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lopidogrel in

lopidogrel in . nstable Angina. to Prevent. ecurrent. vents. Disclaimer. This slide kit presents new data to support the rationale for the use of ADP receptor antagonists for approved and unapproved indications.

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lopidogrel in

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  1. lopidogrel in nstable Angina to Prevent ecurrent vents

  2. Disclaimer • This slide kit presents new data to support the rationale for the use of ADP receptor antagonists for approved and unapproved indications. • The slide kit has been prepared for medical and scientific purposes. It contains information on a use that is not approved by the FDA and should not be construed as an inducement to use clopidogrel for unapproved indications. Neither Sanofi-Synthelabo Inc., Bristol-Myers Squibb nor the partnership recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.

  3. Rationale • Despite treatment with aspirin and heparin, the incidence of MI and CV death during hospitalization remains high, 6-8% • Long term, the incidence of these events remain high at 6-8% per year • The majority of patients (80%) who enter the hospital with acute coronary syndrome (ACS) are already on aspirin therapy • The negative findings of the oral GP IIb/IIIa’s underscores the need for alternative strategies to treat ACS CURE Study Investigators. Eur Heart J. 2000;21:2033-2041. PURSUIT Investigators. Am J Cardiol. 1999;83:1147-1151.

  4. Study Objectives • Primary • Evaluate the early and long-term efficacy of clopidogrel vs placebo, both given in addition to aspirin and other standard therapy in preventing ischemic complications in patients with ACS without ST-segment elevation (unstable angina or non-ST-segment elevation MI) • Secondary • Evaluate the safety of clopidogrel in combination with ASA therapy in patients with ACS CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

  5. Study Design Clopidogrel 300 mg loading dose Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Patients with Acute CoronarySyndrome R 3 months £ double-blind treatment £ 12 months (unstable angina or non-ST-segment elevation MI) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 3 m. Visit 1 m. Visit 6 m. Visit 9 m. Visit 12 m.or Final Visit Discharge Visit Placebo loading dose The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. R = Randomization* In combination with other standard therapy

  6. Key Inclusion Criteria • Age ³ 21 years1 • Suspected UA or NSTEMI (no ST ³ 1.0 mm)2 • Presentation £ 24 hours after onset of symptoms2 • ECG changes compatible with ischemia or elevated cardiac enzymes or troponin I or T ³ 2 x ULN2 1 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.) 2 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

  7. Key Exclusion Criteria • NYHA Class IV heart failure1 • Uncontrolled hypertension2 • Current use of anticoagulants1, clopidogrel, ticlopidine, or NSAIDS2, or GP IIb/IIIa inhibitor within 3 days1 • PCI or CABG within 3 months1 • History of severe thrombocytopenia or neutropenia2 • At high risk for bleeding1 • Contraindications to antithrombotic or antiplatelet therapy1 1 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041. 2 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)

  8. Outcome Definitions • MI: • At least two of the following criteria: chest pain, ECG changes, elevation of cardiac markers or enzymes (Troponin, CK, CK-MB) • Stroke: • Neurological deficit ³ 24 hrs (CT/MRI encouraged) • CV Death: • Excludes any death for which there was no clearly documented non-CV cause • Refractory Ischemia: • In-hosp: recurrent ischemia on max med Rx + ECG changes + intervention £ 1 day • After discharge: Rehosp for UA with ECG changes • Severe Ischemia: • Changes similar to in-hospital refractory ischemia, but no intervention • Recurrent Angina: • All other ischemic chest pain in hospital The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  9. Efficacy Analyses • First Primary End PointFirst occurrence of any component of the cluster of: • Myocardial Infarction • Stroke (ischemic, hemorrhagic, or of uncertain type) • Cardiovascular death • Second Primary End PointFirst occurrence of any component of the cluster of: • Myocardial Infarction • Stroke (ischemic, hemorrhagic, or of uncertain type) • Cardiovascular death • Refractory ischemia The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  10. Baseline Characteristics Placebo N = 6303 Clopidogrel N = 6259 Age (mean) 64.2 64.2 Mean time from pain onset to randomization (hrs) 14.1 14.2 Mean heart rate (beats/min) 73.0 73.2 Mean systolic BP (mm Hg) 134.1 134.4 Female (%) 38.3 38.7 Diagnosis at Entry Unstable Angina (%) 74.9 74.9 Non–ST-segment elevation MI (%) 25.1 25.1 ECG abnormalities (%) 93.9 93.7 The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  11. Patient History PlaceboN = 6303(%) ClopidogrelN = 6259(%) History of MI 32.0 32.4 CABG Surgery/PTCA 18.1 17.7 Stroke 3.7 4.4 Heart Failure 7.8 7.4 Hypertension 57.8 59.9 Diabetes 22.8 22.4 Current or former smoker 60.9 60.6 The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  12. ECG Abnormality Type Placebo(%) Clopidogrel(%) History Abnormal ECG 93.9 93.7 ST-segment Dep > 1 mm 42.0 42.2 ST-segment elevation < 1 mm 3.2 3.2 Major T-wave inversion 25.9 25.4 Other T-wave inversion 11.3 11.5 Other abnormalities 10.9 10.7 The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  13. Primary End Point - MI/Stroke/CV Death 11.4% Placebo + ASA* 9.3% Clopidogrel + ASA* 20% RRR P < 0.001 N = 12,562 0 3 6 9 12 Months of Follow-Up * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  14. MI/Stroke/CV Death within 30 Days Placebo + ASA* Clopidogrel + ASA* 21% RRR P = 0.003 N = 12,562 0 10 20 30 Days of Follow-Up * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  15. Main Efficacy Results - Primary Endpoint Placebo + ASA*N = 6303 Clopidogrel + ASA*N = 6259 Relative Risk Reduction Outcome P value CV death, MI, stroke (Primary 11.4% 9.3% 20% < 0.001end point) MI 6.7% 5.2% 23% Stroke 1.4% 1.2% 14% CV death 5.5% 5.1% 7% * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  16. Second Primary End Point 18.8% 16.5% 14% < 0.001 Refractory Ischemia 9.3% 8.7% 7% NS** Refractory Ischemiain hospital 2.0% 1.4% 32% P < 0.001 Refractory Ischemia after discharge 7.6% 7.6% 1% NS** Severe Ischemia 3.8% 2.8% 26% P = 0.003 Recurrent Ischemia 22.9% 20.9% 9% P = 0.01 Heart Failure†4.4% 3.7% 18% P = 0.03 Main Efficacy Results - Second Primary End Point End Point Placebo + ASA* Clopidogrel + ASA* RRR P value * In combination with standard therapy** Not significant† Heart failure was a secondary end point The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  17. Beneficial Outcomes with Clopidogrel in Various Subgroups Percentage of Patients with Event No. ofPatients Placebo + ASA* Clopidogrel + ASA* Characteristic Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7 £65 yr old 6354 5.4 7.6 > 65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 0.4 0.6 0.8 1.0 1.2 Clopidogrel Better Placebo Better * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. Relative Risk (95% CI)

  18. Thrombolytics 2.0% 1.1% 43% 0.43-0.76 < 0.001 IV GP IIb/IIIa Inhib 7.2% 5.9% 18% 0.72-0.93 0.003 Thrombolytic and IV GP IIb/IIIa Inhibitor Use After Randomization Placebo + ASA*N = 6303 Clopidogrel + ASA*N = 6259 Relative RiskReduction CI P value * As part of standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  19. Definition of Bleeding • Bleeding was defined as “Major” and “Minor” • Major bleeding was defined as follows: • life threatening: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, significant hypotention requiring IV inotropes, requiring surgical intervention, or requiring transfusion of 4 or more units of blood • non-life-threatening: substantially disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of blood • Minor • any other bleeds that led to interruption of study medication The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  20. Major bleeding 2.7% 3.7%** Life-threatening bleeding 1.8% 2.2% † Non-life-threatening bleeding 0.9% 1.5% ‡ Minor bleeding 2.4% 5.1% § Bleeding Results Placebo + ASA*N = 6303 Clopidogrel + ASA*N = 6259 End Point * In combination with standard therapy ** P = 0.001; †P = NS; ‡P= 0.002; § P < 0.001. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  21. Life-Threatening 1.8 2.2 Fatal 0.2 0.2 5 g/dL drop hemoglobin 0.9 0.9 Hypotension-inotropic therapy 0.5 0.5 Surgery required 0.7 0.7 Hemorrhagic stroke 0.1 0.1 4 Blood units 1.0 1.2 Life-Threatening Bleeding Placebo + ASA*N = 6303 (%) Clopidogrel + ASA*N = 6259 (%) * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  22. CURE: 12562 1.5% 2.0% +0.5% IV GP IIb/ IIIa Trials: PRISM-PLUS 1915 0.8% 1.4% +0.6% PURSUIT 9375 9.1% 10.6% +1.5% excluding CABG 1.3% 3.0% +1.7% CAPTURE 1265 1.9% 3.8% +1.9% Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: within 30 Days Trial N Placebo* Active* Diff The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. * In addition to standard therapy including aspirin and heparin PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-97.PURSUIT Investigators. N Engl J Med. 1998;339:436-43.CAPTURE Investigators. Lancet. 1997;349 (9063):1429-1435.

  23. Conclusions • In the CURE study of 12,562 patients with ACS without ST-segment elevation: • clopidogrel demonstrated a 20% relative risk reduction in MI, stroke or cardiovascular death with long-term use† (P <0.001) • the Kaplan-Meier curves began to diverge within hours and continued to diverge over the course of 12 months • clopidogrel also demonstrated a 14% relative risk reduction in MI, stroke, cardiovascular death or refractory ischemia (P <0.001) • Clopidogrel in addition to aspirin and other standard therapy demonstrated an early effect (within hours) and sustained long-term benefit throughout the entire study period of 12 months The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. † Up to 12 months

  24. Conclusions • Minor bleeding was increased, but there was no increase in life-threatening bleeds (including intracranial bleeds) • 18% Relative Risk Reduction in heart failure (P = 0.03) • Significant reductions in the reported use of: • IV GP IIb/IIIa inhibitor: 18% (P = 0.003) • thrombolytics: 43% (P < 0.001) The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  25. PCI-CURE Design • Prospectively designed study of patients undergoing PCI who were randomized to double-blind therapy with clopidogrel or placebo, both in addition to aspirin and other standard therapy in the CURE trial • Objectives • to test the hypothesis that pre-treatment with clopidogrel in addition to aspirin and other standard therapy would be more effective than aspirin and standard therapy alone in preventing major ischemic events within the first 30 days after PCI • to determine if long-term treatment (up to 1 year) with clopidogrel in addition to aspirin and other standard therapy after PCI would provide additional clinical benefit Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  26. PCI-CURE Study Design • Patients randomized to clopidogrel or placebo at CURE trial entry, both in addition to aspirin and standard therapy • All patients undergoing PCI during the course of the CURE trial were included in PCI-CURE • Timing of PCI was at the physician’s discretion • At time of PCI, study drug was interrupted and open-label therapy was initiated for 2-4 weeks • During open-label therapy, thienopyridines in combination with ASA was permitted • Follow-up ranged from 3-12 months Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  27. PCI-CURE Study Design CURE PCI-CURE N = 2,658 patients undergoing PCI Pretreatment Open-label thienopyridine PLACEBO + ASA * N = 1345 End of follow-up Up to 12 months after randomization PCI 30 days post PCI R Open-label thienopyridine CLOPIDOGREL + ASA * N = 1313 Pretreatment * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  28. PCI-CURE End Points • Composite of the following within 30 days of PCI: • myocardial infarction • urgent target-vessel revascularization • cardiovascular death • Composite of the following from PCI to end of follow-up: • myocardial infarction • cardiovascular death Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  29. PCI-CURE Baseline Characteristics • Placebo Clopidogrel + ASA* + ASA* (N = 1345) (N = 1313) • Age (mean, years) 61.4 61.6 • Male (%) 69.9 69.7 • Diabetes (%) 19.0 19.0 • Previous MI (%) 26.0 27.3 • Prior PCI (%) 13.8 13.4 • Prior CABG (%) 13.0 12.0 • ST-segment depression (%) 42.4 43.2 • ST-segment elevation (%) 4.4 5.1 * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  30. PCI-CURE Interventional Characteristics • Placebo Clopidogrel + ASA* + ASA* (N = 1345) (N = 1313) • Overall median days afterrandomization on which PCI was done 10 10 PCI during initial hospitalization 6 6 PCI after initial hospitalization 49 49 • Stent use (%) 81.3 82.4 • Use of open-label thienopyridine Before PCI (%) 24.7 26.4 Overall (%) 84.1 82.9 * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  31. From PCI to 30 days MI, urgent revascularization or CV death 6.4% 4.5% 30% 0.03 From PCI to follow-up CV death or MI 8.0% 6.0% 25% 0.047 • PCI-CURE Efficacy Outcomes Placebo + ASA*N = 1345 Clopidogrel + ASA*N = 1313 RRR P value * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  32. PCI-CURE Overall Long-Term Results Composite of cardiovascular death or MI from randomization to end of follow-up 0.15 12.6% Placebo + ASA* 8.8% 0.10 Clopidogrel + ASA* Cumulative Hazard Rate 0.05 31% RRR P = 0.002N = 2658 0.0 0 100 200 300 400 Days of follow-up * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.

  33. PCI-CURE 30 Day Results Composite of cardiovascular death, MI, or urgent revascularization 0.08 Placebo + ASA* 6.4% 0.06 4.5% Cumulative Hazard Rate 0.04 Clopidogrel+ ASA* 0.02 30% RRR P = 0.03 N = 2658 0.0 0 5 10 15 20 25 30 Days of follow-up * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  34. PCI-CURE Subgroup Analysis Placebo+ ASA* Clopidogrel+ ASA* RR 95% CI Overall 12.6% 8.8% 0.69 0.54-0.87 Stent 11.7% 8.7% 0.73 0.56-0.95 No stent 16.2% 9.4% 0.56 0.34-0.95 Age £ 65 9.8% 5.9% 0.59 0.41-0.84 Age > 65 16.9% 13.4% 0.79 0.57-1.08 Male 11.9% 7.9% 0.65 0.48-0.87 Female 14.1% 11.0% 0.77 0.52-1.15 Diabetes 16.5% 12.9% 0.77 0.48-1.22 No diabetes 11.7% 7.9% 0.66 0.50-0.87 During initial hosp 12.0% 8.3% 0.68 0.50-0.92 After initial hosp 13.8% 9.8% 0.70 0.48-1.02 0.1 1.0 10.0 Clopidogrel Better Placebo Better * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41. Relative Risk (95% CI)

  35. IV GP IIb/ IIIa use 26.6% 20.9% 21% 0.001 Secondrevascularization 17.1% 14.2% 18% 0.049 • PCI-CURE Other Outcomes Placebo + ASA*N = 1345 Clopidogrel + ASA*N = 1313 RRR P value * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  36. From PCI to 30 days Major 1.4% 1.6% † Life threatening 0.7% 0.7% † Minor 0.7% 1.0% † From PCI to end of follow-up Major 2.5% 2.7% † Life threatening 1.3% 1.2% † Minor 2.1% 3.5% ‡ • PCI-CURE Bleeding Outcomes Placebo + ASA* Clopidogrel + ASA* * In combination with standard therapy †P = NS, ‡P = 0.03 Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  37. PCI-CURE Conclusions • For the composite of MI or cardiovascular death in the 2658 patients who underwent PCI in the CURE trial: • clopidogrel plus aspirin* demonstrated a 31% relative risk reduction from randomization to the end of follow-up (P = 0.002) • clopidogrel plus aspirin* demonstrated a 25% relative risk reduction in the composite of MI or cardiovascular death with long-term use† from PCI to end of follow-up (P = 0.04) • clopidogrel in addition to aspirin and other standard therapy provides early beneficial effects and sustained long-term† benefit in ACS patients requiring PCI * In combination with standard therapy † Up to 12 months Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

  38. PCI-CURE Conclusions • Long-term† administration of clopidogrel plus aspirin* resulted in an overall 25% relative risk reduction in MI and CV death from PCI to end of follow-up • Pretreatment with clopidogrel plus aspirin* resulted in a 30% relative risk reduction in CV death, MI and target vessel revascularization in 30 days post PCI • There was an increase in minor bleeding, but was no significant difference in major or life-threatening bleeding between the two treatment groups † Up to 12 months * In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

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