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An Analysis of the ACUITY Trial Lincoff AM, JACC Intv 2008;1:63948 Influence of Timing of Clopidogrel Treatment on the Efficacy and Safety of Bivalirudin in Patients With NSTE-ACS Undergoing PCI

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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;1:63948 PCI Subgroup

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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;1:63948 PCI Subgroup

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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;1:63948 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

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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;1:63948 PCI Subgroup Analysis by clopidogrel timing and randomized treatment arm

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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;1:63948 PCI Subgroup Analysis by clopidogrel timing and randomization to bivalirudin alone vs combined heparin or bivalirudin plus GPIIb/IIIa

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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;1:63948 PCI Subgroup Analysis by clopidogrel timing and randomization to bivalirudin alone vs combined heparin or bivalirudin plus GPIIb/IIIa

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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;1:63948 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

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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 (0.811.20) 0.88 30-day major bleeding 0.53 (0.410.69)

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 (1.052.63) 0.03 30-day major bleeding 0.48 (0.230.98) 0.04 1-year composite ischemia 1.21 (0.881.67) 0.25 1-year death 0.61 (0.281.37) 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;1:63948

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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;1:63948 PCI Subgroup