1. Safety and Efficacy of Switching from Either UFH or Enoxaparin Plus a GP IIb/IIIa Inhibitor to Bivalirudin Monotherapy in Patients with Non-ST Elevation ACS Managed with an Invasive Strategy: Results from the Randomized ACUITY Trial Harvey D. White on behalf of the ACUITY investigators Harvey D. White on behalf of the ACUITY investigators

2. Disclosures  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. Moderate- high risk ACS ACUITY Study Design Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* *Stratified by pre-angiography thienopyridine use or administration Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Medical management PCI CABG

4. Primary Endpoints  Net Clinical Outcomes  Death, MI, unplanned revascularization for ischemia or non- CABG major bleeding  Composite Ischemia  Death, MI or unplanned revascularization for ischemia  Major Bleeding (Non-CABG)  Intracranial, intraocular, or retroperitoneal bleeding  Access site bleed requiring intervention/surgery  Hematoma ≥5 cm  Hgb  ≥4g/dL w/o overt source  Hgb  ≥3g/dL with an overt source  Reoperation for bleeding  Any blood transfusion  Net Clinical Outcomes  Death, MI, unplanned revascularization for ischemia or non- CABG major bleeding  Composite Ischemia  Death, MI or unplanned revascularization for ischemia  Major Bleeding (Non-CABG)  Intracranial, intraocular, or retroperitoneal bleeding  Access site bleed requiring intervention/surgery  Hematoma ≥5 cm  Hgb  ≥4g/dL w/o overt source  Hgb  ≥3g/dL with an overt source  Reoperation for bleeding  Any blood transfusion ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

5. ACUITY: Primary results – 30 days UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.01 P Sup = 0.32 P NI <0.001 P Sup <0.001 Stone GW et al. NEJM 2006;355:2203-16

6. 0306090120150180210240270300330360390 0 5 15 25 Ischemic Composite (%) Days from Randomization 10 20 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 30 day 7.4% 0.36 7.8% 0.34 7.9% — Estimate P (log rank) 16.3% 0.38 16.5% 0.31 16.4% 1 year — p=0.55 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 (0.95-1.17) Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 (0.94-1.16) Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Stone GW. ACC 2007 presentation

7. 0306090120150180210240270300330360390 0 4 5 Mortality (%) Days from Randomization 2 1 Mortality: 524 total deaths at 1-year UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 1.4% 0.53 1.6% 0.39 1.6% — Estimate P (log rank) 4.4% 0.93 4.2% 0.66 3.8% 1 year — p=0.90 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) 30 day 3 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) Stone GW. ACC 2007 presentation

8. Background and Objectives of the Current Analysis  Background  In prior studies, post-randomization crossover from UFH to enoxaparin or vice versa was associated with increased adverse events  In ACUITY, switching at randomization from prior UFH/enoxaparin to bivalirudin monotherapy was associated with significantly improved bleeding while preserving a similar rate of ischemia  Objective  Evaluate the effects of switching from pre- randomization UFH/Enox + GPI to bivalirudin monotherapy at randomization on 30-day and 1-year outcomes  Background  In prior studies, post-randomization crossover from UFH to enoxaparin or vice versa was associated with increased adverse events  In ACUITY, switching at randomization from prior UFH/enoxaparin to bivalirudin monotherapy was associated with significantly improved bleeding while preserving a similar rate of ischemia  Objective  Evaluate the effects of switching from pre- randomization UFH/Enox + GPI to bivalirudin monotherapy at randomization on 30-day and 1-year outcomes

9. ACUITY Overall: Switch from Prior Antithrombin Switch to Bivalirudin better Consistent UFH/Enox + IIb/IIIa better Consistent UFH/Enox + IIb/IIIa better Overall (N=4215) Composite ischemia 0.93 (0.75-1.16) Major bleeding0.49 (0.36-0.66) Overall (N=4215) Mortality0.75 (0.54-1.04) Switch to Bivalirudin better RR (95% CI)HR (95% CI) Risk Ratio ±95% CI Hazard Ratio ±95% CI 30 day Results1 year Results

10. ACUITY PCI: Switch from Prior Antithrombin Risk Ratio ±95% CI Hazard Ratio ±95% CI 30 day Results1 year Results PCI (n=2528) Composite ischemia 1.10 (0.85-1.42) Major bleeding0.52 (0.36-0.74) PCI HIGH RISK* (n=1988) Composite ischemia 1.14 (0.86-1.52) Major bleeding0.56 (0.38-0.81) PCI (n=2528) Mortality0.93 (0.58-1.48) PCI HIGH RISK* (n=1988) Mortality0.99 (0.60-1.63) * High risk = ↑Tn, CKMB or ECG Δ’sWhite HD, ESC 2007. Switch to Bivalirudin better Consistent UFH/Enox + IIb/IIIa better Consistent UFH/Enox + IIb/IIIa better Switch to Bivalirudin better RR (95% CI)HR (95% CI)

11. Study Population – Current Analysis Received UFH/Enox + GPI prior to Randomization N=371 Randomized to UFH/Enox + GPI (consistent therapy) N=207 Randomized to bivalirudin monotherapy (switched therapy) N=164

12. Baseline Characteristics Consistent UFH/Enox + GPI (N=207) Switch to Bivalirudin Monotherapy (N=164) P-value Age (median [range])62 (33-83)61 (31-88)0.74 Age ≥75 years, %14.012.80.74 Female, %26.622.00.30 Diabetes, %25.625.50.98 Current Smoker, %35.038.70.46 Prior MI, %30.226.70.46 Prior PCI, %33.530.10.48 Prior CABG, %18.815.30.38 Family History CAD, %57.549.30.14 Anemia, %19.520.00.91 Hypertension, %63.860.40.50 Hyperlipidemia, %53.048.80.43

13. Consistent UFH/Enox + GPI (N=207) Switch to Bivalirudin Monotherapy (N=164) P-value CKMB/Troponin or ST-segment Deviation, % 87.790.10.49 CKMB/Troponin Elevation, % 79.681.50.65 ST-segment deviation, %42.037.20.35 Prior Thienopyridine exposure*, % 60.960.40.92 Baseline Characteristics *Prior to angiography or PCI

14. 30-Day Outcomes 30 Day Events (%)

15. 30-Day Composite Ischemia Outcomes 30 Day Events (%)

16. 1-Year Outcomes

17. Study Limitations  Small, post-hoc analysis

18. Conclusions  In a small post-hoc analysis, switching from UFH/enoxaparin + a GP IIb/IIIa inhibitor to bivalirudin monotherapy was safe and effective, with an approximate 50% reduction in major bleeding and comparable ischemic events  Results of this analysis are consistent with overall ACUITY findings  In a small post-hoc analysis, switching from UFH/enoxaparin + a GP IIb/IIIa inhibitor to bivalirudin monotherapy was safe and effective, with an approximate 50% reduction in major bleeding and comparable ischemic events  Results of this analysis are consistent with overall ACUITY findings