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Dr Jonathan Day Medical Affairs Manager

Thrombin Specific Anticoagulation Minimising Bleeding Complications in PCI. Dr Jonathan Day Medical Affairs Manager Nycomed UK Ltd., The Magdalen Centre, Oxford Science Park, Oxford, OX4 4GA. Speaking on behalf of Nycomed UK. Platelet aggregation. Platelet activation. ADP. Collagen.

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Dr Jonathan Day Medical Affairs Manager

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  1. Thrombin Specific Anticoagulation Minimising Bleeding Complications in PCI Dr Jonathan Day Medical Affairs Manager Nycomed UK Ltd., The Magdalen Centre, Oxford Science Park, Oxford, OX4 4GA

  2. Speaking on behalf of Nycomed UK

  3. Plateletaggregation Plateletactivation ADP Collagen TXA2 Fibrinogen Fibrin Thrombin THROMBUS PlasmaClottingProcess TissueFactor Prothrombin Thrombin generation in PCI Plaque rupture activates coagulation generating thrombin Forms critical link between: coagulation, inflammation and platelet activation. Coagulation Amplification • Thrombin mediates coagulation • Thrombin amplifies its own generation • Thrombin is the most potent platelet agonist

  4. Thrombin: effects beyond coagulation mediated via PARs • PAR1: A Thrombin Receptor - Sensitive to low [Thrombin] Cell membrane • Pro-thrombotic • Pro-inflammatory • Cell division SR Coughlin, Nature 2000; 407: 258-264 AJ Leger et al. Circulation 2006;113;1244-1254

  5. Thrombin antagonism with bivalirudin • Bivalirudin is a direct and reversible thrombin-specific anticoagulant1-3 • Inhibits clot-bound and circulating thrombin • Inhibits thrombin-mediated platelet activation / aggregation via PAR1 1-3 • Exhibits a linear and predictable dose-response profile4 • no routine ACT monitoring required3 • Bivalirudin has a short, 25-min half-life5 • coagulation times return to normal 1-2 h after treatment cessation6 1Di Nisio M et al. N Engl J Med 2005;353:1028-1040; 2Maraganore JM et al. Biochemistry 1990;29:7095-7101; 3Reed MD, Bell D. Pharmacotherapy 2002;22:105S-111S; 4Kaplan KL. Expert Opin Pharmacother 2003;4:653-666; 5Fox I et al. Thromb Haemost 1993;69:157-163; 6Veale JJ et al. J Extra Corpor Technol 2005;37:296-302.

  6. Ischaemic protection • Bivalirudin inhibits thrombin and thrombin-mediated platelet activation delivering ischaemic protection1,2 • Bivalirudin provides equivalent ischaemic protection to UFH/LMWH plus GP IIb/IIIa inhibitors3,4 REPLACE-2: ischaemic events (n=6002)3 ACUITY (PCI population): ischaemic events (n=7789)4 UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NS, not significant 1. Maraganore JM et al. Biochemistry 1990; 29: 7095-7101. 2. Becker R et al. J Invasive Cardiol 2003; (Suppl 1): 1-15. 3. Lincoff AM et al. JAMA 2003; 289: 853-863. 4. Stone GW et al. AHA abstract 2006.

  7. Bleeding reduction • The short infusion time, short half-life and reversibility of Bivalirudin reduces the risk of bleeding1,2 • Bivalirudin significantly reduces bleeding events compared with UFH/LMWH plus GP IIb/IIIa inhibitors3,4 REPLACE-2: major bleeding (n=6002)3 REPLACE-2: minorbleeding (n=6002)3 ACUITY (PCI population):major bleeding (n=7789)4 ACUITY (PCI population):minor bleeding (n=7789)4 UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NS, not significant 1. Reed MD, Bell D. Pharmacotherapy 2002; 22: 105S-111S. 2. Maraganore JM et al. Biochemistry 1990; 29: 7095-7101. 3. Lincoff AM et al. JAMA 2003; 289: 853-863. 4. Stone GW et al. AHA abstract 2006.

  8. Major bleeding has a considerable clinical impact • Major bleeding associated with: Increased in-hospital mortality 3-5 Increased long-term mortality 3-5 Increased ischaemic complications – MI and CVA 4 • Bleeding results in higher costs 6 • Transfusions independently linked to poor prognosis and mortality7 • Subgroups at higher bleeding risk include3-5,8: Diabetes Elderly patients Female patients Renal impairment 3Kinnaird TD et al. Am J Cardiol 2003;92:930-935; 4Eikelboom JW et al. Circulation 2006;114:774-782; 5Moscucci M et al. Eur Heart J 2003;24:1815-1823; 6Milkovich G, Gibson G. Am J Health Syst Pharm 2003;60(Suppl 3):S15-S21; 7Rao SV et al. JAMA 2004;292:1555-1562; 8 Stone GW. J Invasive Cardiol 2004;16(Suppl G):12-17.

  9. Patients with diabetes have a higher incidence of bleeding in ACUITY Patient major bleeding events at 30 days (%) Patients with diabetes (n=3852 [all patients]; n=2137 [PCI]) Patients without diabetes (n=9857 [all patients]; n=5604 [PCI]) p<0.001 p<0.001 7.5 5.7 5.3 4.2 All patients Patients undergoing PCI • Major bleeding was significantly higher in patients with diabetes compared to those without in the total population1 and in patients undergoing PCI2 1Feit F et al. AHA 2006 abstract; 2Feit F et al. TCT 2006 abstract 30.

  10. Bivalirudin protects patients with diabetes undergoing PCI in ACUITY Patient events at 30 days (%) UFH / LMWH + GP IIb/IIIa inhibitors (n=703) p=0.NS Bivalirudin monotherapy (n=715) p<0.001 9.5 8.3 8.5 4.6 Ischaemic composite Major bleeding • Angiox monotherapy provides dual ischaemic and bleeding protection in ACS patients with diabetes undergoing PCI Feit F et al. TCT 2006 abstract 30.

  11. UFH / LMWH + GP IIb/IIIa inhibitors (n=4603) Bivalirudin monotherapy (n=4612) Bleeding risk increases with age in ACUITY Patient major bleeding events at 30 days (%) 10.1 p<0.0001 in both arms 6.4 5.8 4.6 3.6 3.2 2.2 1.6 <55 55-65 65-75 >75 Age • Significant increase in major bleeding with age Ohman EM et al. AHA 2006 abstract.

  12. Bivalirudin protects elderly ACS patients undergoing PCI Patient events at 30 days (%) UFH / LMWH + GP IIb/IIIa inhibitors (n=455) Bivalirudin monotherapy (n=442) p<0.001 p=0.NS 12.3 12.2 11.0 6.1 Ischaemic composite Major bleeding • Angiox monotherapy provides ischaemic protection with significantly lower major bleeding in ACS patients >75 yrs undergoing PCI compared with heparin + GP IIb/IIIa inhibitors Alexander KP et al. TCT 2006 abstract 37.

  13. And this translates into a significant difference in 1-year mortality among elderly patients (>75 years) 1 year mortality (REPLACE-2) – age >75 years 6.9% P=0.04 3.6% Time from randomization (days) 1-year mortality Heparin + GPIIb/IIIa (N=407) Bivalirudin (N=388) Lincoff AM et al. JAMA. 2004;292:696-703. Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17. Data on file, The Medicines Company.

  14. Major bleeding linked to worse patient prognosis in ACUITY Patient events at 30 days (%) Major bleeding (n=462)No major bleeding (n=7327) p<0.0001 24.2 p<0.001 17.1 p<0.0001 p<0.0001 9.3 7.8 5.4 5.5 0.8 3.0 Ischaemic composite Death MI Unplanned revascularisation for ischaemia • Major bleeding is a predictor of mortality and ischaemic complications1-3 1Manoukian SV et al. TCT 2006 abstract 94; 2Eikelboom JW et al. Circulation 2006;114:774-782; 3Kinnaird TD et al. Am J Cardiol 2003;92:930-935.

  15. Bivalirudin – a solution to a long-term problem • Predictable control due to its unique MoA and short half-life1-5 - Protection against ischaemic events6 - Significantly reduces bleeding events in all patient subgroups6 • Bivalirudin particularly benefits patients at high bleeding risk6 - Diabetics - The Elderly 1Di Nisio M et al. N Engl J Med 2005;353:1028-1040; 2Maraganore JM et al. Biochemistry 1990;29:7095-7101; 3Reed MD, Bell D. Pharmacotherapy 2002;22:105S-111S; 4Fox I et al. Thromb Haemost 1993;69:157-163; 5Kaplan KL. Expert Opin Pharmacother 2003;4:653-666; 6Stone GW et al. N Engl J Med 2006.

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