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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)
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