warfarin
.002
Risk of Stopping Therapy in the First Year Among
Patients Newly Starting Warfarin by Age
0
100
200
Days of Warfarin
Age < 80
Hylek EM et al, Circulation 2007;115(21):2689-2696.
300
Age >=80
400
Optimizing Benefit and Reducing Risk
Hemorrhage
Thrombosis
Strategies To Minimize
Risk Of Hemorrhage
THE FACTS:
Incidence of UGIB and LGIB increases with age.
70% of acute UGIB occur > 60 years of age.
Differential mucosal effect of ASA by age
Incidence of LGIB increases 200-fold from the
3rd to 9th decade of life: diverticulosis,
angiodysplasias, ischemic colitis, malignancy
Bleeding Risk Scores for Warfarin Therapy
Kuijer et al.
Arch Intern Med
1999;159:457-60
Low
Moderate
High
0
1-3
>3
Beyth et al.
Am J Med
1998;105:91-9
0
1-2
Gage et al.
Am Heart J
2006;151:713-9
0-1
2-3
Shireman et al.
Chest
2006;130:1390-6
≤1.07
>1.07 <2.19
1.6 x age + 1.3 x sex +2.2 x cancer with 1 point for
≥60, female or malignancy and 0 if none
≥65 years old; GI bleed in last 2 weeks; previous
stroke; comorbidities (recent MI, Hct < 30%,
≥3
diabetes, Creat > 1.5) with 1 point for presence of
each condition and 0 if absent
HEMORR2HAGES score: liver/renal disease,
ETOH abuse, malignancy, >75 years old, low
platelet count or function, rebleeding risk,
≥4
uncontrolled HTN, anemia, genetic factors
(CYP2C9) risk of fall or stroke, with 1 point for
each risk factor present with 2 points for previous
bleed
(0.49 x age >70) + (0.32 x female) + (0.58 x remote
bleed) + 0.62 x recent bleed) + 0.71 x ETOH/drug
>2.19 abuse) + (0.27 x diabetes) + (0.86 x anemia) +
(0.32 x antiplatelet drug use) with 1 point for
presence of each and 0 if absent
Warfarin Dose by Age
50
Warfarin Weekly Dose, mg
Warfarin Weekly Dose, mg
Derived from two independent
ambulatory populations
45
40
35
30
25
20
<50
50-59
60-69
Age
Female
70-79
80-89
Male
Garcia D, et al. Chest 2005 2005;127:2049-2056
>=90
50
45
40
35
30
25
20
<50
50-59
60-69
Age
Female
70-79
80-89
Male
>=90
Delay in INR Normalization with
Increasing Age
1b
10
INR
6
4
3
2
Index INR 7 - 9 (n = 235)
Median INR half life = 2.3 days
Interquartile Range = (1.7,3.8)
Median days to INR < 4: 1.5 days
Interquartile Range = (1.1,2.5)
1
0.00
0.25
0.50
0.75
Hylek et al, Ann Intern Med. 2001;135:393-400
1.00
Interval (days)
1.25
1.50
1.75
2.00
Risk Factors for INR > 4.0 After
Holding Two Doses of Warfarin
Adjusted Odds Ratio
Warfarin dose, weekly per 10 mg
0.87 (0.79 - 0.97)
Age, per decade
1.18 (1.01 – 1.38)
Decompensated heart failure
2.79 (1.30 – 5.98)
Active malignancy
2.48 (1.11 – 5.57)
Index INR, per unit
1.25 (1.14 – 1.37)
Risk of UGIB with Different Combinations
of Antithrombotic Agents
Mean age=72 years
Hallas J, et al. BMJ doi:10.1136/bmj.38947.697558.AE
Evolving Role for Aspirin
►
►
►
Meta-analysis of 10 trials that compared oral anticoagulant
(OAC) therapy to ASA+OAC.
4,180 patients with either heart valve, AF, or CAD
Combination therapy:
● Lower incidence of thromboembolism (OR 0.66), but the
benefits were limited to patients with valves (OR 0.27).
●
Did not benefit patients with AF (OR 0.99) or CAD (OR
0.69) nor did it influence all cause mortality.
●
Did increase the risk of major bleeding (OR 1.43).
Dentali F, Douketis JD, Lim W, Crowther M.
Arch Intern Med 2007; 167:117-124.
Strategies to Improve Quality of
VKA-Based Anticoagulant Therapy
► Vigilant monitoring around all transitions in care
► Initiate lower doses in most susceptible patient
subsets
► Increase monitoring with medication changes
► Reinforce safety points with patients and
caregivers
► Justify use of concomitant antiplatelet therapy
Summary Points and Conclusions
► Elderly patients with AF are at the highest risk of stroke
and the highest risk of hemorrhage.
► Rates of ischemic stroke significantly exceed rates of ICH
and major extracranial hemorrhage on OAC.
► Intensive efforts to optimize OAC will help to decrease
major bleeding.
► Novel anticoagulants may be safer in the elderly
population due to their wider therapeutic index, shorter
t1/2, lack of dietary interference, and fewer drug
interactions.
Atrial Fibrillation Case Study
Atrial Fibrillation Patient Case Study
► 85-year-old female with AF, HTN, HF, prior TIA,
osteoarthritis and prior diverticular GIB six months
ago, on warfarin, who presents to the ED with
complaints of SOB for several days and black stools.
► Medications: atenolol, lisinopril, lasix, warfarin, ASA
► Most recent INR 3 weeks ago = 3.1
Atrial Fibrillation Case Study
Question 1: This patient’s estimated stroke risk
per year without warfarin is:
a) 5%
b) 12%
c) 20%
d) None of the above
Physical Exam and Pertinent Data
Exam: afebrile, HR 110-130, BP 154/90
lungs-bibasilar rales
COR-irreg irreg
ABD-nontender
guaiac +
ECG:
AF with rapid VR
CXR:
mild pulmonary edema
Labs:
Hct=21, INR=8.0, Troponin -
Atrial Fibrillation Case Study
Question 2: The most appropriate management
strategy for this patient would be to:
a) Stop both aspirin and warfarin – Resume aspirin only
in one week
b) Stop both aspirin and warfarin – Resume warfain
c) Stop both aspirin and warfarin – Resume both
warfarin and aspirin in one week
d) Stop both aspirin and warfarin permanently
Atrial Fibrillation Case Study
Question 3: The patient’s bleeding episode resolves,
she is started back on warfarin, and she returns six
months later with an hematocrit of 35 (her baseline).
Her INR is 3.7. If dabigatran were approved by the
FDA for SPAF, at this point you would:
a) Stop warfarin and put the patient on clopidogrel and
aspirin
b) Adjust the warfarin to achieve an INR of 2.0 - 3.0
c) Transition patient to dabigatran 110mg PO BID
d) Transition patient to dabigatran 150 mg PO Bid
e) Start aspirin only
f) Stop all anticoagulation
New Frontiers in Atrial Fibrillation
The Emerging Role of
New Oral Anticoagulants
Landmark Trials That May
Alter the Landscape of Stroke Prevention in AF
Jeffrey I. Weitz, MD, FRCP, FACP
Professor of Medicine and Biochemistry
McMaster University
Director, Henderson Research Center
Canada Research Chair in Thrombosis
Heart and Stroke Foundation
J.F. Mustard Chair in Cardiovascular Research
Overview of Presentation
► Limitations of warfarin
► New oral anticoagulants
► Role of new agents in AF
Limitations of Warfarin
Limitation
Consequence
Slow onset of action
Overlap with a parenteral
anticoagulant
Genetic variation in metabolism
Variable dose requirements
Multiple food and drug
interactions
Frequent coagulation monitoring
Narrow therapeutic index
Frequent coagulation monitoring
New Oral Anticoagulants for Stroke
Prevention in AF
Direct Inhibitors of Factor Xa
or Thrombin
Comparison of Features of New Oral
Anticoagulants in Advanced Stages of Development
Rivaroxaban
Apixaban
Dabigatran
Etexilate
Target
Xa
Xa
IIa
Molecular Weight
436
460
628
Prodrug
No
No
Yes
Bioavailability (%)
80
50
6
Time to peak (h)
3
3
2
Half-life (h)
9
9-14
12-17
Renal excretion
(%)
65
25
80
None
None
None
Features
Antidote
Comparison of Features of New
Anticoagulants With Those of Warfarin
Features
Warfarin
New Agents
Onset
Slow
Rapid
Dosing
Variable
Fixed
Yes
No
Many
Few
Monitoring
Yes
No
Half-life
Long
Short
Antidote
Yes
No
Food effect
Drug interactions
Which of the Following
Statements is true?
1.
Oral factor Xa inhibitors have a better safety profile
than oral thrombin inhibitors
2.
Of the new oral anticoagulants, dabigatran etexilate
is most advanced in development
3.
Oral factor Xa inhibitors can be safely given to
patients with a creatinine clearance < 30 ml/min
4.
The prothrombin time can be used to monitor all
of the new oral anticoagulants
5.
Fresh frozen plasma will reverse the anticoagulant
effects of the new oral anticoagulants
RE-LY: A Non-inferiority Trial
•Atrial Fibrillation with ≥ 1 Risk Factor
• Absence of Contraindications
• Conducted in 951 centers in 44
countries
Blinded Event Adjudication
R
R
Open
Open
Warfarin
Adjusted
INR 2.0 – 3.0
N=6000
Blinded
Dabigatran
etexilate
110 mg BID
N=6000
Dabigatran
etexilate
150 mg BID
N=6000
RE-LY: Baseline Characteristics
Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
Randomized
6015
6076
6022
Mean age (years)
71.4
71.5
71.6
Male (%)
64.3
63.2
63.3
CHADS2 score
(mean)
0-1 (%)
2
(%)
3+ (%)
2.1
2.2
2.1
32.6
34.7
32.7
32.2
35.2
32.6
30.9
37.0
32.1
Prior stroke/TIA (%)
19.9
20.3
19.8
Prior MI (%)
16.8
16.9
16.1
CHF (%)
32.2
31.8
31.9
Baseline ASA (%)
40.0
38.7
40.6
Warfarin Naïve (%)
49.9
49.8
51.4
Characteristic
Connolly et al., NEJM, 2009
RE-LY: Stroke or Systemic Embolism
Non-inferiority Superiority
p-value
p-value
Dabigatran 110 vs. Warfarin
<0.001
0.34
Dabigatran 150 vs. Warfarin
<0.001
<0.001
Margin = 1.46
0.50
0.75
Dabigatran better
Connolly et al., NEJM, 2009
1.00
1.25
HR (95% CI)
1.50
Warfarin better
RE-LY: Annual Rates of Bleeding
Dabigatran Dabigatran
Warfarin
110mg
150mg
Dabigatran
110mg vs.
Warfarin
Dabigatran
150mg vs.
Warfarin
n
6015
6078
6022
RR
95% CI
p
RR
95% CI
p
Total
14.6%
16.4%
18.2%
0.78
0.74-0.83
<0.001
0.91
0.86-0.97
0.002
Major
2.7 %
3.1 %
3.4 %
0.80
0.69-0.93
0.003
0.93
0.81-1.07
0.31
LifeThreatening
1.2 %
1.5 %
1.8 %
0.68
0.55-0.83
<0.001
0.81
0.66-0.99
0.04
Gastrointestinal
1.1 %
1.5 %
1.0 %
1.10
0.86-1.41
0.43
1.50
1.19-1.89
<0.001
Connolly et al., NEJM, 2009
RE-LY: Intra-cranial Bleeding Rates
RR 0.31 (95% CI: 0.20–0.47)
p<0.001 (sup)
RR 0.40 (95% CI: 0.27–0.60)
p<0.001 (sup)
Number of events
0,74 %
RRR
60%
RRR
69%
0,30 %
0,23 %
Connolly et al., NEJM, 2009
How can dabigatran be more effective
than warfarin yet cause less bleeding?
► Targeted inhibition of thrombin
► Consistent and predictable
anticoagulant effect
RE-LY: Secondary Efficacy Outcomes
According to Treatment Group
Event
Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
Myocardial
infarction
0.7%
0.7%
0.5%
Vascular death
2.4%
2.3%
2.7%
All-cause
mortality
3.8%
3.6%
4.1%
Connolly, et al. N Engl J Med 2009;361:1139-51
Why is There More MI with Dabigatran?
► Chance finding?
► Warfarin superior to dabigatran for
inhibitionof clotting at sites of plaque
disruption?
► Other factors?
RE-LY: Outcomes in Secondary-Prevention
Patients with AF by Treatment Assignment
End point
Warfarin
Dabigatran
110 mg
twice daily
Stroke/ systemic
embolism
(%/year)
2.74
2.32
0.85
(0.59–1.22)
0.37
2.07
0.76
(0.53–1.10)
0.14
Hemorrhagic
stroke (n)
18
2
0.11
(0.03–0.47)
0.003
5
0.27
(0.10–0.72)
0.009
ICH (n)
30
6
0.20
(0.08–0.47)
0.001
13
0.41
(0.21–0.79)
0.007
RR (95% CI)
vs warfarin
p
Dabigatran
150 mg
twice daily
RR (95% CI)
vs warfarin
p
Diener HC et al. American Stroke Association International Stroke Conference 2010;
February 26, 2010; San Antonio, TX.
0.02
Warfarin
Dabigatran 110 mg
0.01
Dabigatran 150 mg
0.0
Cumulative risk
0.03
0.04
RE-LY: Cumulative Risk of ALT or AST
>3x ULN After Randomization
0
0.5
1.0
1.5
Years of follow-up
Connolly, et al. N Engl J Med 2009;361:1139-51
2.0
2.5
Which Dose for Which Patient?
Lower-dose regimen
► Elderly
► Renal insufficiency
► Lower stroke risk (CHADS2 score of 1)
Higher-dose regimen
► Higher stroke risk (CHADS2 score ≥ 2)
Meta-analysis of Ischemic Stroke
or Systemic Embolism
W vs placebo
W vs W low dose
W vs ASA
W vs ASA + clopidogrel
W vs dabigatran 150
0
0.3
0.6
0.9
Favours warfarin
Camm J.: Oral presentation at ESC on Aug 30th 2009.
1.2
1.5 1.8 2.0
Favours other treatment
What About Trials with
Other New Oral Anticoagulants?
► ROCKET – Rivaroxaban
► ARISTOTLE – Apixaban
► ENGAGE - Edoxaban
What about other
indications?
RE-COVERTM Trial Design
Single-dummy
period
Warfarin
placebo
Double-dummy period
Dabigatran etexilate 150 mg bid
Warfarin placebo
30 days
follow up
Objective
confirmation
of VTE
72 h
Dabigatran etexilate placebo bid
Warfarin
Initial parenteral
therapy
E
E= enrolment
R= randomization
R
Until INR 2.0 on
two consecutive
measurements
(8-11 days)
Warfarin
(INR 2.0–3.0)
6 months
End of treatment
Efficacy and Safety Outcomes
Outcome
Dabigatran
Dabigatran
HR (95% CI)
Recurrent VTE
and VTE-related
death
2.4%
2.1%
1.10 (0.65-1.84)
Major bleeding
1.6%
1.9%
0.82 (0.45-1.48)
Schulman et al., N Engl J Med, 2009
Is Warfarin Obsolete?
► New oral anticoagulants are more
convenient
► But, warfarin effective when time in
therapeutic range is high
Cumulative Risk of Stroke, MI,
Systemic Embolism, or Vascular Death
Patients treated at centers with a TTR below or above the study median (65%)
TTR < 65%
12
RR=0.93 (0.70-1.24)
p=0.61
8
OAC
6
RR=2.14 (1.61-2.85)
P=0.0001
10
C+A
4
Event Rate (%)
Event Rate (%)
10
TTR >= 65%
12
8
C+A
6
4
OAC
2
2
0
0
0.0
0.5
1.0
1.5
Years
Connolly, S. J. et al. Circulation 2008;118:2029-2037
0.0
0.5
1.0
Years
1.5
Time in Therapeutic Range (TTR) with
Warfarin in the RE-LY Trial
Group
Relative Risk
Overall
64%
VKA Experienced
61%
VKA Naïve
67%
Relative Risk of Stroke or Systemic Embolism with
According to Geographical Region
Dabigatran Versus Warfarin
Subgroup
All patients
Long-term VKA
therapy
No
Yes
Patients Dabigatran Warfarin
total no.
18,113
110 mg 150 mg
1.53
1.11
Hazard Ratio with P Value
Dabigatran, 100
for
mg (95% CI)
Interaction
1.69
9,123
1.57
1.07
1.67
8,989
1.49
1.15
1.70
Region
North America
6,533
1.19
1.11
1.51
South America
1,134
1.82
0.91
1.68
Western Europe
3,941
1.53
1.26
1.43
Central Europe
South Asia
2,829
1,134
1.22
3.35
0.78
0.84
1.06
4.00
East Asia
1,648
1.87
1.77
2.28
Other
1,072
1.95
0.88
2.27
0.5
1.0
Dabigatran Better
Connolly et al., NEJM 2009
Hazard Ratio with
P Value
Dabigatran,
for
150 mg (95% CI) Interaction
0.72
0.81
0.91
0.11
1.5
Warfarin Better
0.5
1.0
1.5
Dabigatran Better Warfarin Better
Who is Not a Candidate for Dabigatran?
► Stable on warfarin
► Renal impairment
► Severe hepatic disease
► Poor compliance
Unanswered Questions
► Management of patients with severe
coronary artery disease or recent GI
bleeding?
► Will short half-life obviate need for
antidotes?
► Will elimination of monitoring adversely
impact patient care?
Conclusions: RE-LY and New, Oral NonMonitored Anticoagulation
► Dabigatran etexilate is superior to warfarin
for stroke prevention and non-inferior for
VTE treatment
► Dosing of new oral anticoagulants is
critical; are the doses of factor Xa inhibitors
optimal?
► New oral anticoagulants will replace
warfarin, but transition likely to be slow
Atrial Fibrillation Case Study
Atrial Fibrillation Case Study
► Mrs. A. is a 78-year-old woman who is taking
warfarin for stroke prevention on the background
of atrial fibrillation. She also takes ASA 81 mg
daily.
► Her risk factors for stroke include hypertension
and type II diabetes mellitus. Her INR control has
been erratic with values ranging from 1.5 to 6.8.
► For the past two weeks, she has had intermittent
nosebleeds lasting 5 to 20 minutes. She is
anxious to stop warfarin.
Atrial Fibrillation Case Study
Question 1: What is the best approach for this
patient?
(a) Stop the warfarin and the ASA
(b) Stop the ASA, but continue warfarin
(c) Perform CYP2C9 and VKORC1 genotyping to
better identify an appropriate warfarin dose
(d) Stop the warfarin and add clopidogrel 75 mg daily
(e) Continue warfarin and ASA, but monitor the INR
more frequently
Atrial Fibrillation Case Study
The ASA was stopped, but Mrs. A. still
complains of nosebleeds. Despite weekly
monitoring, her INR continues to range from
1.8 to 4.8. A calculated creatinine clearance
is 45 ml/min.
Atrial Fibrillation Case Study
Question 2: If dabigatran were approved for stroke
prevention in patients with atrial fibrillation, what
would you likely do at this point?
(a) Continue on warfarin
(b) Continue on warfarin, but add low-dose vitamin K
(c) Switch from warfarin to dabigatran etexilate 110
mg b.i.d.
(d) Switch from warfarin to dabigatran etexilate 150
mg b.i.d.
(e) Switch from warfarin to ASA and clopidogrel
Atrial Fibrillation and Thromboembolism
Current State of the Art and Science
►
There is a new, quickening rhythm to the pace of
research and clinical advances in atrial fibrillation
►
Etiology of AF is multifactorial and we are just beginning
to understand the inter-relationship among myriad
factors
►
Noninvasive imaging and biomarkers of inflammation
and thrombosis can predict clinical events in AF and may
help guide therapy
►
Risk stratification strategies for AF are useful but
imperfect: advances and refinements are required to
help define role for non-monitored, oral anticoagulants
Atrial Fibrillation and Thromboembolism
Current State of the Art and Science
► Strategies are being developed to improve the safety and
efficacy of vitamin K antagonists (VKAs), but achieving
acceptable TTRs remains a challenge
► Elderly patients with AF are at the highest risk of stroke
and the highest risk of hemorrhage, and therefore
demand special attention
► Novel anticoagulants appear to be safer in the elderly
population due to their wider therapeutic index, shorter
t1/2, lack of dietary interference, and fewer drug
interactions.
Atrial Fibrillation and Thromboembolism
Current State of the Art and Science
►
Dabigatran etexilate is superior to warfarin for stroke
prevention and non-inferior for VTE treatment
► Dosing strategy for new oral anticoagulants is critical:
selecting the appropriate dose in the individual patient to
achieve ideal balance of stroke prevention and bleeding
minimization is a work in progress
► New oral anticoagulants will replace warfarin, and the
transition will impact the landscape of anticoagulation
management
 The RE-LY Trial represents the most compelling evidence
to date for revising, reconsidering, and reshaping our
current VKA-based paradigm for stroke prevention in AF
Atrial Fibrillation and Thromboembolism
Current State of the Art and Science
► At least four trials evaluating the safety and efficacy of
oral, non-monitored anticoagulants for SPAF are in
progress: stay tuned
Thank You
QUESTIONS