Clopidogrel Pretreatment Versus Clopidogrel Exposure Prior to PCI in the ACUITY Trial: Does it Really Matter?

1. 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

2. 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. Affiliation/Financial RelationshipCompany Grant/Research Support The Medicines Company Eli Lilly / Daiichi-Sankyo Consulting Fees/Honoraria Astrazeneca Bristol-Myers Squibb Sanofi aventis The Medicines Company Eli Lilly / Daiichi-Sankyo Portola Pharmaceuticials Cogentus Cardax PlaCor

3. 28-Day Endpoint Per Protocol Death, MI, or UTVR 10 No Pretreatment 8.3% 6.8% Pretreatment 18.5 % RRR p = 0.23 5 0 0 7 14 21 28 Days Post-Randomization TCT 2002

4. Log Odds of Death, MI or UTVR at 28 Days Placebo - 2 P = 0.020 for treatment / timing interaction - 3 - 4 Clopidogrel - 5 - 6 0 5 10 15 20 25 30 Hours Prior to PCI of Study Drug Loading Dose Clopidogrel Loading Dose Timing and Risk of MACE J Am Coll Cardiol 2006

5. Potential Limitations of Clopidogrel Inhibition of ADP-Induced Platelet Function Following 600mg Clopidogrel in 1,001 Patients • Several hour delay in onset, even with loading dose. • Irreversible. • Wide variability in response. Hochholzer W. Circulation 2005;111:

6. % Death, MI or revascularization 10 Abciximab Pinteraction=0.27 Placebo 8 6 4 2 0 <3 h 3-6 h 6-12 h >12 h ISAR REACT: Relationship Between Time of Loading Dose and Outcomes Berger PB. AHA 2003

7. P=0.7 P=0.5 P=0.4 P=0.7 Clopidogrel Treatment – No Differential in Benefit ~85% of patients in each arm received clopidogrel pre-PCI. ~20% were pretreated > 6 hours prior to PCI. 9.8% 9.0% Death, MI, UTVR (%) 7.8% 7.3% 7.2% 8% 7.3% 6.7% 6.6% UFH + GP IIb/IIIa Bivalirudin 4% 0% 435† 396† 2,499† 2,526† 1,807† 1,828† 632† 642† No Clopidogrel <6 hours ≥6 hours clopidogrel pretreatment Saw J J Am Coll Cardiol. 2004;44:1194-1199.

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

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

10. Heparin* + IIb/IIIa (N=2561) 8.4% P (log rank) Estimate 0.15 Bivalirudin + IIb/IIIa (N=2609) 9.4% 0.45 Bivalirudin alone (N=2619) 8.9% Composite Ischemia – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 10 P=0.36 Event Rate (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

11. Influence of Thienopyridine Exposure – PCI pts 30 Day Primary Endpoint Adverse Events 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) Thienopyridine Exposed* Not Thienopyridine Exposed *Thienopyridine at any time, any dose, up to time of PCI Interaction P values = 0.17, 0.19 and 0.65 respectively

12. Editorial: Do High-Risk Patients Need More Antiplatelet Therapy in Addition to Bivalirudin? Waksman R. Lancet 2007;369:881-2

13. 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)

14. 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

15. Clopidogrel pre-hospital N=1820 (24%) Clopidogrel at hospital but pre- randomization N= 2383 (32%) Clopidogrel after randomization N= 3314 (44%) What is known About Clopidogrel Exposure in ACUITY Patients Pre-PCI Underwent PCI and received clopidogrel at some time prior to or during hospitalization N= 7517 No clopidogrel N= 129 Known dose and duration Clopidogrel Pre-angiography N = 928 Clopidogrel Peri- PCI N =1572 Clopidogrel Post-PCI N = 814

16. Timing of Clopidogrel and 30-Day Ischemic Outcomes Percent Composite Ischemic Endpoint GPIIb/IIIa plus heparin GPIIb/IIIa plus bivalirudin 22.0 20 Bivalirudin alone 19.1 12.7 10 10.7 9.4 8.8 8.6 8.7 8.4 8.0 6.8 6.9 0 Pre- Procedural Post-PCI None procedure Timing of Clopidogrel Exposure

17. 30-Day Ischemic Outcomes Based on Antiplatelet Therapy Composite Ischemia % P=0.18 23.3 GPIIb/IIIa antagonist + any anticoagulant 20 Bivalirudin alone P=0.22 14.0 12.6 P=0.77 P=0.36 10 9.7 8.6 8.8 8.2 8.1 0 Pre-PCI N=5131 Peri-PCI N=1572 Post-PCI N=814 None N=129 Timing of Clopidogrel Exposure

18. Timing of Clopidogrel and 30-Day Risk of Ischemic Outcomes Risk ratio (RR) ±95% CI for the triple ischemic endpoint (death, MI, unplanned revascularization) Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15] pinteraction =0.35 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] No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72] 0 1 2 3 4 5 6 7 8 Bivalirudin alone better Heparin + GPIIb/IIIa better

19. Timing of Clopidogrel Pretreatment and Ischemic Outcomes in Patients with Known Dose and Duration Estimated Spline Transformation and 95% C.I. Log Odds for Composite Ischemia (30-Days) 2 1 GPIIb/IIIa antagonist + any anticoagulant 0 Bivalirudin alone -1 -2 -3 -4 0 2 4 6 8 10 12 14 16 18 20 22 24 Duration of Clopidogrel Treatment Prior to PCI (hours)

20. 30-Day Ischemic Outcomes in Troponin + Patients Only Composite Ischemia % P=0.72 23.1 GPIIb/IIIa antagonist + any anticoagulant 20 Bivalirudin alone P=0.13 19.6 P=0.60 P=0.97 13.7 10 9.0 9.1 8.3 8.4 8.2 0 Pre-PCI N=2824 Peri-PCI N=950 Post-PCI N=471 None N=77 Timing of Clopidogrel Exposure

21. Timing of Clopidogrel and 30-Day Risk of Major Bleeding Risk ratio ±95% CI for major bleeding endpoint pinteraction = 0.32 Pre-PCI clopidogrel N=3429, RR 0.48 [95% CI 0.35, 0.64] 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] No Clopidogrel N=88 RR 0.0 0 1 2 Bivalirudin alone better Heparin(s) + GP IIb/IIIa better

22. Clopidogrel Pretreatment Versus Clopidogrel Exposure Prior to PCI in the ACUITY Trial: Does it Really Matter? • 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.