1. C.R.E.D.O. C lopidogrel for the R eduction of E vents D uring O bservation Multicenter Multinational (USA, Canada) Prospective Randomized Double Blind Placebo Controlled Trial From Steinhubl et al, JAMA 2002;228:2411-20

2. C.R.E.D.O. Aim of the Study  Safety and efficacy of a loading dose of Clopidogrel prior to elective PCI  Safety and efficacy of 1 Year vs 1 Month combined treatment with Clopidogrel 75 mg + ASA after elective PCI

3. C.R.E.D.O. Inclusion Criteria  Pts with symptomatic CAD scheduled for PCI without contraindications to antithrombotic or antiplatelet treatment or stent implantation and with no ST segment elevation within 24 hrs or planned staged procedures or recent (<7 days) administration of GP IIb-IIIa inhibitors, clopidogrel or thrombolytics

4. 3-24 hrs before PCI 28 Days and 1 Year Clinical Follow-Up GP IIb-IIIa Inhib. (mainly Abciximab) on prespecified or Bail-out Indications Clopidogrel 75 mg + ASA 325 mg for 1 Month Clopidogrel 75 mg + ASA 325 mg for 1 Month 75 mg Clopidogrel + ASA 325 mg for 1 Year 75 mg Clopidogrel + ASA 325 mg for 1 Year Placebo + ASA 325 mg for 1 Year Placebo + ASA 325 mg for 1 Year 300 mg Clopidogrel Loading Dose + ASA 325 mg 300 mg Clopidogrel Loading Dose + ASA 325 mg Placebo + ASA 325 mg Placebo + ASA 325 mg C.R.E.D.O.

5. C.R.E.D.O. Outcomes  At 28 Days Death, MI, Urgent TVR in the per protocol population (all pts undergoing PCI) with prespecified secondary analysis of pts receiving clopidogrel loading dose or placebo 6 hrs before PCI  At 1 Year Death, MI, Stroke with prespecified secondary endpoints of TVR

6. Power Calculation based on a Power Calculation based on a Retrospective Analysis of 2450 Pts in the EPISTENT trial: 28 Days Events 13.4% No Ticlopidine Ticlopidine Expected No Ticlopidine Ticlopidine Expected Pre-PTCA Pre-PTCA for Clopid. Loading Pre-PTCA Pre-PTCA for Clopid. Loading (expected placebo) Dose + 1 Year 7.5% 8.9% From Steinhubl et al, JACC 1998;32:1366-70 C.R.E.D.O. P<0.01

7. Age (yrs)61+5 62+7 NS Male Sex (%)70.7%72.1%NS Diabetes (%)27.5%25.4%NS Statins (%)53.6%57.5% p=0.07 Ca ++ Chan. Block. (%)25.5%29.4% p=0.08 MI14.313.1 Indication (%) UAP52.553.1NS SA32.832.8 PTCA85.686.2 Treatment (%) Medical8.37.6NS CABG3.94.0 Clinical Characteristics (I) C.R.E.D.O. Clopidogrel Loading Dose + Clopidogrel 1 Year N= 1053 Clopidogrel Loading Dose + Clopidogrel 1 Year N= 1053 Placebo Loading Dose + Clopidogrel 1 Mo N= 1063 Placebo Loading Dose + Clopidogrel 1 Mo N= 1063

8. Received >1 Stent (%) 89.7 88.3 NS Total Stent Length (mm) 24.4 23.5 NS GP IIb-IIIa Antag. (%) 47.4% 43.3% p=0.08 Clopidogrel Loading Dose + Clopidogrel 1 Year N= 900 Clopidogrel Loading Dose + Clopidogrel 1 Year N= 900 Placebo Loading Dose + Clopidogrel 1 Mo N= 915 Placebo Loading Dose + Clopidogrel 1 Mo N= 915 Clinical Characteristics (II) C.R.E.D.O.

9. Death, MI and Urgent TVR at 28 Days Combined EndPoint Occurrence (%) 10 -18.5% Clopid. No Loading Clopid. Loading 0 Days 7 14 21 28 0 4 6 8 2 8.3% 6.8% NS

10. C.R.E.D.O. Death, MI and Urgent TVR at 28 Days Combined EndPoint Occurrence (%) 10 -38.6% 0 Days 7 14 21 28 0 4 6 8 2 P=0.051 Clopid. No Loading Clopid. < 6 Hrs Loading Clopid. > 6 Hrs

11. C.R.E.D.O. Death, MI, Urgent TVR at 28 Days

12. C.R.E.D.O. Death, MI and Stroke at 1 Year Combined EndPoint Occurrence (%) 0 3 6 9 12 Mths 0 5 10 15 -26% Clopid. 1 Mth Clopid. 1 Year 10.5% 8.5% P=.02

13. C.R.E.D.O. Death, MI, Stroke at 1 Year in Key Subgroups 0 1/2 4 24 48 Hrs

14. Death MI Stroke TVR Death MI Stroke TVR 1.7 1 Month Clopidogrel 2.3 6.7 8.4 0.90.9 13.1 13.6 1 Year Clopidogrel 1 Year Primary and Secondary Prespecified EndPoints C.R.E.D.O.

15. 28 Days 1 Year 28 Days 1 Year 4.8 1 Month Clopidogrel P = 0.07 Loading Dose-1 Year Clopidogrel Major Bleedings P = 0.24 C.R.E.D.O. 3.8 8.8 6.7 More than ½ of major procedural bleedings due to CABG

16. C.R.E.D.O. Conclusions  Prolongation of treatment with an ADP inhibitor such as clopidogrel beyond 1 month after PCIreduces the incidence of death/MI at 1 year  There is a strong trend to reduction of death/MI/urgent TVR at 28 days after a loading dose of 300 mg of clopidogrel administered at least 6 hrs before PCI

17. C.R.E.D.O. Questions and Criticisms  Did pretreatment interfere with long-term results?  Did the poor compliance to long-term treatment with clopidogrel (only 63/61% of pts took the study drug) modify results? Can we improve it?  Can we reduce the excess of bleeding?

18. ASA 300 mg Aspirin Dose and Bleeding Events in CURE 1.92 From Peters et al EHJ 2002;Suppl.4:510 Aspirin/Clopidogrel (p=0.042) 2.82 2.24 3.19 3.32 4.63 3.77 4.64 Major or Life Threatening Bleeding Events Aspirin Alone (p=0.057) 12563 Pts with non-ST Elevation ACS

19. C.R.E.D.O.  Will a higher loading dose help? 10 + 10 Pts pretreated with 200 mg Aspirin 0 1/2 4 24 48 Hrs ADP 20 μmol-induced Aggregation From Muller et al, Heart 2001;85:92-93

20. C.R.E.D.O.  Do we still need IIb-IIIa inhibitors in pts with effective clopidogrel pretreatment? ISAR- REACT: after 600 mg loading dose Clopidogrel: Randomization to Abciximab or Placebo

21. TOPSTAR Study From Bonz et al, JACC 2002;40:662-8 Prior 30 min 12 Hrs 48 Hrs Prior 30 min 12 Hrs 48 Hrs 100100 10 128 14 108 87 98 % Platelet Function 109 Pts with 375 mg Clopidogrel and 500 mg ASA 24 Hrs before PCI Placebo bolus + 18 Hrs infusionTirofiban 10 μg + 18 Hrs Infusion

22. TOPSTAR Study From Bonz et al, JACC 2002;40:662-8 Positive Troponin T (>0.01 Positive Troponin T (>0.01 μg/ml) 40% 63% 109 Pts with 375 mg Clopidogrel and 500 mg ASA 24 Hrs before PCI Placebo bolus + 18 Hrs infusionTirofiban 10 μg + 18 Hrs Infusion

23. C.R.E.D.O.  Is 1 Year Treatment Enough? CHARISMA: 15000 Stable Angina Pts with 42 Mths F-Up Death, MI Kaplan-Meier cum. Hazard rates Hazard rates From Metha et al, Lancet 2001;358:527-33 2658 Pts undergoing PCI in the CURE trial

24. C.R.E.D.O. Questions and Criticisms  What about cost-effectiveness?  Mechanism of clinical benefit? prevention of periprocedural damage, TVR late events and non TVR late events  Long-term treatment with clopidogrel advised for pts who receive drug eluting stents (3 mths SIRIUS, 6 mths TAXUS)