Bivalirudin Monotherapy Improves 30-day Clinical Outcomes in Diabetics with

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



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)


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








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


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%



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%




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%



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


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


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.


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)





*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



(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



(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


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


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)


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)


PSup=0.38 PSup<0.0001PSup=0.31 PSup<.001

Major Bleeding (Primary Endpoint)Major Bleeding (Primary Endpoint)


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)


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)


0 1 2


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)


0 1 2



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%


Ischemic Composite EndpointIschemic Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)





Bivalirudin alone (N=4612) 0.307.8%


Major Bleeding EndpointMajor Bleeding Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)





Bivalirudin alone (N=4612) <0.00013.0%





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%




Summary Conclusions: Primary ResultsSummary Conclusions: Primary Results

Endpoint


Ischemic events

Major bleeding






Observed RateRate

Endpoint

Net clinical outcome 11.7%11.7%

Ischemic events 7.3%7.3%

Major bleeding 5.7%5.7%








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





Conclusions: Primary ResultsConclusions: Primary Results




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


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

Documents

Bivalirudin Monotherapy Improves 30-day Clinical Outcomes in Diabetics with