Midwest Cardiovascular

Midwest Cardiovascular

Research Foundation

Research Foundation

Direct Thrombin Inhibitors and Direct Thrombin Inhibitors and GpGp 2b/3a Receptor Blockers in 2b/3a Receptor Blockers in

the Cardiac Cath Labthe Cardiac Cath Lab

Eric J Dippel, MD FACCEric J Dippel, MD FACC

Stable Angina

UnstableAngina

Non–Q-waveMI

Q-wave MI

Plaque Rupture

Adapted from Cannon CP. J Thrombolysis. 1995;2:205-218.

Thrombus FormationThrombus Formation

Events Leading to Thrombus FormationEvents Leading to Thrombus FormationAdhesion Activation Aggregation

Platelet ActivationPlatelet Activation

Resting PlateletResting Platelet Activated PlateletActivated Platelet

ThromboxaneThromboxane

Lysosomes (enzymes)

galactosidases

proteases

Lysosomes (enzymes)

galactosidases

proteases

Amine Storage Granules(Serotonin, ADP, ATP, Ca++)

Amine Storage Granules(Serotonin, ADP, ATP, Ca++)

α - Granules (secreted proteins)• Plasma proteins(fibrinogen, fibronectin, vWF, Factor V, plasminogen)

• Platelet-specific proteins(PF4, β -thromboglobulin proteins)

• Non platelet-specific proteins(thrombospondin, PDGF, amyloid protein precursor)

• Other(vascular permeability factor, IL-1, PADGEM)

α - Granules (secreted proteins)• Plasma proteins(fibrinogen, fibronectin, vWF, Factor V, plasminogen)

• Platelet-specific proteins(PF4, β -thromboglobulin proteins)

• Non platelet-specific proteins(thrombospondin, PDGF, amyloid protein precursor)

• Other(vascular permeability factor, IL-1, PADGEM)

Coagulation CascadeCoagulation Cascade

Coagulation CascadeCoagulation Cascade

Coagulation CascadeCoagulation Cascade

Coagulation CascadeCoagulation Cascade

Ruptured PlaqueRuptured Plaque

Coagulation CascadeCoagulation Cascade

Coagulation CascadeCoagulation Cascade

Coagulation CascadeCoagulation Cascade

Coagulation CascadeCoagulation Cascade

Targets for AntiTargets for Anti--ThromboticsThrombotics

Tissue factor

Plasma clottingcascade

Prothrombin

Thrombin

Fibrinogen Fibrin

Thrombus

Platelet aggregation

Conformational activation of GPIIb/IIIa

Collagen

Thromboxane A2

ADP

AT

AT

Aspirin

TiclopidineClopidogrel

GPIIb/IIIainhibitors

BivalirudinHirudin

Argatroban

FactorXa

LMWHHeparin

Pentasaccharides

Direct XaInhibitors

Fibrinolytics

Tissue Factor Inhibitors

Treatment of Occlusive Treatment of Occlusive Coronary ThrombusCoronary Thrombus

Fibrin

Plasminogenactivators– tPA– rPA– SK– TNK-tPA

Platelets

Antiplatelet therapy– Aspirin– Thienopyridines – GP IIb/IIIa inhibitors

Thrombin

Antithrombin therapy– Heparin– LMWH– Direct thrombin

Cannon CP. J Am Cannon CP. J Am CollColl Cardiol 1999;34:1395Cardiol 1999;34:1395--14021402

Cannon CP. J Am Coll Cardiol 1999;34:1395-1402

PlateletsPlatelets

FibrinFibrin

ThrombinThrombin

Thrombus occluding coronary arteryThrombus occluding coronary arteryThrombolyticThrombolytictherapytherapy

ExposesExposesclotclot--boundboundthrombinthrombin

New thrombinNew thrombingenerationgenerationPlatelet activationPlatelet activationCleaves fibrinogenCleaves fibrinogento fibrinto fibrin

PlasminPlasmin cleaves fibrincleaves fibrin

•• Lyses clotLyses clot↑↑ FDPsFDPs ((antiplateletantiplatelet

and anticoagulant)and anticoagulant)↓↓ FibrinogenFibrinogen

ReperfusionReperfusion

Activates plateletsActivates platelets

PAIPAI--1, thromboxane A1, thromboxane A22,,fibrinogenfibrinogen

↑↑ Platelet activationPlatelet activation↑↑ Thrombin productionThrombin production

VasoconstrictionVasoconstrictionInhibits plasminogen Inhibits plasminogen

activatorsactivators

Thrombus formationThrombus formationVessel reocclusionVessel reocclusion

Heparin RecipeHeparin Recipe

Kleiman. J Inv Card, Dec 2000.

Major Saccharide Components Major Saccharide Components in Pharmaceutical Heparinin Pharmaceutical Heparin

OO OO

OO

NNHHSSOO33--

OO OO

CCOO22--

OOHHOO

OOHH

OONNHHSSOO33

--OO

OOOO

CCOO22--

OOHHOOHH OO

OOHH

CCHH22OOSSOO33--

OOOOOO

NNHHSSOO33--

OOHH

OO

CCHH22

OO

OOSSOO33--CCOO22

--

OOOOSSOO33

--NNHHAAcc

OO

OOHH OOSSOO33--

OO

CCHH22

OOHHOO

OOHH

CCHH22OOSSOO33--

NNHHSSOO33--

OOSSOO33--

OOHHCCOO22--

OO OO

OO

OO

OOHHOO

OOHH

NNHHSSOO33--

OO

OOSSOO33--

CCHH22OOHH

CCHH22

CCOO22--

OOSSOO33--

OOSSOO33--

Trisulfated DisaccharideTrisulfated Disaccharide Disulfated DisaccharideDisulfated Disaccharide

OO OO

OOOOOO

NNHHSSOO33--

OOHH

OO

CCHH22

OO

OOSSOO --CCOO22--

OOOOSSOO33

--NNHHSSOO33

--

OO

OOHH OOSSOO33--

OO

CCHH22

OOHHOO

OOHH

CCHH22OOSSOO33--

NNHHSSOO33--

OOSSOO33--

OOHHCCOO22--

Antithrombin III Pentasaccharide Binding SitesAntithrombin III Pentasaccharide Binding Sites

33

HeparinHeparin

♦♦ NonNon--specific binding to circulating specific binding to circulating proteins, acute phase reactants, and proteins, acute phase reactants, and cellular binding sitescellular binding sites

♦♦ Directly activates plateletsDirectly activates platelets♦♦ Potentiates the platelet response to low Potentiates the platelet response to low

levels of agonists such as ADPlevels of agonists such as ADP♦♦ Unpredictable dose responseUnpredictable dose response

Antithrombotic Therapies and Platelet Antithrombotic Therapies and Platelet Aggregation in Aggregation in NormalsNormals

Xiao Z, Theroux P. Circ 1998;97:251-256

0

2

4

6

8

10

12

14 Saline UFH LMWH ARG

ADP (0.3125 μ M) TRAP (0.625 μ M)

Per

cent

Max

imum

* p < 0.05, ** p < 0.01 vs. control

**

*

*

Platelet Activation by Unfractionated HeparinPlatelet Activation by Unfractionated Heparin

(Normal Subjects) Knight CJ et al. Eur Heart J. 1998;19:1239

0

1

2

3

4

5

0 1 2 3 4 0

1

2

3

4

5Unstimulated ADP 1.0 ( μ mol.1-1)

0 1 2 3 4 Heparin / fragmin (units.ml-1)

Fibr

inog

en B

indi

ng In

dex UFH

LMWH

ProthrombinF 1.2

Va Ca ++

Xa Platelet

F1.2 Thrombin PlateletActivation

Fibrinogen AT III

TAT IIIFPA Fibrin 1

Thrombin Rebound After Cessation of Intravenous Heparin 0.5

0.4

0.3

0.2

0.1

0

14

12

10

8

6

4

2

0

F1.2FPA

Time 0 3 Hr 6 Hr 10 Hr 24 Hr

FPAF 1.2

(*p<0.03; **p<0.001)

1 Miller, Granger, Califf. Circ. 1993;88:I-202

Thrombin Generation Follows Heparin Thrombin Generation Follows Heparin Discontinuation in Patients with Acute Coronary Discontinuation in Patients with Acute Coronary SyndromesSyndromes

0

1

2

3

4

5 B a s e lin e IV H e p a r in W e a nD /C H e p a r in S C H e p a r in W e a n

Baseline 1 Hour 4 Hours 24 Hours

F1.2

(nM

)

1Becker RC. JACC 1999;34:1020

Disadvantages of UFHDisadvantages of UFH

Unfractionated HeparinUnfractionated Heparin

ThrombocytopeniaThrombocytopenia

PoorBioavailability

PoorBioavailability

AnticoagulantResponse Variations

AnticoagulantResponse Variations

BleedingBleeding

Stronger Drug

Interactions

Stronger Drug

Interactions

Heparin/AT complex inhibits thrombin and Factor Heparin/AT complex inhibits thrombin and Factor XaXaMust have adequate AT present for anticoagulant effectMust have adequate AT present for anticoagulant effect

Heparin/LMWH: mechanism of action Heparin/LMWH: mechanism of action Heparin/LMWH: mechanism of action

2

1

AntithrombinThrombin

Heparin

Pentasaccharidesequence

Antithrombin FactorXa

LMWH

Pentasaccharidesequence

Heparin chains with pentasaccharidesequence (~30%)

bind to AT causing a conformational

change

Thrombin inhibition requires “bridging”by heparin chain (at least 18 units)

LMWH has greater activity against Xathan thrombin

Antithrombin

X/E//109.a.1

HirudinHirudin: mechanism of action : mechanism of action

Binds directly to two sites on thrombinBinds directly to two sites on thrombin

Binding is highly specific and almost irreversibleBinding is highly specific and almost irreversible——very long halfvery long half--life may life may account for the high bleed rates seen with account for the high bleed rates seen with hirudinshirudins in clinical trialsin clinical trials

2

1

ThrombinHirudin

Inactivates both circulating and clot-bound thrombin—hirudin displaces thrombin from fibrin

Fibrin

X/E//110.a.1

Structure of Thrombin: Structure of Thrombin: Structure of Thrombin:

(Gly)4

C-terminal dodecapeptide(Exosite 1-binding portion)

2

1

Thrombin

Gly-Pro-Arg-Pro(active-site-binding portion)

Fibrin

A/E//20.b.1

Active SiteActive Site: cleaves fibrinogen and coagulation factors: cleaves fibrinogen and coagulation factors

ExositeExosite Site 1Site 1: activates platelets, activates protein C, anchors fibrinogen: activates platelets, activates protein C, anchors fibrinogen

Bivalirudin: mechanism of action Bivalirudin: mechanism of action Bivalirudin: mechanism of action

(Gly)4

C-terminal dodecapeptide(Exosite 1-binding portion)

2

1

Thrombin

Gly-Pro-Arg-Pro(active-site-binding portion)

Fibrin

Inactivates both circulating and clot-bound thrombin—bivalirudin competitively displaces thrombin from fibrin

Thrombin slowly cleaves Arg3-Pro4 bond, resulting in recovery of thrombin active site function

A/E//20.b.1

Direct Thrombin InhibitorsDirect Thrombin Inhibitors

AngiomaxAngiomax®® (bivalirudin)(bivalirudin)ReversibleReversible

PTCAPTCA25 min25 min

NovastanNovastan®® ((argatrobanargatroban))ReversibleReversible

HITHIT45 min45 min

RefludanRefludan®® (lepirudin)(lepirudin)IrreversibleIrreversible

IndicationIndication: HIT: HITTT1/21/2 = 1.3 hr= 1.3 hr

ThrombinThrombin

ArgatrobanArgatroban: mechanism of action: mechanism of action

ArgatrobanArgatroban only binds near the active site on thrombinonly binds near the active site on thrombin

ArgatrobanArgatroban has a short halfhas a short half--lifelife

2

1

ThrombinArgatroban

54% of argatroban binds to human serum proteins

X/E//111.a.1

Pharmacokinetic ProfilePharmacokinetic Profile

Infusion 2.5 mg/kg/h

[Biv

aliru

din]

Mea

n ng

/mL

Time from start of bivalirudin bolus (hours)

Bolus 0.75 mg/kg

0

2

4

6

8

10

12

14

0 2 4 6 8

t ½ = 25 min.Clearance = 3.4 mL/min/kg

Hemorrhagic outcomesHemorrhagic outcomes

0%

2%

4%

6%

8%

10%

Any majorbleed

3g/dL[Hgb]

Transfuse≥2U

5g/dL[Hgb]

RP or ICbleed

Heparin(N=2151)Bivalirudin(N=2161)

p < 0.001 p < 0.001 p < 0.001 p < 0.001 p = 0.020

20.0%

8.5%

12.7%

3.1%1.2% 1.9%

6.0%

0.0%0%

5%

10%

15%

20%

25%

None(≥90 mL/min)

Mild(60–89 mL/min)

Moderate(30–59 mL/min)

Severe(<30

mL/min)

Bleeding by renal functionBleeding by renal functionIn

cide

nce

of m

ajor

ble

edin

g

Robson, J Invas Cardiol. 2000, 12SupplF: 33F-36F

bivalirudin

heparin

B•A•T

n=275 n=454n=461 n=301n=250 n=12n=7n=256

Mechanical

Distal Embolization

Mechanical Plugging

Serotonin Release

Vasoconstriction

Plaque Rupture

Thrombus

Vasoconstrictive

Platelet aggregate

plugging a

small vessel

Platelet aggregate

plugging a

small vessel

Activated IIb/IIIa

stained red

Activated IIb/IIIa

stained red

Microvascular InjuryMicrovascular Injury

Comparing the Physical Comparing the Physical Differences of the Glycoprotein Differences of the Glycoprotein

2b/3a Inhibitors2b/3a Inhibitors

Platelet Surface

Fibrinogen

2b/3aaV/β3

MAC-1

abciximab

2b/3a

“Small Molecules”

Resting plateletGP IIb/IIIa receptors in

unreceptive state

Inhibition of platelet aggregation

GP IIb/IIIa receptors occupied by antagonistsAgonist

ADP, thrombin, collagen and others

GP IIb/IIIa receptor antagonist

Fibrinogen

Aggregating platelets

GP IIb/IIIa receptors occupied by fibrinogen which forms bridges between adjacent platelets

Response to Platelet Activation

Abciximab Eptifibatide TirofibanPlatelet-bound half-life Long Short Short

(hours) (seconds) (seconds)

Plasma half-life Short Long Long(minutes) (2.5 hr) (1.8 hr)

Drug-to-receptor ratio 1.5–2.0 250–2,5001 >2502

% of dose in bolus ~75%3 <2–5% <2–5%

Dosage adjustment inrenal insufficiency None Yes Yes

1 IMPACT-II and PURSUIT doses.2 RESTORE and PRISM- PLUS doses.3 For any individual receiving a weight-adjusted, 12-hour infusion.

Major Differences AmongMajor Differences AmongGPIIb/IIIa InhibitorsGPIIb/IIIa Inhibitors

Abciximab Eptifibatide Tirofiban↓ Thrombin generation ++ + +↑ Activated clotting time +35 sec +25 sec N/A

Reversibility* 12 hrs 4–6 hrs >4 hrsReversibility with platelets Yes No No

Major Differences AmongMajor Differences AmongGPIIb/IIIa InhibitorsGPIIb/IIIa Inhibitors

Anticoagulant Properties

*50% Return of platelet function without platelet transfusion

Total dose of small moleculeantagonist is a >100-fold

molar excess over GPIIb/IIIa

Total dose of small moleculeantagonist is a >100-fold

molar excess over GPIIb/IIIa

Total dose of abciximabis an ~twofold molar excess

over GPIIb/IIIa

Total dose of abciximabis an ~twofold molar excess

over GPIIb/IIIa

During Drug InfusionDuring Drug Infusion

80% 80%

80%

80%

80%

Numbers represent GPIIb/IIIa receptor occupancy and are an approximation

80%

80%80%

80%

AbciximabAbciximab Small MoleculeSmall Molecule

Platelet Transfusion Rapidly Normalizes Bleeding TimePlatelet Transfusion Rapidly Platelet Transfusion Rapidly Normalizes Bleeding TimeNormalizes Bleeding Time

Abciximab

-

Large pool of free drugto block transfused platelets

Very little free drug to blocktransfused platelets

Immediately After Platelet TransfusionImmediately After Platelet Transfusion

80% 80%

80%

80%

80%

0%

0%

20%

AbciximabAbciximab

80%

80%80%

80%

79%

80%

80%

Small MoleculeSmall Molecule

Numbers represent GPIIb/IIIa receptor occupancy and are an approximation

Months after randomizationIMPACT II: Lancet 1997; 349:1422-28, ACC 1999 Oral presentation, PURSUIT: NEJM 1998; 339:436-43, ESC 1998; Oral

Presentation,PRISM-PLUS: NEJM 1998; 338:1488-97, RESTORE: Circ. 1997; 96:1445-53, JACC 1998; 32:28-34, PARAGON A: Circ 1998; 97:2386-95 ESPRIT: SCAI 2000, Oral Presentation.

-1.0

-0.5

0.0

0.5

1.0

126 36241

.

Absolute Differences over Time

Effects of Small Molecule Therapy on Mortality%

cha

nge

vspl

aceb

o

IMPACT II (n = 4,010)

PURSUIT (n = 9,461)

RESTORE (n = 2,141)

PRISM+ (n = 1,570)

PARAGON A (n = 7,232)

ESPRIT (n = 2,007)

Absolute Differences over TimeAbsolute Differences over Time

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

Months since randomization1 126 36 4824

† p = 0.037* p = 0.071

‡ p = 0.202

Abciximab

CircEPIC: NEJM 1994; 330:956-61, Lancet 1994; 343:881-86, JAMA 1997; 278:479-84, CAPTURE: Lancet 1997; 349:1429-35, ACC 2000 oral pres

., EPILOG: Internal Data, Centocor, EPISTENT: Lancet 1998; 352:87-92, NEJM 1999; 341:319-27, Lancet 1999; 354:2019-24, RAPPORT:. 1998; 98:734-41, ERASER: Circ . 1999; 100; 799-806, ADMIRAL: ETC 2000, oral pres., Neumann : JACC 2000; 35:915-21

*†

‡

EPIC (B&I) (n = 1404)EPILOG (n = 2792)EPISTENT (n = 1603)ERASER (n = 225)

CAPTURE (n = 1265)RAPPORT (n = 483)

ADMIRAL (n = 300)Neumann(n = 401)

Effects of Abciximab Therapy on Mortality%

cha

nge

vspl

aceb

o

Mortality at Maximum Duration of Follow-Up: All Patients

Intention to Treat HR 0.83 (0.73–0.94)

Platelet Thrombi Cause Vessel Occlusion Platelet Thrombi Cause Vessel Occlusion at Site of Injury and Downstreamat Site of Injury and Downstream

Vasocconstriction

Mechanical Obstruction

Vasoconstriction

MechanicalObstruction

Platelet Aggregation

Platelet Attachment at Site of Endothelial Injury

Transient Platelet Aggregation

Stenting the Tip of the IcebergStenting the Tip of the Iceberg

Coronary TreeCoronary Tree----Stenting the Tip of the IcebergStenting the Tip of the Iceberg

3.7%1.0%In-hosp MACEIn-hosp MACE

Sirolimus (n=190)Sirolimus (n=190) Control (n=210)Control (n=210)

%

%

In-hospital MACE Out-of-hosp death|MI TVR (Non-TL) TLR

SIRIUS - Clinical EventsSIRIUS - Clinical EventsAll Events (to 270 days)All Events (to 270 days)

3.2%3.2% 3.8%3.8%TVR (Non-TL)TVR (Non-TL)

P<0.001P<0.001

4.7%4.7%

16.7%16.7%

TLRTLR

7.4%7.4% 7.2%7.2%2.4%2.4%

0.5%0.5%Out-of-hosp death|MIOut-of-hosp death|MI

MetaMeta--analysis of Balloon vs. Stent Trialsanalysis of Balloon vs. Stent Trials11

1.3 1.5

4.8

5.7

1 1

44.7

0

1

2

3

4

5

6

7BalloonStent

30 Day* 6 Month** 30 Day 6 MonthDEATH DEATH / MI

% P

atie

nts

p=0.970

1Kong, Hasselblad, Topol, Califf (submitted)

p=0.997

p=0.106p=0.343

* 3314 pts** 4345 pts (17 trials)

Mortality Follow-up - AbciximabLatest Follow-up in All Randomized Trials

8.6

2.6 2.4

6.7

2.8

4.5

7.3

8.5

6.8

1.71.0

6.3

0.0

4.13.3

6.0

0123456789

10

EPIC (3

years

)EPILOG (1

year)

EPISTENT (1 ye

ar)

CAPTURE (4 ye

ars)

ERASER (6 m

onths)

RAPPORT (6 m

onths)

ADMIRAL (6

months)

Neuman

n (1 ye

ar)

PlaceboAbciximab

% o

f Pat

ient

s

p = 0.037

EPIC: JAMA 1997; 278:479-84 , CAPTURE: Simoons, oral presentation, ACC 2000, EPILOG: Internal Data, Centocor,EPISTENT: Lancet 1999; 354:2019-24, RAPPORT: Circ. 1999; 98:734-41, ERASER Circ. 1999;100:799-806, Neumann: JACC 2000; 35(4):915-921, personal comm, JF Neumann; ADMIRAL: Montelescot, oral presentation, ACC 2000

10 5 0 5 10

Hemorrhage Death, MI, revasc

Heparin +ReoPro (100%)n = 64

Bivalirudin™ +ReoPro (24%)n = 144

% of patients with events at 7 days

75% reductionp-value <0.013

1.4% 2.8%

6.3% 7.8%

Clinical Results of CACHET BC Clinical Results of CACHET BC TrialTrial

REPLACE-2: Design

Multicenter international trial• United States 78% of patients• Europe 15%• Canada 7%• Double-blind, double dummy design

6002

Urgent or elective

PCIpatients

AspirinClopidogrel

Stent

Endpoints30-dayDeathMIRevascHemorrhage

Economics, ischemia6, 12m follow up

BivalirudinProvisional GPIIb/IIIa

Abciximabor

Eptifibatide

Heparin

2994

3008

Lincoff M et al. JAMA 2003

30-day endpoints

7.1%5.8%

4.1%

2.0%

5.2%

9.2%

6.6%

1.6%

3.5%

10.0%

2.4%

7.6%

Death, anyMI, revasc,

bleed

Death, anyMI, revasc

CKMB>3xULN

Major bleed Death, QMI,revasc

Death, QMI,revasc, bleed

Heparin + GPIIb/IIIa (N=3008)Bivalirudin (N=2994)

p=0.329 p=0.328 p=0.197 p<0.001 p=0.178 p=0.002

Lincoff AM et al JAMA 2003; 289: 853-863

All pre-specified endpoints of the trial were met

0 0.5 1 1.5 2

Risk ratio ±95% CIfor death at 6 months

BivalirudinREPLACE-2

N=6002

Mortality vs. heparin at 6 mo

Kong et al 2003Am J Cardiol 2003; 92: 651-5

12 trials – 20,186 patients (Odds ratio)

Karvourni et al 2003J Am Coll Cardiol 2003; 41: 26-32

19 trials 20,137 patients (Risk ratio)

GPIIb/IIIameta-analysis

0 0.5 1 1.5 2

Heparin betterNew Rx better Heparin betterNew Rx better

Odds ratio ±95% CIfor death at 6 months

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

AspirinClopidogrel (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

AspirinClopidogrel (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;292:45-541 Braunwald et al JACC 2002; 2 Bertrand et al. EHJ 2002; 3www.crusade.org; 4SYNERGY. JAMA 2004;292:45-54

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

Ang

iogr

aphy

with

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

Ang

iogr

aphy

with

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

CABGBivalirudin

Alone

UFH or EnoxaparinUFH or EnoxaparinRoutine upstream

GPI in all ptsGPI started in

CCL for PCI onlyR

BivalirudinBivalirudin

RRoutine upstream

GPI in all ptsGPI started in

CCL for PCI only

11.7%11.8% 1.01 (0.90-1.12) <0.0010.93

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) <0.0010.38

Upp

er b

ound

ary

non-

infe

riorit

y

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)

Net clinical outcome

Ischemic composite

Major bleeding

Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)

Upp

er b

ound

ary

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

vent

s (%

)

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

vent

s (%

)

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

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)

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Net Clinical Outcome CompositeNet Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone

ConclusionsConclusions

♦♦ Heparin has significant limitationsHeparin has significant limitations–– Requires a cofactor (ATIII)Requires a cofactor (ATIII)–– NonNon--specific protein bindingspecific protein binding–– Variable dose responseVariable dose response–– Activates plateletsActivates platelets–– ThrombocytopeniaThrombocytopenia–– Thrombin reboundThrombin rebound–– Would not gain FDA approval in 2007Would not gain FDA approval in 2007

Conclusions Conclusions

♦♦ Low risk elective PCILow risk elective PCI–– Bivalirudin alone provides superior clinical Bivalirudin alone provides superior clinical

outcomes compared to UFH alone, and no outcomes compared to UFH alone, and no difference compared to UFH / difference compared to UFH / GpGp 2b3a2b3a

–– Provided they have been adequately preProvided they have been adequately pre--treated with ASA and Plavixtreated with ASA and Plavix

–– Bivalirudin alone has less bleeding than UFH / Bivalirudin alone has less bleeding than UFH / GpGp 2b3a2b3a

ConclusionsConclusions

♦♦ Moderate to high risk PCIModerate to high risk PCI–– No difference in ischemic complications No difference in ischemic complications

comparing bivalirudin alone comparing bivalirudin alone vsvs UFH / UFH / GpGp 2b3a 2b3a vsvs bivalirudin / bivalirudin / GpGp 2b3a2b3a

–– Provided patients are adequately preProvided patients are adequately pre--loaded loaded with ASA and Plavixwith ASA and Plavix

–– Less bleeding with bivalirudin alone Less bleeding with bivalirudin alone vsvs UFH / UFH / GpGp 2b3a 2b3a vsvs bivalirudin / bivalirudin / GpGp 2b3a2b3a

““Death is a very Death is a very good way to cut good way to cut

down on expenses.down on expenses.””Woody AllenWoody AllenLove and DeathLove and Death