Angiomax® (bivalirudin) Inhibits Clot-Bound Thrombin The heparin-AT complex “bounces” off and is not effective against clot-bound thrombin. This reservoir of active thrombin continues to activate platelets and trigger further clotting. Angiomax, has a high affinity for and “sticks” to thrombin, which displaces thrombin from fibrin. Angiomax effectively inhibits both clot-bound and circulating thrombin. Key Message: Angiomax inhibits both circulating and clot-bound thrombin, therefore limiting the explosive burst of thrombin generation. The heparin-AT complex is not effective against clot-bound thrombin. The left panel shows a reservoir of active thrombin that continues to activate platelets and trigger further clotting. The right panel shows that Angiomax, with a high affinity for thrombin, displaces thrombin from fibrin. It demonstrates that Angiomax effectively inhibits clot-bound and circulating thrombin. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. Weitz JI et al. Thromb Res. 2002;106:V275-V284. CM Gibson 2006

Heparin Fails to Effectively Inhibit Clot-Bound Thrombin Clinical levels of UFH inhibit only 20% to 60% of clot-bound thrombin 50 100 0.1 0.2 0.4 1.0 2.0 3.0 4.0 Soluble thrombin Clot-bound thrombin Inhibition (%) Key Message: Heparin, at therapeutic levels, fails to effectively inhibit clot-bound thrombin. Although heparin is the most widely used anticoagulant in PCI, it has many limitations resulting from its mechanism of action. This graph shows the relative ability of heparin to inhibit clot-bound thrombin at concentrations expected in the cath lab (about 1.0 U/mL). A heparin concentration of 0.4 U/mL corresponds approximately with a 5,000-unit bolus and a 1.0 U/mL concentration corresponds with a 10,000-unit bolus. Clot-bound thrombin is an important source of clot extension and propagation of thrombin production. Heparin is not able to effectively inhibit platelet-associated factor Xa as well. Heparin concentration (units/mL) Reproduced with permission of Weitz JI et al. J Clin Invest. 1990;86:388.

Angiomax® (bivalirudin) Inhibits Clot-Bound and Circulating Thrombin Mean % inhibition of fibrinopeptide A production by Angiomax 87% 100% 96% 0% 20% 40% 60% 80% 0.5 M 1.0 M Key Message: Angiomax inhibits both circulating and clot-bound thrombin. Angiomax inhibits fibrinopeptide A – a marker of thrombin activity – for both soluble and clot-bound thrombin. Soluble thrombin Clot-bound thrombin Data on file, The Medicines Company.