BivalirudinBivalirudin: Is It Standard of : Is It Standard of Care in the Care in the CathCath Lab?Lab?

No Heparin with GPI is Still aNo Heparin with GPI is Still aNo, Heparin with GPI is Still a No, Heparin with GPI is Still a Viable OptionViable OptionppRoxana Mehran, Roxana Mehran, MDMD,,

Mount Mount Sinai School of MedicineSinai School of Medicine

Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest

Within the past 12 months, I or my spouse/partner have had a financial Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed belowinterest/arrangement or affiliation with the organization(s) listed belowinterest/arrangement or affiliation with the organization(s) listed below.interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company•• Grant/Research Support Grant/Research Support

to Institution to Institution •• SanofiSanofi/BMS/BMS-- SignificantSignificant•• The Medicines CompanyThe Medicines Company

Affiliation/Financial Relationship Company

•• Consulting Consulting Fees/HonorariaFees/Honoraria

The Medicines CompanyThe Medicines Company

•• Astra Zeneca, Abbott Astra Zeneca, Abbott Vascular, Vascular, RegadoRegadoBiosciences, JanssenBiosciences, Janssen

Disclosure Disclosure StatementStatement

I have led the Clinical I have led the Clinical C di ti C t f thC di ti C t f thCoordinating Center for the Coordinating Center for the HORIZONS AMI study and aHORIZONS AMI study and aHORIZONS AMI study and a HORIZONS AMI study and a strong believer strong believer for the use of for the use of ggBivalirudinBivalirudin in all cases!!!in all cases!!!

Four Anticoagulant ChoicesFour Anticoagulant ChoicesFour Anticoagulant ChoicesFour Anticoagulant ChoicesIIaC IIa

SCAT

IIaHep

Direct antithrombinUFH

AT ATAT Xa ATXa

LMWH PentasaccharideKonkle BA Schafer AI In: Zipes DP Libby P Bonow RO

= saccharide unit.Konkle BA, Schafer AI. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. Vol 2. 7th ed. Philadelphia: Elsevier Saunders; 2005:2067-2092.

Unfractionated HeparinUnfractionated HeparinComplete structure remains unknown • Unbranched heteropolysaccharide chain

Complete structure remains unknown • Unbranched heteropolysaccharide chain

Anti -Xa Anti-IIa

Molecular weight: 2,500 - 57,500 daltonsMolecular weight: 2,500 - 57,500 daltons

COO

Activity Activity

O

OH

O

OH

N

O

OH

O

OO

OH

O

O

OH

N

O

OH

OS

OSO3

O

COO

OOSO3

O

OSO3

N

OSO3

OOO

OR

COO

18 Saccharide Sequence

18 Saccharide Sequence

OH

NHSO3

OH

OH

NHSO3

OSO3

NHSO3

E ti lE ti l

Heparin Co-factor 2

Essential Pentasaccharide

Sequence

Essential Pentasaccharide

SequenceSequenceSequence

TFPI release

Central Role of Platelets and Interaction with Coagulation in the Genesis of Thrombosis

FibrinogenSh PCIShear, PCIPlaque Rupture ThrombinThrombinTissue Tissue

FactorFactor

C ll

Initial

CollagenvWF Amplification

PAR-1X

X

P2Y12

Fibrin+

Initial Activation

Granule

Amplification X

TxA2

ADP

TP

+

Activation

Granule Secretion Platelet Platelet

AggregationAggregationGPIIb/IIIaGPIIb/IIIaActivationActivation

XX

Platelet-FibrinAmplification

COX-1X

Clot FormationAmplification

Adapted from Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-34.

UFH Is Superior to Placebo for ReducingUFH Is Superior to Placebo for ReducingMortality and Reinfarction in STEMIMortality and Reinfarction in STEMI

MetaMeta--Analysis of 26 Randomized TrialsAnalysis of 26 Randomized Trials

d U

FHd

UFH

66

44 P<.001P<.001

Ass

igne

Ass

igne 22

00

P=.4P=.4

Patie

nts

Patie

nts 00

--22

P 04P 04

P=.01P=.01

per 1

000

Ppe

r 100

0 P

P=.03P=.03

--44

--66

P=.04P=.04 Routine ASARoutine ASA68,000 Patients68,000 Patients93% Lysis Rx93% Lysis Rx

Effe

ct p

Effe

ct p

ReRe--MIMI StrokeStroke PEPE Major BleedMajor BleedDeathDeath--88

--1010

Collins R, et al. N Engl J Med. 1997;336:847Collins R, et al. N Engl J Med. 1997;336:847--860.860.

Patients with Unstable AnginaPatients with Unstable AnginaHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPI

2020Death/MI/urg. TVR, %Death/MI/urg. TVR, % ISARISAR--REACT 2REACT 22020

1515

UFH+Abciximab UFH+Abciximab vs.vs. UFH+PlaceboUFH+Placebo1010

55 TroponinTroponin--Negative: RR=0.99 [0.56Negative: RR=0.99 [0.56--1.76]1.76]

0000 55 1010 1515 2020 2525 303000 55 1010 1515 2020 2525 3030

Days after randomizationDays after randomizationISARISAR--REACTREACT--2, JAMA 20062, JAMA 2006

Patients with Stable/Unstable AnginaPatients with Stable/Unstable AnginaHeparin alone orHeparin alone or BivalirudinBivalirudin

Death/MI/urgTVRDeath/MI/urgTVR

Heparin alone or Heparin alone or BivalirudinBivalirudin

ISARISAR--REACT 3 n= 4570REACT 3 n= 45701010

Death/MI/urgTVRDeath/MI/urgTVR

%%

ISARISAR--REACT 3 n= 4570REACT 3 n= 4570

66

88

5.9%5.9%

44

66

5.0%5.0%Bi alir dinBi alir din ss UFHUFH

22 RR = 1.16 [95% CI, 0.91RR = 1.16 [95% CI, 0.91--1.49]1.49]

Bivalirudin Bivalirudin vs.vs. UFHUFH

00

00 55 1010 1515 2020 2525 3030

[[ ]]

00 55 1010 1515 2020 2525 3030Days after randomizationDays after randomization

ISARISAR--REACT, NEJM 2008REACT, NEJM 2008

Patients with Stable/Unstable AnginaPatients with Stable/Unstable AnginaHeparin alone orHeparin alone or BivalirudinBivalirudinHeparin alone or Heparin alone or BivalirudinBivalirudin

P=0.0001P=0.0001

(%)

(%) P=0.008P=0.008

UFH 140 IU/kgUFH 140 IU/kg

cide

nce

cide

nce

P=0.15P=0.15

Inc

Inc

ISARISAR--REACT, NEJM 2008REACT, NEJM 2008

Patients with Stable/Unstable AnginaPatients with Stable/Unstable AnginaHigh or Low Dose HeparinHigh or Low Dose HeparinHigh or Low Dose HeparinHigh or Low Dose Heparin

Death,MI,urgTVR,major BleedingDeath,MI,urgTVR,major Bleeding ISARISAR--REACT 3A n= 4786REACT 3A n= 4786

))

2020HR 0.81 [0.67HR 0.81 [0.67--1.00]; P=0.0451.00]; P=0.045

Adjusted HR 0.75 [0.60Adjusted HR 0.75 [0.60--0.92]; P=0.0070.92]; P=0.007

ndpo

int (

%)

ndpo

int (

%)

1515

adru

ple

enad

rupl

e en

1010 140 U/kg UFH: 8.7%140 U/kg UFH: 8.7%

Qua

Qua

55 100 U/kg UFH: 7.3%100 U/kg UFH: 7.3%

00

Days After InclusionDays After Inclusion00 55 1010 1515 2020 2525 3030

ISARISAR--REACT 3A, Eur Heart J 2010REACT 3A, Eur Heart J 2010

Patients with Stable/Unstable AnginaPatients with Stable/Unstable AnginaHigh or Low Dose HeparinHigh or Low Dose Heparin

HR 0 79 [0 59HR 0 79 [0 59--1 05]; P=0 111 05]; P=0 11 HR 0 87 [0 67HR 0 87 [0 67 1 13] P 0 291 13] P 0 29

High or Low Dose HeparinHigh or Low Dose Heparin

9 99 91212

HR 0.79 [0.59HR 0.79 [0.59--1.05]; P=0.111.05]; P=0.11Adjusted HR 0.71 [0.53Adjusted HR 0.71 [0.53--0.97]; P=0.030.97]; P=0.03

77

HR 0.87 [0.67HR 0.87 [0.67--1.13]; P=0.291.13]; P=0.29Adjusted HR 0.82 [0.62Adjusted HR 0.82 [0.62--1.08]; P=0.151.08]; P=0.15

9.99.9

88

1010

cece(%

)(%

)

(%)

(%) 4.44.4

5.05.055

66

6.26.2

3.63.64.64.6

44

66

Inci

denc

Inci

denc

ncid

ence

ncid

ence

33

44

22

44 InIn11

22

UFH 100 U/kg UFH 100 U/kg

00Major BleedingMajor Bleeding Minor BleedingMinor Bleeding

00Secondary (Triple) Endpoint:Secondary (Triple) Endpoint:

Death, MI or uTVRDeath, MI or uTVR

UFH 140 U/kgUFH 140 U/kg

ISARISAR--REACT 3A, Eur Heart J 2010REACT 3A, Eur Heart J 2010

Patients with NSTEMIPatients with NSTEMIHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPI

2020Death/MI/urg. TVR, %Death/MI/urg. TVR, % ISARISAR--REACT 2REACT 2

2020 n= 1049n= 1049

1515

UFH+Abciximab UFH+Abciximab vs.vs. UFH+PlaceboUFH+Placebo1010

55TroponinTroponin--Positive: RR=0.71 [0.54Positive: RR=0.71 [0.54--0.95]0.95]

0000 55 1010 1515 2020 2525 303000 55 1010 1515 2020 2525 3030

Days after randomizationDays after randomization

ISARISAR--REACT 2, JAMA 2006REACT 2, JAMA 2006

Patients with STEMIPatients with STEMIHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPI

800 Patients with STEMI800 Patients with STEMI800 Patients with STEMI800 Patients with STEMIPretreatment with 600 mg of clopidogrelPretreatment with 600 mg of clopidogrel

Final infarct sizeFinal infarct size

DoubleDouble--blindblind

MeanMean

3030

4040% LV% LV P P = .47= .47

PlaceboPlacebo399 pts399 pts

AbciximabAbciximab401 pts401 pts

15.715.7 16.616.6

1010

2020

399 pts399 pts401 pts401 pts

00

1010

AbciximabAbciximab PlaceboPlacebo

PCIPCI

Primary endpoint:Primary endpoint: Scintigraphic final infarct sizeScintigraphic final infarct sizey py p g pg p

BRAVE 3, Circulation 2009BRAVE 3, Circulation 2009

Patients with STEMIPatients with STEMIHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPIHeparin alone or with GPI

%%

P = .48P = .48P = .46P = .46 P = .39P = .39

Heparin+Abci imabHeparin+Abci imab H i Pl bH i Pl b

BRAVE 3, Circulation 2009BRAVE 3, Circulation 2009

Heparin+AbciximabHeparin+Abciximab Heparin+PlaceboHeparin+Placebo

For primary For primary PCIPCI

IIb/IIIa antagonistsIIb/IIIa antagonistsIIb/IIIa antagonistsIIb/IIIa antagonists

Abciximab in primary PCI metaAbciximab in primary PCI meta--analysisanalysis8 RCTs8 RCTs 3 949 patients with AMI w/I 123 949 patients with AMI w/I 12°° undergoing primary (7) or rescue (1) PCIundergoing primary (7) or rescue (1) PCI8 RCTs 8 RCTs –– 3,949 patients with AMI w/I 123,949 patients with AMI w/I 12°° undergoing primary (7) or rescue (1) PCI undergoing primary (7) or rescue (1) PCI

randomized to abciximab vs. placebo or controlrandomized to abciximab vs. placebo or control

7 RR 0 72RR 0 726.26

7 No abciximabAbciximab

RR 0.72 RR 0.72 [0.55, 0.94] [0.55, 0.94]

P=0.01P=0.01

3.4

4.4

4

5

ality

RR 0.71 RR 0.71 [0.49, 1.02] [0.49, 1.02]

P=0.06P=0.06

2.4

2

3Mor

ta

1

2

030-day mortality Late mortality

66 12 months12 months

De Luca et al. JAMA 2005De Luca et al. JAMA 2005

66--12 months12 months

BivalirudinBivalirudinBivalirudinBivalirudin

Primary endpoints at 30Primary endpoints at 30--daysdaysPrimary endpoints at 30Primary endpoints at 30--daysdays

20

Heparin + GPIIb/IIIa inhibitor (N=1802)Bivalirudin monotherapy (N=1800)Diff =Diff = --2 9% [2 9% [--4 94 9 --0 8]0 8]

15

20

es (%

)

Bivalirudin monotherapy (N 1800)

Diff = Diff = --3.3% [3.3% [--5.0, 5.0, --1.6]1.6]RR =RR = 0 60 [0 46 0 77]0 60 [0 46 0 77]

Diff Diff 2.9% [2.9% [ 4.9, 4.9, 0.8]0.8]RR = RR = 0.76 [0.63, 0.92]0.76 [0.63, 0.92]

PPNINI ≤ 0.0001≤ 0.0001PPsupsup = 0.005= 0.005

8.3

12.1

9.210

15

ent r

ate

Diff = Diff = 0.0% [0.0% [--1.6, 1.5]1.6, 1.5]RR = 0.99RR = 0.99 [0.76, 1.30][0.76, 1.30]

PP = 0 95= 0 95

RR = RR = 0.60 [0.46, 0.77]0.60 [0.46, 0.77]PPNINI ≤ 0.0001≤ 0.0001PPsupsup ≤ 0.0001≤ 0.0001

5.5

8.3

5.44.95

10

day

eve PPsupsup = 0.95= 0.95

11°° endpointendpoint

0

5

30 pp

11°° endpointendpoint Major 2Major 2°° endpointendpoint

Net adverseclinical events

Major bleeding(non CABG)

MACE

Stone GW et al. NEJM 2008;358:2218Stone GW et al. NEJM 2008;358:2218--3030

11--year Allyear All--cause mortalitycause mortality4.8%4.8%

ΔΔ = 1.4%= 1.4%44

55(%

)(%

) 3.4%3.4%3.1%3.1%33

44

Mor

talit

y (

Mor

talit

y (

Diff [95%CI] = Diff [95%CI] = --1.5% [1.5% [--2.8,2.8,--0.1]0.1]2.1%2.1%22

MM [ ][ ] [[ ]]

HR [95%CI] =0.69 [0.50, 0.97] HR [95%CI] =0.69 [0.50, 0.97] PP=0.029=0.029ΔΔ = 1.0%= 1.0%P=0.049P=0.049

11

00

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

Number at riskNumber at riskBivalirudin aloneBivalirudin alone 18001800 17051705 16841684 16691669 15201520

Time in MonthsTime in Months

Heparin + IIb/IIIaHeparin + IIb/IIIa 18021802 16781678 16631663 16461646 14861486

30 Day Stent Thrombosis UFH + GP

IIb/IIIa Bivalirudin(1571)

P

(1553) (1571)

ARC 30d definite or 1 9% 2 5% 0 30probable stent thrombosis* 1.9% 2.5% 0.30

- definite 1 4% 2 2% 0 09definite 1.4% 2.2% 0.09

- probable 0.5% 0.3% 0.24p

- acute (≤24 hrs) 0.3% 1.3% 0.0007

**Protocol definition of stent thrombosis, CEC adjudicatedProtocol definition of stent thrombosis, CEC adjudicatedotoco de t o o ste t t o bos s, C C adjud catedotoco de t o o ste t t o bos s, C C adjud cated

Effects of ClopidogrelEffects of ClopidogrelBIV group: 30 Day Stent ThrombosisBIV group: 30 Day Stent Thrombosis

300 mg LD 600 mg LD P value300 mg LD 600 mg LD P-value

ARC definite or probable* 3.5% 1.7% 0.03

- definite 3.1% 1.5% 0.04

-Probable 0.4% 0.2% 0.61

- acute (≤24 hrs) 1.6% 0.9% 0.26

( ) % %- subacute (>24 hrs – 30d) 2.1% 0.8% 0.03

**Protocol definition of stent thrombosis CEC adjudicatedProtocol definition of stent thrombosis CEC adjudicated

Dangas et al, Dangas et al, JACC 2009JACC 2009

Protocol definition of stent thrombosis, CEC adjudicatedProtocol definition of stent thrombosis, CEC adjudicated

Arterial access site and 30Arterial access site and 30--day nonday non--CABG major or minor bleedingCABG major or minor bleedingCABG major or minor bleedingCABG major or minor bleeding

20 RR =0.56RR =0.56 [0.46, 0.67][0.46, 0.67]P≤ 0 0001P≤ 0 0001

16

15s (%

)

Heparin + GPIIb/IIIa inhibitor (N=1802)

Bivalirudin monotherapy (N=1800)

P≤ 0.0001P≤ 0.0001

8.6 910

vent

rate RR = RR = 0.59 [0.46, 0.77]0.59 [0.46, 0.77]

P≤ 0.0001P≤ 0.0001

3.4 3.45.1

2 75

0-da

y ev RR = RR = 0.79 [0.18, 3.45]0.79 [0.18, 3.45]

P ≤ 0.75P ≤ 0.75RR =0.53RR =0.53 [0.10, 2.82][0.10, 2.82]

P=0.45P=0.45

2.71.8

0

30

Major bleedingFemoral access

(N=3371)

Major bleedingradial/brachialaccess (N=226)

Minor bleedingfemoral access

Minor bleedingradial/brachial

access

Bleeding rates with anticoagulants and Bleeding rates with anticoagulants and antiplatelet agents in primary PCIantiplatelet agents in primary PCI

A ti l tA ti l t A ti l t l t A tA ti l t l t A tAnticoagulantsAnticoagulants Antiplatelet AgentsAntiplatelet Agents

P=0.002P=0.0026

ing

(%)

P=0.79P=0.79

Single Single dosedose

Double Double dosedose4

jor B

leed

i

P=0.52P=0.52

P=0.60P=0.60

P=0 07P=0 072

CA

BG

Maj

P=0.07P=0.07

2.92.4 5 3.1 1.5 1.2 2.2 2.5 0.7 10

TIM

I non

-C

ATOLLATOLL HORIZONSHORIZONS TRITONTRITON PLATOPLATO CURRENTCURRENTn=910n=910 n=3345n=3345 n=2438n=2438 n=8430n=8430 n=6364n=6364

UFH Enox UFH Biv Clop Pras Clop Ticag Clop Clop

T

White HD., European Heart Journal. 2010; In pressWhite HD., European Heart Journal. 2010; In press

Heparin for all?Heparin for all?

BothBoth heparinheparin andand bivalirudinbivalirudin arearegoodgood optionsoptions, , withwith a a possiblepossible

d td t ff bi li dibi li diSTEMISTEMI15%15%advantageadvantage forfor bivalirudinbivalirudin 15%15%

NSTEMINSTEMI45%45%St bl APSt bl APBRAVE 4BRAVE 41200 1200 PatientsPatientswithwithSTEMISTEMI

BRAVE 4BRAVE 41200 1200 PatientsPatientswithwithSTEMISTEMI

NSTEMINSTEMI16%16%45%45%Stable APStable AP

Clopidogrel + Clopidogrel + HeparinHeparinPrasugrel + BivalirudinPrasugrel + BivalirudinPrimaryPrimaryPCIPCI

Clopidogrel + Clopidogrel + HeparinHeparinPrasugrel + BivalirudinPrasugrel + BivalirudinPrimaryPrimaryPCIPCI

24%24%3030--day day outcomesoutcomes

PrimaryPrimaryendpointendpoint:: DeathDeath, MI, , MI, strokestroke, ST, , ST, revascrevasc., ., bleedingbleeding3030--day day outcomesoutcomes

PrimaryPrimaryendpointendpoint:: DeathDeath, MI, , MI, strokestroke, ST, , ST, revascrevasc., ., bleedingbleeding Unstable APUnstable AP

Balancing Safety and EfficacyHigh risk of

ischemic eventsHigh risk of

bleeding events“Sweet spot”

Inhibition of platelet aggregation

Ischemic risk Bleeding riskFerreiro & Angiolillo. Thromb Haemost 2010 (in press)