Clopidogrel Pretreatment Versus Clopidogrel Exposure
Prior to PCI in the ACUITY Trial: Does it Really Matter?
Clopidogrel Pretreatment Versus Clopidogrel Exposure
Prior to PCI in the ACUITY Trial: Does it Really Matter?
Steven R. Steinhubl, Frederick Feit, Antonio Colombo, Ramin Ebrahimi, David A. Cox, Brent T. McLaurin,
Roxana Mehran, George D. Dangas, Steven V. Manoukian, Harvey D. White, A. Michael Lincoff, Jeffery
W. Moses,Michel E. Bertrand, E. Magnus Ohman, Walter Desmet, Gregg W. Stone,
for the ACUITY Investigators
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 below.interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship Company
Grant/Research SupportGrant/Research Support The Medicines CompanyThe Medicines Company
Eli Lilly / Daiichi-SankyoEli Lilly / Daiichi-Sankyo
Consulting Fees/HonorariaConsulting Fees/Honoraria AstrazenecaAstrazeneca
Bristol-Myers SquibbBristol-Myers Squibb
Sanofi aventisSanofi aventis
The Medicines CompanyThe Medicines Company
Eli Lilly / Daiichi-SankyoEli Lilly / Daiichi-Sankyo
Portola PharmaceuticialsPortola Pharmaceuticials
CogentusCogentus
CardaxCardax
PlaCorPlaCor
28-Day Endpoint Per Protocol
0
5
10
0 7 14 21 28
Days Post-Randomization
Death, MI, or UTVR
8.3%
6.8%
18.5 % RRR18.5 % RRR
p = 0.23
Pretreatment
No Pretreatment
TCT 2002
Clopidogrel Loading Dose Timing and Risk of MACE
- 6
- 5
- 4
- 3
- 2
0 5 10 15 20 25 30Hours Prior to PCI of Study Drug Loading Dose
Log Odds of Death, MI or UTVR at 28 Days
Placebo
Clopidogrel
P = 0.020for treatment / timing
interaction
J Am Coll Cardiol 2006
Hochholzer W. Circulation 2005;111:
Inhibition of ADP-Induced Platelet Function Following 600mg Clopidogrel in 1,001 Patients
Potential Limitations of Clopidogrel
1. Several hour delay in onset, even with loading dose.2. Irreversible.3. Wide variability in response.
0
2
4
6
8
10
<3 h 3-6 h 6-12 h >12 h
% Death, MI or revascularization
Pinteraction=0.27
Abciximab
Placebo
ISAR REACT: Relationship Between ISAR REACT: Relationship Between Time of Loading Dose and OutcomesTime of Loading Dose and Outcomes
Berger PB. AHA 2003
P=0.7P=0.5P=0.4
P=0.7
9.0%
6.7% 6.6%7.3%
9.8%
7.3% 7.2% 7.8%
0%
4%
8%
Noclopidogrel
Clopidogrelpretreatment
<6 hours ≥6 hours
UFH + GP IIb/IIIaBivalirudin
435† 396† 2,499† 2,526† 1,828†1,807† 632† 642†
Clopidogrel Treatment – No Differential in Benefit
Saw J J Am Coll Cardiol. 2004;44:1194-1199.
Dea
th,
MI,
UT
VR
(%
)
~85% of patients in each arm received clopidogrel pre-PCI.
~20% were pretreated > 6 hours prior to PCI.
Moderateand highrisk ACS
(n=13,819)
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
Aspirin in allClopidogrel
dosing and timingper local practice
UFH/Enox+ GP IIb/IIIa(n=4,603)
Bivalirudin+ GP IIb/IIIa(n=4,604)
BivalirudinAlone
(n=4,612)
R*
*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration
Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)
Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)
Medicalmanagement
PCI
CABG
Management Strategy (N=13,819)Management Strategy (N=13,819)
56.4%
11.4%32.2%CABG (n=1,539)CABG (n=1,539)
Medical Rx (n=4,491)Medical Rx (n=4,491)
PCI (n=7,789)PCI (n=7,789)
Heparin + IIb/IIIaN = 2,561
Bivalirudin + IIb/IIIaN = 2,609
Bivalirudin aloneN = 2,619
Composite Ischemia – PCI ptsComposite Ischemia – PCI pts
0
5
10
15
0 5 10 15 20 25 30 35
Eve
nt
Rat
e (%
)
Days from Randomization
*Heparin=unfractionated or enoxaparin*Heparin=unfractionated or enoxaparin
Estimate P(log rank)
8.4%Heparin* + IIb/IIIa (N=2561)
Bivalirudin + IIb/IIIa (N=2609) 0.159.4%
Bivalirudin alone (N=2619) 0.458.9%
Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone
P=0.36
13.8%
8.4%7.2%
8.1%
11.1%
3.6%
Net clinicaloutcomes
Ischemiccomposite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=1722)
Bivalirudin Alone (N=1789)
11.8%
7.5%
5.7%
10.3%
12.7%
3.5%
Net clinicaloutcomes
Ischemiccomposite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=811)
Bivalirudin Alone (N=804)
Thienopyridine Exposed* Not Thienopyridine Exposed
Influence of Thienopyridine Exposure – PCI ptsInfluence of Thienopyridine Exposure – PCI pts
RR [95%CI]
0.81 (0.68-0.96)
RR [95%CI]
0.96 (0.77-1.20)
RR [95%CI]
0.50 (0.37-0.67)
RR [95%CI]
1.07 (0.83-1.39)
RR [95%CI]
1.37 (1.00-1.88)
RR [95%CI]
0.61 (0.39-0.97)
Interaction P values = 0.17, 0.19 and 0.65 respectivelyInteraction P values = 0.17, 0.19 and 0.65 respectively
30 Day Primary Endpoint Adverse Events30 Day Primary Endpoint Adverse Events
*Thienopyridine at any time, any dose, up to time of PCI
Editorial: Do High-Risk Patients Need More Antiplatelet Therapy in Addition to
Bivalirudin?
Waksman R. Lancet 2007;369:881-2
IIa RecommendationFor UA/NSTEMI patients in whom an initial invasive strategy isselected, it is reasonable to omit upstream administration of anintravenous GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than plannedcatheterization or PCI. (Level of Evidence: B)
Method of Analysis of Timing of Clopidogrel
• Timing for the initiation of clopidogrel was a priori designated as:– pre-PCI if it was initiated at any time
prior to the PCI.– Peri-PCI if it was initiated after
angiography and within 30 minutes of the end of PCI.
– Post-PCI if it was initiated > 30 minutes after PCI
Underwent PCI and received clopidogrel at some time prior to or during hospitalization
N= 7517
Clopidogrel pre-hospital
N=1820 (24%)
Clopidogrel at hospital but
pre- randomizationN= 2383 (32%)
Clopidogrel after
randomizationN= 3314 (44%)
Clopidogrel Pre-angiography N = 928
Clopidogrel Peri- PCI N =1572
Clopidogrel Post-PCI N = 814
No clopidogrel
N= 129
Known dose and duration
What is known About Clopidogrel Exposure in ACUITY Patients Pre-PCI
GPIIb/IIIa plus heparin
GPIIb/IIIa plus bivalirudin
Bivalirudin alone
8.6
6.8
8.7
6.9
8.8 9.410.7
19.1
8.0 8.4
12.7
22.0
0
10
20
Pre-procedure
Procedural Post-PCI None
Timing of Clopidogrel Exposure
Percent Composite Ischemic Endpoint
Timing of Clopidogrel and 30-Day Ischemic Outcomes
Timing of Clopidogrel Exposure
Composite Ischemia %
8.89.7
14.0
8.18.6
12.6
23.3
8.2
0
10
20
Pre-PCIN=5131
Peri-PCIN=1572
Post-PCIN=814
NoneN=129
GPIIb/IIIa antagonist + any anticoagulant
Bivalirudin alone
P=0.36 P=0.77
P=0.22
P=0.18
30-Day Ischemic Outcomes Based on Antiplatelet Therapy
Risk ratio (RR) ±95% CI for the triple ischemic endpoint(death, MI, unplanned revascularization)
Bivalirudin alone better Heparin + GPIIb/IIIa better
Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92]
Post-PCI Clopidgrel N=519 RR 1.48 [95% CI 0.89, 2.47]
Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15]
No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72]
pinteraction =0.35
0 1 2 3 4 5 6 7 8
Timing of Clopidogrel and 30-Day Risk of Ischemic Outcomes
Estimated Spline Transformation and 95% C.I. Log Odds for Composite Ischemia (30-Days)
Duration of Clopidogrel Treatment Prior to PCI (hours)
-4
-3
-2
-1
0
1
2
0 2 4 6 8 10 12 14 16 18 20 22 24
GPIIb/IIIa antagonist + any anticoagulant
Bivalirudin alone
Timing of Clopidogrel Pretreatment and Ischemic Outcomes in Patients with
Known Dose and Duration
9.0 9.1
19.6
8.4 8.3
13.7
23.1
8.2
0
10
20
Timing of Clopidogrel Exposure
Composite Ischemia %
Pre-PCIN=2824
Peri-PCIN=950
Post-PCIN=471
NoneN=77
GPIIb/IIIa antagonist + any anticoagulant
Bivalirudin alone
P=0.60
P=0.72
P=0.13
P=0.97
30-Day Ischemic Outcomes in Troponin + Patients Only
Risk ratio ±95% CI for major bleeding endpoint
Bivalirudin alone better Heparin(s) + GP IIb/IIIa better
pinteraction = 0.32
Peri-PCI ClopidogrelN=1044, RR 0.80 [95% CI 0.45, 1.42]
Post-PCI ClopidogrelN=519 RR 0.58 [95% CI 0.27, 1.22]
Pre-PCI clopidogrel N=3429, RR 0.48 [95% CI 0.35, 0.64]
No ClopidogrelN=88 RR 0.0
0 1 2
Timing of Clopidogrel and 30-Day Risk of Major Bleeding
• In ACUITY, patients who received clopidogrel either prior to, or at the time of PCI achieved similar ischemic event rates and significantly less bleeding when randomization to bivalirudin alone versus a GPIIb/IIIa antagonist, irrespective of troponin status.
• There was a non-significant trend towards worse ischemic outcomes among patients receiving clopidogrel after PCI or no clopidogrel at all.
• The desire or ability to pretreat an ACS patient with clopidogrel prior to PCI should not influence the choice of antithrombotic therapy.
Clopidogrel Pretreatment Versus Clopidogrel Exposure Prior to PCI in the
ACUITY Trial: Does it Really Matter?
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