Jointly Sponsored by the University of Massachusetts Medical School Office of Continuing Education and CMEducation Resources, LLC.

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Accreditation Information
Jointly Sponsored by the University of
Massachusetts Medical School Office of Continuing
Education and CMEducation Resources,
LLC. Funded by an Independent Educational
Grant from The Medicines Company
3
Program Requirements
Instructions for Receiving Category 1 AMA
Credit Participants This SlideCAST is a
CME-certified program that must be viewed in its
entirety to receive CME credit. You should view
the slides in their original order, and then
access either the online CME test or the PDF test
form as directed at the end of the program. If
program content or total number of slides are
expanded, reduced, or modified in any way, the
program no longer qualifies for CME. Presenters
This SlideCAST is a CME-certified program that
must be presented in its entirety for your
audience to receive CME credit. You should
present the slides in their original order,
either as a Powerpoint presentation or in print
form, and then distribute CME answer sheets
(accessed at the end of the program) or instruct
your audience how to access the test online. If
program content or total number of slides are
expanded, reduced, or modified in any way, the
program no longer qualifies for CME and must be
reviewed and certified by your own institution.
4
Accreditation Information
Intended Audience This SlideCAST is designed
for interventional cardiologists, cardiologists,
and emergency medicine physicians, and other
healthcare providers caring for patients with
acute cardiovascular disease. Registration
Enrollment for this SlideCAST is
complimentary, and clinicians are invited to
participate in this CME-certified program and/or
share this invitation with other colleagues,
departmental staff members, and healthcare
professionals. Grantor Support Supported by
an independent educational grant from The
Medicines Company, Inc.
5
Accreditation Information
Accreditation Information
Accreditation Statement for Jointly-Sponsored
Programs This activity has been planned and
implemented in accordance with the Essential
Areas and Policies of the Accreditation Council
for Continuing Medical Education through the
joint sponsorship of The University of
Massachusetts Medical School and CMEducation
Resources, LLC. The University of Massachusetts
Medical School is accredited by the ACCME to
provide continuing medical education for
physicians. Credit Designation Statement The
University of Massachusetts Medical School
designates this educational activity for a
maximum of 1.5 AMA PRA Category 1 Credit(s). 
Physicians should only claim credit commensurate
with the extent of their participation in the
activity.
6
Accreditation Information
Policy on Faculty And Provider Disclosure It is
the policy of the University of Massachusetts
Medical School to ensure fair balance,
independence, objectivity and scientific rigor in
all activities.  All faculty participating in CME
activities sponsored by the University of
Massachusetts Medical School are required to
present evidence-based data, identify and
reference off-label product use and disclose all
relevant financial relationships with those
supporting the activity or others whose products
or services are discussed.  Faculty disclosure
will be provided in the activity materials. For
additional CME-certified programs in
cardiovascular health Please visit us at
www.EDICTforACS.com (click anywhere on banner
below)
7
ACS Forum Leadership Panel

• Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FACP
• Associate Director, Cleveland
• Clinic Cardiovascular Coordinating Center
• Staff, Cardiac, Peripheral, and
• Carotid Intervention
• Associate Professor of Medicine
• Department of Cardiovascular Medicine
• Cleveland Clinic Foundation
• Frederick Feit, MD, FACC
• Director
• Cardiac Catheterization and Interventional
  Cardiology
• Bellevue Hospital Center
• Associate Professor of Medicine
• New York University School of Medicine
• New York, NY

Deborah Diercks, MD Assistant Professor of
Medicine Department of Emergency
Medicine University of California Davis,
California James Ferguson III, MD Associate
Director, Cardiology Research Texas Heart
Institute at St. Luke's Episcopal
Hospital Associate Professor Baylor College of
Medicine Clinical Assistant Professor University
of Texas Health Science Center at
Houston Christopher Granger, MD Associate
Professor of Medicine Director of Cardiac Care
Unit Division of Cardiovascular Medicine Duke
University Medical Center
8
ACS Forum Leadership Panel
Judd E. Hollander, MD Professor Clinical Research
Director Department of Emergency
Medicine University of Pennsylvania Philadelphia,
PA David M. Lang, DO, FACOEP, FACEP
Chief Emergency Medicine Mount Sinai Medical
Center Miami Beach, FL Steven V. Manoukian, MD,
FACC Director, Interventional Cardiology Emory-Cra
wford Long Hospital Emory University School of
Medicine President American Heart Association,
Atlanta Division Atlanta, GA
Ralph G. Nader, MD, FACC, FACP, FSCAI Co-Medical
Director Cardiovascular Labs at
Mount-Sinai/Miami Heart Miami, FL E. Magnus
Ohman, MD, FRCPI, FACC Professor of
Medicine Director, Program for Advanced Coronary
Disease Division of Cardiology Duke University
Medical Center Durham, NC
9
ACS Forum Leadership Panel
Charles Pollack, MD, FACEP Chairman, Department
of Emergency Medicine Pennsylvania
Hospital Professor of Emergency
Medicine University of Pennsylvania School of
Medicine Philadelphia, PA Sunil V. Rao
MD Assistant Professor of Medicine Duke
University Medical Center Director, Cardiac
Catheterization Laboratories Durham VA Medical
Center Durham, NC
10
ACS Leadership Panel Financial Disclosures
Deepak L. Bhatt, MD Consultant/Honoraria or
Grant/Research Support Astra Zeneca,
Bristol-Myers Squibb, Eli Lilly, Eisai, Glaxo
Smith Kline, Millennium, Paringenix, PDL,
Schering Plough, sanofi-aventis, The Medicines
Company. Deborah Diercks, MD Grants/Research
Support Invoice Technology, The Medicines
Company. Consultant Invoice Technology,
sanofi-aventis U.S., Astellas. Speakers Bureau
Bristol-Myers Squibb, Schering-Plough,
sanofi-aventis U.S Frederick Feit, MD
Consultant The Medicines Company James
Ferguson III, MD Grant/Research Support Eisai
Pharmaceuticals, The Medicines Company.
Vitatron/Medtronic. Consulting/Honoraria Bristol
Myers-Squibb, Eisai Pharmaceuticals,
GlaxoSmithKline, Prism Pharmaceuticals,
sanofi-aventis, Schering-Plough, Takeda, The
Medicines Company, Therox. Speakers Bureau
Bristol Myers-Squibb, sanofi-aventis,
Schering-Plough Ralph G. Nader, MD Nothing to
disclose. E. Magnus Ohman, MD Research Grants
Berlex, sanofi-aventis, Schering-Plough
Corporation, Bristol Meyer Squibb, Millennium.
Stockholder Medtronic. Consultant Response
Biomedical, Liposcience, Inovise Medical
11
ACS Leadership Panel Financial Disclosures
Christopher Granger, MD Educational Grants
and/or Research Support Alexion, Astra Zeneca,
Procter and Gamble, sanofi-aventis, Novartis,
Boehringer Ingelheim, Genentech, and Berlex
Judd E. Hollander, MD Grant/Research Support
sanofi-aventis, Biosite, Scios, The Medicines
Company. Consultant sanofi-aventis, Biosite,
Scios, The Medicines Company. Speakers Bureau
sanofi-aventis, Biosite, Scios, The Medicines
Company David Lang, DO Honoraria Roche and
Pfizer. Consultant Aventis Steven V. Manoukian,
MD Grant/ Research Support The Medicines
Company Speakers Bureau The Medicines
Company Charles Pollack, MD Grant/Research
Support GlaxoSmithKline. Consultant The
Medicines Company, Schering-Plough,
sanofi-aventis, BMS, Genentech. Speakers Bureau
Schering-Plough, sanofi-aventis, BMS,
Genentech Sunil V. Rao, MD Consultant
sanofi-aventis, The Medicines Company, Pfizer,
Cordis. Research funding Agency for Healthcare
Research Quality, National Institute for Aging,
American College of Cardiology
12
ACS Faculty Review Committee
Thomas Amidon, MD The Hope Heart Institute Atul
Aggarwal, MD Nebraska Heart Institute Himanshu
Aggarwal, MD Nebraska Heart Institute Keith
Benzuly, MD, FACC Northwestern University Joseph
J. Brennan Jr., MD Yale University School of
Medicine Carl Chudnofsky, MD Albert Einstein
Medical Center
Michael J. Cowley, MD Medical College of
Virginia Harold Dauerman, MD University of
Vermont William J. French, MD UCLA Medical
Center Satyendra Giri, MD Baystate Health
Systems Paul A. Gurbel, MD Johns Hopkins
University
Complete affiliations and financial disclosures
for Review Committee members are listed at end
of slide deck.
13
ACS Faculty Review Committee
Tim Henry, MD Minneapolis Heart Institute Kurt
Kleinschmidt, MD UT Southwestern Medical
Center James Leggett, MD Hope Heart
Institute Glenn Levine, MD Baylor College of
Medicine John J. Lopez, MD University of
Chicago Reginald Low, MD University of
California, Davis
Roberto Medina, MD Florida Medical Clinic Barry
L. Molk, MD, FACC University of Colorado
Reynaldo Mulingtapang, MD University of South
Florida Robert A. Mulliken, MD University of
Chicago Hospitals Sandeep Nathan, MD, FACC Rush
Medical College Paul E. Pepe, MD, MPH UT
Southwestern Medical Center
Complete affiliations and financial disclosures
for Review Committee members are listed at end of
slide deck.
14
ACS Faculty Review Committee
David J. Robinson, MD, MS, FACEP UT Health
Sciences Center Joseph F. Stella, DO, FACC Heart
Care Centers of Illinois Rex J. Winters, MD Long
Beach Memorial Heart Institute
Robert N. Piana, MD Vanderbilt University
Vincent J. Pompili, MD, FACC Case School of
Medicine Matthew J. Price, MD Scripps
Clinic Douglas J. Spriggs, MD, FACC University
of South Florida Lowell H. Steen, Jr.,
MD Loyoyla University Chicago
Complete affiliations and financial disclosures
for Review Committee members are listed at end of
slide deck.
15
Educational Objectives

• As a result of this educational platform,
  interventional cardiologists and emergency
  physicians will be able to assess and implement
  optimal antithrombotic strategies for patients
  with NSTEMI.
• As a result of this educational platform,
  participants will understand impact of specific
  pharmacologic agents on outcomes, including
  ischemic endpoints, bleeding, and mortality for
  patients with ACS.
• As a result of this session, participants are
  able to discuss the impact that new trials are
  likely to have on future management of patients
  with ACS.
• As a result of this session, participants will
  learn to apply AHA/ACC, ACCP, and other national
  guidelines in order to optimize therapy ACS.

16
Critical Challenges in Cardiovascular Medicine
A Science-to-Strategy Analysis of Landmark
Trials in Acute Coronary Syndromes
(ACS) Applying New Data and Established
Guidelines to the Practice of Interventional
Cardiology and Emergency Medicine A
CME-Certified Activity Developed by the
National Experts' Educational Forum in
Cardiovascular Disease
17
ACS Program Agenda

• Background
• Coagulation and anticoagulant therapy
• Role of thrombin
• Risk stratification
• Balancing outcomes and bleeding

18
ACS Program Agenda (cont.)

• Recent landmark clinical trials
• ICTUS
• ISAR-REACT 2
• SYNERGY
• OASIS 5
• ACUITY
• Antithrombotic strategy
• Timing
• PCI
• Conclusions
• Conclusions about ACS management
• Frequent Questions

19
Background

• Coagulation and anticoagulant therapy
• Role of thrombin
• Risk stratification
• Balancing outcomes and bleeding

20
Co-Existent Stable and Acute Lesions
Chronic Atherosclerosis
Acute Thrombosis
Fuster V et al. J Am Coll Cardiol
200546937-954.
21
Sites of Antithrombotic Drug Action
Tissue factor
Collagen
Aspirin
Plasma clotting cascade
ADP
Clopidogrel Prasugrel Cangrelor
Fondaparinux
Thromboxane A2
AT
Prothrombin
AT
Factor Xa
Heparin LMWHs
Platelet activation
Eptifibatide Abciximab Tirofiban (GPI)
AT
Thrombin
Platelet aggregation
Bivalirudin Hirudin Argatroban
Fibrinogen
Fibrin
Thrombus
Fibrinolytics
22
Actions of Thrombin on Blood Cells and Blood
Vessels
Lymphocyte
Endothelium
Monocyte
Platelet
Neutrophil

• Serine protease generated at sites of vascular
  injury.
• Potent platelet activator (PAR-protease
  activated receptor).
• Elicits host of responses in vascular
  endothelium
• - Shape permeability changes
• - Mobilization of adhesive molecules to
  endothelial surface
• - Stimulation of autocoid and cytokine
  production.
• Chemotactic for monocytes.
• Mitogenic for lymphocytes mesenchymal cells.

Smooth Muscle cell
Coughlin SR, Nature 2000 407 258-264
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Antithrombotic and AntiplateletTherapy in ACS
ACC/AHA Guideline Update for UA and NSTEMI. 2002.
24
Milestones in ACS Management
ICTUS
ISAR-REACT 2
ACUITY
SYNERGY
1994
1995
1996
1997
1998
1999
2000
2002
2003
2004
2005
2006
2001
Ischemic risk
Bleeding risk
Adapted from and with the courtesy of Steven
Manoukian, MD.
25
Evolving ACS Therapies and Patterns of
Antithrombotic Use
1992
1995
1998
2001
2004
2007
UFH
2004
1997
1999
SYNERGY
LMWH
TIMI 11B
2006
2003
2001
Bivalirudin
Anti-thrombotic agents
ACUITY
REPLACE 2
ASA
EPISTENT
ESPRIT
IIb/IIIa antagonists
ISAR REACT
PURSUIT
GUSTO 4
ISAR-REACT 2
2004
1995
1998
2001
2000
CURE
Clopidogrel
Anti-platelet agents
Width of bar represents approximate degree of
use of antiplatelet or anticoagulants at a
particular time
26
ECG and Outcome in TACTICS/TIMI 18
Risk Stratification
Death / MI / Rehospitalization at 6 Months
ST-segment ?s ( n 852 )
No ST-segment ?s ( n 1368 )
Cannon et al. N Engl J Med 2001 344 1879-87
27
Troponin and Outcome in TACTICS/TIMI 18
Risk Stratification
6 Months
30 Days
lt0.001
lt0.001
Tn T gt 0.01 ng/ml
Tn T gt 0.01 ng/ml
0.082
0.002
Death/MI/hosp
Death/MI/hosp
Death/MI
Death/MI
Conservative
0.46
Tn T lt 0.01 ng/ml
Tn T lt 0.01 ng/ml
Invasive
0.80
0.58
0.90
Death/MI/hosp
Death/MI
Death/MI/hosp
Death/MI
Cannon et al. N Engl J Med 2001 344 1879-87
28
Inpatient Therapies Administered To Patients Who
Had NSTE-ACS From 1987 To 2000
Watkins S et al. Am J Cardiol 2005961349-1355.
29
Crude Mortality Rates For Patients Who Had
NSTE-ACS From 1987 To 2000
Watkins S et al. Am J Cardiol 2005961349-1355.
30
CRUSADE In-Hospital Outcomes
No. of Events () by Hospital Adherence Quartile
Population 1 (Lowest) 2 4 4 (Highest) P
value Overall (N 64775) (n 12329) (n
15255) (n 18364) (n 18827) Death 784
(6.36) 772 (5.06) 850 (4.63) 786 (4.17)
lt.001 Death/MI 1119 (9.08) 1280 (8.39) 1223
(6.66) 1201 (6.38) lt.001 Stroke 96
(0.78) 146 (0.96) 171 (0.93) 134 (0.71) .31
CHF 908 (7.36) 1747 (11.45) 1727 (9.40) 1541
(8.19) .24 NSTEMI (N 57260) (n 9892) (n
12597) (n 18149) (n 16622) Death 760
(7.68) 701 (5.56) 843 (4.64) 718 (4.32) lt.001
Death/MI 1055 (10.67) 1128 (8.95) 1206
(6.64) 1105 (6.65) lt.001 Stroke 96 (0.80)
146 (0.98) 171 (0.94) 134 (0.72) .25 CHF 862
(8.71) 1368 (10.68) 1851 (10.20) 1424
(8.57) .13 Indicates in-hospital death or
recurrent MI.
Peterson, E.D. et al. JAMA 20062951912-1920.
31
Evolving Paradigm for Evaluating ACS Management
Strategies
Composite Adverse Event Endpoints

• Death
• MI
• Urgent TVR

Ischemic Complications
32
Evolving Paradigm for Evaluating ACS Management
Strategies
Composite Adverse Event Endpoints

• Major Bleeding
• Minor Bleeding
• Thrombocytopenia

• Death
• MI
• Urgent TVR

Ischemic Complications
Hemorrhage HIT
33
Evolving Paradigm for Evaluating ACS Management
Strategies
Composite Adverse Event Endpoints

• Cost
• Ease of Use
• Duration of Therapy
• Accounting for Bleeding and Ischemic Endpoints

• Death
• Major Disability

Periprocedural Complications
Clinical Benefit
34
Balancing Events and Bleeding
Risk of events
Risk of bleeding
Hemostasis
Thrombosis
Two sides of the same coin
35
Recent Landmark Trials
The Evolving World of ACS

• Science
• Recent Trials
• Clinical Strategies

36
ACS Trials Qualifiers and Disclaimers

• Optimizing ACS management is a work in progress
• Inconsistency is the only consistency
• Trial designs differ
• Variability in risk profiles of patients
  studied
• Dose and dosing variations (approved versus
  off-label)
• Confounding variables
• Imperfect meta-analyses
• Evidence basis for ACS care is evolving rapidly
• Individualized approaches are based on
  aggregate evidence and guidelines should eclipse
  deterministic, one size fits all strategy to
  patient care

37
Platelet Thrombus
Bhatt DL and Topol EJ. Nature Reviews Drug
Discovery 2003 215-28.
38
Background Current Management of ACS
Year 2002 ACC/AHA Guidelines

• Early invasive strategy if moderate-high risk1,2
• - Median time to cath 21 hours3
• Revascularization with PCI or CABG1,2
• - 55 PCI, 12 CABG, 33 medical mgt3
• Triple anti-platelet therapy1,2
• - Aspirin
• - Clopidogrel (initiated pre or post angiography)
• - GP IIb/IIIa inhibitors
• - started upstream in all pts or in the CCL for
  PCI
• Unfractionated or LMW heparin1,2,4

1 Braunwald et al JACC 2002 2 Bertrand et al.
EHJ 2002 3www.crusade.org 4SYNERGY. JAMA
200429245-54
39
(12 of total, 15 of those undergoing cath)
Surgery
CRUSADE Registry 10/04-9/05 n35,897
No disease
Medical Rx
(52 of total, 63 of those undergoing cath)
Medical Rx (cath)
PCI
(82 of total)
Cath
Patient X
Medical Rx (no cath)
(18 of total)
Medical Rx
Time
ACS Management Pathways
40
Case for Invasive Management

• FRISC II
• TACTICS

41
FRISC II Mortality at One-Year Invasive versus
Non-invasive Management Strategies
.04
Non-invasive (n1235)
.03
Probability of death
.02
Invasive (n1222)
.01
Invasive Noninvasive RR (95 CI)
p 2.2 4.0 0.56 (0.35 - 0.89) 0.018
0.00
360
180
90
30
0
Lancet. 1999 354701-7
42
FRISC II Clinical End Points at 5 years
End point Invasive strategy () Noninvasive strategy () Relative risk (95 CI)
Death or MI 19.9 24.5 0.81 (0.690.95)
All-cause mortality 9.7 10.1 0.95 (0.751.21)
MI 12.9 17.7 0.73 (0.600.89)
Lagerqvist B. World Congress of Cardiology 2006
September 4, 2006 Barcelona, Spain.
43
TACTICS Primary Endpoint Death, MI, Rehosp for
ACS at 6 Months
20
16
Patients
12
8
4
0
0
1
2
3
4
5
6
Time (months)
Cannon CP, Weintraub WS. N Engl J Med. 2001 Jun
21344(25)1879-87.
44
Death or Myocardial at 5 Years in High-, Medium-,
and Low-risk Patients
End point Invasive strategy () Noninvasive strategy () Relative risk (95 CI)
Death or MI in high-risk patients (FRISC 47) 32.7 41.6 0.79 (0.640.97)
Death or MI in medium-risk patients (FRISC 23) 14.6 20.4 0.72 (0.551.13)
Death or MI in low-risk patients (FRISC 01) 10.3 8.2 1.26 (0.662.40)
Lagerqvist B. World Congress of Cardiology 2006
September 4, 2006 Barcelona, Spain.
45
Invasive Management of UA/NSTEMI Meta-analysis
? Death/MI at 17 mo. F/U
Odds Ratio Death or MI
Trial
Inv
Cons
TIMI 3B
5.1
8.1
VANQWISH
27.2
28.0
MATE
12.0
8.9
FRISC II
4.3
11.4
TACTICS
4.0
5.3
VINO
4.8
14.8
RITA 3
7.4
10.9
OR 0.82, P0.001
TOTAL
7.4
11.0
0.2
0.5
1
2
5
Favors Conservative
Favors Invasive
Mehta SR et al. JAMA 20052932908-17
46
Recent Clinical Trials

• ICTUS
• ISAR-REACT
• ISAR REACT-2
• SYNERGY
• OASIS-5
• ACUITY

47
ICTUS
Question to be answered

• Does a selectively invasive strategy with maximal
  medical therapy for ACS patients produce outcomes
  comparable to a mandatory invasive strategy?

48
ICTUS

• 1200 ACS patients
• Presenting within 1 day of onset of chest pain
• 42 Dutch hospitals (12 were high-volume PCI
  centers)
• ? Troponin T ( 0.03 µg/L)
• Either ECG evidence of ischemia or documented Hx
  CAD
• Randomized
• Early invasive (n604)
• Angio within 24-48 hours
• PCI within 48 hours, CABG as soon as
  possible
• Selective invasive (n596)
• Angio for refractory angina, provokable
  ischemia

Primary Endpoint Death / MI / rehospitalization
at 1 year
N Engl J Med 2005 353 1095-1104
49
ICTUS
Early Invasive Selective Invasive
Death 2.2 2.0
MI 14.6 9.4
Rehospitalization 7.0 10.9
Total 21.7 20.4
N Engl J Med 2005 353 1095-1104
50
ICTUS
30
Early invasive strategy
25
20
Cumulative Event Rate ()
15
Selectively invasive strategy
10
5
0 1 2 3 4 5 6 7 8
9 10 11 12
Months
(RR 1.07 95 percent CI, 0.87 to 1.33 P0.33)
N Engl J Med 2005 353 1095-1104
51
ICTUSConclusions/Caveats

• In the presence of guideline-consistent medical
  therapy for ACS, a selectively invasive strategy
  is an alternative
• Sensitive protocol definition of MI
• 53 of patients underwent catheterization during
  hospitalization
• Implications of ICTUS trial for current American
  practice are uncertain

52
Even with ICTUS . . .
All-Cause Mortality
Deaths, n Follow
up Invasive Conservative Months
Study FRISC-II TRUCS TIMI-18 VINO RITA-3 ISAR-COOL
ICTUS Overall RR (95 CI) 0.75 (0.63-0.90)
45 67 24 3 9 12 37 39 6 2 9 6
102 132 60 0 3 1 15 15 12
0.1 1 10
Favors Early Invasive Therapy
Favors Conservative Therapy
Bavry et al. J Am Coll Cardiol 2006 48 1319-25
53
Even with ICTUS . . .
All-cause mortality as a function of time of
angio and extent of revascularization
Relative Risk Reduction, P Value Patients,
n
Characteristic
Angiography lt 24 hrs
18 0.26 3,961 27 0.002 4,414 12 0.55 2,630 22
0.03 3,158 37 0.01 2,587
Angiography gt 24 hrs
Small difference in revasc between treatment arms
Intermediate difference in revasc between
treatment arms
Large difference in revasc between treatment arms
0.4 1 1.4
Favors Early Invasive Therapy
Favors Conservative Therapy
Bavry et al. J Am Coll Cardiol 2006 48 1319-25
54
ISAR-REACT

• Question to be answered

• In elective patients receiving 600 mg oral
  clopidogrel load, at least 2 hours pre-PCI, does
  the addition of a GP IIb/IIIa receptor antagonist
  improve ischemic endpoints?

55
ISAR-REACT

• 2159 patients undergoing elective PCI
• Excluded
• IDDM
• MI within 14 days
• ACS
• ? troponin
• All got 600 mg oral clopidogrel load at least 2
  hours pre-PCI
• Randomized (double blind)
• Abciximab (n1079 - UFH 70 U/kg)
• Placebo (n1080 - UFH 140 U/kg)

Primary Endpoint Death / MI / Urgent TVR at 30
days
Kastrati et al. N Engl J Med. 2004350 232238
56
ISAR-REACTEvents at 30 Days
Abciximab Placebo
4.2 4.06 0.3 0.3 0.4 0.5
3.3 3.3 1.7 1.5 2.0
1.6
Death / MI / Urgent TVR
Death
Q-wave MI
Non Q-wave MI
Large MI
Death / Large MI
Kastrati et al. N Engl J Med. 2004350 232238
57
ISAR-REACTBleeding Events
Abciximab Placebo
1.1 0.7 2.5 1.9 0.9 0
2.4 0.9
TIMI Major bleed
TIMI Minor bleed
Thrombocytopenia
Transfusion
Kastrati et al. N Engl J Med. 2004350 232238
58
ISAR-REACT Conclusions/Caveats

• With clopidogrel pretreatment, in elective PCI,
  the addition of a GP IIb/IIIa receptor antagonist
  does not significantly improve ischemic outcomes,
  and may increase bleeding.

59
ISAR-REACT 2

• Question to be answered

• Is a GP IIb/IIIa receptor antagonist required in
  patients with ACS going to PCI, or is high dose
  clopidogrel sufficient?

60
ISAR-REACT 2 Trial Study Design
2022 patients with an episode of angina within
the preceding 48 hours Elevated troponin T or
new ST-segment changes or presumed new
BBB Significant lesions in a native vessel or
bypass graft undergoing PCI
Pre-treatment with high dose (600mg) clopidogrel
at least 2 hours pre-procedure
Abciximab n1012

• Placebo
• n1010

• Primary Endpoint Composite of death, MI, and
  urgent target vessel revascularization (TVR) due
  to myocardial ischemia within 30 days
• Secondary Endpoint In-hospital major and minor
  bleeding

Kastrati A, Mehilli J , et al. JAMA. 2006 Apr
5295(13)1531-8
61
ISAR-REACT 2 Primary Endpoint
Composite of death, MI, or urgent TVR due to
Myocardial Ischemia within 30 days ()
( n 2022 )
p0.03
Kastrati A, Mehilli J , et al. JAMA. 2006 Apr
5295(13)1531-8
62
ISAR-REACT 2 Individual Endpoints
In-hospital Major and Minor Bleeding () pNS
Kastrati A, Mehilli J , et al. JAMA. 2006 Apr
5295(13)1531-8
63
ISAR-REACT 2 Troponin Status
Troponin negative ( lt0.03µg/L, n973)
Troponin positive (gt0.03 µg/L, n1049)
p0.02
p0.98
Primary Events
Kastrati A, Mehilli J , et al. JAMA. 2006 Apr
5295(13)1531-8
64
ISAR-REACT 2 Bleeding
In-hospital Major and Minor Bleeding () pNS
Kastrati A, Mehilli J , et al. JAMA. 2006 Apr
5295(13)1531-8
65
ISAR-REACT 2 Trial Conclusions/Caveats

• Even with clopidogrel pretreatment, heparin
  therapy alone is inadequate to prevent ischemic
  events in high risk ACS patients undergoing PCI
• This effect was primarily present in
  troponin-positive patients

66
LMWH in UA/NSTEMIEffects on triple endpoints
Day FRIC 6 (dalteparin n 1,482) FRAXIS 14
(nadroparin n 2,357) ESSENCE P
0.032 14 (enoxaparin n 3,171) TIMI 11B P
0.029 14 (enoxaparin n 3,910)
0.75 1 1.5
LMWH better UFH better
Triple endpoint death, MI, recurrent ischemia ?
urgent revascularization
Braunwald E, et al. J Am Coll Cardiol.
2002401366.
67
SYNERGY
Question to be answered

• What is the role of enoxaparin in patients with
  nonST segment elevation ACS at high risk for
  ischemic cardiac complications managed with an
  early invasive approach ?

68
Study Design
High-riskACS Patients
Early invasive strategy Other therapy per ACC/AHA
guidelines (ASA, ?-blocker, ACE, clopidogrel, GP
IIb/IIIa)
Primary endpoint Death or MI at 30 days
SYNERGY Trial Investigators. JAMA 200429245-54
69
SYNERGY Primary Results (30 Days)

• Enoxaparin UFH Unadjusted (n 4,993) (n
  4,985) P value
• Death and MI 14.0 14.5 0.40
• Death 3.2 3.1 0.71
• MI 11.7 12.7 0.14

SYNERGY Trial Investigators. JAMA 200429245-54
70
SYNERGY Death and MI at 30 Days
Hazard Ratio (95 CI)
30-day Death/MI
HR 0.96 (0.86 1.06)
0.8 1.0 1.2
0.8
1
1.2
Enoxaparin UFH Better Better
SYNERGY Trial Investigators. JAMA 200429245-54
71
SYNGERY Bleeding Events
Enoxaparin UFH P value (n
4,993) (n 4,985)

• GUSTO severe 2.7 2.2 0.08
• TIMI major (clinical) 9.1 7.6 0.008
• CABG-related 6.8 5.9 0.08
• Non-CABG-related 2.4 1.8 0.03
• Hb/HCT drop (algorithm) 15.2 12.5 lt 0.001
• Any RBC transfusion 17.0 16.0 0.16
• ICH lt 0.1 lt 0.1 NS

SYNERGY Trial Investigators. JAMA 200429245-54
72
SYNERGY Conclusions/Caveats

• Enoxaparin was not superior to unfractionated
  heparin but was noninferior for nonST-segment
  elevation ACS.
• More bleeding was observed with enoxaparin
• Enoxaparin was not noninferior to unfractionated
  heparin for nonST-segment elevation ACS in
  high-risk patients being managed with a rapid
  transition to intervention

73
Heparin, LMWH and Pentasaccharide
anti-IIa effect
anti-Xa effect
Xa
AT
IIa
AT
Chain length-dependent
Not chain length dependent
Pure anti-Xa effect
Pentasaccharide
74
OASIS-5

• Question to be answered

• Is fondaparinux an alternative to enoxaparin
  in higher-risk ACS patients?

75
OASIS-5 Study Design
Patients w/ NSTE ACS
Chest pain lt 24 hours 2/3 Age gt 60 ST-segment
? ? cardiac markers
Exclude Age lt 21 Contraindication to
enox Hemorrhagic stroke lt 12 mo Creat gt 3 mg/dL
(265 umol/L)
Randomize
n 20,000
Fondaparinux 2.5 mg sc qd
Enoxaparin 1 mg/kg sc bid
ASA, clopidogrel, IIb/IIIa, planned cath per
local practice200
PCI lt 6 h IV fondaparinux 2.5 mg w/o IIb/IIIa,
0 w/ IIb/IIIa PCI gt 6h IV fondaparinux 5 mg w/o
IIb/IIIa, 2.5 mg w/ IIb/IIIa
PCI lt 6 h no UFH PCI gt 6h IV UFH 100 U/kg w/o
IIb/IIIa 60 U/kg w/ IIb/IIIa
Outcomes
Primary Efficacy Death, MI, refractory
ischemia at 9 days Safety Major bleeding
at 9 days Risk/Benefit Death, MI,
refractory ischemia and major bleeding at 9 days
Secondary Above and each component separately
at day 30 and 6 months
Yusuf S, et al. N Engl J Med. 2006354(14)1464-76
76
OASIS 5 Efficacy and Safety at Day 9
Bleeding
Death, MI, RI
Cumulative Hazard
Cumulative Hazard
Hazard ratio 1.01 (95 CI, 0.90-1.13)
Hazard ratio 0.52 (95 CI, 0.44-0.61)
Days
Days
Fondaparinux
Enoxaparin
Yusuf S, et al. N Engl J Med. 2006354(14)1464-76
77
Efficacy End Points at 6 Months
End point Enoxaparin Fondaparinux P value
Death/MI/ refractory ischemia 13.2 12.3 0.06
Death/MI 11.4 10.5 0.05
Death 6.5 5.8 0.05
MI 6.6 6.3
Stroke 1.7 1.3 0.04
Death/MI/stroke 12.5 11.3 0.007
Yusuf S, et al. N Engl J Med. 2006354(14)1464-76
78
PCIProcedural Complications
Events (30 Days) Enoxaparin n3089 Fondaparinux n3118 P value
Any UFH during PCI 53.8 18.8
Any procedural complication 8.6 9.6 0.18
Abrupt closure 1.1 1.5 0.20
Catheter thrombus 0.5 1.3 0.001
Vascular access 8.1 3.3 lt0.0001
Pseudo-aneurysm 1.6 1.0 0.39
Large hematoma 4.4 1.6 lt0.0001

Yusuf S, et al. N Engl J Med. 2006354(14)1464-76
79
OASIS-5 Conclusions/Caveats

• Among patients with NSTE-ACS, fondaparinux was
  non-inferior for primary composite endpoint of
  death, MI or refractory ischemia at day 9
  compared with enoxaparin.
• There was a significant reduction in the safety
  endpoint of major bleeding at 9 days and the
  secondary endpoint of mortality at 30 days and 6
  months.
• In the OASIS-5 trial, the relationship between
  bleeding and mortality requires further
  investigation
• The optimal approach to using fondaparinux in the
  catheterization lab has yet to be defined, and
  therefore, its use in this setting is currently
  not recommended

80
Sites of Antithrombotic Drug Action
Tissue factor
Collagen
Aspirin
Plasma clotting cascade
ADP
Clopidogrel Prasugrel Cangrelor
Fondaparinux
Thromboxane A2
AT
Prothrombin
AT
Factor Xa
Heparin LMWHs
Platelet activation
Eptifibatide Abciximab Tirofiban (GPI)
AT
Thrombin
Platelet aggregation
Bivalirudin Hirudin Argatroban
Fibrinogen
Fibrin
Thrombus
Fibrinolytics
81
Bivalirudin as an Alternative to UFH/LMWH

• Advantages of the direct thrombin inhibitor
  bivalirudin
• No requirement for anti-thrombin III
• Effective on clot-bound thrombin
• Inhibits thrombin-mediated platelet activation
• No interactions with PF-4
• Plasma half-life 25 minutes
• No requirement for anticoagulant monitoring
• Clinical results with bivalirudin in PCI
• In REPLACE 2, bivalirudin showed similar
  protection from ischemic events as UFH GP
  IIb/IIIa inhibitors, with markedly reduced
  bleeding1
• Not previously tested in contemporary ACS patients

REPLACE 2. Lincoff AM et al. JAMA
2003289853-863
82
REPLACE-2 Quadruple Endpoint
30 Day Primary Endpoint Components
of Patients
12
Heparin GP IIb/IIIa (n 3008)
10
Bivalirudin (n 2994)
9.2
10.0
8
7.0
6
6.2
p lt0.001
4
4
4.1
2
2.4
0.4
1.4
0.2
1.2
0
Composite
Death
MI
Urgent
Major
Revasc
Bleeding
Lincoff AM et al JAMA 2003289853-863
83
REPLACE-2 ACS Subgroup
Death - 1 Year ()
Death, MI, UR - 30 Days ()
15
4
Heparin GP IIb/IIIa
Heparin GP IIb/IIIa
12
Bivalirudin
3
Bivalirudin
9
2.5
8.7
2
2.0
7.4
6
8.0
6.8
1.5
1.8
1
3
0
0
ACS
No ACS
ACS
No ACS
n 1330
n 1330
n 4495
n 4495
Rajagopal V, Lincoff AM et al. AHJ 2005.
84
ACUITY
Questions to be answered

• When given with a GP IIb/IIIa antagonist, does
  bivalirudin provide benefit over UFH/enoxaparin
  in moderate and high risk ACS patients managed
  invasively ?

• When given by itself (with provisional GP IIb/IIa
  usage) is a strategy of bivalirudin alone
  comparable to the use of UFH/enoxaparin plus a GP
  IIb/IIIa antagonist in moderate and high risk ACS
  patients managed invasively?

85
Bivalirudin in ACS Hypotheses

• In moderate- and high-risk patients patients with
  ACS undergoing an invasive strategy, compared to
  UFH or LMWH GP IIb/IIIa inhibitors
• Bivalirudin GP IIb/IIIa inhibitors will result
  in less adverse ischemic events and less bleeding
• Bivalirudin alone will result in similar rates of
  ischemic events and markedly reduced bleeding

86
Inclusion/Exclusion Criteria
Moderate-high risk unstable angina or NSTEMI
Inclusion Criteria
Exclusion Criteria

• Age 18 years
• Chest pain 10 within 24h
• At least one of
• New ST depression or transient ST elevation 1
  mm
• Troponin I, T, or CKMB
• Documented CAD
• All other 4 TIMI risk criteria
• Age 65 years
• Aspirin within 7 days
• 2 angina episodes w/i 24h
• 3 cardiac risk factors
• Written informed consent

• No angiography within 72h
• Acute STEMI or shock
• Bleeding diathesis or major bleed within 2 weeks
• Platelet count 100,000/mm3
• INR gt1.5 control
• CrCl 30 ml/min
• Abcx or 2 prior LMWH doses
• Prior UFH, LMWH (1 dose), eptifibatide and
  tirofiban were allowed
• Allergy to drugs, contrast

ACUITY Design. Stone GW et al. AHJ 200414876475
87
Study Design First Randomization

• Moderate-high risk unstable angina or NSTEMI
  undergoing an invasive strategy (N 13,819)

Moderate- high risk ACS
Aspirin in all Clopidogrel dosing and timing per
local practice
Stratified by pre-angiography thienopyridine use
or administration
ACUITY Design. Stone GW et al. AHJ 200414876475
88
Study Design Second Randomization

• Moderate-high risk unstable angina or NSTEMI
  undergoing an invasive strategy (N 13,819)

Moderate- high risk ACS
Angiography within 72h
Aspirin in all Clopidogrel dosing and timing per
local practice
ACUITY Design. Stone GW et al. AHJ 200414876475
89
ACUITY Study Medications

• Anti-thrombin agents (started pre angiography)

UF Heparin Enoxaparin Bivalirudin
U/Kg mg/Kg mg/kg
Bolus 60 1.0 sc bid 0.1 iv
Infusion/h 121 0.25 iv
PCI ACT 200-250s 0.30 iv bolus2 0.75 iv bolus3 0.50 bolus iv 1.75/h infusion iv4
CABG Per institution Per institution Per institution5
Medical mgt None6 None6 None6
1 Target aPTT 50-75 seconds 2 If last enoxaparin
dose 8h - lt16h before PCI 3 If maintenance dose
discontinued or 16h from last dose 4
Discontinued at end of PCI with option to
continue at 0.25mg/kg for 4-12h if GPIIb/IIIa
inhibitor not used 5 Bivalirudin option for
off-pump same as PCI dose. For on-pump
bivalirudin discontinued 2 hours before 6 Option
to continue with pre-PCI anti-thrombotic regimen
at physician discretion
This is an off-label dose used in the ACUITY
Trial
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
90
ACUITY Primary Endpoints (30 day)

• Net Clinical Outcome
• Death, MI, unplanned revascularization for
  ischemia or non-CABG major bleeding
• Composite Ischemic
• Death, MI or unplanned revascularization for
  ischemia
• Non-CABG Major Bleeding Endpoint
• Intracranial, intraocular, or retroperitoneal
  bleeding
• Access site bleed requiring intervention/surgery
• Hematoma 5 cm
• Hgb ?4g/dL w/o overt source
• Hgb ?3g/dL with an overt source
• Reoperation for bleeding
• Any blood transfusion

Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
91
3 Primary Endpoints (at 30 Days)
1. Composite net clinical benefit 2. Ischemic
composite or 3. Major bleeding

• Death from any cause
• Myocardial infarction
• - During medical Rx Any biomarker elevation
  gtULN
• - Post PCI CKMB gtULN with new Q waves or gt3x
  ULN w/o Q waves
• - Post CABG CKMB gt5x ULN with new Q waves, gt10x
  ULN w/o Q waves
• Unplanned revascularization for ischemia

Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
92
3 Primary Endpoints (at 30 Days)
1. Composite net clinical benefit 2. Ischemic
composite or 3. Major bleeding

• Non CABG related bleeding
• Intracranial bleeding or intraocular bleeding
• Retroperitoneal bleeding
• Access site bleed requiring intervention/surgery
  
• Hematoma 5 cm
• Hgb ?3g/dL with an overt source or ?4g/dL w/o
  overt source
• Blood product transfusion
• - Reoperation for bleeding

Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
93
Primary Results by Treatment
UFH/Enox GP IIb/IIIa Bivalirudin GP IIb/IIIa Bivalirudin GP IIb/IIIa Bivalirudinalone Bivalirudinalone
Endpoint Rate Rate P Value Rate P Value
Net clinical outcome 11.7 11.8 lt0.001 NI 10.1 0.015 Sup
Ischemic events 7.3 7.7 0.007 NI 7.8 0.011 NI
Major bleeding 5.7 5.3 0.001 NI 3.0 lt0.001 Sup
NI non-inferiority Sup superiority
Gregg Stone, ACC 2006 Presentation
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
94
Components of the Ischemic Composite
UFH/Enoxaparin GPI vs. Bivalirudin GPI vs.
Bivalirudin alone
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
95
Ischemic Composite Endpoint
UFH/Enoxaparin GPI vs. Bivalirudin GPI vs.
Bivalirudin Alone
15
P (log rank)
Estimate
UFH/Enoxaparin IIb/IIIa (N4603)
7.3
Bivalirudin IIb/IIIa (N4604)
0.37
7.7
0.30
Bivalirudin alone (N4612)
7.8
10
Cumulative Events ()
5
0
0
5
10
15
20
25
30
35
Days from Randomization
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
96
Major Bleeding Endpoint
UFH/Enoxaparin GPI vs. Bivalirudin GPI vs.
Bivalirudin Alone
P (log rank)
Estimate
Bivalirudin IIb/IIIa (N4604)
0.41
5.3
Bivalirudin alone (N4612)
lt0.0001
3.0
Cumulative Events ()
Days from Randomization
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
97
Net Clinical Outcome Composite Endpoint
UFH/Enoxaparin GPI vs. Bivalirudin GPI vs.
Bivalirudin Alone
15
10
Cumulative Events ()
5
0
0
5
10
15
20
25
30
35
Days from Randomization
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
98
Primary Endpoint Measures (ITT)

• Heparin IIb/IIIa vs. Bivalirudin IIb/IIIa
  vs. Bivalirudin Alone

Heparinunfractionated or enoxaparin
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
99
Major Bleeding Endpoints
UFH/Enoxaparin GPI vs. Bivalirudin GPI vs.
Bivalirudin alone
Heparin

GPI
(
N

4603)
Bivalirudin

GPI
(
N

4604)
Bivalirudin alone
(
N

4612)
PSup0.38
PSuplt0.0001
PSup0.31
PSuplt.001
11.8
11.1
30 day events ()
9.1
5.7
5.3
3.0
All major bleeding
Non CABG major bleeding (primary endpoint)
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
100
Bleeding Endpoints (Non-CABG)
Bleeding Scale UFH/Enoxaparin GP IIb/IIIa (N4,603) Bivalirudin GP IIb/IIIa (N4,604) Bivalirudin alone (N4,612) P1 Value P2 Value
ACUITY Scale
- Any 23.9 23.7 14.2 0.88 lt0.001
- Major 5.7 5.3 3.0 0.38 lt0.001
- Minor 21.6 21.7 12.8 0.84 lt0.001
TIMI Scale
- Any 6.6 6.4 3.9 0.67 lt0.001
- Major 1.8 1.6 0.9 0.42 lt0.001
- Minor 6.4 6.1 3.7 0.52 lt0.001
Blood transfusion 2.7 2.6 1.6 0.70 lt0.001
P1 BivalirudinGPI vs. UFH/EnoxGPI P2
Bivalirudin alone vs. UFH/EnoxGPI
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
101
ACUITY Major Bleeding
UFH/Enoxaparin GP IIb/IIIa (N4,603) Bivalirudin GP IIb/IIIa (N4,604) Bivalirudin alone (N4,612)
Any major bleeding 5.7 5.3 3.0
Intracranial 0.07 0.04 0.07
Retroperitoneal 0.5 0.6 0.2
Access site 2.6 2.6 0.8
- req interv/surgery 0.3 0.5 0.2
- hematoma 5 cm 2.2 2.2 0.7
Hgb ? 3 g/dL with overt source 2.2 1.8 1.0
Hgb ? 4 g/dL with no overt source 0.8 0.7 0.7
Blood transfusion 2.7 2.6 1.6
Reoperation for bleed 0.04 0.1 0.1
Plt0.05
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
102
Net Clinical Outcome Composite
UFH/Enoxaparin IIb/IIIa vs. Bivalirudin Alone
UFH/Enox IIb/IIIa
Risk ratio 95 CI
Bival Alone
P
Pint
RR (95 CI)
Age lt65 (n5051) Age 65 (n4164)
0.89
Men (n6444) Women (n2771)
0.91
Diabetes (n2585) No diabetes (n6630)
0.28
CrCl 60 (n6993)CrCl lt60 (n1644)
0.43
US (n5224)OUS (n3991)
0.47
Bivalirudin alone better
UFH/Enox IIb/IIIa better
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
103
ACUITY Conclusions/Caveats

• ACUITY compares two new strategies against the
  currently defined standard of care in ACS
  patients managed with an early invasive strategy
• Bivalirudin plus IIb/IIIa had similar ischemic
  outcomes, similar bleeding, and similar net
  clinical benefit to heparin plus IIb/IIIa
• Bivalirudin alone (with provisional IIb/IIIa use)
  had similar ischemic outcomes, less bleeding, and
  superior net clinical benefit to heparin plus
  IIb/IIIa
• Whether or not reductions in bleeding will
  translate into longer-term reductions in
  mortality is yet to be determined

104
ACUITY Timing Trial

• Question to be answered

• Is there an advantage to using a GP IIb/IIIa
  antagonist routinely upstream in rapidly,
  invasively managed ACS patients, versus selective
  use in the cath lab for PCI?

105
Study Design Second Randomization

• Moderate-high risk unstable angina or NSTEMI
  undergoing an invasive strategy (N 13,800)

Moderate- high risk ACS
Angiography within 72h
Aspirin in all Clopidogrel dosing and timing per
local practice
ACUITY Design. Stone GW et al. AHJ 200414876475
106
Timing TrialNet Clinical Outcome Composite
Endpoint
Upstream llb/llla vs. Selective llb/lllvs.
Bivalirudin Alone
Stone G. American College of Cardiology 2006
Scientific Sessions March 12, 2006 Atlanta, GA.
107
ACUITY Timing Trial Conclusions/Caveats

• The ACUITY Timing trial compared the outcomes
  with upstream GPI use with the outcomes for
  selective, in-lab use for PCI in rapidly
  invasively managed ACS patients additional
  comparisons were made to the bivalirudin-alone
  arm
• Upstream IIb/IIIa use was associated with
  slightly fewer ischemic events, slightly more
  bleeding, and identical net clinical benefit to a
  selective in-lab IIb/IIIa strategy
• In comparison to the IIb/IIIa arms, bivalirudin
  alone had comparable ischemic outcomes, less
  bleeding, and superior net clinical benefit.
• Future analyses will need to focus on the
  duration of therapy, and look more closely at
  comparisons with the bivalirudin-alone strategy

108
ACUITYPCI Subset

• Question to be answered

• What were the outcomes in the ACUITY patients
  who underwent PCI?

109
Management Strategy (N13,819)
Medical Rx (n4,491)
CABG (n1,539)
32.2
11.4
56.4
PCI (n7,789)
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
110
Baseline CharacteristicsPCI

Baseline Characteristics Heparin IIb/IIIa (N2561) Bivalirudin IIb/IIIa (N2609) Bivalirudin alone (N2619)
Baseline cardiac biomarker ?or ST-segments ? 76.8 75.2 77.0
Troponin ? 64.8 62.6 66.2
Thienopyridine Exposure 68.0 67.4 69.0
GPI inhibitor during PCI 96.6 96.7 9.1
Admission to start of first PCI hr 19.7 19.3 19.6
Stent implanted 92.7 93.1 92.7
Drug-eluting stents 60.9 59.7 59.6
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
111
ACUITYPCI Major Bleeding
UFH/Enoxaparin GPI vs. Bivalirudin GPI vs.
Bivalirudin Alone
HeparinGPI (N2561)
BivalirudinGPI (N2609)
Bivalirudin alone (N2619)
PSup0.32
PSuplt0.0001
30 day events ()
7.5
6.8
3.5
Non CABG major bleeding (primary endpoint)
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
112
Components of IschemiaPCI pts
Heparin IIb/IIIa vs. Bivalirudin IIb/IIIa
vs. Bivalirudin Alone
HeparinGPI (N2561)
BivalirudinGPI (N2609)
Bivalirudin alone (N2619)
9.3
30 day events ()
8.8
8.2
6.5
6.6
5.6
3.7
3.2
3.2
1.1
1.1
0.9
Composite
Death
Myocardial
Unplanned
ischemia
infarction
revasc for
ischemia
Heparinunfractionated or enoxaparin
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
113
REPLACE-2 vs. ACUITY PCI
ACUITY PCI
REPLACE-2 (PCI)
plt0.001
plt0.001
p 0.40
p 0.45
p 0.30
p 0.49
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
Lincoff et al. JAMA. 2004292696-703.
R2 major bleeding definition applied to both
114
Troponin () PatientsPCI
UFH/Enoxaparin IIb/IIIa vs. Bivalirudin Alone
RR 95CI 0.93 0.77-1.12
RR 95CI 1.12 0.88-1.42
RR 95CI 0.59 0.44-0.80
Interaction P values 0.46, 0.86 and 0.28
respectively
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
115
Thienopyridine Exposure
RR 95CI 0.81 (0.68-0.96)
RR 95CI 0.96 (0.77-1.20)
RR 95CI 0.50 (0.37-0.67)
RR 95CI 1.07 (0.83-1.39)
RR 95CI 1.37 (1.00-1.88)
RR 95CI 0.61 (0.39-0.97)
Thienopyridine Exposed
Not Thienopyridine Exposed
Interaction P values 0.17, 0.19 and 0.65
respectively
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16.
116
ACUITYPCI Conclusions/Caveats

• PCI patients in ACUITY demonstrated outcomes
  similar to those of the overall triali. e.,
  comparable ischemic outcomes, less bleeding, and
  superior net clinical outcomes
• This was true even in troponin () patients,
  although in this case net clinical outcomes were
  noninferior with bivalirudin monotherapy
• A controversial subgroup are patients with or
  without clopidogrel exposure prior to
  intervention In patients not exposed to
  clopidogrel, bivalirudin monotherapy was
  associated with a slightly higher rate of
  ischemic events. The significance of this is
  uncertain at present.

117
ConclusionsRecent ACS Trials

• ICTUSIn troponin () patients, a selective
  invasive management strategy may be an option,
  but there was a high use of angiography and
  revascularization in the selective arm.
• ISAR REACT 2Clopidogrel loading alone is not
  sufficient in ACS patients Troponin () patients
  derive significant benefit with GP IIb/IIIa
  antagonists
• SYNERGYEnoxaparin is an alternative in
  invasively managed patients, but may have
  slightly higher bleeding, especially when UFH is
  indiscriminately added in the cath lab

118
ConclusionsRecent ACS Trials

• OASIS 5Fondaparinux has less bleeding than
  enoxaparin, non-inferior clinical outcomes at 9
  days, and less death and death/MI at 6 months
  UFH is probably required in the cath labdose
  unknown.
• ACUITYBivalirudin with provisional GPI has less
  bleeding than UFH/LMWH GPI, comparable ischemic
  outcomes, and superior net clinical benefit.
  Bivalirudin GPI is comparable to UFH/LMWH GPI

119
ConclusionsACS Management

• NSTE-ACS is common and associated with high
  morbidity and mortality
• Early invasive strategy is preferred in
  higher-risk individuals
• Early initiation of appropriate antiplatelet and
  antithrombin therapy is important for reduction
  of ischemic events
• Balancing the risk of ischemic and bleeding
  complications is essential to maximize clinical
  benefit in individual patients
• The evidence base and strategies for optimal
  management of NSTE-ACS continue to evolve

120
CME Test
Complimentary CME Test To access the
complimentary CME test, program participants must
have internet access. Participants can access
the on-line evaluation form and receive instant
online notification of credit by going to
EDICTforACS.com and clicking on the program icon
(see below).
121
ACS Faculty Review Committee
Thomas Amidon, MD Medical Director The Hope Heart
Institute Overlake Internal Medicine
Associates Seattle, WA Atul Aggarwal,
MD Nebraska Heart Institute Lincoln, NE Himanshu
Aggarwal, MD Nebraska Heart Institute St. Frances
Med Center Grand Island, NE Keith Benzuly, MD,
FACC Assistant Professor of Medicine Bluhm
Cardiovascular Institute Northwestern
University Feinberg School of Medicine Chicago,
IL
Joseph J. Brennan Jr., MD Associate Professor of
Medicine, Cardiology Director, Interventional
Fellowship Program Yale University School of
Medicine New Haven, CT Carl Chudnofsky,
MD Chairman Department of Emergency
Medicine Albert Einstein Medical
Center Philadelphia, PA Michael J. Cowley,
MD Professor Department of Internal
Medicine Division of Cardiology Medical College
of Virginia Virginia Commonwealth
University Richmond, VA
122
ACS Faculty Review Committee
Harold Dauerman, MD Director, Cardiovascular
Catheterization Laboratory Professor of
Medicine Fletcher Allen Health Care University of
Vermont College of Medicine Burlington,
VT William J. French, MD Medical
Director Catheterization Laboratory UCLA Medical
Center Los Angeles, CA Satyendra Giri,
MD Section Chief Vascular Medicine
Program Baystate Health Systems Springfield, MA
Paul A. Gurbel, MD Helen Dalsheimer Director of
the Division of Cardiology at Sinai Hospital of
Baltimore Associate Professor of
Medicine Division of Cardiology Johns Hopkins
University School of Medicine Baltimore, MD Tim
Henry, MD Minneapolis Heart Institute
Foundation Associate Professor University of
Minnesota School of Medicine Minneapolis,
MD Kurt Kleinschmidt, MD Associate
Professor Director of Toxicology Fellowship
Program UT Southwestern Medical Center Dallas, TX
123
ACS Faculty Review Committee
James Leggett, MD Associate Medical Director Hope
Heart Institute Seattle, WA Glen Levine,
MD Director, Cardiac Catheterization
Lab Associate Professor of Medicine Baylor
College of Medicine Chief, Critical Cardiac
Care Houston VA Medical Center Houston, TX John
J. Lopez, MD Associate Professor of
Medicine Director Cardiac Catheterization and
Interventional Cardiology University of
Chicago Chicago, IL Reginald Low, MD Chief,
Division of Cardiovascular Medicine University of
California, Davis Davis, CA
Barry L. Molk, MD, FACC Associate Clinical
Professor University of Colorado Health Science
Center Aurora Denver Cardiology
Associates Denver, CO Reynaldo Mulingtapang,
MD Assistant Professor of Medicine Director,
University of South Florida Interventional
Cardiology Program Tampa, FL Robert A. Mulliken,
MD Medical Director, Emergency Department Universi
ty of Chicago Hospitals Associate
Professor University of Chicago School of
Medicine Chicago, IL Sandeep Nathan, MD,
FACC Assistant Professor of Medicine Rush Medical
College, Section of Cardiology Rush University
Medical Center Director, Cardiovascular
Intervention Chicago, IL
124
ACS Faculty Review Committee
Robert N. Piana, MD Associate Professor of
Medicine Vanderbilt University School of
Medicine Director, Cardiac Catheterization
Laboratories Nashville, TN Vincent J. Pompili,
MD, FACC Director of Interventional
Cardiology University Hospitals Associate
Professor of Medicine Case School of
Medicine Cleveland, OH Matthew J. Price,
MD Director Cardiac Catheterization
Laboratory Scripps Clinic Division of
Cardiovascular Diseases La Jolla, CA David J.
Robinson, MD, MS, FACEP Associate Professor,
Research Director and Vice-Chair Dept. of
Emergency Medicine University of Texas Health
Sciences Center Houston, TX
Joseph F. Stella, DO, FACC Heart Care Centers of
Illinois Clinical Assistant Professor Loyola
University Medical Center Chicago, IL Paul E.
Pepe, MD, MPH Riggs Family Chair in Emergency
Medicine Professor and Division
Chairman Emergency Medicine University of Texas
Southwestern Medical Center Dallas, TX Douglas
J. Spriggs, MD, FACC Clinical Assistant
Professor Depts. of Internal Medicine and Family
Practice University of South Florida College of
Medi