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 Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany Grant/Research SupportThe Medicines Company Eli Lilly / Daiichi-Sankyo Consulting Fees/HonorariaAstrazeneca Bristol-Myers Squibb Sanofi aventis The Medicines Company Eli Lilly / Daiichi-Sankyo Portola Pharmaceuticials CogentusCardaxPlaCor

28-Day Endpoint Per Protocol Days Post-Randomization Death, MI, or UTVR 8.3% 6.8% 18.5 % RRR p = 0.23 Pretreatment No Pretreatment TCT 2002

Clopidogrel Loading Dose Timing and Risk of MACE Hours Prior to PCI of Study Drug Loading Dose Log Odds of Death, MI or UTVR at 28 Days Placebo Clopidogrel P = for 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.

<3 h3-6 h6-12 h>12 h % Death, MI or revascularization P interaction =0.27 Abciximab Placebo ISAR REACT: Relationship Between Time of Loading Dose and Outcomes Berger PB. AHA 2003

P=0.7P=0.5P=0.4P= % 6.7%6.6% 7.3% 9.8% 7.3% 7.2% 7.8% 0% 4% 8% No clopidogrel Clopidogrel pretreatment <6 hours≥6 hours UFH + GP IIb/IIIa Bivalirudin 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: Death, MI, UTVR (%) ~85% of patients in each arm received clopidogrel pre-PCI. ~20% were pretreated > 6 hours prior to PCI.

Moderate and high risk ACS (n=13,819) Study Design – First Randomization Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice Aspirin in all Clopidogrel dosing and timing per local practice UFH/Enox + GP IIb/IIIa (n=4,603) Bivalirudin + GP IIb/IIIa (n=4,604) Bivalirudin Alone (n=4,612) R* *Stratified by pre-angiography thienopyridine use or administration Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Medical management PCI CABG

Management Strategy (N=13,819) 56.4% 11.4% 32.2% CABG (n=1,539) Medical Rx (n=4,491) PCI (n=7,789) Heparin + IIb/IIIa N = 2,561 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619

Composite Ischemia – PCI pts Event Rate (%) Days from Randomization *Heparin=unfractionated or enoxaparin Estimate P (log rank) 8.4% Heparin* + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) % Bivalirudin alone (N=2619) % Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P=0.36

Thienopyridine Exposed*Not Thienopyridine Exposed Influence of Thienopyridine Exposure – PCI pts RR [95%CI] 0.81 ( ) RR [95%CI] 0.96 ( ) RR [95%CI] 0.50 ( ) RR [95%CI] 1.07 ( ) RR [95%CI] 1.37 ( ) RR [95%CI] 0.61 ( ) Interaction P values = 0.17, 0.19 and 0.65 respectively 30 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 Recommendation For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit upstream administration of an intravenous 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 planned catheterization 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- randomization N= 2383 (32%) Clopidogrel after randomization N= 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 Pre- procedure ProceduralPost-PCINone Timing of Clopidogrel Exposure Percent Composite Ischemic Endpoint Timing of Clopidogrel and 30-Day Ischemic Outcomes

Timing of Clopidogrel Exposure Composite Ischemia % 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= Day Ischemic Outcomes Based on Antiplatelet Therapy

Risk ratio (RR) ±95% CI for the triple ischemic endpoint (death, MI, unplanned revascularization) Bivalirudin alone betterHeparin + 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] p interaction = 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) GPIIb/IIIa antagonist + any anticoagulant Bivalirudin alone Timing of Clopidogrel Pretreatment and Ischemic Outcomes in Patients with Known Dose and Duration

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= Day Ischemic Outcomes in Troponin + Patients Only

Risk ratio ±95% CI for major bleeding endpoint Bivalirudin alone betterHeparin(s) + GP IIb/IIIa better p interaction = 0.32 Peri-PCI Clopidogrel N=1044, RR 0.80 [95% CI 0.45, 1.42] Post-PCI Clopidogrel N=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 Clopidogrel N=88 RR 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?