Transcript Document 7127828

Mechanisms ● Mortality ● Therapeutics
Critical Advances in the Science and Medicine of
Thromboembolic Disease
A Year 2009 Panvascular Science-to-Strategy Update
Program Co-Chairman
John H. Alexander, MD, MHS, FACC
Associate Professor of Medicine
Division of Cardiovascular Medicine
Duke University Medical Center
Duke Clinical Research Institute
Durham, North Carolina
Program Co-Chairman
Stavros V. Konstantinides, MD
Professor of Medicine
Vice Chairman
Department of Cardiology
and Pulmonology
University of Goettingen, Germany
Welcome and Program Overview
CME-accredited symposium jointly sponsored by the University of
Massachusetts Medical Center, office of CME and CMEducation
Resources, LLC
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 session, participants will:
► Learn about advances in oral anticoagulation based on new
mechanisms involving inhibition of the coagulation cascade and
possible implications for prophylaxis of thromboembolic and
atherothrombotic events in the setting of ACS (secondary prevention)
and atrial fibrillation (residual risk reduction).
► Learn how to evaluate and analyze anticoagulation strategies—alone
and in combination with antiplatelet agents and risk factors affecting
thromboembolism— across the panvascular, arterial, and venous
spectrum.
► Learn about advances in oral anticoagulation based on new
mechanisms involving inhibition of the coagulation cascade and
possible implications for prophylaxis of VTE in multiple settings.
Program Faculty
Program Co-Chairman
John H. Alexander, MD, MHS, FACC
Associate Professor of Medicine
Division of Cardiovascular Medicine
Duke University Medical Center
Duke Clinical Research Institute
Durham, North Carolina
Program Co-Chairman
Stavros V. Konstantinides, MD
Professor of Medicine
Vice Chairman
Department of Cardiology and
Pulmonology
University of Goettingen, Germany
Deepak L. Bhatt, MD, MPH,
FACC, FAHA, FSCAI
Chief of Cardiology
VA Boston Healthcare System
Director, Integrated Interventional
Cardiovascular Program,
Brigham and Women’s Hospital and the VA
Boston Healthcare System
Senior Investigator, TIMI Group
Harvard Medical School
Boston, Massachusetts
Sunil V. Rao, MD
Director of Interventional Cardiology
Veterans Administration Medical Center
Division of Cardiovascular Medicine
Duke University Medical Center
Durham, North Carolina
Faculty COI Financial Disclosures
John H. Alexander, MD, MHS, FACC
Program Co-Chairman
Research Support: Bristol Myers Squibb, Medtronic Japan, NIH, Portola Pharma,
Regado Biosciences, Medicure, Millennium Pharmaceuticals, Momenta Pharma,
Schering Plough
Consulting / Honorarium: Adolor, Astra Zeneca, Daiichi Sankyo, Medicure, NIH,
Novartis, Pfizer
Stavros V. Konstantinides, MD
Program Co-Chairman
Lecture fees: Bayer HealthCare, Bristol-Myers Squibb, Boehringer Ingelheim, CSL
Behring, Daiichi Sankyo, GlaxoSmithKline, sanofi-aventis
Faculty COI Financial Disclosures
Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI
Consultant: Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi
Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic,
Millennium, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering
Plough, Takeda, The Medicines Company, Vertex.
Principal Investigator for several potentially related studies. His institution has
received funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, sanofiaventis, The Medicines Company.
This presentation discusses off-label and/or investigational uses of various drugs
and devices
Sunil V. Rao, MD
Consultant: sanofi-aventis, The Medicines Company, Cordis Corporation
Research funding: Cordis Corporation, Momenta Pharmaceuticals, Portola
Pharmaceuticals
Off-label uses of drugs/devices will be discussed: Fondaparinux in NSTE ACS,
Enoxaparin in PCI, Bivalirudin in NSTE ACS
The Panvascular Thrombosis Crisis
Epidemiology and Challenges
► Venous thromboembolism (VTE), atrial fibrillation (AF) and
acute coronary syndromes (ACS) are worldwide health
problems.
► Convergence is emerging between venous and arterial
thrombotic disease: shared risk factors and risk-benefit
decisions for anticoagulation management.
► It makes sense to determine whether a combination of
antiplatelet- and anticoagulation-directed interventions
might optimize clinical (thrombosis-related) outcomes,
while mitigating adverse bleeding events.
Challenges in VTE Prevention
► Effective prophylaxis and treatment are available:
however, VTE prophylaxis is under-used and guideline
adherence is poor.
► Results from studies employing factor Xa inhibitors for
primary VTE prophylaxis appear promising.
► Can we do better? What are the emerging strategies?
With anticoagulants? With other classes (e.g. statins)?
Challenges in Secondary
Prevention of ACS
► Demographic (i.e., an aging population) and procedural
(i.e., post-stenting requirements for dual antiplatelet
therapy) factors, produce challenging clinical scenarios in
which triple therapy (TT) with dual antiplatelet therapy
(thienopyridine plus ASA) and systemic anticoagulation
may be required.
► In ACS patients, despite trials demonstrating incremental
benefit in MACE reduction with TT, clinicians are reluctant
to invoke TT in all but the highest risk patients (ACS,
STENT, plus AFIB)
► Can we do better? How do we do better? Role of Factor
Xa inhibition?
Bleeding: The Red Line in the Sand
► Bleeding is the "red line in the sand," the omnipresent
pushback factor that limits how far we can push
antithrombotic therapy.
► Bleeding complications appear to affect clinical outcomes,
including thrombosis events: however the mechanism is
unclear, but it may be due to transfusion-related effects or,
cessation of, failure to initiate, or down-titratation of
antithrombotic therapy in patients who are at risk of or
have manifested bleeding complications.
Bleeding: Antithrombotic Challenge
► Every antithrombotic strategy has its "unique" profile of
pitfalls, limitations, and clinical challenges:
1) Warfarin (variability, consistency of INR target control,
monitoring, pharmacogenomic variability)
2) UFH (overdosing or under-dosing)
3) LMWH (excessive bleeding in ACS?)
4) GPIs (ultra-potent at cost of bleeding risk, costly)
5) Prasugrel (high potency and challenges in high bleeding risk
subgroups)
► Can we do better? What strategies work? What do
trials teach us? What does the profile for Factor Xa
inhibitors look like?
Solutions to Current Limitations of
Antithrombotic Therapy
► Strategies to maintain antithrombotic efficacy, while
reducing bleeding risk take multiple forms:
1) Use of alternative agents with "ideally balanced" anticoagulant
and anti-ischemic effects (e.g. bivalirudin during PCI)
2) Pharmacogenomic analysis (warfaring, thienopyridines)
3) Patient-centered monitoring of INR
4) Bolus infusion of GPI at time of procedure
5) Novel approaches with new mechanisms of action (i.e. factor Xa
and direct thrombin inhibition).
► Are these solutions good enough? What is the evidence?
Can we do better? How do we find out?
Solutions to Current Limitations of
Antithrombotic Therapy
► Factor Xa inhibitors are being evaluated in clinical
trials to determine whether or not they can achieve a
more favorable balance between bleeding and
thrombosis prevention/treatment across the vascular
spectrum
► We don't know the precise answer to this question
yet, although there are some favorable signals.
Thinking Inside the Box
For Better and Worse
Arterial
Thrombosis/ACS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Antithrombotic
Effects
Venous
Thromboembolism (VTE)
Anticoagulation
Antiplatelet Agents
Combination Therapy
Dosing
Special Populations
Risk-Benefit Analysis
Panvascular Considerations
Pharmacogenomics
Point-of-Care Testing
Emerging Therapies
Bleeding
Panvascular Crisis in Thrombosis Medicine
Welcome to the Program
Panvascular Crisis in Thrombosis Medicine
Thromboprophylaxis Across
the Arteriovenous Spectrum
The Evolving Role of Factor Xa Inhibition
Stavros Konstantinides, MD
Heart Center
Department of Cardiology and Pulmonology
Goettingen, Germany
Thromboprophylaxis Across the A-V Spectrum
► Current concepts and management of
arterial and venous thrombosis
► The ‘Thrombosis Continuum’:
Clinical evidence, pathophysiological
background
► Novel antithrombotic strategies
Acute Coronary Syndromes
Pathophysiology
CV risk factors:
• Arterial hypertension
• Hyperlipoproteinemia
• Smoking
• Diabetes
• [Obesity]
Libby P. Circulation 2001;104:365-72
Acute Coronary Syndromes
Antiplatelet Therapy
Primary Therapeutic Target
Aspirin
GPI
Thienopyridines
Ruggeri ZM. Nat Med 2002;8:1227-34
Acute Coronary Syndromes
Anticoagulants Part of the Therapeutic Strategy
1988
ASA
1992
ASA+
Heparin
1998
ASA+
Heparin+
AntiGPIIbIIIa
12–15 %
8–12 %
6–10 %
Death / MI
< 1988
16–20 %
2003
ASA+
LMWH +
Clopidogrel +
Intervention
4–8 %
Atrial Fibrillation - Impact on the Population
Projected number of
persons with AF (millions) in the US
16
Most common significant cardiac arrhythmia

4.5 million people in the EU, 2.2 million in the US
14
12
10
10.3
11.7
12.1
2045
2050
9.4
8
8.4
7.5
6
4 5.1
11.1
6.1
5.6
6.8
2
0
2000
2005
2010
2015
2020
2025
2030
Year
Assuming no further increase in age-adjusted AF incidence
Miyasaka et al. Circulation 2006
2035
2040
Atrial Fibrillation
Risk factors for thrombosis (stroke)
Therapy
High risk of stroke
► Prior
thromboembolism (stroke, TIA, systemic embolism)
► Rheumatic
mitral stenosis
Oral VKA
► More
than one of: age ≥75 years, hypertension, heart failure,
impaired LV systolic function, or diabetes mellitus
Moderate risk of stroke
► Only
one of: age ≥75 years, hypertension, heart failure,
impaired LV systolic function, or diabetes mellitus
Low risk of stroke
► ‘Lone’ AF
(no other risk factors)
Oral VKA or
aspirin
Aspirin
ACC/AHA/ESC 2006
Oral VKA target INR is 2.5 (range 2–3); aspirin is recommended at 81–325 mg/day
Fuster et al., Circulation 2006
Venous Thromboembolism
► Annual incidence of
VTE in the US:
350,000-600,000
► Annual mortality:
100,000
► More deaths than from
breast cancer, AIDS,
car accidents
Venous Thromboembolism
Initial Anticoagulation and Secondary Prevention
Recommendation
LMWH or fondaparinux recommended form of
initial treatment for most patients
„Idiopathic“ VTE: VKA for at least 3 months
„Idiopathic“ VTE, low bleeding risk, stable INR:
consider long-term anticoagulation
Class
Level
I (1)
A (A)
I
A
IIb
B
Venous Vs. Arterial Thrombosis –
Traditional Concept
‘Distinct’ Entities, Overlapping Therapeutic Modalities
Anticoagulants for VTE
►Primary prevention
● After orthopedic surgery
● After general surgery
● In cancer patients
►Treatment/secondary
prevention
A/C for arterial thrombosis
►‘Secondary’ Prevention
● Stroke in patients with
atrial fibrillation
● Acute coronary
syndromes
Thromboprophylaxis
Across the A-V Spectrum
► Current concepts and management of
arterial and venous thrombosis
► The ‘Thrombosis Continuum’:
Clinical evidence, pathophysiological
background
► Novel antithrombotic strategies
The Thrombosis Continuum:
Clinical Evidence
Relative Risk (RR) of Arterial Events in PE Patients
CV Event
1 Year RR
2-20 Year RR
Acute MI
2.6
1.3
Stroke
2.9
1.3
Sorensen HT. Lancet 2007; 370: 1773-1779
The Thrombosis Continuum:
Clinical Evidence
Cardiovascular Risk Factors and VTE (n=63,552 pts)
Risk Factor
Relative Risk
Obesity
2.3
Hypertension
1.5
Diabetes
1.4
Cigarettes
1.2
High Cholesterol
1.2
Ageno W. Circulation 2008; 117: 93-102
Links Between Venous and
Arterial Thrombosis
Tissue Injury and the ‘Extrinsic’ Pathway
Links Between Venous
and Arterial Thrombosis
Platelets and the ‘Intrinsic’ Pathway
Activated
platelet
Thrombin
receptor
Fibrin crosslinking
Risk Factors Linking Venous and
Arterial Thromboembolism
 Mechanical injury to the vessel wall:
activation of platelets and coagulation
proteins
 Inflammatory mechanisms: role of obesity,
hyperlipoproteinemia
 Thrombophilic states: Increased fibrin
turnover
Venous and Arterial Thrombosis –
Evolving Concept
One Entity, One Indication for Anticoagulation
Anticoagulants for VTE
A/C for arterial thrombosis
►Primary prevention
►‘Secondary’ Prevention
● After orthopedic surgery
● After general surgery
● In cancer patients
►Treatment/secondary prevention
● Stroke in patients with
atrial fibrillation
● Acute coronary
syndromes
Thromboprophylaxis
Across the A-V Spectrum
► Current concepts and management of arterial and
venous thrombosis
► The ‘Thrombosis Continuum’:
Clinical evidence, pathophysiological background
► Novel antithrombotic strategies:
Focus on key factors of both arterial and venous
thrombosis
Challenges with Current
Oral Anticoagulants
 Maintaining INR in therapeutic range by regular
monitoring
 Vigilance for drug interactions
 Patient education on diet
►Undertreatment: Physicians’ fear of the risk of
bleed lead them to under-dosing
►Poor and inconsistent patient follow-up and
monitoring
Therapeutic vs.
Toxic Range for Warfarin
15.0
Intracranial
Hemorrhage
Odds Ratio
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
Risks of Anticoagulation With VKA
Meta-analysis of 33 studies (4,374 patient-years)
Early vs. late
phase of A/C
Bleeding rate
(major bleeding)
Intracranial
bleeding rate
Case fatality
rate
First 3 months
2.06 %
1.48%
9.3%
2.74% per year
0.65% per year
9.1%
After first 3
months
Linkins et al. Ann Intern Med 2003;139:893-900
Actual VTE Prophylaxis - ENDORSE
68,183 patients; 32 countries; 358 sites
First patient enrolled August 2, 2006; Last patient enrolled January 4, 2007
Lancet 2008; 371: 387-394
VTE Prophylaxis –
Poor Worldwide Status
52% at risk for VTE
(50% received ACCPrecommended prophylaxis)
Surgical
Medical
64% at risk for VTE
42% at risk for VTE
59% received ACCPrecommended prophylaxis
40% received ACCPrecommended prophylaxis
New Oral Anticoagulants –
Direct Thrombin Inhibitors
XIIa
XIa
VIIa
Tissue
Factor
IXa
Xa
II
×
Factor IIa
(thrombin)
Dabigatran
Dabigatran Study Program
Primary VTE Prophylaxis (completed)
Acute Treatment of VTE
Secondary VTE Prophylaxis
Stroke Prophylaxis
in Patients with AF
RENOVATE: Primary Efficacy End Point
All VTE Episodes, all Deaths
P<0.001 for non-inferiority
Event rate (%)
P<0.001 for non-inferiority
Dabigatran
Eriksson BI et al Lancet 2007; 370:949-56
RENOVATE: Safety End Point
Event rate (%)
Severe Bleeding
Dabigatran
Eriksson BI et al Lancet 2007; 370:949-56
REMODEL: Primary Efficacy End Point
All VTE, all Deaths
Event rate (%)
P=0.017 for non-inferiority
Dabigatran
Eriksson BI et al. J Thromb Haemost 2007;5:2178-2185
P<0.001 for non-inferiority
New Oral Anticoagulants –
Direct Factor Xa Inhibitors
XIIa
XIa
IXa
×
Xa
Factor II
(prothrombin)
Fibrinogen
Fibrin clot
Tissue
Factor
VIIa
Rivaroxaban
Apixaban
YM150
DU-176b
LY517717
Betrixaban
TAK 442
Rivaroxaban
Study Program
Preclinical phase
Indication
VTE-Prevention
Phase IIa
ODIXaHIP
Phase IIb
Phase III
ODIXa
HIP (od)
ODIXa
HIP2 (bid)
ODIXa
KNEE
(bid)
Therapy of PE/DVT
SPAF
ACS
EINSTEIN
ODIXa
DVT (od) DVT (bid)
ODIXa EINSTEIN
DVT (bid) DVT (od)
ATLAS
ACS
TIMI 46
(od, bid)
ROCKET
AF (od)
RECORD1
HIP (od)
RECORD3
KNEE (od)
EINSTEIN
DVT/PE
(od)
RECORD2
HIP (od)
RECORD4
KNEE (od)
EINSTEIN
EXTENSION (od)
Rivaroxaban - RECORD 3
20
Total VTE
RRR 49%
Enoxaparin
40 mg od
Rivaroxaban 10 mg od
Incidence (%)
15
10
Major VTE
5
Symptomatic VTE
RRR 62%
2.6%
18.9%
9.6%
RRR 65%
Major bleeding
2.0%
1.0%
0
Lassen M. N Engl J Med 2008;358:2776-2786
0.7%
0.5%
NS
0.6%
Rivaroxaban - RECORD 1
5
Rivaroxaban 10 mg once daily
Enoxaparin 40 mg once daily
Total VTE
Incidence (%)
4
3.7%
RRR 70%
3
Major VTE
2.0%
RRR 88%
2
Symptomatic VTE
1.1%
Major bleeding
1
0.5%
0.2%
0
Eriksson B. N Engl J Med 2008:358:2765-2775
0.3%
0.1%
0.3%
Apixaban - Features
►
Oral, direct, selective factor Xa inhibitor
►
Concentration-dependent anticoagulation
►
No reactive intermediates
►
No organ toxicity or LFT abnormalities in
chronic toxicology studies
►
Low likelihood of drug interactions or
QTc prolongation
►
Good oral bioavailability
►
No drug-food interactions
►
Balanced elimination (~25% renal)
►
Half-life ~12 hrs
He et al., ASH, 2006, Lassen, et al ASH, 2006
O
N
NH2
N
O
O
N
N
O
Apixaban - Antithrombotic Effects in vivo
(Carotid Arterial Thrombosis in the Rabbit)
Dose dependent effects of apixaban,
fondaparinux and warfarin on integrated blood flow
Wong PC, et al. J Thromb Haemost 2008;6:820-829
Apixaban - Antithrombotic Effects in vivo
(Arteriovenous Shunt Thrombosis in the Rabbit)
Dose dependent effects of apixaban,
fondaparinux and warfarin on thrombus weight
Wong PC, et al. . J Thromb Haemost 2008;6:820-829
Apixaban - Antithrombotic Effects in vivo
(Venous Thrombosis in the Rabbit)
Dose dependent effects of apixaban,
fondaparinux and warfarin on thrombus weight
Wong PC, et al. . J Thromb Haemost 2008;6:820-829
Apixaban Clinical Study Program
Indication
Status
VTE Prevention in Major Orthopedic
Surgery (ADVANCE 1, 2, 3)
Phase III
VTE Prevention in Acutely Ill Medical
Patients (ADOPT)
Phase III
VTE Prevention in Cancer Patients
Phase II
Acute and Extended VTE Treatment
Planning Phase III
Stroke Prevention in Atrial Fibrillation
(ARISTOTLE, AVERROES)
Phase III
Prevention of Thrombotic Events in recent
ACS (APPRAISE, Circulation 2009)
Phase II
Apixaban Phase 3 - VTE Prevention
ADVANCE-1
CV185034
VTE prevention after knee replacement surgery (N ~ 3000)
ADVANCE-2
CV185047
VTE prevention after knee replacement surgery (N ~ 3000)
ADVANCE-3
CV185035
VTE prevention after hip replacement surgery (N ~ 4000)
ADOPT
CV185036
VTE prevention in acutely ill medical patients (N ~ 6500)
•30d vs. ~6d enoxaparin 40mg QD followed by
placebo post-discharge (superiority)
•
•
12d vs. enoxaparin 30mg BID (superiority)
12d vs. enoxaparin 40mg QD (superiority)
•
35d vs. enoxaparin 40mg QD (noninferiority)
ADVANCE–2 - LATE-BREAKING
Apixaban in Total Knee Replacement
► Randomized double-blind trial comparing apixaban with
enoxaparin for thromboprophylaxis after total knee replacement
(TNR)
► 3057 patients from 125 sites in 27 countries were randomized
► Compared efficacy and safety of apixaban 2.5 mg orally bid with
enoxaparin 40 mg subcutaneously (sc) once daily for preventing
VTE after TKR
► HYPOTHESIS: Apixaban would be non-inferior to enoxaparin
based on a pre-specified margin for the primary efficacy outcome
in which the upper limit of the two-sided 95% CI is < 1.25 for
relative risk and < 0.056 for the absolute risk difference.
Gallus, A.S. et. al., LB-MO-005, ISTH 2009
ADVANCE–2
RRR=0.50
P=0.019
RRR=0.62
P<0.001
n=243
n=243
n=147
Enoxaparin
Apixaban
Gallus, A.S. et. al., LB-MO-005, ISTH 2009
Major VTE
Primary Efficacy Outcome
Final Efficacy Outcomes
n=26
n=13
Enoxaparin
Apixaban
ADVANCE–2
Safety Results
► Clinically relevant bleeding (major or clinically relevant nonmajor) occurred in 53 patients (3.5%) and 72 patients (4.8%)
given apixaban and enoxaparin respectively (P= 0.09, adjusted
risk difference, -1.2%, 95% CI - 2.7 to 0.2%).
► Two apixaban patients died from PE and one enoxaparin
patient died from bleeding.
► One additional patient given apixaban died from multi-organ
system failure, with clinically suspected sepsis and hepatitis.
► Rates of elevated liver transaminases were low (1.5 to 1.7%)
and similar between the groups
Gallus, A.S. et. al., LB-MO-005, ISTH 2009
Apixaban in Patients with Metastatic Cancer
A Randomized Phase II Feasibility Study
► A randomized double blind phase II trial with apixaban
► Patients with metastatic cancer on 1st or 2nd line chemotherapy
received study once daily for 12 weeks; either 5, 10 or 20mg
compared to placebo
► Primary outcome was the proportion of patients remaining free of
major bleeding (MB), clinically relevant non-major bleeding (CRNMB),
VTE, and grade >3 adverse events considered to be
probably/definitely related to study drug.
► Apixapan was well tolerated in patients with advanced cancer on CTx.
Major bleeding and thrombosis were very low in all groups.
► Phase II results support need for further studies
Liebman et al. PP-WE-489. ISTH 2009
Apixaban Phase 3 (Ongoing) –
Stroke Prevention in AF
ARISTOTLE
CV185030
Stroke prevention in patients with atrial
fibrillation
(N ~ 15,000)
AVERROES
CV185048
Stroke prevention in patients with atrial
fibrillation not able to receive warfarin
(N ~ 5,600)
Treatment for up to two years with 5 mg BID
apixaban vs. warfarin (INR 2 -3)
Treatment for up to two years with 5 mg BID
apixaban vs. aspirin
APPRAISE: Apixaban After ACS
A Randomized Phase II Dose-Ranging Study
Efficacy: CV death, MI, severe
recurrent ischemia, stroke
APPRAISE Investigators. Circulation 2009;119:2877-2885
Major or clinically relevant
nonmajor bleeding
The Thrombosis Continuum
Conclusions
► Arterial and venous thrombosis are not two different entities,
but rather two ends of the thrombosis continuum.
► Novel oral anticoagulants directly targeting Factor Xa or
thrombin offer:
 a predictable and stable anticoagulant effect, rapid on- and
offset;
 no drug-food interactions, ↓↓ drug-drug interactions;
 balanced elimination, no organ toxicity.
► In the late-breaking ADVANCE 2 trial, apixaban 2.5 mg orally
bid was more effective than enoxaparin 40 mg once daily for
preventing VTE after TKR, including major VTE.
► ADVANCE 1 and 2 indicate a favorable risk-benefit profile of
apixaban relative to both approved enoxaparin regimens for
thromboprophylaxis after TKR.
The Thrombosis Continuum
Conclusions (2)
► Ongoing studies will demonstrate whether the
novel oral anticoagulants will be capable of
replacing VKA:
 in the treatment/secondary prevention of
venous thromboembolism;
 in stroke prevention in atrial fibrillation;
 in secondary prevention of acute
coronary syndromes.
Mechanisms ● Mortality ● Therapeutics
Atrial Fibrillation
Challenges, Trials, and Current Status of
Triple Drug Therapy in High Risk Patients
Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI
Chief of Cardiology
VA Boston Healthcare System
Director, Integrated Interventional Cardiovascular Program,
Brigham and Women’s Hospital and the VA Boston Healthcare System
Senior Investigator, TIMI Group
Harvard Medical School
Boston, Massachusetts
Atherothrombosis:
Clinical Manifestations
Acute coronary syndromes
– STEMI
– NSTEMI
– Unstable angina
Stable CAD
Atrial Fibrillation
Angioplasty
Bare metal stent
Drug eluting stent
CABG
Abdominal aortic
aneurysm (AAA)
Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
Stroke
TIA
Intracranial stenosis
Carotid artery stenosis
CEA
Carotid stenting
Renal artery stenosis
Renal artery stenting
Peripheral arterial disease
Acute limb ischemia
Claudication
Amputation
Endovascular stenting
Peripheral bypass
Abnormal ABI
Polyvascular Disease ~15% of Patients with
Stable Atherosclerosis
~25% of Patients with CAD Also Have Disease in
Other Arterial Territories
CAD = coronary artery disease
PAD = peripheral arterial disease
CVD = cerebrovascular disease
CAD
8.4%
1.6%
4.7%
CVD
PAD
Bhatt DL, Steg PG, Ohman EM, et al, on behalf of the REACH Investigators. JAMA 2006;295:180-189.
Patients (%)
One-Year CV Event Rates Increase with
Number of Symptomatic Disease Locations
CV Death
Non-Fatal MI
Non-Fatal Stroke
CV Death/
MI/Stroke
CV Death/
MI/Stroke/Hosp*
MI=myocardial infarction;
*Such as transient ischemic attack, unstable angina, worsening of peripheral arterial disease;
adjusted for age and gender
Steg PG, Bhatt DL, Wilson PF, et al, on behalf of the REACH Investigators. JAMA 2007;297:1197-1206.
Atrial Fibrillation and Atherothrombosis:
Risks and Management
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
Atrial Fibrillation in CAD:
Prevalence in the REACH Registry
37,724 stable outpatients with CAD
AF, atrial fibrillation.
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
CV Event Frequency in AF and
non-AF Patients
Combined event of CV death and/or nonfatal MI and/or nonfatal stroke in patients with vs without history of
AF are shown after adjustment of age, gender, and classical risk factors
Patients with a history of AF
Event rate of CV
death/MI/Stroke (%)
10
AF
Non-AF
5
0
0
2
4
6
8
10
12
Time (months)
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
Annual Rate of CV Death/MI/Stroke in
AF and Non-AF Patients
**
**
*p<0.05
**p<0.01
Multivariate analysis
**
**
Stroke Risk According to CHADS2 Score
Score
Annual Risk (%)
0
1.9
1
2.8
2
4.0
3
5.9
4
8.5
5
12.5
6
18.2
CHADS2 risk score: 1 point for each congestive heart failure,
hypertension, age > 75 years, diabetes; 2 points for prior stroke
Rubboli A, et al. Ann Med. 2008;40(6):428-36.
Annual CV Event Risk in
AF Patients by CHADS2 Score
Annual event rate (%)
CHADS2 score classification was useful in predicting not only stroke but also CV death in stable outpatients
with or at high-risk for atherothrombosis, but not as useful in the prediction of nonfatal MI
CHADS2 score
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
Annual Rate of Serious Bleeding in
AF Patients with/without Anticoagulant
4,725 stable CAD outpatients with atrial fibrillation
P = 0.0025
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
Medication Use and Risk Factor Control in
AF and Non-AF Patients
Approximately 50% of patients with AF receive anticoagulation therapy. Oral anticoagulants
are underused in patients who have a history of AF
AF +
AF –
(n=6,814)
(n=56,775)
Aspirin
49.51
69.44
< 0.0001
Any two antiplatelet agents
9.66
13.58
< 0.0001
Oral anticoagulants
36.17
3.83
< 0.0001
At least one lipid lowering agent
87.74
89.77
< 0.0001
At least one CV agent
97.58
95.67
< 0.0001
At least one anti-diabetic agent
81.76
86.85
< 0.0001
Variable, %
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
P value
Summary
►
High prevalence of AF among patients with or at high-risk of
atherothrombosis
►
Lower use of oral anticoagulants in AF patients even though they
have risk factors for ischemic stroke, probably due to the use of
antiplatelet agents for the treatment of atherothrombosis
►
1-year follow-up data show that the presence of AF was associated
with serious and multiple CV events including a higher rate of allcause and CV mortality, nonfatal stroke and a modest increase in
the risk of nonfatal MI and unstable angina
►
There is a need for the optimal antithrombotic therapy among AF
patients to be clarified to balance the increased risk of thrombotic
events and the increased risk of bleeding associated with combined
anticoagulant and antiplatelet therapy
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
Ruiz-Nodar JM, et al. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25.
Antithrombotic Regimen Adopted in
Atrial Fibrillation Patients at Discharge
Whole cohort
Chronic
Paroxysmal
n = 426
n=256
n=170
213 (50)
143 (55.8)
70 (41.3)
174 (40.8)
90 (35.2)
84 (49.5)
Coumarin + ASA (%)
8 (1.9)
6 (2.3)
2 (1.2)
Coumarin + clopidogrel
16 (3.7)
13 (5.1)
3 (1.7)
Coumarin monotherapy (%)
5 (1.2)
2 (0.8)
3 (1.7)
ASA monotherapy (%)
5 (1.2)
0
5 (2.9)
Clopidogrel monotherapy (%)
5 (1.2)
2 (0.8)
3 (1.7)
Coumarin + ASA +
clopidogrel (%)
ASA + Clopidogrel (%)
P
Value
<0.01
The p value is for the comparison of the chronic AF vs paroxysmal AF groups (Fisher test p<0.01)
Ruiz-Nodar JM, et al. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25.
Events During Follow-up
Whole
cohort
n = 373
n=196
Not
Anticoagulated
Anticoagulated
n=178
P
Value
Major bleeding (%)
12.3
14.9
9.0
0.19
Minor bleeding (%)
11.0
12.6
9.0
0.32
Embolism (%)
4.2
1.7
6.9
0.02
Death (%)
22.6
17.8
27.8
0.02
Acute myocardial infarction (%)
8.4
6.5
10.4
0.14
Target vessel revascularization(%)
7.7
7.1
8.4
0.3
Target vessel failure (%)
9.2
9.2
16.7
<0.01
Revascularization of
other lesions (%)
7.1
5.9
8.5
0.25
Subacute or late thrombosis (%)
1.2
1.2
1.3
0.65
MACE (%)
32.3
26.5
38.7
0.01
MAE (%)
36.6
31.8
41.9
0.03
Ruiz-Nodar JM, et al. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25.
Anticoagulation Use at Discharge
Major Bleeding
Event-free survival
1.0
0.8
0.6
0.4
No anticoagulation
use at discharge
0.2
Anticoagulation
use at discharge
0.0
0
500
1000
1500
Days of followup
Ruiz-Nodar JM, et al. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25.
2000
Anticoagulation Use at Discharge
Major Adverse Cardiovascular Events
Event-free survival
1.0
0.8
0.6
0.4
0.2
No anticoagulation
use at discharge
0.0
Anticoagulation
use at discharge
0
500
1000
1500
Days of followup
Ruiz-Nodar JM, et al. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25.
2000
Anticoagulation Use at Discharge
All-cause mortality
Event-free survival
1.0
0.8
0.6
0.4
No anticoagulation
use at discharge
0.2
Anticoagulation
use at discharge
0.0
0
200 400 600 800 1000 1200 1400
Days of followup
Ruiz-Nodar JM, et al. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25.
Cox Regression for the Analysis of Major
Adverse Cardiovascular Events
Variables
ß
SE
P Value
HR
95% CI
Age
0.06
0.02
0.02
1.07
1.01-1.12
Type of AF
0.41
0.53
0.44
1.51
0.53-4.31
Hypertension
-0.36
0.43
0.40
0.69
0.30-1.61
Diabetes
-0.23
0.35
0.51
0.80
0.40-1.58
Congestive heart failure or low LVEF
-0.15
0.35
0.67
0.86
0.43-1.71
Renal failure
-0.89
0.66
0.18
0.41
0.11-1.50
Previous stroke
0.22
0.49
0.65
1.24
0.48-3.25
Previous aspirin
0.23
0.41
0.58
1.25
0.57-2.78
Previous clopidogrel
-0.13
0.41
0.75
0.88
0.40-1.95
Previous oral anticoagulation
-0.76
0.50
0.12
0.47
0.18-1.23
Use of DES
-0.35
0.33
0.29
0.70
0.36-1.35
Nonanticoagulation at discharge
1.59
0.42
<0.01
4.9
2.17-11.09
Complete revascularization
-0.68
0.33
0.07
0.51
0.27-1.17
Ruiz-Nodar JM, et al. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25.
Manzano-Fernández S, et al. Chest. 2008 Sep;134(3):559-67. Epub 2008 Jul 18.
Survival Analysis of
Early Major Bleeding Complications
Early Major Bleeding
Cumulative Survival
1.0
0.8
0.6
0.4
TAT
Non-TAT
0.2
0.1
0
8
16
24
32
40
Hours of Follow Up
Manzano-Fernández S, et al. Chest. 2008 Sep;134(3):559-67. Epub 2008 Jul 18.
48
Survival Analysis of
Late Major Bleeding Complications
Late Major Bleeding
Cumulative Survival
1.0
0.8
0.6
0.4
TAT
Non-TAT
0.2
0.1
2
4
6
10
Hours of Follow Up
Manzano-Fernández S, et al. Chest. 2008 Sep;134(3):559-67. Epub 2008 Jul 18.
12
Survival Analysis of
Major Adverse Cardiovascular Events
Major Adverse Cardiovascular Events
Cumulative Survival
1.0
0.8
0.6
0.4
TAT
Non-TAT
0.2
0.1
2
4
6
10
12
Months of Follow-up
Manzano-Fernández S, et al. Chest. 2008 Sep;134(3):559-67. Epub 2008 Jul 18.
Rubboli A,, et al. Ann Med. 2008;40(6):428-36.
Major Bleeding in Patients Receiving Triple
Therapy After Coronary Artery Stenting
Triple Therapy of Warfarin, Aspirin, and Clopidogrel
Author
At 30 days
At 6 months
At > 12months
2/66 (3.1%)
NR
NR
Mattichak SJ et al. (7)
NR
5/40 (12.5%)
8/40 (21%)
Khurram Z et al. (8)
NR
NR
7/107 (6.6%)
2/180 (1.1%)
NR
NR
Lip GYH & Karpha M (10)
0/6 (0%)
NR
NR
Karjalainen PP et al. (11)
NR
NR
7/106 (6.6%)
DeEugenio D et al. (12)
NR
14/97 (14%)
NR
3/20 (15%)
NR
NR
NR (34/580; 5.9%)
NR
NR
Wang TY et al. (15)
NR
NR
NR
Ruiz-Nodar JM et al. (16)
NR
NR
NR (36/242; 14.9%
NR
7/272 (2.6%)
(39/852; 4.6%,
including ref 14)
NR
6/127 (4.7%)
28/380 (7.4%)
(64/622; 10.3%,
including ref. 16)
Orford JL et al. (5)
Porter A et al. (9)
Rubboli A et al. (13)
Nguyen MC et al. (14)
Rogacka R et al. (17)
Total
Rubboli A,, et al. Ann Med. 2008;40(6):428-36.
19/137 (13.9%)
Recommended Antithrombotic Strategies
Coronary artery stenting patients with atrial fibrillation at intermediate or high
thromboembolic risk (in whom oral anticoagulation therapy is required)
Hemorrhagic
Risk
Clinical
Setting
Elective
Low or
Intermediate
Elective
ACS
Stent
Implanted
Bare-metal
Recommendations
1 month: triple therapy of warfarin (INR 2.03.0)+aspirin <100 mg/day+ clopidogrel 75
mg/day+PPI
Lifelong: warfarin (INR 2.0-3.0) alone
Drugeluting
3 (-olimus group) to 6 (paclitaxel) months: triple
therapy of warfarin (INR 2.0-3.0)+aspirin <100
mg/day + clopidogrel 75 mg/day + PPI
up to 12th month: combination of warfarin (INR
2.0-3.0)+clopidogrel 75 mg/day
Lifelong: warfarin (INR 2.0-3.0) alone
Baremetal/drug
eluting
6 months: triple therapy of warfarin (INR 2.03.0)+aspirin <100 mg/day+ clopidogrel 75
mg/day+PPI up to 12th month: combination of
warfarin (INR 2.0-3.0)+clopidogrel 75 mg/day
Lifelong: warfarin (INR 2.0-3.0) alone
Rubboli A,, et al. Ann Med. 2008;40(6):428-36.
Recommended Antithrombotic Strategies
Coronary artery stenting patients with atrial fibrillation at intermediate or high
thromboembolic risk (in whom oral anticoagulation therapy is required)
Hemorrhagic
Risk
Clinical
Setting
Elective
Stent
Implanted
Recommendations
Bare-metal
2 to 4 weeks: triple therapy of warfarin (INR 2.03.0)+aspirin < 100 mg/day+ clopidogrel 75
mg/day+ PPI
Lifelong: warfarin (INR 2.0-3.0) alone
Bare-metal
2 to 4 weeks: triple therapy of warfarin (INR 2.03.0)+aspirin < 100 mg/day+ clopidogrel 75
mg/day+PPI up to 12th month: combination of
warfarin (INR 2.0-3.0)+clopidogrel
75 mg/day
Lifelong: warfarin (INR 2.03.0) alone
High
ACS
Rubboli A,, et al. Ann Med. 2008;40(6):428-36.
Holmes DR, et al. J. Am. Coll. Cardiol. 2009;54;95-109
ACC/AHA/SCAI and ESC Recommendations
for Aspirin Administration
Timing
ACC/AHA/SCAI
ESC
Patients already taking daily long-term
aspirin should take 75 to 325 mg of
aspirin before PCI is performed (Class I,
LOE: A)
Before
PCI
After
PCI
Patients not already taking long-term
aspirin should be given 300 to 325 mg of
aspirin at least 2 h and preferably 24 h
before PCI (Class I, LOE: C)
Patients not already taking
daily aspirin should be given a
loading dose of 500 mg orally 3
h before procedure or 300 mg
intravenously directly before
the procedure (Class I, LOE: B)
If a bare-metal stent has been placed,
aspirin 162 to 325 mg daily should be
given for at least 1 month, and then daily
long-term aspirin should be continued
indefinitely at doses of 75 to 162 mg
(Class I, LOE: B)
For chronic use, there is no
need for doses higher than 100
mg daily (Class I, LOE: B)
Holmes DR, et al. J. Am. Coll. Cardiol. 2009;54;95-109
After Bare-Metal Stent Placement, ASA Plus
Thienopyridine Reduces Cardiac Events Compared
With ASA Alone or With Oral Antithrombins
MACE,%*
Patients
Studied,
n
Patients
Treated,
n
ASA +
Thienopyridine
ASA +
Warfarin
ASA
Only
p
Value
517
626
1.6
6.2
-
0.01
473
485
5.7
8.6
-
0.37
STARS (26)
1,653
1,965
0.5
2.7
3.6
0.0001
MATTIS (27)
350
350
5.6
11.0
-
0.07
Hall et al (28)
226
358
0.8
-
3.9
0.1
Study
(Ref #)
ISAR (24)
FANTASTIC
(25)
Holmes DR, et al. J. Am. Coll. Cardiol. 2009;54;95-109
* Major Adverse Cardiovascular Events
Triple Therapy vs. Dual Antiplatelet Therapy in Patients
Requiring Oral Anticoagulation and Undergoing PCI
Outcome with Triple Therapy
(vs. Dual Antiplatelet Therapy)
Absolute
Reduction of
Myocardial
Infarction
Absolute
Reduction
of Stroke
Absolute
Reduction of
Stent
Thrombosis
Absolute
Increase
of Major
Bleeding
Khurram et al (53)
NA
NA
NA
6.6%
DeEugenio et al (79)
NA
NA
NA
11%*
Karjalainen et al (57)
-2.6%
6.0%
4.0%
-5.2%
Ruiz-Nodar et al (59)
3.9%
5.2%*†
0.1%
5.9%
Sarafoff et al (80)
-1.2%
2.8%
1.2%
-1.7%
Rossine et al (81)
0%
1%
1%
0.9%
Author (Ref #)
†Stroke
Holmes DR, et al. J. Am. Coll. Cardiol. 2009;54;95-109
*P <0.05
+ any thromboembolism
Conclusions
►
Thrombosis is critical in multiple cardiovascular
syndromes
►
Still a significant unmet need in patients with
atherothrombosis
►
Atrial fibrillation - a potent risk factor for numerous CV
outcomes
►
ACS/PCI – an important part of this atherothrombotic
continuum
►
Novel pathways to prevent thrombosis likely to yield
benefit
Panvascular Crisis in Thrombosis Medicine
Antithrombotic Therapy Post-Acute Coronary
Syndrome: Achieving Effective Prevention of
Thrombosis Related Events
Factor Xa Inhibition and the Optimal Balance Between
Anti-Ischemic Efficacy and Bleeding Risk
John H. Alexander, MD, MHS
Associate Professor of Medicine / Cardiology
Duke University medical Center
Duke Clinical Research Institute
CVD: A Global Epidemic
2002
World pop.: 6.12 billion
Deaths:
56.6 million
CVD deaths: 16.6 million
Low and
middle
income
Gaziano TA. Circ 2005.
High
income
Lumen
Thrombus
Plaque
Red
Blood
Cells
Thrombus
Platelet
Aggregate
Fibrin
Atherosclerotic
Plaque
Long-Term Antithrombotic Therapy at Hospital
Discharge after UA/NSTEMI
UA/NSTEMI
Patient Groups at
Discharge
Summary: Give everybody…..
 Aspirin
Medical Therapy
without Stent
Bare Metal Stent
Group
Drug Eluting
Stent Group
75-325 mg/day indefinitely
ASA 75 to 162 mg/d indefinitely
(Class I, LOE: A)
 Clopidogrel
&
ASA 162 to 325 mg/d for at least 1
month, then 75 to 162 mg/d
indefinitely (Class I, LOE: A)
ASA 162 to 325 mg/d for at
least 3 to 6 months, then 75 to
162 mg/d indefinitely
(Class I, LOE: A)
75 mg/day for at least a
&
Clopidogrel 75 mg/d for at least 1
month and up to 1 year
(Class I, LOE:B)
Clopidogrel 75 mg/d at least 1
month (Class I, LOE: A) and up
to 1 year (Class I, LOE: B)
year
Does this work?
Yes
Add: Warfarin (INR 2.0 to 2.5)
(Class IIb, LOE: B)
&
Clopidogrel 75 mg/d for at
least 1 year (Class I, LOE: B)
Indication for
Anticoagulation?
No
Continue with dual antiplatelet
therapy as above
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 11. INR = international normalized ratio; LOE = level of evidence.
CURE
Clopidogrel Plus Aspirin in ACS
11.4%
Placebo
+ ASA
20%
Relative Risk
Reduction
9.3%
Clopidogrel
+ ASA
P = 0.00009†
N = 12,562
0
3
6
9
Months of Follow-Up
CURE Investigators NEJM 2001;345:494-502
12
CHARISMA
Long-Term Clopidogrel, Prior MI Subgroup
Primary Outcome Event Rate (%)
10
N=3,846
8.3%
8
Placebo + ASA
Clopidogrel + ASA
6.6%
6
4
2
HR=0.77 (95% CI 0.61–0.98)
P = 0.03
0
0
6
12
18
Months Since Randomization
J Am Coll Cardiol. 2007;49:1982-1988.
24
30
CURE
Bleeding Complications
Placebo Clopidogrel RR
95% CI
p
6,303
6,259
Major
2.7%
3.6%
1.34
1.10-1.64
0.003
Minor
8.6%
15.3%
1.78
1.61-1.96
<0.0001
Transfusion
(2+Units)
2.2%
2.8%
1.28
1.02-1.59
0.03
Venous Thrombosis
Blood Flow Stasis
Inhibiting one
molecule of
factor Xa can
inhibit the
generation of
50 molecules
of thrombin
Arterial Thrombosis
Plaque Rupture
Factor X Activation
Thrombin Generation
Platelet Activation
Fibrin Formation
Thrombosis
Novel
Anticoagulants
TTP889
TTP889
Rivaroxaban
Rivaroxaban
Apixaban
Apixaban
LY517717
LY517717
YM150
YM150
DU-176b
DU-176b
Betrixaban
Betrixaban
TAKTAK
442 442
813893
813893
TFPI
TFPI(tifacogin)
(tifacogin)
rNAPc2
rNAPc2
TF/VIIa
X
IX
VIIIa
Aptamer/antidote
Aptamer/antidote
IXa
Va
Xa
APC (drotrecogin alfa)
sTM (ART-123)
ATIII
II
ATI-5923
ATI-5923
Otamixaban
Otamixaban
DX-9065a
IIa
Dabigatran
AZD0837
Fibrinogen
Fondaparinux
Fondaparinux
Idraparinux
Idraparinux
Fibrin
Adapted from Turpie and Weitz & Bates, J Thromb Haemost 2007
Apixaban
Characteristics

O
N

H2N
N
OMe
O



N


N
O


Oral bioavailability: 58%
No food effect
Low volume distribution
Half-life: T1/2 ≈ 12 h
Multiple elimination pathways:
25% renal
No CYP inhibition / induction
Highly selective for factor Xa
No reactive intermediates
No organ toxicity, LFT
abnormalities, or QTc
prolongation
Pinto DJ et al. J Med Chem. 2007;50:5339-5356.
He K et al. Poster presented at: 48th Annual Meeting of the American Society of
Hematology; December 2006; Orlando, FL. Poster 38-I.
Frost C et al. Poster presented at: 21st Congress of the International Society of
Thrombosis and Haemostasis; July 2007; Geneva, Switzerland.
Lassen MR et al. J Thromb Haem. 2007;5:2368-2375.
Apixaban, an Oral, Direct, Selective Factor Xa
Inhibitor, in Combination With Antiplatelet
Therapy After Acute Coronary Syndrome:
Results of the Apixaban for Prevention of Acute
Ischemic and Safety Events (APPRAISE) Trial
APPRAISE Steering Committee and Investigators.
Circulation. 2009;119:2877-2885.
Inclusion Criteria


Age 18–90 years
Recent (7 days) acute coronary syndrome




Symptoms of myocardial ischemia lasting at least 10 minutes
Elevated cardiac markers (Tn T or I, CK-MB) or ST elevation / depression (≥1.0 mm)
Clinically stable, receiving standard post-ACS care
At least 1 additional risk factor for recurrent ischemic event









Age 65 years
Both elevated cardiac markers and ST deviation
Diabetes mellitus
Prior MI within the past 12 months
Prior ischemic stroke, TIA, or asymptomatic carotid stenosis
Peripheral vascular disease
Prior symptomatic CHF or a left ventricular EF <40%
Non-revascularized multivessel CAD
Mild to moderate renal insufficiency (CrCl <90 ml/min)
Exclusion Criteria

Planned catheterization, PCI, CABG or other invasive procedure

Persistent severe HTN (SBP ≥180, DBP ≥110 mmHg)

Severe renal dysfunction (CrCl <30 ml/min)

Active bleeding or at high risk for bleeding

Acute pericarditis or pericardial effusion

Recent stroke (3 months)

Severe heart failure (NYHA Class IV)

Platelet count 100,000/mm3, hemoglobin 10g/dl

Need for ongoing parenteral or oral anticoagulant

Chronic NSAID or high-dose (>325 mg/day) aspirin
Study Design
Phase A = 547
Recent (7 days) Acute Coronary
Syndrome
plus at least one
additional
risk factor•Randomized, double-blind.
Phase
A
1:1:1
Placebo
n=184
Apixaban
2.5 mg BID
n=179
Apixaban
10 mg QD
n=184
Interim analysis (DSMB review)
Phase B = 1168
Placebo
n=427
Total = 1715
Phase B
3:1:1:2:2
Apixaban
2.5 mg BID
n=138
Apixaban
10 mg QD
n=134
Apixaban
10 mg BID
n=248
•Study drug for 6 months.
•Aspirin 165 mg/d.
•Clopidogrel per MD discretion
(stratified randomization)
Discontinued early due to
excess bleeding in patients
receiving apixaban and
dual antiplatelet therapy
Apixaban
20 mg QD
n=221
Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH)
Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic stroke
ISTH* Bleeding Definitions

Major Bleeding – Bleeding…





with a fall in hemoglobin of ≥2 g/dL, or
with transfusion of ≥2 units of PRBC or whole blood, or
that occurs in a critical location, i.e., intracranial, intraspinal,
intraocular, retroperitoneal, intraarticular or pericardial, or
that causes death
Clinically Relevant Non-Major Bleeding – Bleeding…


that does not meet criteria for major bleeding, and
that requires any medical or surgical intervention to treat the
bleeding
*ISTH – International Society of Thrombosis and Haemostasis
Baseline Characteristics
Placebo
N
611
Median (IQR) Age, yrs
60 (52,69)
Age ≥75 yrs, %
11.0
Female, %
25.7
Mean weight, kg
81.8
Diabetes mellitus, %
23.2
Recent prior MI, %
4.7
Cerebrovascular disease, %
4.9
Peripheral vascular disease, %
3.9
CHF or LVEF < 40%, %
9.7
Residual multivessel CAD, %
25.0
Mild or moderate renal insufficiency, % 32.1
Apixaban
2.5 mg BID
317
62 (53,69)
14.2
23.7
81.3
21.8
7.9
4.1
6.6
18.0
26.8
33.4
10 mg QD
318
61 (52,69)
12.3
27.0
82.5
22.3
5.7
5.0
4.4
15.7
25.8
28.6
Index Event and Concomitant Medications
Placebo
N
599
Index Event
ST-elevation MI, %
61.6
PCI, %
64.8
Clopidogrel, %
75.6
Mean time to study drug, days
4.3
Concomitant Medications During Trial
Aspirin, %
100.0
Clopidogrel, %
78.1
Beta blockers, %
92.0
Ace-Inhibitors or ARBs, %
87.3
Calcium blockers, %
20.5
Nitrates, %
36.7
Statins, %
88.3
Apixaban
2.5 mg BID
315
10 mg QD
315
62.2
62.2
73.0
4.2
67.0
64.8
76.5
4.1
99.7
77.1
92.7
85.1
25.1
41.3
87.0
99.7
77.5
92.1
82.9
19.7
41.3
87.9
Bleeding
10%
ISTH and TIMI Scales
7.9%
8%
Placebo, n=599
Apixaban 2.5 mg BID, n=315
Apixaban 10 mg QD, n=315
5.7%
6%
4%
3.0%
2%
1.6%
1.9%
0.8%
0.8%
1.0%
1.3%
1.0%
0.3%
0.0%
0%
ISTH Major/CRNM
ISTH Major
TIMI Major/Minor
TIMI Major
ISTH Major or CRNM Bleeding
ISTH Major or CRNM Bleeding
HR 2.45
95% CI 1.31 to 4.61
p = 0.005
Apix 10 mg QD
HR 1.78
95% CI 0.91 to 3.48
p = 0.09
Apix 2.5 mg BID
Placebo
Weeks
Bleeding by Clopidogrel Status
10%
ISTH Major or CRNM Bleeding
9.1%
Placebo
Apixaban 2.5 mg BID
8%
Apixaban 10 mg QD
7.0%
6%
4.1%
4%
3.1%
2.7%
2.4%
2%
0%
Clopidogrel
N
453
230
No Clopidogrel
241
146
85
74
Bleeding During Phase B
10%
Includes only patients randomized and treated and events that occurred
through October 1, 2007 when the 10mg BID and 20mg QD arms were discontinued
7.8%
8%
7.3%
Placebo, n=362
Apixaban 2.5 mg BID, n=119
Apixaban 10 mg QD, n=108
6%
5.5%
5.6%
Apixaban 10 mg BID, n=244
Apixaban 20 mg QD, n=218
4.1%
4%
2.9%
2%
0.8%
0.8%
0.0%
0%
ISTH Major/CRNM
0.0%
ISTH Major
Ischemic Outcomes
10%
Placebo, n=611
8.7%
Apixaban 2.5 mg BID, n=317
8%
7.6%
Apixaban 10 mg QD, n=318
6%
6.0%
5.2%
5.4%
4%
3.1%
2%
0%
CV Death, MI, SRI, Stroke
CV Death, MI, Stroke
CV Death, MI, SRI or Stroke
Ischemic Outcome
Placebo
HR: 0.73
Apix 2.5 mg BID 95% CI: 0.44 to 1.19
p = 0.21
HR: 0.61
Apix 10 mg QD 95% CI: 0.35 to 1.04
p = 0.07
Weeks
Ischemic Events by Clopidogrel Status
CV Death, MI, SRI or Stroke
16%
Placebo
15.4%
Apixaban 2.5 mg BID
12%
12.9%
Apixaban 10 mg QD
9.3%
8%
6.5%
5.6%
4.9%
4%
0%
Clopidogrel
N
462
232
243
No Clopidogrel
149
85
75
C. Michael Gibson, Jessica L. Mega, Christopher J.
Hammett, Vasil Hricak, Pascual Bordes, Adam
Witkowski, Valentin Markov, Paul Burton,
and Eugene Braunwald for the TIMI 46 Study Group
Anti-Xa Therapy to Lower cardiovascular events in addition to
Aspirin with or without thienopyridine therapy in Subjects
with Acute Coronary Syndrome – Thrombolysis in
Myocardial Infarction 46 Trial
Mega J et al. Lancet 2009
STUDY DESIGN
Recent ACS Patients
Stabilized 1-7 Days Post-Index Event
Aspirin 75-100 mg
MD Decision to Treat with Clopidogrel
NO
STRATUM 1
ASA Alone
N=761
YES
N = 3,491
STRATUM 2
ASA + Clop.
N=2,730
PLACEBO
N=253
RIVA QD
N=254
RIVA BID
N=254
PLACEBO
N=907
RIVA QD
N=912
RIVA BID
N=911
5 mg (77)
10 mg (98)
20 mg (78)
5 mg (77)
10 mg (99)
20 mg (78)
2.5 mg (77)
5 mg (97)
10 mg (80)
5 mg (74)
10 mg (428)
15 mg (178)
20 mg (227)
5 mg (78)
10 mg (430)
15 mg (178)
20 mg (226)
2.5 mg (76)
5 mg (430)
7.5 mg (178)
10 mg (227)
Treat for 6 Months
Gibson CM, AHA 2008
SAFETY EVALUATION:
EXPANDED TIMI BLEEDING CLASSIFICATION
Clinically Significant Bleeding - Any of the following:
TIMI Major – Intracranial bleeding or clinically overt
bleeding associated with a drop in Hgb of > 5g/dl or
absolute drop in Hct of > 15%
TIMI Minor - Clinically overt bleeding (including bleeding
evident on imaging studies) associated with a fall in Hgb of
> 3 gm/dL but < 5 gm/dL from baseline
Bleeding Requiring Medical Attention – Bleeding requiring
either medical attention, medical treatment, surgical
treatment that does not meet the above criteria (e.g. a
nosebleed)
* A transfusion is counted as 1 g/dl or 3% Hct
Gibson CM, AHA 2008
PRIMARY SAFETY ENDPOINT:
CLINICALLY SIGNIFICANT BLEEDING
Clinically Significant Bleeding (%)
(= TIMI Major, TIMI Minor, Bleed Req. Med. Attn.)
15
Total Daily Dose:
15.3%
Rivaroxaban 20 mg ----
Rivaroxaban 15 mg ---Rivaroxaban 10 mg ----
12.7%
Rivaroxaban 5 mg ----
10
5
Placebo ---
10.9%
6.1%
HR
5.1
(3.4-7.4)
3.6
(2.3-5.6)
3.4
(2.3-4.9)
2.2
(1.25-3.91)
3.3%
*p<0.01 for
placebo Vs Riva
0
5mg. p<0.001
180
90
120
150
60
0
30
for Riva
Days After Start of Treatment
10,15,20mg vs
Kaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio;
placebo
Gibson
CM, AHA 2008
CI=Confidence Interval
SAFETY ENDPOINTS:
TIMI Major, TIMI Minor and Bleeding Req. Med. Attn.
Rate (%)
20
ASA Alone
15
P trend<0.001
9.6
10
5
0
0
0
Plac 5
2.1
10
4.1
0
0.4
0
0 0.6
20
Plac
5
10
TIMI Major
1.6 1.9
Plac 5
20
10
20
Med Attention
TIMI Minor
Rate (%)
P trend<0.0001
Plac 5
10
15
20
TIMI Major
P trend=p value for dose response over actual dose values.
Plac
5
10
15
TIMI Minor
20
Plac
5
10
15
20
Med Attention
Gibson CM, AHA 2008
SECONDARY EFFICACY ENDPOINT:
Incidence of Death / MI / Stroke
Stratum 2: ASA + Clop.
Stratum 1: ASA Alone
4.7
P trend = 0.01
HR
0.67
8.0
HR
0.58
7.0
HR
0.37
4.7
n=253
n=154
n=196
n=158
Death / MI / Stroke (%)
Death / MI / Stroke (%)
11.9
HR
1.24
P trend = 0.72
3.8
n=907
HR
0.70
HR
O.71
2.7
2.7
n=154
n=860
HR
0.79
3.0
n=356
n=453
TDD
Gibson CM, AHA 2008
Apixaban Better / Apixaban Worse
APPRAISE – Net Clinical Benefit
CV Death/MI/SRI/CVA vs. ISTH Major Bleeding
Apixaban 5 mg
2.0%
1.0%
Apixaban 10 mg
0.4%
0.0%
-1.0%
-0.4%
-2.0%
-3.0%
-3.2%
-4.0%
-4.4%
-5.0%
Clopidogrel
No Clopidogrel
Rivaroxaban Better / Rivaroxaban Worse
ATLAS – Net Clinical Benefit
Death/MI/CVA vs. TIMI Major Bleeding
Rivaroxaban 5 mg
2.0%
Rivaroxaban 10 mg
1.0%
0.2%
0.0%
-1.0%
-0.6%
-2.0%
-3.0%
-2.8%
-4.0%
-3.9%
-5.0%
Clopidogrel
No Clopidogrel
Ischemic Events
Bleeding
CV Death/MI/SRI/CVA
ISTH and TIMI
16%
16%
15.4%
Placebo
Apixaban 10 mg QD
Placebo
Apixaban 10 mg QD
12%
12%
9.3%
8.7%
8%
8%
6.0%
6.5%
4.9%
4%
4%
1.9%
1.3%
0.8%
1.0%
0.8%
0.3%
0%
0%
Overall
Clopidogrel
No Clopidogrel
ISTH Major
TIMI Major/Minor
TIMI Major
Recent Acute Coronary Syndrome
(STEMI or NSTE-ACS)
Randomize 1:1
N=10,800
Stratified by Antiplatelet Regimen
Double blind
Apixaban 5 mg BID
• Aspirin
• Other antiplatelet at MD
discretion
Placebo
Start study drug ASAP after acute care stabilization / parenteral anticoagulation
Event Driven
Primary: Death, MI, Ischemic Stroke
Secondary: Death, MI, Severe Recurrent Ischemia, Ischemic stroke
Safety: Major Bleeding
Conclusions

Following acute coronary syndrome patients remain
at high risk for….


recurrent ischemic events
bleeding (largely secondary to antithrombotic therapy)

Inhibition of factor Xa with an oral factor Xa inhibitor
has the potential to reduce ischemic events but will
probably also increase in bleeding

The ideal level of inhibition of factor Xa will require
further study and may depend on….



patient characteristics
concomitant medications
time from the ACS event
Mechanisms ● Mortality ● Therapeutics
Challenges in Managing Bleeding Risk
Across the Spectrum of
Arterial and Venous Thromboprophylaxis
Sunil V. Rao, MD
Director of Interventional Cardiology
Veterans Administration Medical Center
Division of Cardiovascular Medicine
Duke University Medical Center
Durham, North Carolina
Strategies for Mitigating Bleeding Risk
AGENDA
►
Bleeding incidence and risk across the spectrum of
arterial and venous thrombotic disease
 Atrial fibrillation, VTE, ACS
►
Bleeding risk with currently available antithrombotic
therapy
 Antiplatelets, Anticoagulants
►
Bleeding and associated adverse outcomes
►
Strategies to mitigate bleeding risk
Currently Available Antithrombotic Agents
and Bleeding Risk
►Warfarin – narrow therapeutic window
►UFH – difficulty dosing appropriately, HIT(TS)
►LMWH – Renal function, Dosing
►Glycoprotein IIb/IIIa inhibitors – Profound
inhibition of platelet aggregation
►Clopidogrel – Surgical issues
►Prasugrel – Higher antiplatelet effect
Mitigating Bleeding Risk
►Warfarin – pharmacogenomic approaches
►UFH & LMWH – Appropriate dosing
►GP IIb/IIIa inhibitors – Bailout use, dosing
►Alternative anticoagulants – direct thrombin
inhibitors, Factor Xa inhibitors
New Anticoagulants
ORAL
PARENTERAL
TF/VIIa
TTP889
TTP889
TFPI (tifacogin)
(tifacogin)
TFPI
X
Rivaroxaban
Rivaroxaban
Apixaban
Apixaban
LY517717
LY517717
YM150
YM150
DU-176b
DU-176b
Betrixaban
Betrixaban
TAK442
442
TAK
IX
VIIIa
APC
APC (drotrecogin
(drotrecogin alfa)
alfa)
sTM
(ART-123)
sTM
(ART-123)
IXa
Va
Xa
AT
II
Dabigatran
Dabigatran
DX-9065a
DX-9065a
IIa
Fibrinogen
Adapted from Weitz & Bates, J Thromb Haemost 2007
Fondaparinux
Fondaparinux
Idraparinux
Idraparinux
Fibrin
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
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
7.0
Observational
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
2.0-3.0
0.5
1.0
71
VTE Treatment: Clinical Outcomes
Efficacy and Safety LMWH vs UFH
UFH
Enoxaparin 1.5 mg/kg, SC, Qday
Enoxaparin 1mg/kg, SC, Q12hrs
Merli G, et al. Ann Intern Med. 2001;134:191-202.
Outpatient Bleeding Risk
Warfarin Therapy
Months
Low Risk
(RF 0)
Intermediate
Risk (RF 1-2)
High Risk
(RF 3-4)
3 months
2%
5%
23%
12 months
3%
12%
48%
Risk Factors (1 point for each risk factor)
► Age > 65 yrs
► History of GI Bleed
► Recent MI,
► HCT < 30%
► Cr > 1.5 mg/dl
► History DM
Beyth R, et al Am J Med 1998;105(2):91-99
CRUSADE In-Hospital Outcomes
Death
3.6%
Re-Infarction
1.8%
CHF
6.6%
Cardiogenic Shock
2.2%
Stroke
0.7%
RBC Transfusion*
9.1%
*Excluding CABG-related transfusions
CRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)
SYNERGY: Death and MI at 30 Days
Freedom from Death / MI
1.0
Hazard Ratio (95% CI)
0.95
30-day Death/MI

0.9
HR 0.96 (0.86 – 1.06)
0.85
Enoxaparin
UFH
0.8
0.8
0
5
10
15
20
25
30
Days from Randomization
SYNERGY Trial Investigators. JAMA 2004;292:45-54
Enoxaparin
Better
1
UFH
Better
1.2
SYNERGY Bleeding Events
Enoxaparin (%)
UFH (%)
P-value
GUSTO severe*
2.7
2.2
0.08
TIMI major*
CABG-related
Non-CABG-related
9.1
6.8
2.4
7.6
5.9
1.8
0.008
0.08
0.03
Stroke*
1.0
0.9
NS
TIMI minor
12.5
12.3
0.80
Any transfusion
17.0
16.0
0.16
* Primary safety endpoints
SYNERGY Trial Investigators. JAMA 2004;292:45-54
Clopidogrel Safety Results
CURE
Major bleeding1,2
Minor bleeding1,2
PCI CURE3
Major
Minor
CLARITY2
Major bleeding
PCI CARITY4
TIMI major bleeding
TIMI minor bleeding
COMMIT2
Major noncerebral or
cerebral bleeding
CHARISMA5
GUSTO severe bleeding
Clopidogrel
Placebo
P value
3.7%
5.1%
2.7%
2.4%
0.001
<0.001
2.5%
2.1%
2.7%
3.5%
0.64
0.03
1.3%
1.1%
NS
0.5%
1.4%
1.1%
0.8%
NS
NS
0.6%
0.5%
0.59
1.7%
1.3%
0.09
1. CURE Trial Investigators. N Engl J Med. 2001;345:494. 2. PLAVIX Prescribing Information. sanofi-aventis U.S. LLC.
3. Mehta et al, for the CURE Investigators. Lancet. 2001;358:527. 4. Sabatine et al. JAMA. 2005;294:1224.
5. Bhatt et al. N Engl J Med. 2006;354:1706.
TRITON Bleeding Events:
Safety Cohort (N=13,457)
Non-CABG
Life Threatening
TIMI Major Bleeds
ARD 0.6%
HR 1.32
P=0.03
ARD 0.5%
HR 1.52
P=0.01
Wiviott et al. N Engl J Med. 2007;357:2001.
Nonfatal
ARD 0.2%
HR 1.252
P=0.23
Fatal
ARD 0.3%
HR 4.192
P=0.002
ICH
ARD 0%
HR 1.122
P=0.74
Baseline Major Bleeding and Mortality Risk in
CRUSADE N=68,270
Mortality Risk Tertiles
1%
7.6%
23.5%
(5,199)
(16,044)
9.4%
15.1%
8.4%
(6,403)
(10,320)
(5,762)
23.4%
9.9%
2%
High
(706)
Mod
Low
(15,974)
Low
(6,748)
Mod
Bleeding Risk Tertiles
Alexander KA, et. al. ACC 2008
(1,114)
High
Bleeding in the Setting of Therapy for
Atrial Fibrillation, VTE, and ACS
►Bleeding is the most common complication of
antithrombotic/anticoagulant therapy
►Bleeding risk varies with antithrombotic choice
►Risk factors for bleeding can be readily identified
with existing risk models
►These risk factors overlap with risk factors for
mortality
Influence of Bleeding Events on Warfarin Prescription
N=530 physicians in Ontario
Comparison
period (days
after exposure)
No. of physicians
evaluated
Warfarin use
ACE Inhibitor
use
0-90
530
0.79 (0.62 to 1.00)
1.13 (0.87 to 1.47)
91-180
521
0.60 (0.46 to 0.79)
1.16 (0.90 to 1.51)
181-270
488
0.61 (0.46 to 0.81)
1.11 (0.84-1.46)
271-360
469
0.72 (0.54 to 0.97)
1/06 (0.79 to 1.41)
0-90
704
0.95 (0.75-1.19)
0.88 (0.70 to 1.11)
91-180
664
1.05 (0.82 to 1.34)
0.99 (0.78 to 1.26)
181-270
656
1.22 (0.96 to 1.55)
1.17 (0.92 to 1.50)
271-360
621
1.23 (0.96 to 1.58)
1.08 (0.84 to 1.40)
Bleeding Analysis
Stroke Analysis
Choudhury NK, et. al. BMJ 2006
.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 on Warfarin
Age < 80
Hylek EM et al, Circulation 2007;115(21):2689-2696.
300
Age > 80
400
Bleeding and Adverse Events in VTE
Higher risk
Lower risk
Adjusted Hazard Ratio
N=1897 pts. With VTE in Worcester, MA
Recurrent VTE
Spencer FA, et. al. Thromb Haemost. 2009
Total Mortality
Bleeding & Outcomes
N=26,452 pts from PURSUIT, GUSTO IIb, PARAGON A & B
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
log rank p-value for all four categories <0.0001
log-rank p-value for no bleeding vs. mild bleeding = 0.02
log-rank p-value for mild vs. moderate bleeding <0.0001
log-rank p-value for moderate vs. severe <0.001
Rao SV, et al. Am J Cardiol. 2005
Impact of MI and Major Bleeding (non-CABG) in
the First 30 Days on Risk of Death Over 1 Year
1 year
Estimate
Both MI and Major Bleed (N=94)
Major Bleed only (without MI) (N=551)
MI only (without Major Bleed) (N=611)
No MI or Major Bleed (N=12,557)
30
28.9%
12.5%
8.6%
3.4%
28.9%
Mortality (%)
25
20
15
12.5%
10
8.6%
5
3.4%
0
0
30 60 90 120 150 180 210 240 270 300 330 360 390
Days from Randomization
Mehra R, et. al. EHJ 2009
Bleeding and Evidence-based Therapies
N=2498 ACS patients from the PREMIER Registry
Discharge ASA and thienopyridine
Patients with bleeding vs. patients without bleeding
Wang TY, et. al. Circulation 2008
“Nuisance” Bleeding and Drug Discontinuation

N=2360 unselected pts.
receiving DES

Prospective data
collection

Major events
adjudicated

Serebruany bleeding
classification*
Alarming bleeding
Internal
bleeding
Nuisance bleeding
*Alarming bleeding = ICH, life-threatening, + transfusion
Internal bleeding = hematoma, epistaxis, mouth or vaginal,
Melena, IO, hematuria or hematemesis
Nuisance bleeding = bruising, petechiae, ecchymosis
Roy P, et. al. AJC 2008
Bleeding and Mortality in
Atrial Fibrillation, VTE, and ACS
► Bleeding is associated with increased mortality and
morbidity across the spectrum of arterial and venous
thrombotic diseases
► In ACS, this risk may be higher than with recurrent
ischemia given modern treatment strategies
► In ACS the risk associated with bleeding appears to
persist beyond 30 days
► Bleeding is associated with lower use of evidencebased medicine in at-risk patients
Warfarin Pharmacogenomics
►
3 Groups: Low-dose,
Intermediate-dose, Highdose
►
Fixed dose (35 mg/wk):
Not helpful for low- or
high-dose
►
Genomic data most
helpful for Low-dose or
High-dose groups
►
Less helpful for
Intermediate-dose group
NEJM 2009;360:753-764
Major Bleeding by ASA Dose
N=12,562 pts in CURE
ASA dose
Clop + ASA
ASA
< 100 mg
2.6%
2.0%
100 – 200 mg
3.5%
2.3%
> 200 mg
4.9%
4.0%
Peters RJ, et. al. Circulation 2003
Excessive Dosing of
Anticoagulants by Age
70
64.5
% Excessive Dose
60
50
37 38.5
40
28.7
30
20
33.1
12.5 12.5
16.5
8.5
10
0
LMW Heparin
yrs 65 <
Alexander KP, et. al. JAMA 2005
UF Heparin
yrs 65-75
GP IIb/IIIa
yrs 75>
Excess Dosing of GP IIb/IIIa and Bleeding in Women
N=32,601 patients from CRUSADE
Overall1.46 (1.22, 1.73)
Women 1.72 (1.30, 2.28)
Men 1.27 (0.97, 1.66)
0.5
Alexander KP, et. al. Circulation 2006
1.0
1.5
2.0
2.5
Excess Dosing More Likely to Bleed
Reducing Bleeding Risk
►Pharmacogenomic data may be helpful at the
extremes of warfarin dosing
►Appropriate dosing of UFH/LMWH/GPI is
essential to reduce bleeding risk
►For long-term antiplatelet therapy, reduction in
ASA dose can reduce bleeding risk
►What about newer agents?
New Anticoagulants
ORAL
PARENTERAL
TF/VIIa
TTP889
TTP889
TFPI
TFPI (tifacogin)
(tifacogin)
X
Rivaroxaban
Rivaroxaban
Apixaban
Apixaban
LY517717
LY517717
YM150
YM150
DU-176b
DU-176b
Betrixaban
Betrixaban
TAK
TAK442
442
IX
VIIIa
APC (drotrecogin alfa)
(ART-123)
sTMsTM
(ART-123)
IXa
Va
Xa
AT
II
Dabigatran
Dabigatran
DX-9065a
DX-9065a
IIa
Fibrinogen
Adapted from Weitz & Bates, J Thromb Haemost 2007
Fondaparinux
Fondaparinux
Idraparinux
Idraparinux
Fibrin
OASIS 5 – Fondaparinux in NSTE ACS
0.01 0.02 0.02
0.03 0.05 0.04
0.01
0.03 0.04
0.06
Enoxaparin
Enoxaparin
HR 0.53
95% CI 0.45-0.62
P<<0.00001
Fondaparinux
HR 1.01
HR 0.83
CI 0.90-1.13
-0.97
CI 0.71
95%95%
Fondaparinux
P=0.022
Enoxaparin
Fondaparinux
0.0
0.0
0.0
Cumulative Hazard
Cumulative
Hazard
Cumulative
Hazard0.03
0.01
0.02
30
Day
Mortality:
9
9 Days
Day
Bleeding:
Death/MI/RI:
Major
0 00
3
1
6
OASIS 5 Investigators NEJM 2006
2 9
3 12
3
55
4415
18
Days
Days
Days
66
21
77
24
2788
3099
Harmonizing Outcomes with Revascularization and Stents in AMI
≥3400* pts with STEMI with symptom onset ≤12 hours
Aspirin, thienopyridine
R
1:1
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Emergent angiography, followed by triage to…
CABG – Primary PCI – Medical Rx
3000 pts eligible for stent randomization
Bare metal stent
*To rand 3000 stent pts
R
1:3
TAXUS paclitaxel-eluting stent
Clinical FU at 30 days, 6 months,
1 year, and then yearly through 5 years
30 Day Mortality
Death (%)
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
3.1%
2.1%
HR [95%CI] =
0.66 [0.44, 1.00]
P=0.048
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
Time in Days
1800
1802
Stone GW et al. NEJM 2008.
1758
1764
1751
1748
1746
1736
1742
1728
1729
1707
1666
1630
1-Year All-Cause Mortality
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
5
4.8%
Δ = 1.4%
Mortality (%)
4
3.4%
3.1%
3
2
Diff [95%CI] =
-1.5% [-2.8,-0.1]
HR [95%CI] =
0.69 [0.50, 0.97]
P=0.029
2.1%
Δ = 1.0%
1
P=0.049
0
0
1
2
3
4
5
6
7
8
9 10 11 12
Time in Months
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
1800
1802
Stone GW et al. TCT 2008.
1705
1678
1684
1663
1669
1646
1520
1486
Comparison of Novel Oral
Anticoagulants with Warfarin
Drug
Target
Dosing
Factor Xa
Fixed,
once daily
Apixaban
Factor Xa
Fixed,
twice daily
Dabigatran
Factor IIa
(thrombin)
Fixed,
twice daily
Rivaroxaban
Warfarin
Vitamin K
Coag
monitorin
g
Variable,
once daily
No
No
No
Yes
Half
life (h)
9
9–14
14–17
40
Renal
cleared
(%)
Interacts
65
Potent
CYP3A4
inhibitors*
25
Potent
CYP3A4
inhibitors*
100
Proton
pump
inhibitors
0
Multiple
drugs,
dietary
vitamin K
*Includes ketoconazole, macrolides (eg, clarithromycin), and protease inhibitors
(eg, atazanavir)
Eikelboom JW, Weitz JI. Circulation 2007; 116: 131-133
Apixaban
►
Oral, direct, selective factor Xa inhibitor
►
Produces concentration-dependent
anticoagulation
►
No formation of reactive intermediates
►
No organ toxicity or LFT abnormalities in
chronic toxicology studies
►
Low likelihood of drug interactions or
QTc prolongation
►
Good oral bioavailability
►
No food effect
►
Balanced elimination (~25% renal)
►
Half-life ~12 hrs
He et al., ASH, 2006, Lassen, et al ASH, 2006
O
N
NH2
N
O
O
N
N
O
Apixaban for Prevention of VTE After
Major Orthopaedic Surgery
►
Apixaban od and bid (total daily doses 5-20mg) were assessed
relative to enoxaparin and warfarin, in 1,217 patients
Total VTE and All-Cause Mortality (%)
30
26.6
25
Percent
Percent
30
20
15
15.6
25
20
15
10.6
8.6
10
10
6.8
5
0
Major Bleeding (%)
5
5mg
10mg
20mg
Apixaban
(Total Daily Dose)
Lassen et al. Blood 2006
Warfarin
(INR
1.8-3.0)
Enoxaparin
(30mg bid)
0
1.3
1.6
5mg
10mg
3.0
0
20mg
Apixaban
(Total Daily Dose)
Warfarin
(INR
1.8-3.0)
0
Enoxaparin
(30mg bid)
Apixaban for the Treatment of DVT:
The Botticelli-DVT Study
►
10
Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to
low molecular weight heparin (LMWH) or fondaparinux followed by
VKA, in 520 patients
Composite of Symptomatic
Recurrent VTE and Deterioration
of Thrombotic Burden (%)
10
8
8
6
5.6
4.2
4
2.6
Percent
6.0
Percent
Major Bleeding (%)
6
4
2
2
0.8
0.8
0
0
0
0
5mg
bid
Büller, Eur Heart J 2006
10mg
bid
Apixaban
20mg LMWH/
fondaparinux
bid
+ VKA
5mg
bid
10mg
bid
Apixaban
20mg
bid
LMWH/
fondaparinux
+ VKA
Incidence of Bleeding Events for QD and BID
Doses of Apixaban and Comparators
Incidence of bleeding events (%)
18
Major
16
Minor
14
12
10
8
6
4
2
0
-2
5 QD
2.5
BID
10 QD 5 BID 20 QD
-4
Apixaban
Lassen MR, et al. J Thromb Haemost 2007; 5: 2368–75.
10
BID
Enox
Warf
Proportion with ISTH Major or CRNM Bleeding
APPRAISE: Major or Clinically Relevant
Nonmajor Bleeding
Proportion of patients with major or clinically relevant
nonmajor bleeding by baseline clopidogrel status
Alexander, at al. Circulation. 2009 Jun 9;119(22):2877-85. Epub 2009 May 26.
APPRAISE: Composite of ISTH Major and
Clinically Relevant Nonmajor (CRNM) Bleeding
Proportion with
ISTH Major or CRNM Bleeding
0.1
Apixaban 10 mg QD
0.08
Apixaban 2.5 mg BID
0.06
0.04
Placebo
0.02
0
0
4
8
12
16
20
24
28
Weeks from Randomization
Alexander, at al. Circulation. 2009 Jun 9;119(22):2877-85. Epub 2009 May 26.
Atrial Fibrillation with At Least
One Additional Risk Factor for Stroke
Aristotle
Apixaban 5 mg oral twice daily
+
Warfarin placebo
Randomize
Double blind
(n = 15,000)





Age ≥ 75 years
Prior stroke, TIA or SE
CHF or LVEF ≤ 40%
Diabetes mellitus
Hypertension
Apixaban placebo twice daily
+
Warfarin (target INR 2-3)
Warfarin/warfarin placebo adjusted by INR/sham INR
based on encrypted point-of-care testing device
Primary outcome: stroke and systemic embolism
Other outcomes: Death, MI, bleeding
Stratified by warfarin-naïve status
448 events over anticipated 2 year median follow-up;
>90% power to show non-inferiority
Bleeding Across the Spectrum of Arterial and
Venous Thrombotic Syndromes
Conclusions
► Bleeding is a common complication of
anticoagulant and antiplatelet therapy in atrial
fibrillation, VTE, and ACS
► Bleeding is associated with increased risk for
mortality and morbidity
► This risk may be partially explained by
discontinuation of evidence-bssed therapy in
patients who develop bleeding complications
Bleeding Across the Spectrum of Arterial and
Venous Thrombotic Syndromes
Conclusions

Managing bleeding risk is a clinical priority
 Maintain INR in appropriate range
Difficult to do in clinical practice
Genomic data only helps at the extremes
 Reduce ASA dose
 Dose anticoagulants appropriately
 Use radial approach
Bleeding Across the Spectrum of Arterial and
Venous Thrombotic Syndromes
Conclusions
► Newer anti-Xa agents may maintain appropriate
antithrombotic effect while reducing bleeding
risk
► Agents are being studied across the spectrum
of arterial and venous thrombotic syndromes