1. Clopidogrel in ACS: Overview Investigator, TIMI Study Group Associate Physician, Cardiovascular Division, BWH Assistant Professor of Medicine, Harvard Medical School Marc S. Sabatine, MD, MPH

2. Clopidogrel: Mechanism ADP = adenosine diphosphate, TXA 2 = thromboxane A 2, COX = cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101:199-209. Collagen Thrombin TXA 2 ADP Receptor (P2Y 12 ) TXA 2 ADP ADP GP IIb/IIIa receptor Activation COX Clopidogrel Ticlopidine Fibrinogen

3. Clopidogrel in NSTE ACS: CURE CURE. NEJM 2001;345:494-502 12,563 Pts, GP IIb/IIIa & early invasive approach discouraged RR 0.80, p<0.001 Clopidogrel (9.3%) Placebo (11.4%) CV Death, MI, Stroke Months of follow-up 03 6 912 0.0 0.02 0.04 0.06 0.08 0.10 0.12 0.14

4. Yusuf S et al. Circulation 2003;107:966-972 CURE: Very Early Efficacy of Clopidogrel in NSTE ACS Hours After Randomization 0.0 0.005 0.010 0.015 0.020 0.025 024681012141618202224 P=.003 Placebo + Aspirin (n=6303) Clopidogrel + Aspirin (n=6259) 34% Relative Risk Reduction CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours Cumulative Hazard Rate

5. Fox et al. Circulation. 2004;110:1202-1208. Medical Rx Group Placebo Clopidogrel RR: 0.80 (0.69-0.92) 0.20 4 0.15 0.10 0.05 0.0 100200300 Clopidogrel 0.20 4 0.15 0.10 0.05 0.0 100200300 PCI Group Placebo RR: 0.72 (0.57-0.90) 0.20 4 0.15 0.10 0.05 0.0 100200300 CABG Group Placebo Clopidogrel RR: 0.89 (0.71-1.11) CURE: Benefit by Revascularization CVD/MI/Stroke

6. CURE Safety Results RR 1.38 (95% CI 1.13-1.67) P=0.001 NEJM 2001;345:494-502

7. Clopidogrel in STEMI Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups

8. Clopidogrel in STEMI PlaceboClopidogrel 36%  P<0.0001 36%  P<0.0001 Sabatine MS et al. NEJM 2005; 352: 1179 days CV Death, MI, or Urg Revasc (%) 0 5 10 15 051015202530 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20%20%

9. Bleeding Outcome Clopidogrel (%) Placebo (%) P value Through angiography TIMI major (Hgb  >5 g/dL or ICH) 1.31.1NS TIMI minor (Hgb  3-5 g/dL) 1.00.5NS Intracranial hemorrhage 0.50.7NS Through 30 days TIMI major 1.91.7NS In those undergoing CABG 7.57.2NS CABG w/in 5 d of study med 9.17.9NS TIMI minor 1.60.9NS Sabatine MS et al. NEJM 2005; 352: 1179

10. COMMIT: Clopidogrel (75 mg qd) in STEMI 9% relative risk reduction (P=.002) Placebo (10.1%) Clopidogrel (9.3%) Days Death, MI, Stroke (%) 98765432109876543210 0 Mortality (%) Days Placebo (8.1%) Clopidogrel (7.5%) 7% relative risk reduction (P=.03) 7654321076543210 714212807142128 COMMIT Collaborative Group. Lancet. 2005;366:1607. 45,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)

11. Type Clopidogrel Placebo (n=22,958) (n=22,891) Cerebral Fatal3940 Non-fatal1615 Non-cerebral Fatal3637 Non-fatal4636 Any major bleed134 124 (0.58%) (0.54%) COMMIT: Major bleed in hospital Chen Z et al. Lancet 2005;366:1607-21.

12. PCI – Rx following PCI Following percutaneous coronary intervention (PCI), treatment with ADP receptor blockers such as ticlopidine or clopidogrel reduces thrombotic & ischemic complications. Aspirin Aspirin + warfarin Aspirin + ticlopidine P=0.001 CREDO Steinhubl et al. JAMA. 2002; 288: 2411. 12 10 8 6 4 2 0 STARS Leon et al. NEJM 1998; 339: 1665. 036912 Months after PCI 11.5% 8.5% Placebo + ASA Clopidogrel + ASA 27% RRR P = 0.02 Death/MI/stroke

13. PCI – PCI-CLARITY Design 30-day clinical follow-up 933 underwent PCI during index hosp. 930 underwent PCI during index hosp. 3491 Patients Randomized into CLARITY-TIMI 28 1752assigned clopidogrel 300 mg  75 mg/d 1739assigned placebo Open-label clopidogrel w/ loading dose recommended (CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT) A n g i o g r a p h y

14. PCI – CV Death, MI, or Stroke following PCI 0 2 4 6 8 0102030 Days post PCI Percentage with outcome (%) No Pretreatment – 6.2% Clopidogrel – 3.6% Pretreatment 46%46% Odds Ratio 0.54 (95% CI 0.35-0.85) P=0.008 Odds Ratio 0.54 (95% CI 0.35-0.85) P=0.008 Sabatine MS et al. JAMA 2005;294:1224-32

15. Clopidogrel No TrialPretreatmentPretreatment PCI-CURE3.65.1 CREDOn/an/a PCI-CLARITY4.06.1 Overall3.75.5 ClopidogrelNo TrialPretreatmentPretreatment PCI-CURE2.94.4 CREDO6.07.1 PCI-CLARITY3.35.4 Overall3.95.5 Meta-Analysis of Clopidogrel Pretreatment 1.00.252.00.5 1.00.252.00.5 OR (95% CI) CV Death or MI after PCI (%) MI before PCI (%) OR 0.67 P=0.005 P=0.005 Favors Pretreatment Favors No Pretreatment OR 0.71 P=0.004 P=0.004 Sabatine MS et al. JAMA 2005;294:1224-32

16. TrialClopi PreRxNo PreRx PCI-CURE27/1039 (2.6)39/988 (3.9) CREDO26/473 (5.5)34/519 (6.6) PCI-CLARITY22/639 (3.4)30/615 (4.9) OVERALL75/2151 (3.5)103/2122 (4.9) TrialClopi PreRxNo PreRx PCI-CURE14/274 (5.1)23/357 (6.4) CREDO29/427 (6.8)32/396 (8.1) PCI-CLARITY12/288 (4.2)28/310 (9.0) OVERALL55/989 (5.6)83/1063 (7.8) Efficacy of Clopidogrel PreRx by GPI Use 1.00.252.00.5 1.00.252.00.5 OR (95% CI) OR 0.72 (0.53-0.98)P=0.03 (0.53-0.98)P=0.03 Favors PreRx Favors No PreRx OR 0.69 (0.47-1.00)P=0.05 (0.47-1.00)P=0.05 Without GPI P=0.85 for heterogeneity by GPI use With GPI Sabatine MS et al. AHJ in press.

17. Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA): Study Design Double-blind treatment up to 1,040 primary efficacy events occur* Aspirin 75–162 mg once daily Clopidogrel 75 mg once daily (n=7600) Placebo 1 tab once daily (n=7600) Aspirin 75-162 mg once daily Final study visit (fixed study end date) 1-month visit 3-month visit Patients 45 years or older who are at high risk of atherothrombotic events R = randomization. N=15,603 R Bhatt et al. Am Heart J. 2004;148:263 *Event-driven trial: primary efficacy outcome of vascular death, MI, stroke Visits every 6 months (12 m, 18 m…), and intermediate phone calls in between (15 m, 21m…) 6-month visit

18. Overall Population: Primary Efficacy Outcome (CV Death, MI, or Stroke) Bhatt DL et al. NEJM 2006;354:1706-17 Cumulative event rate (%) 0 2 4 6 8 Months since randomization 0 612182430 Placebo + ASA 7.3% Clopidogrel + ASA 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22

19. Overall Population: Safety Results Clopidogrel Placebo + ASA+ ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI)p value GUSTO Severe Bleeding130 (1.7)104 (1.3)1.25 (0.97, 1.61)0.09 Fatal Bleeding26 (0.3)17 (0.2)1.53 (0.83, 2.82)0.17 Primary ICH26 (0.3)27 (0.3)0.96 (0.56, 1.65)0.89 GUSTO Moderate Bleeding164 (2.1)101 (1.3)1.62 (1.27, 2.08)<0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL et al. NEJM 2006;354:1706-17

20. CHARISMA Study: Primary Efficacy Results (CV Death, MI, or Stroke) by Prespecified Entry Category PopulationRR (95% CI)P value Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998)0.046 (n=12,153) Multiple Risk Factors 1.20 (0.91, 1.59)0.20 (n=3284) Overall Population0.93 (0.83, 1.05)0.22 (n=15,603) 0.60.8 1.41.2 Clopidogrel BetterPlacebo Better 1.6 0.4 (P interaction =0.045) Bhatt DL et al. NEJM 2006;354:1706-17

21. Primary Endpoint (CV Death, MI, or Stroke) in Patients with Previous MI, IS, or PAD “CAPRIE-like Cohort” RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01 Primary outcome event rate (%) 0 2 4 6 8 10 Months since randomization 0 612182430 Clopidogrel + ASA 7.3% Placebo + ASA 8.8% N=9,478 Bhatt DL et al. JACC 2007;49:1982

22. Conclusions Upstream clopidogrel given across the spectrum of ACS  death and ischemic complications Treatment benefit emerges early and is comparable regardless of ultimate revasc. Treatment mandated in patients after stenting Clopidogrel pretreatment before PCI  death or ischemic complications after PCI, regardless of GP IIb/IIIa use Long-term use not beneficial in 1° prevention; may be beneficial in 2° prevention

23. Clopidogrel in the Guidelines SettingSocietyRecommendationGrade UA/ NSTEMI ACC/AHA 2007 300 mg upstream in INV strategy 300 mg upstream + GPI in INV 300 mg ASAP in CONS strategy I IIa I ESC 2007 300 mg immediately in all patientsI STEMI (non 1  PCI) ACC/AHA 2007 75 mg in all patients 300 mg load if age <75 yrs I IIa PCI ACC/AHA/ SCAI 2005 300 mg  6 hrs before PCI I ESC 2005 300 mg  6 hrs before PCI I