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Dr. Harvey White on behalf of the ACUITY investigators

ACUITY PCI A Prospective Trial of Patients with ACS Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors.

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Dr. Harvey White on behalf of the ACUITY investigators

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  1. ACUITY PCI A Prospective Trial of Patients with ACS Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors Dr. Harvey White on behalf of the ACUITY investigators

  2. Disclosure Harvey D. White • Research Grants: • Alexion, Fournier Laboratories, Sanofi Aventis, Johnson & Johnson, Eli Lilly, Proctor & Gamble, Merck Sharpe & Dohme, Schering Plough, Roche, The Medicines Company, Glaxo Smith Kline, Pfizer, Neuren Pharmaceuticals, NIH • Consultant: • Sanofi Aventis, The Medicines Company

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

  4. Study Design – Second Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy UFH/Enox + GP IIb/IIIa (n=4,603) GP IIb/IIIa upstream (N=2294) GPIIb/IIIa CCL for PCI (N=2309) Moderate and high risk ACS (n=13,819) Bivalirudin + GP IIb/IIIa (n=4,604) GP IIb/IIIa upstream (N=2311) R* GP IIb/IIIa CCL for PCI (N=2293) Bivalirudin Alone (n=4,612) Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration

  5. ACUITY Primary Endpoints Net Clinical Outcome (Composite Ischemia, Non-CABG Major Bleeding) Composite Ischemia: • Death from any cause • Myocardial infarction • During medical Rx: Any biomarker elevation >ULN • Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves • Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves • Unplanned revascularization for ischemia Non-CABG Major Bleeding • Intracranial bleeding or intraocular bleeding • Retroperitoneal bleeding • Access site bleed requiring intervention/surgery • Hematoma ≥5 cm • Hgb  ≥ 3 g/dL with , or  ≥ 4 g/dL without overt source • Blood product transfusion • Reoperation for bleeding

  6. UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone PNI <0.001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PNI <0.001 PSup <0.001 ACUITY: Primary results – 30 days Stone GW et al. NEJM 2006;355:2203-16

  7. Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia) 30 day P (log rank) 1 year P (log rank) Estimate Estimate p=0.55 UFH/Enoxaparin + IIb/IIIa 7.4% — 16.3% — 0.36 0.38 Bivalirudin + IIb/IIIa 7.8% 16.5% 0.34 0.31 Bivalirudin alone 7.9% 16.4% UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 25 20 15 Ischemic Composite (%) 10 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 (0.94-1.16) 5 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 (0.95-1.17) 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007 presentation

  8. Mortality: 524 total deaths at 1-year p=0.90 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone P (log rank) 1 year P (log rank) Estimate Estimate 1.4% — 4.4% — 0.53 0.93 1.6% 4.2% 0.39 0.66 1.6% 3.8% UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 5 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) 4 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) 3 Mortality (%) 2 30 day 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007 presentation

  9. To examine the long-term outcomes of bivalirudin ± GP IIb/IIIa inhibition compared to UFH/Enoxaparin + GP IIb/IIIa inhibition in moderate and high risk ACS patients undergoing PCI Overall primary clinical endpoints at 1 year Outcomes in patients switched to bivalirudin monotherapy from UFH or enoxaparin Analysis of the relative impact of iatrogenic bleeding complications on long-term outcome Goals of the present analysis

  10. UFH/Enox + GP IIb/IIIa N = 2,561 Bivalirudin + GP IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619 Management Strategy (N=13,819) Medical Rx (n=4,491) CABG (n=1,539) 32.5% 11.1% 56.4% PCI (n=7,789)

  11. ACUITY PCI: Baseline Characteristics * creatinine clearance <60 mL/min Stone GW et al. Lancet 2007;369:907-19

  12. ACUITY PCI: Baseline High Risk Features * 84.0% had +biomarkers or baseline ST 97% of all pts had +biomarkers or baseline ST, or were TIMI Int/High risk Stone GW et al. Lancet 2007;369:907-19

  13. UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone P=0.10 P=0.057 P=0.16 P=0.45 P=0.32 <0.0001 ACUITY PCI: Primary results – 30 days Stone GW et al. Lancet 2007;369:907-19

  14. ACUITY PCI: Bleeding – 30 days *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor Stone GW et al. Lancet 2007;369:907-19

  15. ACUITY PCI: Primary Results – 1 Year Hazard Ratio ±95% CI HR (95% CI) Bivalirudin Better UFH/Enox+ IIb/IIIa Better

  16. 30 day Estimate P (log rank) UFH/Enoxaparin + IIb/IIIa 0.9% — Bivalirudin + IIb/IIIa 0.45 1.2% Bivalirudin alone 0.63 1.1% 1 year P (log rank) Estimate 3.1% — 0.70 2.4% 0.48 2.2% ACUITY PCI: Early and Late Mortality UFH/Enox + GP IIb/IIIavs.Bivalirudin + GP IIb/IIIavs.Bivalirudin Alone p=0.78 Mortality (%) Days from Randomization

  17. ACUITY PCI: Influence of 30 day Major Bleeding and MI on Late Mortality Hazard Ratio ±95% CI HR (95% CI) P-Value Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates

  18. ACUITY PCI: Impact of Bleeding on LOS

  19. ACUITY PCI: High Risk* patients 1 year Results 30 day Results Hazard Ratio±95% CI Risk Ratio±95% CI RR (95% CI) HR (95% CI) UFH/Enox+ IIb/IIIa better Bivalirudin better Bivalirudin better UFH/Enox+ IIb/IIIa better * High risk = ↑Tn, CKMB or ECG Δ’s

  20. ACUITY PCI: Impact of clopidogrel Bivalirudin better UFH/Enox + IIb/IIIa better Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

  21. ACUITY PCI: Impact of clopidogrel Bivalirudin better UFH/Enox + IIb/IIIa Better Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

  22. ACUITY PCI: Switch from Prior Antithrombin 30 day Results 1 year Results Risk Ratio±95% CI Hazard Ratio±95% CI RR (95% CI) HR (95% CI) Switch to Bivalirudin better Switch to Bivalirudin better Consistent UFH/Enox + IIb/IIIa better Consistent UFH/Enox + IIb/IIIa better * High risk = ↑Tn, CKMB or ECG Δ’s

  23. ACUITY PCI: Antithrombin Naïve Patients 30 day Results 1 year Results Risk Ratio±95% CI Hazard Ratio±95% CI RR (95% CI) HR (95% CI) UFH/Enox + IIb/IIIa better UFH/Enox + IIb/IIIa better Bivalirudin better Bivalirudin better * High risk = ↑Tn, CKMB or ECG Δ’s

  24. This analysis is of post-randomization outcomes The ACUITY PCI sub-study was under-powered for subgroup comparisons All analyses should be considered hypothesis generating Study Limitations

  25. In patients with moderate and high risk ACS undergoing PCI Bivalirudin alone results in similar 1 year mortality to UFH/enoxaparin plus GP IIb/IIIa inhibition regardless of patient risk, prior antithrombin therapy and clopidogrel exposure Switching from UFH or enoxaparin to bivalirudin enables patients to achieve significant reductions in bleeding at 30 days and similar mortality at 1 year These results substantiate the strong relationship between bleeding complications and late mortality in PCI patients Conclusions and Clinical Implications

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