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Prospective, Randomized Comparison of Routine Upfront Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes: The ACUITY Timing Trial. Gregg W. Stone MD for the ACUITY Investigators. Disclosure. Gregg W. Stone - PowerPoint PPT Presentation
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Gregg W. Stone MD
for the ACUITY Investigators
Gregg W. Stone MD
for the ACUITY Investigators
Prospective, Randomized Comparison of Heparin Plus IIb/IIIa Inhibition and
Bivalirudin With or Without IIb/IIIa Inhibition in Patients with Acute Coronary Syndromes
Prospective, Randomized Comparison of Heparin Plus IIb/IIIa Inhibition and
Bivalirudin With or Without IIb/IIIa Inhibition in Patients with Acute Coronary Syndromes
Background: Current Management of ACSBackground: Current Management of ACS
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
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 2004;292:45-54
1 Braunwald et al JACC 2002; 2 Bertrand et al. EHJ 2002; 3www.crusade.org; 4SYNERGY. JAMA 2004;292:45-54
Bivalirudin as an Alternative to UFH/LMWHBivalirudin 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 Similar protection from ischemic events as UFH +
GP IIb/IIIa inhibitors, with markedly reduced bleeding1
Not previously tested in contemporary ACS patients
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 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 2003;289:853-863 REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863
In moderate-high risk 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
In moderate-high risk 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
Bivalirudin in ACS: Hypotheses
Moderate-high risk
ACS
Study Design – First RandomizationStudy Design – First Randomization
An
gio
gra
ph
y w
ith
in 7
2h
Aspirin in allClopidogrel
dosing and timingper local practice
Aspirin in allClopidogrel
dosing and timingper local practice
UFH orEnoxaparin+ GP IIb/IIIa
Bivalirudin+ GP IIb/IIIa
BivalirudinAlone
R*
*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)
ACUITY Design. Stone GW et al. AHJ 2004;148:764–75ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
Medicalmanagement
PCI
CABG
Moderate-high risk
ACS
Study Design – Second RandomizationStudy Design – Second Randomization
An
gio
gra
ph
y w
ith
in 7
2h
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)
ACUITY Design. Stone GW et al. AHJ 2004;148:764–75ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
Aspirin in allClopidogrel
dosing and timingper local practice
Aspirin in allClopidogrel
dosing and timingper local practice
Medicalmanagement
PCI
CABG
BivalirudinAlone
UFH or EnoxaparinUFH or EnoxaparinRoutine upstream
GPI in all ptsGPI started in
CCL for PCI only
R
BivalirudinBivalirudin
R
Routine upstream GPI in all ptsGPI started in
CCL for PCI only
Major Entry CriteriaMajor Entry 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
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
Inclusion CriteriaInclusion Criteria Exclusion CriteriaExclusion Criteria No angiography within 72h Acute STEMI or shock Bleeding diathesis or major
bleed within 2 weeks Platelet count ≤100,000/mm3
INR >1.5 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
No angiography within 72h Acute STEMI or shock Bleeding diathesis or major
bleed within 2 weeks Platelet count ≤100,000/mm3
INR >1.5 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
Moderate-high risk unstable angina or NSTEMIModerate-high risk unstable angina or NSTEMI
ACUITY Design. Stone GW et al. AHJ 2004;148:764–75ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
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
PCIACT
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
Study MedicationsStudy Medications Anti-thrombin agents (started pre angiography) Anti-thrombin agents (started pre angiography)
1 Target aPTT 50-75 seconds2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion
3 Primary Endpoints (at 30 Days)3 Primary Endpoints (at 30 Days)
1. Composite net clinical benefit =1. Composite net clinical benefit =
2. Ischemic composite2. Ischemic composite
3. Major bleeding3. Major bleedingoror
Death from any cause Myocardial infarction
- During medical Rx: Any biomarker elevation >ULN
- Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves
- Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves
Unplanned revascularization for ischemia
3 Primary Endpoints (at 30 Days)3 Primary Endpoints (at 30 Days)
1. Composite net clinical benefit =1. Composite net clinical benefit =
2. Ischemic composite2. Ischemic composite
3. Major bleeding3. Major bleedingoror
Non CABG related bleeding
- Intracranial bleeding or intraocular bleeding- Intracranial bleeding or intraocular bleeding
-- Retroperitoneal bleedingRetroperitoneal bleeding-Access site bleed requiring intervention/surgeryAccess site bleed requiring intervention/surgery
- Hematoma ≥5 cmHematoma ≥5 cm
-- Hgb Hgb ≥3g/dL with an overt source or ≥3g/dL with an overt source or ≥4g/dL w/o overt source≥4g/dL w/o overt source
-- Blood product transfusionBlood product transfusion Reoperation for bleeding
Anticipated event rates on UFH/Enox + GP IIb/IIIa Ischemic composite: 6.5% Major bleeding: 9.0% Net clinical outcome: 12.4%
Significance testing Sequential non-inferiority and superiority tests Non-inferiority tests: One-sided =0.025; =25% Superiority tests: Two sided =0.05 Hochberg procedure1 used to control type I error
Sample size estimate = 13,800 patients
Anticipated event rates on UFH/Enox + GP IIb/IIIa Ischemic composite: 6.5% Major bleeding: 9.0% Net clinical outcome: 12.4%
Significance testing Sequential non-inferiority and superiority tests Non-inferiority tests: One-sided =0.025; =25% Superiority tests: Two sided =0.05 Hochberg procedure1 used to control type I error
Sample size estimate = 13,800 patients
Statistical PlanStatistical Plan
1Benjamini & Hochberg. J R Stat Soc 19951Benjamini & Hochberg. J R Stat Soc 1995
NI = non-inferiority; Sup = superiority
Event Rates and Power CalculationsEvent Rates and Power Calculations
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Predicted RateRate
Endpoint
Net clinical outcome 12.4%12.4%
Ischemic events 6.5%6.5%
Major bleeding 9.0%9.0%
NI = non-inferiority; Sup = superiority
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
Predicted RateRate RateRate PowerPower
Endpoint NINI SupSup
Net clinical outcome 12.4%12.4% 10.3%10.3% 99%99% 88%88%
Ischemic events 6.5%6.5% 5.3%5.3% 99%99% 67%67%
Major bleeding 9.0%9.0% 7.5%7.5% 99%99% 73%73%
Event Rates and Power CalculationsEvent Rates and Power Calculations
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
BivalirudinBivalirudinalonealone
Predicted RateRate RateRate PowerPower RateRate PowerPower
Endpoint NINI SupSup NINI SupSup
Net clinical outcome 12.4%12.4% 10.3%10.3% 99%99% 88%88% 10.5%10.5% 99%99% 81%81%
Ischemic events 6.5%6.5% 5.3%5.3% 99%99% 67%67% 6.5%6.5% 87%87% --
Major bleeding 9.0%9.0% 7.5%7.5% 99%99% 73%73% 6.0%6.0% 99%99% 99%99%
NI = non-inferiority; Sup = superiority
Event Rates and Power CalculationsEvent Rates and Power Calculations
Study OrganizationStudy Organization
Principal Investigator Gregg W. Stone Columbia University, NYC, NY
Executive Committee Michel Bertrand Hosp. Cardiologique, Lambersart, France
A. Michael Lincoff Cleveland Clinic, Cleveland, Ohio
Jeffrey W. Moses Columbia University, NYC, NY
Magnus Ohman Duke University, Durham,
NC
Harvey D. White Green Lane Hosp.,
Auckland, NZ
Principal Investigator Gregg W. Stone Columbia University, NYC, NY
Executive Committee Michel Bertrand Hosp. Cardiologique, Lambersart, France
A. Michael Lincoff Cleveland Clinic, Cleveland, Ohio
Jeffrey W. Moses Columbia University, NYC, NY
Magnus Ohman Duke University, Durham,
NC
Harvey D. White Green Lane Hosp.,
Auckland, NZ
Study OrganizationStudy Organization
Frederick Feit (Chair)New York UniversityNYC, NY
Antonio Columbo (EU Chair)Ospedael San RaphaelMilano, Italy
Ramin EbrahimiVA Medical Ctr West Los AngelesLos Angelas, CA
Lars Hvilsted RasmussenAlborg Sygehus, Afdeling SydAlborg, Denmark
Hans-Jürgen RupprechtGpr Klinikum Rüsselsheim Rüsselsheim, Germany
Phil AylwardFlinders Medical CentreBedford Park, Australia
Frederick Feit (Chair)New York UniversityNYC, NY
Antonio Columbo (EU Chair)Ospedael San RaphaelMilano, Italy
Ramin EbrahimiVA Medical Ctr West Los AngelesLos Angelas, CA
Lars Hvilsted RasmussenAlborg Sygehus, Afdeling SydAlborg, Denmark
Hans-Jürgen RupprechtGpr Klinikum Rüsselsheim Rüsselsheim, Germany
Phil AylwardFlinders Medical CentreBedford Park, Australia
Angel CequierCiutat Sanitària Belvitge
Barcelona, Spain
Walter DesmetUniversity Hospital, Gasthuisberg Leuven, Belgium
Harold DariusKrankenhaus NeuköllnBerlin, Germany
Martial HamonUniversity HospitalCaen Cedex, France
James HoekstraWake Forest University
Lewisville, NC
Charles V. PollackPennsylvania Hospital
Philadelphia, PA
Angel CequierCiutat Sanitària Belvitge
Barcelona, Spain
Walter DesmetUniversity Hospital, Gasthuisberg Leuven, Belgium
Harold DariusKrankenhaus NeuköllnBerlin, Germany
Martial HamonUniversity HospitalCaen Cedex, France
James HoekstraWake Forest University
Lewisville, NC
Charles V. PollackPennsylvania Hospital
Philadelphia, PA
Steering Committee
Study OrganizationStudy Organization
Statistical Committee Stuart Pocock London School of Hygiene and Tropical
Medicine, London, UK
Jim Ware Harvard University, Boston, Mass.
Data Monitoring The Medicines Company/Nycomed
Data Management eTrials/The Medicines Company
Clinical Events Committee Roxana Mehran, Director Cardiovascular Research Foundation, NY
Angio. Core Laboratory Alexandra Lansky, Director Cardiovascular Research Foundation, NY
Health Economics and David J. Cohen (Chair) Cost-Effectiveness Beth Israel Deaconess, Boston, Mass.
Statistical Committee Stuart Pocock London School of Hygiene and Tropical
Medicine, London, UK
Jim Ware Harvard University, Boston, Mass.
Data Monitoring The Medicines Company/Nycomed
Data Management eTrials/The Medicines Company
Clinical Events Committee Roxana Mehran, Director Cardiovascular Research Foundation, NY
Angio. Core Laboratory Alexandra Lansky, Director Cardiovascular Research Foundation, NY
Health Economics and David J. Cohen (Chair) Cost-Effectiveness Beth Israel Deaconess, Boston, Mass.
Study OrganizationStudy Organization
Biomarker Substudy George Dangas (Chair) Columbia University, NYC, NYW. Craig Hooper CDC, Atlanta, GASteven R. Steinhubl University of Kentucky, Lexington, KY
Data Safety and Bernard J. Gersh (Chair)Monitoring Committee Mayo Clinic, Rochester, Minn
David Faxon Brigham & Women’s Hosp., Boston, Mass.
Spencer King Fuqua Heart Center, Atlanta, GA
Stuart Pocock London, UK
Hartzell Schaff Mayo Clinic, Rochester, Minn
David O. Williams Rhode Island Hosp., Providence, RI
Biomarker Substudy George Dangas (Chair) Columbia University, NYC, NYW. Craig Hooper CDC, Atlanta, GASteven R. Steinhubl University of Kentucky, Lexington, KY
Data Safety and Bernard J. Gersh (Chair)Monitoring Committee Mayo Clinic, Rochester, Minn
David Faxon Brigham & Women’s Hosp., Boston, Mass.
Spencer King Fuqua Heart Center, Atlanta, GA
Stuart Pocock London, UK
Hartzell Schaff Mayo Clinic, Rochester, Minn
David O. Williams Rhode Island Hosp., Providence, RI
ACUITY EnrollmentACUITY Enrollment
USA (246)USA (246)
Canada (26)Canada (26)
(17) Australia(17) Australia
(25) Spain(25) Spain
(8) France(8) France(12) UK(12) UK
(4) Norway (4) Norway
Finland (3)Finland (3)
Poland (1)Poland (1)Germany (66)Germany (66)
Austria (4)Austria (4)
(4) Netherlands(4) Netherlands(5) Belgium(5) Belgium
Italy (15)Italy (15)
Sweden (6)Sweden (6)
(4) New Zealand(4) New Zealand
(5) Denmark(5) Denmark
13,819 pts randomized at 448 centers in 17 countries13,819 pts randomized at 448 centers in 17 countries
7851 (56.8%) USA7851 (56.8%) USA
438 (3.2%) Canada438 (3.2%) Canada
499 (3.6%) Australia499 (3.6%) Australia
547 (4.0%) Spain547 (4.0%) Spain
155 (1.1%) France155 (1.1%) France162 (1.2%) UK162 (1.2%) UK
89 (0.6%) Norway89 (0.6%) Norway
Finland 51 (0.4%) Finland 51 (0.4%)
Poland 14 (0.1%) Poland 14 (0.1%) Germany 2561 (18.5%) Germany 2561 (18.5%)
Austria 356 (2.6%) Austria 356 (2.6%)
132 (1.0%) Netherlands132 (1.0%) Netherlands198 (1.4%) Belgium198 (1.4%) Belgium
Italy 238 (1.7%) Italy 238 (1.7%)
Sweden 175 (1.3%) Sweden 175 (1.3%)
203 (1.5%) New Zealand203 (1.5%) New Zealand
150 (1.1%) Denmark150 (1.1%) Denmark
ACUITY EnrollmentACUITY Enrollment13,819 pts randomized at 448 centers in 17 countries13,819 pts randomized at 448 centers in 17 countries
Top 20 EnrollersTop 20 EnrollersB. McLaurin, MD
Anderson Area Medical Center, Anderson, SC
D. Cox, MDMid Carolina Cardiology, Charlotte, NC
M. Zubair Jafar, MDHudson Valley HeartCenter, Poughkeepsie, NY
H. Chandna, MDVictoria Heart and Vascular Center, Victoria, TX
F. Harmann, MDUniversittsklilnik Schleswig-Holstein Campus Lbeck, Lbeck, Germany
F. Leisch, MDAllgemeines ffentl.
Krankenhaus der Landershauptstadt Linz,
Linz, Austria
M. Desaga, MDKlinikum Dachu der
Landeshaupstadt Linz,Linz, Germany
B. McLaurin, MDAnderson Area Medical Center, Anderson, SC
D. Cox, MDMid Carolina Cardiology, Charlotte, NC
M. Zubair Jafar, MDHudson Valley HeartCenter, Poughkeepsie, NY
H. Chandna, MDVictoria Heart and Vascular Center, Victoria, TX
F. Harmann, MDUniversittsklilnik Schleswig-Holstein Campus Lbeck, Lbeck, Germany
F. Leisch, MDAllgemeines ffentl.
Krankenhaus der Landershauptstadt Linz,
Linz, Austria
M. Desaga, MDKlinikum Dachu der
Landeshaupstadt Linz,Linz, Germany
S. Konstantinides, MDGeorge-August-Universitt Gttingen Goettingen, Germany
K. E. Hauptmann, MDKrankenhaus der
Barmherzigen Bruder Medizinische Klinkill,
Trier, Germany
E. Mostel, MDPalm Beach Gardens Medical Center/Palm Beach Cardiology,Palm Beach Gardens, FL
A. Cequier, MDCiutat Santaria Bellvitge, Barcelona, Spain
M. Mockel, MDCharite Universitatsmedizin Berlin, Germany
S. Konstantinides, MDGeorge-August-Universitt Gttingen Goettingen, Germany
K. E. Hauptmann, MDKrankenhaus der
Barmherzigen Bruder Medizinische Klinkill,
Trier, Germany
E. Mostel, MDPalm Beach Gardens Medical Center/Palm Beach Cardiology,Palm Beach Gardens, FL
A. Cequier, MDCiutat Santaria Bellvitge, Barcelona, Spain
M. Mockel, MDCharite Universitatsmedizin Berlin, Germany
R.H. Strasser, MDTechnische UniversittDresden, Dresden, Germany
T. Stuckey, MDLebauer CV Research
Foundation, Greensboro, NC
I. H. Lieber, MDNorth Houston Heart Center,
Kingwood, TX
R. Zelman, MDCape Cod Research Institute,
Hyannis, MA
J. Neuzner, MDKlinikum Kassel GmbH,Kassel, GA
K. Huber, MDWelhelminespital der StadtWien, Vienna, Austria
H. White, MDAuckland City Hospital,
Auckland, New Zealand
M. Buerke, MDKlinikum der Martin-Luther-
Universitt Halle-Wittenber,Halle, Germany
R.H. Strasser, MDTechnische UniversittDresden, Dresden, Germany
T. Stuckey, MDLebauer CV Research
Foundation, Greensboro, NC
I. H. Lieber, MDNorth Houston Heart Center,
Kingwood, TX
R. Zelman, MDCape Cod Research Institute,
Hyannis, MA
J. Neuzner, MDKlinikum Kassel GmbH,Kassel, GA
K. Huber, MDWelhelminespital der StadtWien, Vienna, Austria
H. White, MDAuckland City Hospital,
Auckland, New Zealand
M. Buerke, MDKlinikum der Martin-Luther-
Universitt Halle-Wittenber,Halle, Germany
Study Design – Patient FlowStudy Design – Patient Flow
UFH/Enox+ GP IIb/IIIa
(N=4,603)
Bivalirudin+ GP IIb/IIIa
(N=4,604)
BivalirudinAlone
(N=4,612)
R*
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy
GPI upstream (N=2294)
GPI CCL for PCI (N=2309)
GPI upstream (N=2311)
GPI CCL for PCI (N=2293)
Aspirin in allClopidogrel
dosing and timingper local practice
Aspirin in allClopidogrel
dosing and timingper local practice
*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration
Moderate-high risk
ACS
Baseline CharacteristicsBaseline Characteristics
UFH/Enoxaparin + GP IIb/IIIa(N=4,603)
Bivalirudin + GP IIb/IIIa
(N=4,604)
Bivalirudin alone
(N=4,612)
Age (median [range], yrs) 63 [23-91] 63 [21-95] 63 [20-92]
Male 70.6% 69.9% 69.3%
Diabetes 28.4% 27.7% 28.1%
- Insulin requiring 8.5% 8.6% 8.8%
Hypertension 66.8% 67.2% 67.1%
Hyperlipidemia 57.2% 57.4% 57.0%
Current smoker 29.0% 29.3% 29.0%
Prior MI 31.6% 30.5% 31.8%
Prior PCI 39.0% 37.8% 39.9%
Prior CABG 18.2% 17.4% 18.1%
Renal insufficiency 5.7% 6.0% 5.7%
Baseline High Risk FeaturesBaseline High Risk Features
UFH/Enoxaparin + GP IIb/IIIa(N=4,603)
Bivalirudin + GP IIb/IIIa
(N=4,604)
Bivalirudin alone(N=4,612)
Biomarker or ST 71.3% 70.1% 70.9%
- Biomarker + 58.1% 56.9% 58.5%
- ST-segment 35.2% 35.4% 34.3%
Biomarker + ST 21.9% 22.2% 21.9%
TIMI Risk Score
- Low (0-2) 16.1% 15.4% 15.6%
- Intermediate (3-4) 53.7% 55.5% 54.5%
- High (5-7) 30.3% 29.1% 29.9%
Invasive ManagementInvasive Management
UFH/Enoxaparin + GP IIb/IIIa(N=4,603)
Bivalirudin + GP IIb/IIIa
(N=4,604)
Bivalirudin alone
(N=4,612)
Angiography 99.2% 98.8% 98.9%
Adm. to angio (h) 19.7 (7.0-29.3)† 19.5 (7.0-28.2)† 19.8 (7.3-29.0)†
Drug* to angio/interv (h) 5.6 (1.6-22.5)† 5.0 (1.4-21.4)† 5.2 (1.5-22.5)†
Actual procedure
PCI 55.6% 56.7% 56.8%
CABG 11.9% 10.8% 10.6%
Medical therapy 32.4% 32.5% 32.6%
*In patients receiving study antithrombin pre angiography*In patients receiving study antithrombin pre angiography †median (IQR)
Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)
11.7%
7.3%5.7% 5.3%
11.8%
7.7%
Net clinicaloutcome
Ischemic composite Major bleeding
30 d
ay e
ven
ts (
%)
UFH/Enoxaparin+GPI (N=4603) Bivalirudin+GPI (N=4604)
UFH/Enoxaparin + GPI vs. Bivalirudin + GPIUFH/Enoxaparin + GPI vs. Bivalirudin + GPI
PNI <0.0001PSup = 0.93
PNI = 0.007PSup = 0.39
PNI =0.0001PSup = 0.38
11.7%11.8% 1.01 (0.90-1.12)<0.001
0.93
0 1 2
Risk ratio±95% CI
Risk ratio±95% CI
Primaryendpoint
Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)UFH/Enoxaparin + GPI vs. Bivalirudin + GPIUFH/Enoxaparin + GPI vs. Bivalirudin + GPI
Net clinical outcome
Ischemic composite
Major bleeding
Bivalirudin + IIb/IIIa betterBivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
Bival+ IIb/IIIa
UFH/Enox+ IIb/IIIa
RR (95% CI)p value
(non inferior)(superior)
7.3%7.7% 1.07 (0.92-1.23)0.0150.39
5.7%5.3% 0.93 (0.78-1.10)<0.001
0.38
Upp
er b
oun
dary
non
-infe
riorit
y
Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)
11.7%
7.3%5.7%
3.0%
10.1%
7.8%
Net clinicaloutcome
Ischemic composite Major bleeding
30 d
ay e
ven
ts (
%)
UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)
UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone
PNI <0.0001PSup = 0.015
PNI = 0.011PSup = 0.32
PNI <0.0001PSup <0.0001
0 1 2
Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)
Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
Risk ratio±95% CI
Risk ratio±95% CI
Primaryendpoint
Bivalalone
UFH/Enox+ IIb/IIIa
RR (95% CI)
Net clinical outcome
Ischemic composite
Major bleeding
Upp
er b
oun
dary
non
-infe
riorit
y
11.7%10.1% 0.86 (0.77-0.97)<0.0010.015
7.3%7.8% 1.08 (0.93-1.24)0.020.32
5.7%3.0% 0.53 (0.43-0.65)<0.001<0.001
p value(non inferior)
(superior)
UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone
Components of the Ischemic CompositeComponents of the Ischemic Composite
7.3%
1.3%
4.9%
2.3%2.7%2.4%
5.0%
7.7%
1.5% 1.6%
7.8%
5.4%
Ischemiccomposite
Death Myocardialinfarction
Unplannedrevasc forischemia
30 d
ay e
ven
ts (
%)
UFH/Enox+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
PSup = 0.32 PSup = 0.34 PSup = 0.35 PSup = 0.78
Major Bleeding EndpointsMajor Bleeding Endpoints
11.8%
5.7%
11.1%
5.3%
3.0%
9.1%
All major bleeding Non CABG major bleeding(primary endpoint)
30 d
ay e
ven
ts (
%)
Heparin+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
PSup=0.38 PSup<0.0001PSup=0.31 PSup<.001
Major Bleeding (Primary Endpoint)Major Bleeding (Primary Endpoint)
UFH/Enoxaparin + GP IIb/IIIa(N=4,603)
Bivalirudin + GP
IIb/IIIa(N=4,604)
Bivalirudin alone
(N=4,612)
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%
Values in yellow = P<0.05Values in yellow = P<0.05
Minor Bleeding (Non CABG)Minor Bleeding (Non CABG)UFH/Enoxaparin
+ GP IIb/IIIa(N=4,603)
Bivalirudin + GP
IIb/IIIa(N=4,604)
Bivalirudin alone(N=4,612)
Any minor bleeding 21.6% 21.7% 12.8%
• Ecchymoses 5.6% 5.9% 3.6%
• Epistaxis 1.4% 1.9% 0.7%
• GI bleeding 2.8% 1.8% 1.1%
• GU bleeding 0.8% 1.1% 0.3%
• Puncture site 14.7% 14.3% 8.2%
• Hemopericardium 0.1% 0.1% 0.0%
• Pulmonary 0.3% 0.5% 0.1%
• Other 2.1% 2.6% 1.1%
Values in yellow = P<0.05Values in yellow = P<0.05
Bleeding Endpoints (Non-CABG)Bleeding Endpoints (Non-CABG)
UFH/Enoxaparin + GP IIb/IIIa(N=4,603)
Bivalirudin + GP
IIb/IIIa(N=4,604)
Bivalirudin
alone(N=4,612)
P1
ValueP2
Value
ACUITY Scale
- Any 23.9% 23.7% 14.2% 0.88 <0.001
- Major 5.7% 5.3% 3.0% 0.38 <0.001
- Minor 21.6% 21.7% 12.8% 0.84 <0.001
TIMI Scale
- Any 6.6% 6.4% 3.9% 0.67 <0.001
- Major 1.8% 1.6% 0.9% 0.42 <0.001
- Minor 6.4% 6.1% 3.7% 0.52 <0.001
Blood transfusion 2.7% 2.6% 1.6% 0.70 <0.001
P1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P2 = Bivalirudin alone vs. UFH/Enox+GPIP1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P2 = Bivalirudin alone vs. UFH/Enox+GPI
0 1 2
Net Clinical Outcome CompositeNet Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Men (n=6444)Women (n=2771)
Diabetes (n=2585)No diabetes (n=6630)
CrCl ≥60 (n=6993)CrCl <60 (n=1644)
Age <65 (n=5051)Age ≥65 (n=4164)
Risk ratio±95% CI
Risk ratio±95% CI
BivalAlone
UFH/Enox+ IIb/IIIa
7.8%12.9%
US (n=5224)OUS (n=3991)
10.6%9.5%
8.9%16.1%
10.8%9.8%
9.5%11.6%
9.2%14.7%
11.8%11.5%
10.4%16.8%
13.7%10.9%
10.9%13.5%
P Pint
0.86 (0.71-1.03)0.88 (0.75-1.02)
0.90 (0.77-1.05)0.82 (0.68-0.98)
0.86 (0.74-0.99)0.96 (0.77-1.19)
0.79 (0.64-0.97)0.90 (0.78-1.04)
0.87 (0.75-1.00)0.86 (0.70-1.04)
0.090.09
0.160.03
0.030.71
0.020.16
0.050.12
0.89
0.47
0.43
0.28
0.91
RR (95% CI)
Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
0 1 2
Net Clinical Outcome CompositeNet Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Yes (n=3197)No (n=6008)
Low (0-2) (n=1291)Intermed (3-4) (n=4407)
High (5-7) (n=2449)
Elevated (n=5368)Normal (n=3841)
Risk ratio±95% CI
Risk ratio±95% CI
BivalAlone
UFH/Enox+ IIb/IIIa
9.2%11.3%
12.2%11.1%
P Pint
0.76 (0.65-0.89)1.02 (0.86-1.21)
12.2%7.1%
13.3%9.4%
0.92 (0.80-1.06)0.75 (0.61-0.93)
0.230.01
<0.0010.83
0.35
0.02
0.18
13.0%8.6%
13.7%10.6%
0.96 (0.80-1.14)0.81 (0.69-0.95)
0.610.01 0.42
Biomarkers (CK/Trop)
ST Deviation
TIMI Risk Score
Pre Thienopyridine
6.4% 10.2% 0.63 (0.43-0.91) 0.019.4% 10.2% 0.92 (0.77-1.10) 0.34
13.9% 15.2% 0.92 (0.76-1.11) 0.36
Yes (n=5192)No (n=4023)
RR (95% CI)
Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
0 1 2
Net Clinical Outcome CompositeNet Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
BivalAlone
UFH/Enox+ IIb/IIIa
P Pint
0.59
11.6% 13.3% 0.87 (0.75-1.00) 0.09
10.6% 18.2% 0.97 (0.75-1.26) 0.84
5.1% 6.5% 0.78 (0.58-1.04) 0.09
0.62
8.3% 9.8% 0.85 (0.67-1.06) 0.15
9.2% 9.4% 0.98 (0.78-1.23) 0.86
12.5% 14.4% 0.87 (0.73-1.05) 0.14
0.56
9.1% 10.0% 0.91 (0.73-1.12) 0.36
6.7% 7.1% 0.94 (0.80-1.10) 0.46
10.6% 12.6% 0.84 (0.65-1.10) 0.21
RR (95% CI)
PCI (n=5170)
CABG (n=1048)
Medical (n=2989)
No prior AT (n=3290)
Consistent Rx (n=5519)
Crossover (n=3211)
A-thrombin crossover
Early (<3.0 h)
Intermediate (3.0-19.7 h)
Late (≥19.7 h)
Risk ratio±95% CI
Risk ratio±95% CI
Actual treatment
Rand. to angio/interv.tertiles
Net Clinical Outcome Composite EndpointNet Clinical Outcome Composite Endpoint
0
5
10
15
0 5 10 15 20 25 30 35
Cu
mu
lati
ve E
ven
ts (
%)
Days from Randomization
Estimate P(log rank)
11.7%UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604) 0.8911.8%
Bivalirudin alone (N=4612) 0.01410.1%
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
Ischemic Composite EndpointIschemic Composite Endpoint
0
5
10
15
0 5 10 15 20 25 30 35
Cu
mu
lati
ve E
ven
ts (
%)
Days from Randomization
Estimate P(log rank)
7.3%UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604) 0.377.7%
Bivalirudin alone (N=4612) 0.307.8%
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
Major Bleeding EndpointMajor Bleeding Endpoint
0
5
10
15
0 5 10 15 20 25 30 35
Cu
mu
lati
ve E
ven
ts (
%)
Days from Randomization
Estimate P(log rank)
5.7%UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604) 0.415.3%
Bivalirudin alone (N=4612) <0.00013.0%
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
BivalirudinBivalirudinalonealone
Predicted RateRate RateRate PowerPower RateRate PowerPower
Endpoint NINI SupSup NINI SupSup
Net clinical outcome 12.4%12.4% 10.3%10.3% 99%99% 88%88% 10.5%10.5% 99%99% 81%81%
Ischemic events 6.5%6.5% 5.3%5.3% 99%99% 67%67% 6.5%6.5% 87%87% --
Major bleeding 9.0%9.0% 7.5%7.5% 99%99% 73%73% 6.0%6.0% 99%99% 99%99%
NI = non-inferiority; Sup = superiority
Event Rates and Power CalculationsEvent Rates and Power Calculations
NI = non-inferiority; Sup = superiority
Summary Conclusions: Primary ResultsSummary Conclusions: Primary Results
Endpoint
Net clinical outcome
Ischemic events
Major bleeding
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
BivalirudinBivalirudinalonealone
NI = non-inferiority; Sup = superiority
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Observed RateRate
Endpoint
Net clinical outcome 11.7%11.7%
Ischemic events 7.3%7.3%
Major bleeding 5.7%5.7%
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
BivalirudinBivalirudinalonealone
Summary Conclusions: Primary ResultsSummary Conclusions: Primary Results
Summary Conclusions: Primary ResultsSummary Conclusions: Primary Results
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
Observed RateRate RateRate PPValueValueEndpoint
Net clinical outcome 11.7%11.7% 11.8%11.8% <0.001 NI<0.001 NI
Ischemic events 7.3%7.3% 7.7%7.7% 0.007 NI0.007 NI
Major bleeding 5.7%5.7% 5.3%5.3% 0.001 NI0.001 NI
NI = non-inferiority; Sup = superiority
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
BivalirudinBivalirudinalonealone
Conclusions: Primary ResultsConclusions: Primary Results
UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa
Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa
BivalirudinBivalirudinalonealone
Observed RateRate RateRate PPValueValue
RateRate PPValueValueEndpoint
Net clinical outcome 11.7%11.7% 11.8%11.8% <0.001 NI<0.001 NI 10.1%10.1% 0.015 Sup0.015 Sup
Ischemic events 7.3%7.3% 7.7%7.7% 0.007 NI0.007 NI 7.8%7.8% 0.011 NI0.011 NI
Major bleeding 5.7%5.7% 5.3%5.3% 0.001 NI0.001 NI 3.0%3.0% <0.001 Sup<0.001 Sup
NI = non-inferiority; Sup = superiority
Clinical ImplicationsClinical Implications
In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP IIb/IIIa inhibitors
Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin
However, compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition
A bivalirudin alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days
In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP IIb/IIIa inhibitors
Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin
However, compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition
A bivalirudin alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days