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Dr Jonathan Day Senior Director Global Medical The Medicines Company

Bivalirudin Advancing Anticoagulation in ACS . Dr Jonathan Day Senior Director Global Medical The Medicines Company . MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee) . ANGIOX ® (bivalirudin) indication.

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Dr Jonathan Day Senior Director Global Medical The Medicines Company

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  1. Bivalirudin Advancing Anticoagulation in ACS Dr Jonathan Day Senior Director Global Medical The Medicines Company

  2. MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee)

  3. ANGIOX® (bivalirudin) indication • Bivalirudin is indicated as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) • Bivalirudin is indicated for the treatment of adult patients with acute coronary syndromes (unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention. • Bivalirudin should be administered with aspirin and clopidogrel Please see full Prescribing Information.

  4. Indirect versus direct thrombin inhibition Indirect inhibition by heparin requires the presence of antithrombin, the actual inhibitor.1 ANGIOX inhibits thrombin directly with high affinity and specificity.2 ANGIOX provides effective thrombin inhibition to prevent thrombosis and thrombin-mediated platelet effects.2 2. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Please see full Prescribing Information.

  5. ANGIOX® (bivalirudin) effectively inhibits clot-bound thrombin The heparin-antithrombin complex is not effective against clot-bound thrombin.1 This reservoir of active thrombin continues to activate platelets and trigger further clotting.1 ANGIOX, with a high affinity for thrombin, displaces thrombin from fibrin.2 ANGIOX effectively inhibits clot-bound and circulating thrombin.2 1. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. 2. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Please see full Prescribing Information.

  6. Return to haemostasis—safety advantage When heparin dissociates from cells/proteins, there can be an anticoagulant effect even when it is not needed. This may explain the prolonged bleeding risk after discontinuation of heparin.1 ANGIOX is cleaved by thrombin, allowing thrombin to quickly recover hemostatic activity upon discontinuation of ANGIOX.2 The natural reversibility and the short, 25-minute half-life may explain the significantly lower bleeding rates seen in clinical trials.3 1. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S. 2. ANGIOX Prescribing Information. The Medicines Company; UK Ltd. 2008. Please see full Prescribing Information.

  7. Broad spectrum of experience with bivalirudin in clinical trials 27,735 patients undergoing invasive management of CAD Increasing risk of ischemic complications REPLACE-2 (N=6,002) CAD Planned PCI BAT (N=4,312) UA, NQWMI Planned PTCA ACUITY (N=13,819) NSTE-ACS PCI <72h HORIZONS (N=3,602) STEMI Emergency PCI Lincoff et al JAMA, 2003 Bittl et al AHJ, 2001 Stone et al NEJM, 2006 Stone et al NEJM, 2007

  8. Ischemic protection, less major bleeding and reduced mortality in acute management of CAD 14,407 patients in REPLACE-2, ACUITY and HORIZONS† Bivalirudin alone better Heparin + GP IIb/IIIa better † All patients administered ASA and clopidogrel *includes stroke for HORIZONS patients Data on file: The Medicines Company

  9. Significant reduction in all-cause mortality 14,407 patients in REPLACE-2, ACUITY and HORIZONS† Bivalirudin alone better Heparin + GP IIb/IIIa better † All patients administered ASA and clopidogrel Data on file: The Medicines Company

  10. HORIZONS 30 Day Mortality: Cardiac and Non Cardiac HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 2.9% Death (%) Cardiac 1.8% Non cardiac 0.3% 0.2% Time in Days Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)

  11. 30 Day MACE – GPI Choice In the control arm (53%) received abciximab and (47%) received eptifibatide. In the control arm MACE was independent of GP IIb/IIIa (interaction p-value for MACE = 0.5820).

  12. 30 Day MACE – 300 vs 600mg Clopidogrel 34.6% of patients received 300 mg and 65.2% of patients received 600 mg . Outcomes were independent of the clopidogrel loading dose (interaction p-value = 0.7571).

  13. Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) HORIZONS 1-Year Mortality: Cardiac and Non Cardiac HR [95%CI] = 0.57 [0.38, 0.84] P=0.005 3.8% Δ = 1.7% 2.9% Cardiac Mortality (%) 2.1% Δ = 1.1% P=0.03 Non Cardiac 1.3% 1.1% Time in Months Number at risk Bivalirudin alone 1800 1705 1684 1669 1520 Heparin+GPIIb/IIIa 1802 1678 1663 1646 1486 Mehran R, TCT 2008

  14. HORIZONS 30 Day Mortality: Low Risk Trial?

  15. HORIZONS Subgroup Analysis Major Adverse Cardiovascular Events at 30 Days [ITT Population] Data on file: The Medicines Company

  16. HORIZONS Subgroup Analysis Major Bleeding (non-CABG) at 30 Days [ITT Population] Data on file: The Medicines Company

  17. HORIZONS Subgroup Analysis Death at 30 Days [ITT Population] Data on file: The Medicines Company

  18. HORIZONS 30 Day Bleeding Endpoints *Primary endpoint; **Life threatening ## Intracranial bleeding, Intraocular, GI, GU, Pleural, Pulmonary, Head and Neck,Epistaxis, Haemoptysis, Haematemesis, Gingival, Malaena Data on file: The Medicines Company

  19. 30 Day Stent Thrombosis (N=3,124) *Protocol definition of stent thrombosis, CEC adjudicated

  20. Bivalirudin UFH + GP IIb/IIIa 30 Day Stent Thrombosis (N=3,124) 5 4 3 Estimated Event Rate (%) 30 2 23 19 1 4 0 0 0.5 1 5 10 15 20 25 30 Days from Randomisation Patients at Risk

  21. 30 Day Stent Thrombosis – Risk of Subsequent Death Data on file: The Medicines Company Analysis of safety population in all patients receiving stents

  22. Conclusions • In HORIZONS-AMI the significant reductions in cardiac-related death at 30-days and 1-year are important. • For every 96 patients with STEMI undergoing primary PCI with bivalirudin compared to conventional therapies one cardiac related death might be avoided (1 yr: NNT=58). • The important implications of the HORIZONS study are now reflected in the recently updated ESC guidelines for the management of patients with STEMI undergoing primary PCI where bivalirudin received a (Class IIa-B) recommendation [Van De Werf et al., 2008]. • In conclusion, the favourable risk–benefit profile of bivalirudin, make it clinically important alternative to current treatments for the contemporary management of ACS patients undergoing PCI.

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