Efficacy and safety of early versus late glycoprotein IIb...
Transcript of Efficacy and safety of early versus late glycoprotein IIb...
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Efficacy and safety of early versus
late glycoprotein IIb/IIIa inhibitors in
ACS patients undergoing PCI
Konstantinos Aznaouridis
1st Department of Cardiology
Athens Medical School
Hippokration Hospital
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Disclosures: NONE
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Ruptured TCF and
luminal thrombus
ACS: Causes & SolutionsThe cause The solution
Revascularization with
stenting (in most pts) to
stabilize the ruptured plaque
STEMI: PCI ~90%
NSTE-ACS: PCI~70%
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ACS: What is the role of PCI?
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ACS: What really matters to the patient?
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Platelet activation
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Parenteral GP IIB/IIA Inhibitors
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Early potent antiplatelet therapy
Adjunctive use in PCI improves outcomes
May improve flow
May limit infarct size (and thus complications)
Rationale of GP IIB/IIIA Inhibitors
use in ACS
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ACS: Impact of MI and bleeding on mortality
Rao et al, JAMA 2004
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GP IIB/IIA Inhibitors in STEMI / pPCI
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GP IIB/IIA Inhibitors in primary PCI
Several trials performed before the routine use of stenting/DAPT, mostly using
abciximab, had documented clinical benefits but increased bleeding with GP
IIb/IIIa inhibitors in unselected pts undergoing primary PCI with UFH.
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Trials performed before the routine use of DAPT
documented no clinical benefits and increased bleeding of
GP IIb/IIIa inhibitors (mostly abciximab) in unselected pts
undergoing primary PCI with UFH.
Meta-analysis of 10,085 pts
De Luca et al, Eur Heart J 2009
GP IIB/IIA Inhibitors in primary PCI
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In high-risk pts undergoing primary PCI with UFH, a mortality benefit of
GP IIb/IIIa inhibitors (mostly abciximab) was documented.
Meta-analysis of 10,085 pts
De Luca et al, Eur Heart J 2009
GP IIB/IIA Inhibitors in primary PCI
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EUROTRANSFER Registry of 1,086 pts
Dziewiertz et al, Int J Cardiol 2010
Only ~25% received >300 mg clopidogrel before cath lab
Compared to downstream use of abciximab, upstream abciximab before
pPCI (>30 min before balloon) is associated with improved outcomes in
pts>65y, without increasing bleeding
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
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Early upstream use of abciximab before pPCI improves mortality
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
De Luca et al, J Thromb Hemost 2011
EGYPT-ALT
An individual patients data meta-analysis of 722 pts
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Early upstream use of abciximab before pPCI improves mortality
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
De Luca et al, J Thromb Hemost 2011
EGYPT-ALT
An individual patients data meta-analysis of 722 pts
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Routine upstream use of bolus abciximab before pPCI did not yield
clinical benefit compared with routine use in the catheterization
laboratory
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
FINESSE Trial90-day events
Ellis et al, NEJM 2008
All pts received
abciximab post-PCI
for 12h
DAPT: All pts
received ASA, no
data for clopidogrel
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Routine upstream use of bolus abciximab before pPCI increased
bleeding compared with routine use in the catheterization laboratory
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
Ellis et al, NEJM 2008
FINESSE Trial90-day bleeding
All pts received
abciximab post-PCI
for 12h
DAPT: All pts
received ASA, no
data for clopidogrel
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Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI (high-risk pts)
Herrmann et al, JACC Cardiovasc Interv 2009
FINESSE Trial90-day MACE
Routine upstream use of abciximab before pPCI in high risk STEMI pts (TIMI
risk score>3) who present within 4 h of symptom onset to non-PCI hospitals
might derive a survival benefit.
FINESSE Trial1-year mortality
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Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
Ten Berg et al, JACC 2010
On -TIME 2 Trial
ST resolution
Early, pre-hospital initiation of high bolus tirofiban + infusion for up to 18h
(vs provisional use of tirofiban in the cath lab), in addition to high-dose
clopidogrel, improves the markers of reperfusion after pPCI in patients with
STEMI.
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Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
Ten Berg et al, JACC 2010
On-TIME 2 Trial30-day MACE
Early, pre-hospital initiation of high bolus tirofiban + infusion for up to 18h
(vs provisional use of tirofiban in the cath lab), in addition to high-dose
clopidogrel, improves the clinical outcome after pPCI in patients with
STEMI.
On-TIME 2 Trial1-year MACE
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Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
Ten Berg et al, JACC 2010
On-TIME 2 Trial30-day bleeding
Early, pre-hospital initiation of high bolus tirofiban + infusion for up to 18h
(vs provisional use of tirofiban in the cath lab), in addition to high-dose
clopidogrel, does not increase bleeding.
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Upstream vs. downstream use of GP IIB/IIA
Inhibitors in primary PCI
Ohlmann et al, Circ Cardiovasc Interv 2012
Early, pre-hospital bolus abciximab + 12h
infusion post-pPCI (vs routine bolus
abciximab in the cath lab pre-pPCI + 12h
infusion post-pPCI) does not improve ST
resolution or outcomes
300 or 600 mg
clopidogrel loading
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In STEMI pts preloaded with 600 mg of clopidogrel, upstream
use of abciximab before pPCI did not reduce infarct size and
did not improve MACE
Outcomes in STEMI with GP IIB/IIA : importance
of preloading with P2Y12 receptor antagonists
BRAVE-3 TrialInfarct size 30-day MACE
Mehilli et al, Circulation 2009
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Stone et al, NEJM 2008
Outcomes in STEMI with GP IIB/IIA : importance
of anticoaggulation
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In STEMI pts preloaded with 300 or 600 mg of clopidogrel, there is no clear
benefit from upstream use of GP IIb/IIIa inhibitor (abciximab bolus + 12h inf. or
eptifibatide double bolus + 12-18h inf.) + UFH, compared to bivalirudin (with
bail-out GP IIb/IIIa inhibitor)
HORIZONS-AMI Trial
Composite adverse events
Bleeding
Stone et al, NEJM 2008
MACE
Outcomes in STEMI with GP IIB/IIA : importance
of anticoaggulation
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GP IIb/IIIa Inhibitors use in STEMI
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GP IIb/IIIa Inhibitors use in STEMI
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GP IIB/IIA Inhibitors in PCI for
NSTE-ACS
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20
15
10
5
0
0 5 10 15 20 25 30
Days After Randomization
Placebo Group (N=1010)
Abciximab Group (N=1012)
Troponin >0.03 µg/L
Log-Rank p = 0.02
Troponin <0.03 µg/L
Log-Rank p = .98
%
GP IIb/IIIa Inhibitors use in NSTE-ACS
ISAR-REACT 2 TrialDeath + MI + urgent TVR
Kastrati et al: JAMA 2006
In NSTE-ACS pts undergoing PCI after pretreatment with 600 mg of clopidogrel, abciximab
(bolus during cath + 12h infusion) improves outcomes.
The benefit appears to be confined to patients presenting with an elevated troponin level.
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Moderate-
to high-
risk
ACS
ACUITY Study Design:First Randomization
An
gio
gra
ph
y w
ith
in 7
2 h
Aspirin in all;Clopidogrel dosing
and timingper local practice
UFH or enox+ GP IIb/IIIa
n=4603
Bivalirudin+ GP IIb/IIIa
n=4604
Bivalirudinalone
n=4,612
R*
Moderate- to high-risk patients with UA or NSTEMI
undergoing an invasive strategy (N = 13,819)
Medical
management
PCI
CABG
Stone et al: Am Heart J 2004
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in NSTE-ACS
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Moderate-
to high-
risk ACS
Aspirin in all;Clopidogrel dosing
and timingper local practice
BivalirudinaloneN=4612
UFH or Enoxaparin
Routine upstream GPI in all pts (2294)
GPI started in CCLfor PCI only (2309)
R
Bivalirudin
R
Routine upstream GPI in all pts (2311)
GPI started in CCL for PCI only (2293)
UF
H, E
no
xap
arin
,
or B
iva
lirud
in
Routine upstream
GPI in all pts
n=4603
Deferred GPI
for PCI only
N=4604
vs
Primary analysis
Secondary
analysis
Moderate- to high-risk patients with UA or NSTEMI
undergoing an invasive strategy (N = 13,819)
ACUITY Study Design:Second Randomization
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in NSTE-ACS
Stone et al: Am Heart J 2004
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ACUITY Study
GP IIb/IIIa inhibitors were used in 55.7% of patients for 13.1 h in the deferred selective
strategy and in 98.3% of patients for 18.3 h (pre-treatment median 4 h) in the routine
upstream strategy. 64% of patients received thienopyridines before angiography /PCI.
Stone et al: JAMA 2007
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in NSTE-ACS
Routine upstream use of GP IIB/IIA inh. in moderate/high risk NSTE-ACS pts
undergoing an early invasive strategy does not improve outcomes and
increases bleeding.
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Early-ACS Trial
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in NSTE-ACS
Giugliano et al: NEJM 2009
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Early-ACS Trial
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in NSTE-ACS
Giugliano et al: NEJM 2009
-In patients with high-risk NSTE-ACS, the use of eptifibatide 12 hours or
more before angiography was not superior to the provisional use of
eptifibatide after angiography.
-Similar findings in important subgroups (diabetics, trop +)
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Early-ACS Trial
Upstream vs. downstream use of GP IIB/IIA
Inhibitors in NSTE-ACS
Giugliano et al: NEJM 2009
In patients with high-risk NSTE-ACS, the use of eptifibatide 12 hours or
more before angiography (compared to the provisional use of
eptifibatide after angiography) is associated with an increased risk of
non–life-threatening bleeding and need for transfusion.
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Upstream vs. downstream use of GP IIB/IIA
Inhibitors in NSTE-ACS
Tricoci et al: Circ Cardiovasc Qual Outcomes 2011
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GP IIb/IIIa Inhibitors use in NSTE-ACS
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Type, dose and timing of oral antiplatelet treatment
300 vs. 600 mg loading dose of clopidogrel
Clopidogrel vs. ticagrelor / prasugrel
GP IIb/IIIa Inhibitors use in ACS
Type of anticoaggulant
UFH vs. bivalirudin
What biases the evaluation of early vs. late GPI
treatment in trials?
Definition of early/late GPI use
Early: prehospital vs. just before angio, bolus vs bolus + infusion
Late: provisional GPI vs routine GPI
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-In patients with ACS treated with
PCI, prasugrel reduces the risk of CV events
regardless of whether or not a GP IIb/IIIa
inhibitor is used.
- The use of a GP IIb/IIIa inhibitor increases
bleeding (HR~1,6), but does not accentuate
the relative risk of bleeding with prasugrel as
compared with clopidogrel.
TRITON-TIMI 38 Trial (55% use of GP IIb/IIIa inh.)
O’Donoghue et al, JACC 2009
Hoschholzer et al, Circulation 2011
GP IIb/IIIa Inhibitors use in ACS in the era of
new P2Y12 receptor antagonists
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GP IIb/IIIa Inhibitors use in ACS in the era of
intense antithrombotic treatment
In clopidogrel pretreated NSTE-ACS pts
treated with PCI, UFH + GP IIb/IIa inh. is
associated with similar ischemic events but
more bleeding compared to bivalirudin.
Pooled analysis of ACUITY and ISAR-REACT4 Trials
Ndrepepa et al, Cir Cardiovasc Interv 2012
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GP IIb/IIIa Inhibitors use in ACS in the era of
intense antithrombotic treatment
In STEMI, prasugrel + a bolus only of GP
IIb/IIIa inhibitor, obviates the need of post-
bolus infusion and almost completely
abolishes residual variability of platelet
aggregation
Valgimigli et al, JACC Cardiovasc Interv 2012
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GP IIb/IIIa Inhibitors use in ACS
Conclusions
In the era of potent DAPT (particularly when prasugrel or ticagrelor is used),
the role of routine (upstream or downstream) use of GP IIb/IIIa inhibitors in
ACS patients undergoing PCI is not definitive.
In STEMI, use of GP IIb/IIIa inhibitors as bailout therapy in the event of
angiographic evidence of large thrombus, slow or no-reflow and other
thrombotic complications is reasonable (but not yet proven in a randomized
trial).
In STEMI, routine upstream use of GP IIb/IIIa inhibitors is not
recommended. Upstream use may be beneficial in high-risk pts not
adequately preloaded with P2Y12 receptor inhibitors who will not take
bivalirudin during pPCI.
In NSTE-ACS, “upstream” PCI (early invasive strategy) is perhaps more
important than upstream GP IIb/IIIa inhibitors.
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Trial design
Bivalirudin0.75 mg/kg bolus1.75 mg/kg/h procedure
Provisional abciximab or eptifibatide
6000PCI
Patients
Urgent or elective
PCI
3000
3000
Aspirin
Plavix
PCI Heparin65 U/kg
AbciximaborEptifibatide
Endpoints
30-day• Death• MI• Revasc• Hemorrhage
Economics
1-year mortality
1 : 1 randomization
REPLACE – 2 Trial Design
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REPLACE - 2
109.2
0.4 0.2
6.27
1.4 1.2
4.1
2.4
0
5
10
15
Composite Death MI Urg TVR Major
Bleed
Heparin + GP 2b/3a (n=3008)
Bivalirudin (n=2994)
%Primary Endpoint
p=0.324
p=0.255
p=0.43
p=0.435
p<0.001
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REPLACE - 2
5.8 6.6
0.4 0.4
25.7
13.4
1.4 1.2 1.7 10
10
20
30
CK-MB Q MI Minor
Bleed
Transfuse Thrombo
Heparin + GP 2b/3a
Bivalirudin
%Outcomes
p=ns
p=nsp=ns
p=ns
p<0.001
cytopenia