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

2. 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 administration 1 ● 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 PCI Subgroup

3. 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 PCI Subgroup

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

5. GPIIb/IIIa plus heparin GPIIb/IIIa plus bivalirudin Bivalirudin alone 8.8 6.9 8.5 8.9 9.5 10.8 19.5 8.1 8.6 12.6 23.3 0 10 20 Pre-procedure N=5131 Peri-PCI N=1572 Post-PCI N=814 None N=129 Timing of Clopidogrel Exposure % Composite Ischemia 30-Day Ischemic Outcomes P=0.46 P=0.29 P=0.13 P=0.08 Lincoff AM, JACC Intv 2008;1:639–48 PCI Subgroup ● Analysis by clopidogrel timing and randomized treatment arm

6. Timing of Clopidogrel Exposure Composite Ischemia % 8.8 9.7 14.0 8.1 8.6 12.6 23.3 8.2 0 10 20 Pre-PCI N=5131 Peri-PCI N=1572 Post-PCI N=814 None N=129 GPIIb/IIIa antagonist + any anticoagulant Bivalirudin alone P=0.36 P=0.77 P=0.22 P=0.18 30-Day Ischemic Outcomes 8.8 Lincoff AM, JACC Intv 2008;1:639–48 PCI Subgroup ●Analysis by clopidogrel timing and randomization to bivalirudin alone vs combined heparin or bivalirudin plus GPIIb/IIIa

7. 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-PCI N=2824 Peri-PCI N=950 Post-PCI N=471 None N=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+ PCI Patients Lincoff AM, JACC Intv 2008;1:639–48 PCI Subgroup ●Analysis by clopidogrel timing and randomization to bivalirudin alone vs combined heparin or bivalirudin plus GPIIb/IIIa

8. 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 0 1 2 024681012141618202224 GPIIb/IIIa antagonist + any anticoagulant Bivalirudin alone 30-Day Ischemic Outcomes Lincoff AM, JACC Intv 2008;1:639–48 ● 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 PCI Subgroup

9. Outcomes and clopidogrel administration Pre* - or Peri † -PCI PCI patientsRisk Ratio 95% CIRR (95% CI) p-value Bivalirudin monotherapy better (N=2284) UFH/enoxaparin + GP IIb/IIIa better (N=2189) 30-day composite ischemia 0.98 (0.81–1.20) 0.88 30-day major bleeding 0.53 (0.41–0.69) <0.0001 1-year composite ischemia 1.05 (0.93–1.19) 0.45 1-year death 1.05 (0.75–1.46) 0.79 PCI Subgroup 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

10. Outcomes and clopidogrel administration Post-PCI ‡ or None § PCI patientsRR 95% CIRR (95% CI) p-value Bivalirudin monotherapy better (N=290) UFH/enoxaparin + GP IIb/IIIa better (N=317) 30-day composite ischemia 1.66 (1.05–2.63) 0.03 30-day major bleeding 0.48 (0.23–0.98) 0.04 1-year composite ischemia 1.21 (0.88–1.67) 0.25 1-year death 0.61 (0.28–1.37) 0.23 PCI Subgroup 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

11. ● 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 Conclusions Lincoff AM, JACC Intv 2008;1:639–48 PCI Subgroup