1. An Analysis of the ACUITY Trial Lincoff AM, JACC Intv 2008;1:639–48
Influence of Timing of Clopidogrel Treatment on the Efficacy and Safety of Bivalirudin in Patients With NSTE-ACS Undergoing PCI
Stone p2203/Abstract/ Conclusions
Lincoff p853/Abstract/ Conclusions
An Analysis of the ACUITY Trial
Lincoff AM, JACC Intv 2008;1:639–48
Key Message: HORIZONS AMI builds on a wealth of experience with bivalirudin across a spectrum of patients with acute coronary syndromes (ACS) undergoing PCI and supports the major landmark trials REPLACE-21 and ACUITY.2
References
1. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:
2. Stone GW, McLaruin BT, Cox DA, for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:
Lincoff p853/Abstract/ Conclusions
Stone p2203/Abstract/ Conclusions 1

2. PCI Subgroup
Background
In REPLACE-2 (elective or urgent PCI), bivalirudin was not inferior to heparin plus a GP IIb/IIIa inhibitor in reducing ischemic events and the efficacy of bivalirudin was not influenced by the timing of clopidogrel administration1
In contrast, preliminary analysis of the ACUITY trial found an interaction of borderline significance (p= 0.054) between clopidogrel exposure and randomized therapy on 30-day composite ischemia,2 leading to the suggestion that the use of bivalirudin monotherapy should be limited to NSTE ACS patients in whom clopidogrel pre- treatment is given .
This post-hoc analysis of the ACUITY trial, evaluated the timing of the initiation of clopidogrel treatment in patients undergoing PCI to determine whether clopidogrel pre-treatment is especially beneficial or necessary in patients not receiving a GP IIb/IIIa antagonist.
1: Saw et al
2. Stone GW. NEJM
Lincoff AM, JACC Intv 2008;1:639–48

3. Method of analysis for clopidogrel timing study
PCI Subgroup
Method of analysis for clopidogrel timing study
Timing for the initiation of clopidogrel was a priori designated as:
Pre-angiography if initiated at any time prior to the angiography
Peri-PCI if initiated after angiography and within 30 minutes of the end of PCI
Post-PCI if initiated > 30 minutes after PCI
No clopidogrel. Patients who did not receive clopidogrel (or ticlopidine) at any time before or after PCI.
Lincoff AM, JACC Intv 2008;1:639–48

4. Clopidogrel pre-hospital Clopidogrel at hospital pre- randomization
PCI Subgroup
Clopidogrel study population
All ACUITY patients N= 13,518
Medical management N= 4491
CABG N= 1539
Missing data N=47
PCI patients N= 7789
Ticlopidine N=96
Underwent PCI and received clopidogrel at some time prior to or during hospitalization N= 7517
No clopidogrel N= 129
Clopidogrel pre-hospital
N=1820
Clopidogrel at hospital pre- randomization
N= 2383
Pre-angiography cohort
Peri-PCI cohort
Post-PCI cohort
No clopidogrel
Known dose and duration
Clopidogrel pre-angiography
N= 928
Clopidogrel peri-PCI
N=1572
Clopidogrel post-PCI
N=814
Lincoff AM, JACC Intv 2008;1:639–48

5. Timing of Clopidogrel Exposure
PCI Subgroup
30-Day Ischemic Outcomes
Analysis by clopidogrel timing and randomized treatment arm
P=0.08
GPIIb/IIIa plus heparin
GPIIb/IIIa plus bivalirudin
Bivalirudin alone
23.3 20
19.5
P=0.13
P=0.29
P=0.46
% Composite Ischemia
12.6
8.9
10.8 10
9.5
8.8
8.9
8.1
8.6
8.5
6.9
Pre-procedure
N=5131
Peri-PCI
N=1572
Post-PCI
N=814
None
N=129
Timing of Clopidogrel Exposure
Lincoff AM, JACC Intv 2008;1:639–48

6. Timing of Clopidogrel Exposure
PCI Subgroup
30-Day Ischemic Outcomes
Analysis by clopidogrel timing and randomization to bivalirudin alone vs combined heparin or bivalirudin plus GPIIb/IIIa
P=0.18
23.3
GPIIb/IIIa antagonist + any anticoagulant 20
Bivalirudin alone
P=0.22
14.0
Composite Ischemia %
P=0.77
12.6
P=0.36
9.7 10
8.8
8.6
8.1
8.2
8.8
Pre-PCI
N=5131
Peri-PCI
N=1572
Post-PCI
N=814
None
N=129
Timing of Clopidogrel Exposure
Lincoff AM, JACC Intv 2008;1:639–48

7. Timing of Clopidogrel Exposure
PCI Subgroup
30-Day Ischemic Outcomes in Troponin+ PCI Patients
Analysis by clopidogrel timing and randomization to bivalirudin alone vs combined heparin or bivalirudin plus GPIIb/IIIa
P=0.72
23.1
GPIIb/IIIa antagonist + any anticoagulant 20
19.6
Bivalirudin alone
P=0.13
13.7
Composite Ischemia %
P=0.60
P=0.97
9.0 10
9.1
8.4
8.2
8.3
Pre-PCI
N=2824
Peri-PCI
N=950
Post-PCI
N=471
None
N=77
Timing of Clopidogrel Exposure
Lincoff AM, JACC Intv 2008;1:639–48

8. 30-Day Ischemic Outcomes
PCI Subgroup
30-Day Ischemic Outcomes
Patients with known time of clopidogrel administration (n=928)
Analysis by duration of cloplidogrel treatment pre-PCI and randomization to bivalirudin alone vs combined heparin or bivalirudin plus GPIIb/IIIa
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 1 2 4 6 8 10 12 14 16 18 20 22 24
GPIIb/IIIa antagonist + any anticoagulant
Bivalirudin alone
Lincoff AM, JACC Intv 2008;1:639–48

9. Outcomes and clopidogrel administration Pre* - or Peri† -PCI
PCI Subgroup
Outcomes and clopidogrel administration Pre* - or Peri† -PCI
PCI patients
Risk Ratio 95% CI
RR (95% CI) p-value
DOF for pre-PCI
Table / subgroup: PCI patients received clopidogrel prior to the end of angiography/row 2(C)
DOF for peri-PCI
Table / subgroup: PCI patients received clopidogrel after the end of angiography and within 30-minutes following PCI/row 2(C)
30-day composite ischemia
0.98 (0.81–1.20)
30-day major bleeding
0.53 (0.41–0.69) <0.0001
1-year composite ischemia
1.05 (0.93–1.19)
1-year death
1.05 (0.75–1.46)
DOF for post-PCI
Table / subgroup: PCI patients received clopidogrel after 30-minutes following PCI/row 2(C)
DOF for no
Table / subgroup: PCI patients without clopidogrel/row 2(C)
DOF
Table / all subgroups/row 2(C)
In ACS patients undergoing PCI, there were no significant differences in 30-day risk of triple ischemic endpoint (death, MI, unplanned revascularization) between treatment groups regardless of whether clopidogrel was administered before or after the procedure.
The initial dosing and timing of clopidogrel were left to investigator discretion per local standards, though a ≥300 mg loading dose was recommended no later than 2 hours after PCI in all patients per protocol. Clopidogrel 75 mg daily was recommended for 1 year in all patients after PCI.
Data regarding clopidogrel pretreatment was determined through the case report form. For this analysis, clopidogrel pretreatment was categorized a priori as 
Prior/preprocedural includes the following groups: prehospital, if patient received clopidogrel prior to presentation to the randomization hospital; prerandomization, if patient received clopidogrel prerandomization but at the randomization hospital; postrandomization and preangiography, if patient received clopidogrel after study randomization and prior to angiography
Periprocedural includes patients in whom clopidogrel was initiated after the time of angiography and within 30 minutes after PCI procedure
Postprocedure is defined as any time >30 minutes after PCI within the index hospitalization
No clopidogrel includes patients who had no documentation of receiving clopidogrel (or ticlopidine) at any time before or after the PCI procedure
Note that the exact time and amount of clopidogrel is not known for the “prehospital” or “prerandomization” groups, only for patients who received clopidogrel at any point after randomization. Patients who received ticlopidine were excluded from this analysis.
References
Data on file. The Medicines Company, Parsippany, NJ.
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet. 2007;369:
Bivalirudin monotherapy better
(N=2284)
UFH/enoxaparin + GP IIb/IIIa better
(N=2189)
ANG-PSL / slide 78
Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine.
*Pre-PCI = patients who received clopidogrel either prehospital, prerandomization, postrandomization, or preangiography.
†Periprocedural = patients who received clopidogrel after angiography and within 30 minutes after PCI procedure.
Lincoff AM, JACC Intv 2008;1:639–48 9

10. Outcomes and clopidogrel administration Post-PCI‡ or None§
PCI Subgroup
Outcomes and clopidogrel administration Post-PCI‡ or None§
PCI patients
RR 95% CI
RR (95% CI) p-value
DOF for pre-PCI
Table / subgroup: PCI patients received clopidogrel prior to the end of angiography/row 2(C)
DOF for peri-PCI
Table / subgroup: PCI patients received clopidogrel after the end of angiography and within 30-minutes following PCI/row 2(C)
30-day composite ischemia
1.66 (1.05–2.63)
30-day major bleeding
0.48 (0.23–0.98)
1-year composite ischemia
1.21 (0.88–1.67)
1-year death
0.61 (0.28–1.37)
DOF for post-PCI
Table / subgroup: PCI patients received clopidogrel after 30-minutes following PCI/row 2(C)
DOF for no
Table / subgroup: PCI patients without clopidogrel/row 2(C)
DOF
Table / all subgroups/row 2(C)
In ACS patients undergoing PCI, there were no significant differences in 30-day risk of triple ischemic endpoint (death, MI, unplanned revascularization) between treatment groups regardless of whether clopidogrel was administered before or after the procedure.
The initial dosing and timing of clopidogrel were left to investigator discretion per local standards, though a ≥300 mg loading dose was recommended no later than 2 hours after PCI in all patients per protocol. Clopidogrel 75 mg daily was recommended for 1 year in all patients after PCI.
Data regarding clopidogrel pretreatment was determined through the case report form. For this analysis, clopidogrel pretreatment was categorized a priori as 
Prior/preprocedural includes the following groups: prehospital, if patient received clopidogrel prior to presentation to the randomization hospital; prerandomization, if patient received clopidogrel prerandomization but at the randomization hospital; postrandomization and preangiography, if patient received clopidogrel after study randomization and prior to angiography
Periprocedural includes patients in whom clopidogrel was initiated after the time of angiography and within 30 minutes after PCI procedure
Postprocedure is defined as any time >30 minutes after PCI within the index hospitalization
No clopidogrel includes patients who had no documentation of receiving clopidogrel (or ticlopidine) at any time before or after the PCI procedure
Note that the exact time and amount of clopidogrel is not known for the “prehospital” or “prerandomization” groups, only for patients who received clopidogrel at any point after randomization. Patients who received ticlopidine were excluded from this analysis.
References
Data on file. The Medicines Company, Parsippany, NJ.
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet. 2007;369:
Bivalirudin monotherapy better
(N=290)
UFH/enoxaparin + GP IIb/IIIa better
(N=317)
ANG-PSL / slide 78
Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine.
‡Postprocedure = patients who received clopidogrel any time >30 minutes after PCI within the index hospitalization.
§No clopidogrel = patients who had no documentation of receiving clopidogrel at any time before or after the PCI procedure.
Lincoff AM, JACC Intv 2008;1:639–48 10

11. PCI Subgroup
Conclusions
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 randomized to bivalirudin alone vs a GPIIb/IIIa antagonist, irrespective of troponin status.
Among patients for whom clopidogrel will be given more than 30 min or not at all after PCI, an antithrombotic regimen that includes GP IIb/IIIa inhibition may provide better protection against ischemic events than does bivalirudin alone.
These data are reassuring for the treatment of patients with NSTE-ACS who undergo diagnostic catheterization and PCI with bivalirudin alone without clopidogrel pre-loading
Lincoff AM, JACC Intv 2008;1:639–48