Transcript Slide 1

New Dimensions and
Landmark Practice Advances
National Experts in Cardiovascular Medicine
Illuminate and Debate
New Frontiers in Atrial Fibrillation
Emerging Perspectives in Thrombosis Mitigation for the
Cardiovascular Specialist—Translating Evidence into Action
Program Moderator
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Welcome and Program Overview
CME-accredited 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
Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies
COI: Full faculty disclosures provided in syllabus and at the beginning
of the program
Program Educational Objectives
As a result of this educational activity, participants will learn about:
► Advances in oral anticoagulation based on new mechanisms involving
inhibition of the coagulation cascade and possible implications for
prophylaxis of arterial thromboembolism in the setting of atrial fibrillation.
► The mechanisms involved in thromboembolic prevention and the
rationale for identifying agents with predictable anticoagulation, in the
absence of clinical monitoring.
► Current ACCP, ACC, AHA, and AAN guidelines for stroke prevention in
the setting of AF.
► Novel approaches for residual risk reduction and secondary prevention
of adverse thromboembolic events (stroke) in the setting of atrial
fibrillation, and related conditions.
Program Faculty
Program Moderator
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
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
Elaine M. Hylek, MD, MPH
Associate Professor of Medicine
Department of Medicine
Director, Thrombosis Clinic and
Anticoagulation Service
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
Faculty COI Disclosures
Samuel Z. Goldhaber, MD
Research Support: BMS, Boehringer-Ingelheim, Eisai, Johnson and Johnson, sanofiaventis
Consultant: BMS, Boehringer-Ingelheim, Eisai, Medscape, Merck, sanofi-aventis,
Vortex
Jonathan L. Halperin, MD
Consulting fees from the following companies involved in development of
investigational drugs or devices: Astellas Pharma, U.S., Bayer HealthCare, Biotronik,
Inc., Boehringer Ingelheim, Daiichi Sankyo Pharma, Johnson & Johnson, Portola
Pharmaceuticals, and sanofi-aventis
Elaine M. Hylek, MD, MPH
Steering Committee: Bristol-Myers Squibb
Advisory Board: Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, sanofiaventis
Jeffrey I. Weitz, MD, FRCP, FACP
Grants/Research Support: CIHR, HSFO, CFI, ORF
Speakers Bureau: Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, DaiichiSankyo, Bayer, Pfizer, The Medicines Company, Eisai, Takeda
New Frontiers in Atrial Fibrillation
ATRIAL FIBRILLATION
Current Challenges
in Thrombosis Medicine for the
Cardiovascular Specialist
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Atrial Fibrillation: Twice as Common
as Previously Suspected
► Incidence increased 13% over past
20 years
► In USA, 12-16 million will be affected
by 2050
► Increasing obesity and increasing
age are risk factors that help explain
rise in incidence
Miyasaka Y. Circulation 2006; 114: 119-125
AF Prevalence: Age and Gender
Prevalence, percent
Prevalence of atrial fibrillation with age
Age, years
JAMA 2001; 285: 2370
Mortality Rates in AF
► Double the overall age and gender
matched population
► No reduction in past two decades
► Mortality 9-fold higher during 1st 4
months after diagnosis
Miyasaka Y, et al. JACC 2007; 49: 986-992
Risk Factors for Stroke
Risk Factor
Relative Risk
Old Stroke/TIA
2.5
Hypertension
1.6
CHF
1.4
Increased age
1.4/10 years
DM
1.7
CAD
1.5
Arch Intern Med 1994; 154: 1449-1457
Atrial Fibrillation: A Risk Factor
for Vascular Events
•
•
•
•
•
RISK FACTORS for THROMBOSIS
Hypertension
Hyperlipidemia
Age
Diabetes Mellitus
Smoking
Atherosclerosis/Atherothrombosis
Atherosclerosis/Atherothrombosis
MI
MI
AF
Stroke, MI, Vascular Death
Wolf PA et al. Arch Intern Med 1987; 147: 1561-1564
Leckey R et al. Can J Cardiol 2000; 16: 481-485
CHF
CHF
Thrombus in Left Atrial Appendage
Associated with Stroke
Thrombus
Thrombus in left
atrial appendage is
correlated with
increased
thromboembolic risk
in AF
Chimowitz. Stroke 1993; 24: 1015
Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622
Left Atrial
Appendage
One Sixth of all Strokes
Attributable to AF
Framingham Study
30
20
AF prevalence
Strokes attributable
to AF
%
10
0
50–59
60–69
70–79
80–89
Age Range (years)
Wolf et al. Stroke 1991; 22: 983-988
Problems with Established
Therapy: Warfarin
► Delayed onset/offset
► Unpredictable dose response
► Narrow therapeutic range
► Drug–drug, drug–food interactions
► Problematic monitoring
► High bleeding rate
► Slow reversibility
First Month of Warfarin Therapy has
High Bleeding Rate
Bleeding Type
Head Bleed
Major NonHead Bleed
1st Month
Warfarin
0.92%
(annualized)
1.2%
(annualized)
Subsequent
Warfarin
0.46% per year
0.61% per year
Fang MC. J Am Geriatr Soc 2006; 54: 1231-1236
FDA Adds “Black Box”
Warning/Precaution for Warfarin
October 6, 2006
Warning: Bleeding Risk
August 16, 2007
Precaution: “Consider a lower initial
warfarin dose for patients with certain
genetic variations.”
Learning Objectives
►
Warfarin dosing and genetics
►
FDA warfarin labeling vs. NHLBI Randomized
Clinical Trial
Warfarin: Advantages
1. INR assesses anticoagulant level
2. Multiple antidotes available
3. Omitting one or two doses usually is not clinically
problematic
4. Introduced in 1954. Has “stood the test of time.”
No liver toxicity
5. Ability to maintain target INR is improving
(Now > 60% in top facilities)
6. No anticoagulant has demonstrated superior
efficacy or safety
7. Inexpensive
Warfarin: Walking a Tightrope
►
Excessive dose precipitates
hemorrhage
►
Inadequate dose predisposes to stroke
and pulmonary embolism
►
Dosing nomograms are awkward,
cumbersome
►
Dosing by trial and error predominates
Therapeutic Range for Warfarin
INR Values at Stroke or ICH
Odds Ratio
15.0
Stroke
Intracranial
Hemorrhage
10.0
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
Hylek, EM et al. N Engl J Med. 2003;349:1019-2614
“Most intracranial hemorrhages (62%)
occur at INRs < 3.0”
Fang MC et al. Ann Intern Med. 2004;141:745-52
Reduction of Stroke in AF – Warfarin
Compared with Placebo
Adjusted-dose warfarin compared with placebo
Relative risk reduction (95% CI)
AFASAK I
SPAF
BAATAF
CAFA
SPINAF
EAFT
62% (48% to 72%)
All trials (n=6)
100
50
Warfarin better
Hart et al. Ann Intern Med 1999; 131: 492-501
0
-50
-100
Warfarin worse
ACTIVE W Trial
OAC
• Standard Care (INR 2.0 – 3.0)
• INR at least monthly
Clopidogrel plus ASA
• Clopidogrel 75 mg once daily
• ASA 75-100 mg once daily
ACTIVE W: Outcome Events
Primary Outcome
• Stroke, Non-CNS Systemic
Embolism, MI, Vascular Death
Safety Outcome
• Major Bleeding
0.10
ACTIVE W: Stroke, Non-CNS Embolism,
MI and Vascular Death
5.64 %/year
P = 0.0002
0.04
0.06
Clopidogrel+ASA
3.93 %/year
0.02
OAC
0.0
Cumulative Hazard Rates
0.08
RR = 1.45
# at Risk
C+A
OAC
0.0
0.5
3335
3371
3149
3220
Years
1.0
2387
2453
1.5
916
911
ACTIVE W: Major Bleeding
RR = 1.06
0.03
P = 0.67
0.01
0.02
2.2 %/year
OAC
Clopidogrel+ASA
0.0
Cumulative Hazard Rates
0.04
2.4 %/year
# at Risk
C+A
OAC
0.0
0.5
3335
3371
3172
3212
Lancet. 2006;367:1903-1912, 1877-1878
Years
1.0
2403
2423
1.5
914
901
The Frontiers of Thrombosis:
Mitigation (Stroke Reduction) in
Atrial Fibrillation
New oral anticoagulants, given in fixed dose
without laboratory coagulation monitoring,
may improve and expand on existing
anticoagulation options. We will hear about
these exciting development tonight.
New Frontiers in Atrial Fibrillation
Challenges in Stroke Prevention
for Patients with Atrial Fibrillation
Achieving Balance Between
Prevention of Thromboembolism
and Risk of Bleeding
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
Projected U.S. Prevalence of AF
Projected Number of People with AF
(millions)
An Expanding Epidemic
18
16
14
12
10
8
Based on Projected Incidence
6
Based on Current Incidence
4
2
0
Year
Miyakasa Y, et al. Circulation 2006; 114: 119.
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
Priorities in the Management of AF
The Patient Care Pathway
Rhythm Control
Prevention of
Thromboembolism
Rate Control
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%
50%
Hart R, et al. Ann Intern Med 2007;146:857.
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 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
INR at the Time of Stroke or Bleeding
Efficacy and Safety of Warfarin
20
Odds Ratio
15
Ischemic Stroke
Intracranial bleeding
10
5
1
1.0
2.0
3.0
4.0
5.0
6.0
International Normalized Ratio
Fang MC, et al. Ann Intern Med 2004; 141:745.
Hylek EM, et al. N Engl J Med 1996; 335:540.
7.0
8.0
Warfarin for Atrial Fibrillation
Limitations Lead to Inadequate Treatment
Adequacy of Anticoagulation in
Patients with AF in Primary Care Practice
No warfarin
65%
INR above
target
6%
INR in
target range
15%
Subtherapeutic INR
13%
Samsa GP, et al. Arch Intern Med 2000;160:967.
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
ACTIVE-A
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
Cumulative Incidence
0.15
28% RRR
408 (3.3%/year)
HR 0.72
(95% CI, 0.62–0.83)
p <0.001
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.
Warfarin Dosing and Genomics
CYP2C9 – Gene encoding cytochrome P450
hepatic enzyme responsible for primary
clearance of S-warfarin, the active enantiomer;
variant alleles are associated with sensitivity to
warfarin.
VKORC1 – Gene encoding vitamin K epoxide
reductase complex 1; variant alleles are
associated with warfarin resistance.
Warfarin Dosing and Genomics
Keeping Ahead of the Data
Intervention Period:
Informed by genetic/clinical
information
Dose Initiation
1
2
3
4,
5
Dose Titration
6
7
8
…
Objective: To compare the effect of pharmacogenetic &
clinical warfarin dosing algorithms on initial proportion of
time in therapeutic range of anticoagulation intensity
The Ideal Anticoagulant
Wide Therapeutic Margin
Safe Therapeutic
Range
Thrombosis
Thrombosis
Dose, Concentration, or Intensity of
Anticoagulation
Bleeding
New Anticoagulant Development
The Clinical Trial Pathway
DVT/VTE
Prophylaxis
Orthopaedic
Surgery
DVT/VTE
Treatment
AFib/Stroke
Prophylaxis
Arterial
Disease
Other
Potential
Indications
Investigational Anticoagulant Targets
ORAL
PARENTERAL
TF/VIIa
TFPI (tifacogin)
TTP889
X
IX
VIIIa
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
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
SPORTIF III and V
Stroke and Systemic Embolism
Ximelagatran Better
Warfarin Better
-0.66
SPORTIF III
p=0.10
+0.45
p=0.13
SPORTIF V
-0.03
p=0.94
Pooled
-4
-3
-2
-1
0
1
Difference in Absolute Event Rates
(Ximelagatran – Warfarin)
SPORTIF-V Investigators. JAMA 2005; 293: 690-8.
2
3
4
SPORTIF III and V
Secondary Stroke Prevention
Δ = –0.44%/year
95% CI –1.86, 0.98; p=0.625
Event Rate (%/year)
p=NS
Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279
Major Bleeding Complications
SPORTIF III and V
On-treatment Analysis
Event Rate (%/year)
p=0.054
SPORTIF III
Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279
SPORTIF V
Pooled
SPORTIF III and V
Liver Enzyme Elevations
ALT >3 x ULN
Number of patients
Warfarin
Ximelagatran
80
60
Incidence (%)
100
40
ALT >3x ULN
20
0
1
2
3
4
5
6
7
8
9 10 11 12 13 15 16 18 21 27
Months
Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279
Emerging Anticoagulants
Potential Alternatives to Warfarin
Thrombin inhibitors Factor Xa inhibitors
Direct, oral
Ximelagatran
Indirect, parenteral
Idraparinux
Dabigatran
(RE-LY Trial)
Direct, oral
Rivaroxaban
Apixaban
Edoxaban
others
Oral Factor Xa Inhibitors
Ongoing Phase III Trials for Prevention of Stroke and Systemic
Embolism in Patients with AF
Trial
Acronym
Drug
Dose
Comparator
N
Risk
factors
ROCKET-AF
Rivaroxaban
20 mg*
qd
Warfarin
(INR 2-3)
14,000
≥2
ARISTOTLE
Apixaban
5 mg
bid
Warfarin
(INR 2-3)
15,000
≥1
ENGAGE-AF
Edoxaban
30 mg bid
60 mg* qd
Warfarin
(INR 2-3)
16,500
≥2
* Adjusted based on renal function
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
(%/y)
Dronedarone
(%/y)
HR
(95% CI)
p
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
Stroke
Hohnloser SH, et al. N Engl J Med 2009; 360: 668-78.
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
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.
New Frontiers in Atrial Fibrillation
Stroke Prevention
in High Risk Populations
The Journey from Warfarin to
New Options and Strategies
Elaine M. Hylek, MD, MPH
Associate Professor of Medicine
Department of Medicine
Director, Thrombosis Clinic and Anticoagulation Service
Boston University Medical Center
Boston, Massachusetts
Projected Number of Persons
with AF (Millions)
Projected Number of Persons with AF in
the U.S. Between 2000 and 2050
15.2
16
15.9
13.1
14
10.2
12
11.7
8.9
10
7.7
10.3
6.7
8
6
5.1
5.9
8.4
5.1
11.1
11.7
12.1
9.4
7.5
6.1
4
15.9
6.8
5.6
2
0
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
Year
Assumes no further increase in age-adjusted AF incidence (blue curve) and assumes a
continued increase in incidence rate as evident in 1980 to 2000 (yellow curve)
Miyasaka, Y. et al. Circulation 2006;114:119-125
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
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
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+
Per 1,000 Person Years
Incidence of Heart Failure* by Age and Sex
(Framingham Heart Study: 1980-2003)
45
40
35
30
25
20
15
10
5
0
41.9
32.7
22.3
14.8
9.2
4.7
65-74
75-84
Age
Men
Women
* MD review of medical records using strict diagnostic criteria
Source: NHLBI
85+
Prevalence of Heart Failure by Age and Sex
(NHANES: 2005-2006)
Percent of Population
16
13.8
14
12.2
12
9.3
10
8
4.8
6
4
2
2.2
0.1
0.2
1.2
0
20-39
40-59
Age
Men
Source: NCHS and NHLBI
60-79
Women
80+
Prevalence of Dementia
North America: 6.9% prevalence; 63% increase 20102030; 151% increase 2010-2050
“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.
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
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
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
Adjusted Odds Ratios for Ischemic Stroke and Intracranial
Bleeding in Relation to Intensity of Anticoagulation
Odds Ratio
15.0
Intracranial
Bleed
Stroke
10.0
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
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
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
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.
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
Caveats Relating to Published
Data on Hemorrhage
Randomized trials
- Enrolled few patients ≥ 80 years
- Highly selected, closely monitored
- Vitamin K antagonist at entry
Prospective cohort studies
- Predominantly non-inception cohort studies of
prevalent warfarin use (survivor bias)
- Enrolled few patients ≥ 80 years
- Varying definitions of bleeding
- Most conducted within anticoagulation clinic setting
Baseline Characteristics AF Trials
Year published
N
Age, yrs
Female
Prior stroke
Hypertension
CHF
Diabetes
CHADS2 score
Historical trials
SPORTIF III/V
1989-1993
3,763
69
29%
5%
2003-2005
7,327
71
31%
21%
45%
26%
13%
NA
77%
18%
18%
NA
ACTIVE W
RE-LY
2006
6,706
70
33%
15%
2009
18,113
72
37%
20%
83%
21%
21%
2.0
79%
32%
23%
2.1
0.04 0.06 0.08 0.10
0.02
0.00
Cumulative Proportion
with Major Hemorrhage
Cumulative Incidence of Major Bleeding 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
.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
Major Hemorrhagic Events and Warfarin
Terminations by CHADS2 Score
CHADS2
Score
N
Major
Bleed
(N)
Bleeding
Rates
%
Taken Off
Therapy (N)
Taken Off
Rates
%
0
42
1
3.17
5
15.84
1
121
4
4.35
16
17.39
2
181
3
2.08
19
13.16
3
94
12
19.7
20
32.84
≥4
34
6
23.63
9
35.44
Total
472
26
Hylek EM et al, Circulation 2007;115(21):2689-2696.
69
How Do We Reconcile
These Disparate Rates?
► Inception versus prevalent?
► Burden of hemorrhagic risk factors?
► Post-discharge versus outpatient?
► Prevalence of combination therapy?
► Degree of initial selection bias?
► Observation period?
Optimizing Benefit and Reducing Risk
Hemorrhage
Thrombosis
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
Maintenance Warfarin Dose by Age
INR Target 2-3
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
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)
Causes of Elevated INRs
► Initiation
► Decreased vitamin K intake
► Potentiating Medications
► Decompensated heart failure
► Chemotherapy
► Warfarin dosing error
► Binge alcohol consumption
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
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
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
► Promise of novel anticoagulants
Incidence of Intracranial Hemorrhage
Dabigatran vs Warfarin (RE-LY)
Anticoagulant/Dose
ICH
RR
P
Dabigatran 110 mg BID
0.23%
0.29
<0.001
Dabigatran 150 mg BID
0.30%
0.41
<0.001
Warfarin (open label)
0.74%
REF
REF
Connolly et al., NEJM, 2009
Risk Factors for Intracranial Hemorrhage
► INR intensity
► Age
► Aspirin therapy
► Ischemic cerebrovascular disease
► Hypertension
► Trauma
► Vasculopathy-Leukoaraiosis, amyloid angiopathy
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.
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
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
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
Is Warfarin Obsolete?
► New oral anticoagulants are more
convenient
► But, warfarin effective when time in
therapeutic range is high
Cumulative risk of stroke, myocardial infarction, systemic embolism, or
vascular death for patients treated at centers with a TTR below or above
the study median (65%)
12
12
TTR >= 65%
TTR < 65%
10
RR=0.93 (0.70-1.24)
p=0.61
8
6
OAC
C+A
4
Event Rate (%)
Event Rate (%)
10
RR=2.14 (1.61-2.85)
P=0.0001
8
6
C+A
4
2
2
OAC
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 Dabigatran
Versus Warfarin According to Geographical Region
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
► Dosing of new oral anticoagulants is
critical: are the doses of factor Xa
inhibitors optimal?
► New oral anticoagulants will replace
warfarin, but transition may be slow
New Frontiers in Atrial Fibrillation
Atrial Fibrillation
Current Challenges in Thrombosis Medicine
for the Cardiovascular Specialist
Discussion, Comments, and The Way Forward
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Warfarin is Not Just Sitting Around
It is fighting back with:
1) Excellent efficacy (ACTIVE)
2) Pharmacogenetics analysis
3) Point-of-care testing
4) Low cost
5) Track Record (approved in 1954)
The “Red Line” in the Sand
Can rapid turnaround genetic testing
reduce the “Educated Guessing
Game” and “Play of Chance” in
warfarin dosing?
Warfarin Pharmacogenomics
1. Cytochrome P450 2C9 genotyping
identifies mutations associated with
impaired warfarin metabolism.
2. Vitamin K receptor polymorphism testing
can identify whether patients require low,
intermediate, or high doses of warfarin.
Schwartz UI. NEJM 2008; 358: 999
Percent with Dose Estimates within 20% of Actual Dose
Pharmacogenetic Algorithm versus Clinical Algorithm
versus Fixed-Dose Approach
Warfarin Pharmacogenetics Consortium. NEJM 2009;360:753-764
Genotype vs Standard Warfarin
Dosing (N=206) Couma-Gen Trial
►
Rapid turnaround CYP2C9 and VKORC1
testing vs. “empiric”
►
Primary endpoint: TTR
►
Smaller and fewer dosing changes with
genetic testing
►
No difference in TTR
Circulation 2007; 116: 2563-2570
Warfarin Clinical Dosing Nomogram
NEJM 2009; 360: 753-764
PHARMACOGENETIC
NOMOGRAM
NEJM 2009; 360: 753-764
Warfarin Pharmacogenetics
Routine use of CYP2C9 and
VKORC1 genotyping in patients
who begin warfarin therapy
is not supported by evidence
currently available.
Pharmacotherapy 2008; 28: 1084-1087
Genetic Testing for Warfarin Remains
Unproven: NHLBI Trial
About 1,200 Patients will be randomized to:
1.Genetic plus clinical guided nomogram,
versus
1.Clinically-guided nomogram
Results will be available in 2012
NHLBI Trial: 2009-2012
Primary Endpoint:
% Time in Therapeutic Range (TTR)
Hypothesis:
60% TTR in Clinical arm versus
> 72% TTR in Genetics Plus Clinical Nomogram
arm
Clinical Trials # NCT00839657
Self-Monitoring INR
Meta-analysis of 14 RCTS
►
►
►
Reduced TE events (55% fewer)
Reduced all-cause mortality (39% less)
Reduced major bleeds (35% fewer)
Benefits increase further with self-dosing
► 73% fewer TE events
► 63% lower all-cause mortality
Heneghan C. Lancet 2006; 367: 404-411
March 19, 2008: Medicare Expanded
Reimbursement for Home INR Monitoring
►
Medicare used to cover only mechanical
heart valves
►
Now will reimburse VTE (after 3 months of
warfarin) and permanent atrial fibrillation
►
Aetna follows new Medicare guidelines
(and surely others will, too)
Will Novel Anticoagulants Warrant
Additional Costs?
1. Does this require deconstruction,
demobilization, and/or reconstruction of
anticoagulation management services?
2. Will patients require monitoring of renal/
hepatic function?
Novel Oral Anticoagulants
1. Noninferiority may not suffice, but superiority
findings (150 mg dose) in RE-LY are
encouraging.
2. Superiority may be necessary to alter
prescribing behavior.
3. More trials will be forthcoming.
4. Beware of off-label use.
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: Cumulative Hazard Rates for the Primary
Outcome of Stroke or Systemic Embolism
0.05
1.0
Warfarin
0.04
0.8
Dabigatran
110 mg
0.03
0.6
0.02
Dabigatran
150 mg
0.01
0.4
0.00
0
0.2
6
12
18
24
30
0.0
0
Warfarin
Dabigatran 110 mg
Dabigatran 150 mg
6022
6015
6076
6
12
18
5862
5862
5939
5718
5710
5779
4593
4593
4682
Connolly, et al. N Engl J Med 2009;361:1139-51
24
2890
2945
3044
30
1322
1385
1429
Relative Risk of Stroke or Systemic Embolism
with Dabigatran versus Warfarin: RE-LY
Hazard Ratio with
Dabigatran, 110 mg(95% CI)
Dabigatran Better
Connolly, et al. N Engl J Med 2009;361:1139-51
Warfarin Better
Hazard Ratio with
Dabigatran, 150 mg(95% CI)
Dabigatran Better
Warfarin Better
Relative Risk of Stroke or Systemic Embolism
with Dabigatran versus Warfarin: RE-LY
Hazard Ratio with
Dabigatran, 110 mg(95% CI)
Connolly, et al. N Engl J Med 2009;361:1139-51
Hazard Ratio with
Dabigatran, 150 mg(95% CI)
RE-LY: Analysis and Comments
► RE-LY participants who were randomly assigned
to receive warfarin would have needed to have an
INR time within the therapeutic range (TTR)
approximately 79% of the time to have a stroke rate
as low as that in the group receiving 150 mg of
dabigatran.
► Even with diligent, patient self-monitoring or
pharmacogenetic dosing, such tight control is
unlikely in real world practice.
Gage, B N Engl J Med 361;12 nejm.org September 17, 2009
Connolly SJ, Pogue J, Eikelboom J, et al. Circulation 2008;118:202937.
Time in Therapeutic Range (TTR) in
Community-Based Practice: Ranges
101 Community-Based Practices in 38 States (1)
► Mean TTR was 66.5%, but varies widely, with 37% having TTR
above 75%, and 34% with TTR below 60%
► Mean TTR for new warfarin users (57.5%) lower than prevalent
users for first six months
► TTR of patients with warfarin interruptions had TTR of 61.6%
►TTR rates vary widely and are affected by new warfarin use,
procedural interruptions and INR target range
Meta-Analysis (2)
► TTR was 55%
Rose, AJ Thromb Haemost. 2008 Oct;6(10):1647-54.
Baker WL et al, J Manag Care Pharm. 2009 Apr;15(3):244-5
RE-LY: Analysis and Comments
► To prevent one nonhemorrhagic stroke, the
number of patients who would need to be
treated with dabigatran at a dose of 150 mg
twice daily, rather than warfarin, is
approximately 357.
► The number of patients who would need to be
treated with dabigatran (rather than warfarin) to
prevent one hemorrhagic stroke
is approximately 370.
Discussion: Novel Oral Anticoagulants
Where Do We Stand, November 12, 2009?
1. “In summary although there are qualifications, we
can rely on RE-LY.”
Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial)
2. 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.
Discussion: Novel Oral Anticoagulants
Discussion, Questions, and Comments