1. Bivalirudin: Myths vs Reality? Dr Reman McDonagh Nycomed UK Ltd Conflict of Interest: Senior Manager working for Nycomed UK Ltd

2. Bivalirudin in PCI: An Overview A direct, specific and reversible inhibitor of thrombin that inhibits both circulating and clot-bound thrombin Short half life and predictable dose response Simple dosage regimen & no routine monitoring Acute ischaemic events and long-term clinical outcomes comparable with that of heparin plus planned GP IIb/IIIa blockade but associated with significantly less bleeding Early 2-hour based sheath removal and ambulation Potential cost savings

3. Myths Bivalirudin has no data versus heparin + GPI in: –Platelet inhibition –Diabetics –Unstable angina/ACS –Complex anatomy –AMI Bleeding is not an important factor to consider in PCI

4. 110% 90 70 50 30 10 0.010.11101001000 Angiox concentration (μg/mL) Thrombin Therapeutic plasma level range Thrombin is the most potent platelet agonist known Platelet inhibition occurs well below therapeutic levels of Angiox Angiox Inhibits Platelets via Thrombin Aggregation in response to thrombin (%) Adapted from Weitz J et al. Am J Cardiol. 2001;88(suppl 1):83G.

5. SEM=scanning electron micrograph. *All SEMs were acquired at a magnification of 4000X with the investigator blinded to treatment. Control plateletsPlatelets treated with Angiox Platelets treated with UFH Angiox: No Direct Platelet Activation Direct platelet activation by UFH but not Angiox* Data on file, The Medicines Company.

6. *Unstable angina at any time, within preceding 48 hours or before. † Acute coronary syndromes defined as unstable angina within preceding 48 hours or MI within prior 7 days. n=1,330 n=2,533 One-Year Mortality in High Risk Subgroups Cumulative mortality at 1 year 0% 2% 4% 6% 8% CrCL≤60 n=1010 6.8% 4.1% Age>75 n=795 6.9% 3.6% Age>65 4.3% 2.9% Diabetes 3.9% 2.3% UA* 3.0% 1.4% UA* or ACS † 2.6% 1.5% ACS † 1.8% 1.5% Heparin + GPI Angiox n=2,489 n=1,606 n=2,046 Lincoff AM et al. JAMA. 2003;289:853-863. Lincoff AM et al. JAMA. 2004;292:696-703. Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17.

7. Mortality through 1-year Gurm, et al JACC 2005 ; 45:1932– 8 Data on file, The Medicines Company Follow-up in days Survival after PCI Diabetic patients, based on randomization arm 2.7% 2.2% Cumulative Percentage of Events Time from randomization in days (N=418) (N=454) P=0.67 ► Subgroup: Diabetes = Yes ► Eptifibatide stratum 5.3% 2.4% Cumulative Percentage of Events Time from randomization in days P=0.04 (N=364) (N=384) ► Subgroup: Diabetes = Yes ► Abciximab stratum Event is defined as the first time occurrence within the period. P-values are based on Log-rank test.

8. Bleeding outcomes p = 0.76p = 0.69p = <0.001 Non DM N=4368 H+GPI Bival N=784 N=840 DM N=1624 ITT population Diabetic pop H+GPI Bival N=784 N=840 Gurm, et al JACC 2005 ; 45:1932– 8

9. *Unstable angina at any time, within preceding 48 hours or before. † Acute coronary syndromes defined as unstable angina within preceding 48 hours or MI within prior 7 days. n=1,330 n=2,533 One-Year Mortality in High Risk Subgroups Cumulative mortality at 1 year 0% 2% 4% 6% 8% CrCL≤60 n= 1010.8% 4.1% Age>75 n=795 6.9% 3.6% Age>65 4.3% 2.9% Diabetes 3.9% 2.3% UA* 3.0% 1.4% UA* or ACS † 2.6% 1.5% ACS † 1.8% 1.5% Heparin + GPI Angiox n=2,489 n=1,606n=2,046 Lincoff AM et al. JAMA. 2003;289:853-863. Lincoff AM et al. JAMA. 2004;292:696-703. Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17. 6

10. p = 0.016p = 0.049p = 0.701 Cumulative deaths at 12 months RR  53% RR  35% RR  17% One-year Mortality in Pre-specified ACS Subgroups Lincoff AM et al. JAMA. 2004;292:696-703. Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17.

11. Heparin + GPIIb/IIIa (N=1486) Bivalirudin (N=1506) 2.7% 1.9% Subgroup: Lesion score B2/C P=0.15 Time from randomization in days Cumulative Percentage of Events Event is defined as the first time occurrence within the period. P-values are based on Log-rank test. One-year Mortality in Patients with High risk lesions Data on file, The Medicines Company

12. –Single arm, open label, 13 U.S. centers –Patients with STEMI Less than 12 hours duration No prior thrombolytic therapy Primary PCI required –Patient population matched to CADILLAC Stella F. Presented Oct 20, 2005 TCT

13. Clinical Outcomes, BIAMI (N=201) 30 Days, % Death Reinfarction Disabling stroke* Ischemic TLR COMPOSITE 2.0 0.5 1.0 1.5 3.6 Subacute thrombosis1.0 Blood product transfusion2.0 Intracranial hemorrhage0.0 Thrombocytopenia1.5 * 2 Strokes Post CABG Stella F. Presented Oct 20, 2005 TCT

14. Clinical Outcomes, Comparison to CADILLAC BIAMI (N=201) Abciximab/Stent (N=524) 30 Days, % Death Reinfarction Disabling stroke* Ischemic TLR COMPOSITE 2.0 0.5 1.0 1.5 3.6 2.7 0.8 0.2 1.6 4.4 Subacute thrombosis1.00.0 Blood product transfusion2.05.0 Intracranial hemorrhage0.00.2 Thrombocytopenia1.54.0 * 2 Strokes Post CABG Stella F. Presented Oct 20, 2005 TCT

15. PCI is Associated With Bleeding* Almost 1 in 5 PCI patients experience clinically significant bleed Retrospective analysis of 10,974 “real world” patients at 3 centers –TIMI major 588 (5.4%) Hemorrhagic strokes 15 Retroperitoneal 30 Gastrointestinal63 Hematoma370 –TIMI minor1,394 (12.7%) Gastrointestinal 88 Retroperitoneal 11 Hematoma 823 –Transfusion(5.4%) –None8,992 (81.9%) Kinnaird TD et al. Am J Cardiol. 2003;92:930-935. *Bleeding includes both TIMI major and TIMI minor bleeding.

16. PCI-Associated Bleeding Increases the Risk of Death Kinnaird TD et al. Am J Cardiol. 2003;92:930-935. *P<0.001 vs no bleeding. † P<0.001 vs minor bleeding. * † *

17.  -41% P<0.001 Angiox Provides Significant Reductions in Bleeding Events Significant reductions in every parameter *Data on file, The Medicines Company. Lincoff AM et al. JAMA. 2003;289:853-863.  -32% P=0.02  -68% P<0.001  -66% P<0.001  -59% P<0.001 Protocol Major Any Transfusion Access Site Retroperitoneal + Organs* Thrombocytopenia

18. Myths Bivalirudin has no data versus heparin + GPI in: –Platelet inhibition –Diabetics –Unstable angina/ACS –Complex anatomy –AMI Bleeding is not an important factor to consider in PCI

19. Myths Reality Bivalirudin has no data versus heparin + GPI in: √Platelet inhibition √Diabetics √Unstable angina/ACS √Complex anatomy √AMI Bleeding is not an important factor to consider in PCI