1. 1 Replace Heparin and Improve Outcomes New Antithrombotic Strategies in ACS Patients Undergoing PCI ANG-PSL-XXX-XXX

2. 2 Overview Thrombin’s critical role Clot burden in the ACS patient Mechanistic rationale for switching patients to ANGIOMAX ® (bivalirudin) for PCI Why is there concern about switching anticoagulants in ACS treatment? –Lessons from SYNERGY Clinical evidence in support of switching to ANGIOMAX ACUITY PCI Subgroup Analysis: 1-Year Mortality Results ACS=acute coronary syndromes; ACUITY=Acute Catheterization and Urgent Intervention Triage strategY; AT=antithrombin; PCI=percutaneous coronary intervention; SYNERGY=Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors.

3. 3 Why ANGIOMAX ® (bivalirudin)? The Critical Role of Thrombin Thrombin is the link between vessel injury, coagulation, and platelet response Vessel Injury Platelet activation Platelet aggregation Fibrinogen Fibrin Thrombin Plasma clotting factors Prothrombin Tissue factor Collagen ADP platelet activation ADP TXA 2 =adenosine diphosphate/thromboxane A2. Coughlin SR. Nature. 2000;407:258-264; Monroe DM et al. Arterioscler Thromb Vasc Biol. 2002;22:1381-1389.

4. 4 Thrombin Promotes Platelet Activation and Clotting Thrombin is the link between tissue injury, coagulation, and platelet response Coughlin SR. Nature. 2000;407:258-264; Monroe DM et al. Arterioscler Thromb Vasc Biol. 2002;22:1381-1389. Platelet activation Platelet Aggregation Fibrinogen Fibrin Thrombin is a critical mediator in hemostasis and thrombosis Thrombin begets thrombin Thrombin is a platelet agonist; elicits multiple responses in platelets Thrombin Plasma clotting factors Prothrombin

5. 5 Indirect inhibition by heparin requires the presence of AT, the actual inhibitor. Indirect Versus Direct Thrombin Inhibition ANGIOMAX ® (bivalirudin) inhibits thrombin directly with high affinity and specificity. ANGIOMAX provides rapid, effective thrombin inhibition to prevent thrombosis and thrombin-mediated platelet effects. AT=antithrombin. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. Weitz JI et al. Thromb Res. 2002;106:V275-V284.

6. 6 Clot Burden in ACS Many ACS patients already have significant clot burden –94% of patients with UA have angioscopic-evident clot –Only 13% of clots are identified by angiography Brummel KE et al. Blood. 2002;100:148-152. White CJ et al. In: Textbook of Interventional Cardiology. 2003:873-891. T=red, globular mass of thrombus (clot); UA=unstable angina; W=guidewire within the lumen. Clot contains activated platelets and active thrombin, which continues to activate and recruit more platelets –96% of thrombin is still being generated after the clot is visible

7. 7 Heparin Fails to Effectively Inhibit Clot-Bound Thrombin Therapeutic levels of UFH inhibit only 20% to 60% of clot-bound thrombin Heparin concentration (units/mL) Inhibition (%) Weitz JI et al. J Clin Invest. 1990;86:388. Reproduced with permission. ©1990 American Society for Clinical Investigation. UFH=unfractionated heparin.

8. 8 Soluble thrombin Clot-bound thrombin 0.5  M ANGIOMAX 1.0  M ANGIOMAX Mean inhibition of fibrinopeptide A production by ANGIOMAX Data on file. The Medicines Company, Parsippany, NJ. ANGIOMAX ® (bivalirudin) Inhibits Clot-Bound and Circulating Thrombin Inhibition (%) ANGIOMAX is 100% effective against clot-bound thrombin

9. 9 Heparin (long strand) binds to other plasma proteins (colored molecules) and platelets, reducing the availability of heparin to bind to AT. Heparin-binding proteins are elevated in ACS. Heparin Binds to Plasma Proteins; ANGIOMAX ® (bivalirudin) Binds Specifically to Thrombin ANGIOMAX (bright blue) binds only to thrombin (orange). ANGIOMAX is not neutralized by other plasma proteins or platelets; it remains fully active near thrombus. ACS=acute coronary syndromes. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Wittkowsky AK. Pharmacotherapy. 2002;22(6 Pt 2):97S-104S.

10. 10 Heparin is neutralized by PF4, which is present in high concentrations near vascular injury. Thrombin continues activating platelets. PF4/heparin complex antibodies activate platelets, causing thrombocytopenia as well as HIT/TS. ANGIOMAX ® (bivalirudin) does not bind to PF4, and remains fully active. There is no risk of HIT/TS or other thrombotic events associated with PF4/heparin antibodies. Consequences of Nonspecific Binding HIT/TS=heparin-induced thrombocytopenia thrombosis syndrome; PF4=platelet factor 4. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Williams RT et al. Circulation. 2003;107:2307-2312.

11. 11 Heparin Increases Platelet Activation Heparin makes platelets more reactive to activation by other agonists such as ADP. Heparin binds to the platelet GP IIb/IIIa receptor. Given the various ways heparin increases platelet activation, its use may actually increase the need for antiplatelet agents. ADP=adenosine diphosphate. Becker R et al. J Invasive Cardiol. 2003;(suppl):1-15. Sobel M et al. J Vasc Surg. 2001;33:587-594. Xiao Z et al. Circulation. 1998;97:251-256.

12. 12 ANGIOMAX ® (bivalirudin): No Platelet Activation *All scanning electron micrographs were acquired at a magnification of 4,000x with the investigator blinded to treatment. Control platelets Direct platelet activation by UFH but not ANGIOMAX* Anand SX et al. Am J Cardiol. 2007;100:417-424. Reproduced with permission. ©2007 Elsevier Health Science Journals. Platelets treated with UFH Platelets treated with ANGIOMAX

13. 13 ANGIOMAX ® (bivalirudin) Inhibits Platelets Via Thrombin Thrombin is the most potent known physiologic platelet agonist Platelet inhibition occurs well below therapeutic levels of ANGIOMAX Adapted from Weitz J et al. Am J Cardiol. 2001;88(5 suppl 1):83G. 110 90 70 50 30 10 0.010.11101001000 Concentration of ANGIOMAX (μg/mL) Thrombin Therapeutic plasma level range Aggregation in response to thrombin (%)

14. 14 Return to Hemostasis—Safety Advantage ANGIOMAX ® (bivalirudin) is cleaved by thrombin, allowing thrombin to quickly recover hemostatic activity upon discontinuation of ANGIOMAX. 2 The natural reversibility and the short, 25-minute half-life may explain the significantly lower bleeding rates seen in clinical trials. 3 When heparin dissociates from cells/proteins, there can be an anticoagulant effect even when it's not needed. This may explain the prolonged bleeding risk after discontinuation of heparin. 1 1. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S. 2. Weitz JI et al. Thromb Res. 2002;106:V275-V284. 3. ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

15. 15 ANGIOMAX ® (bivalirudin) Has Predictable Pharmacology ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005. Robson R. J Invasive Cardiol. 2000;12(suppl F):33F-36F. Data on file. The Medicines Company, Parsippany, NJ. *Modeled data. PCI=percutaneous coronary intervention. Infusion 2.5 mg/kg/hour Estimated (ANGIOMAX) mean (μg/mL) Time from start of bolus of ANGIOMAX (h) Infusion 1.75 mg/kg/hour* Bolus 1 mg/kg Bolus 0.75 mg/kg* 25-minute half-life 1 Plasma level of ANGIOMAX shown to reduce risk of ischemia in PCI 2

16. 16 ANGIOMAX ® (bivalirudin)—Unique Mechanism of Action Overcomes the Limitations of Heparin Direct thrombin inhibitor that is reversible via thrombin yielding a 25-minute half-life –Heparin requires antithrombin to be able to deactivate thrombin Inhibits clot-bound and circulating thrombin –Heparin fails to effectively inhibit clot-bound thrombin Inhibits thrombin-mediated platelet aggregation and does not activate platelets –Heparin activates platelets Provides predictable pharmacology and linear pharmacokinetics –Heparin is unpredictable and has nonlinear pharmacokinetics

17. 17 Switching to ANGIOMAX ® (bivalirudin) for PCI Delivers Improved Outcomes ANG-PSL-484-XXX

18. 18 SYNERGY: Switching Between Heparins SYNERGY overall primary end point results –No difference in the composite of death/MI with enoxaparin compared with UFH –Significant increase in bleeding (TIMI major) with enoxaparin compared with UFH Patients who crossed over after randomization from UFH to enoxaparin or vice versa had –Increased rates of death/MI at 30 days compared with those who did not cross over –More bleeding complications (transfusions) Ferguson JJ et al. JAMA. 2004;292:45-54. MI=myocardial infarction; TIMI=Thrombosis in Myocardial Infarction.

19. 19 SYNERGY: 30-Day Death/MI Patients who crossed over from UFH to enoxaparin or vice versa had increased rates of death/MI within 30 days compared with those on consistent therapy* Death/MI at 30 days (%) n=677n=45n=593n=103 *Postrandomization crossovers. Ferguson JJ et al. JAMA. 2004;292:45-54.

20. 20 SYNERGY: 30-Day Transfusions The rate of transfusion doubled in patients who crossed over from UFH to enoxaparin or vice versa within 30 days compared with those on consistent therapy* Transfusions at 30 days (%) n=724n=72n=671n=179 *Postrandomization crossovers. Ferguson JJ et al. JAMA. 2004;292:45-54.

21. 21 SYNERGY: Switching Between Heparins The SYNERGY trial suggested that changing therapies between UFH and enoxaparin (or vice versa) resulted in an increased risk of bleeding Do these findings apply to ANGIOMAX ® (bivalirudin)? Is it better to switch to ANGIOMAX or stay on consistent heparin therapy?

22. 22 Evidence to Support Switching to ANGIOMAX ® (bivalirudin) BAT analysis (Bittl) –Evaluate switching in era of conservative management –Switching to ANGIOMAX improved ischemic and bleeding outcomes –Improvements more profound in higher risk strata SWITCH study (Waksman) –Impact (safety) of switching, relative to last enoxaparin dose –Switching outcomes consistent with other ANGIOMAX trials REPLACE-2 analysis (Gibson) –Data in patients undergoing PCI –Switching to ANGIOMAX associated with improved bleeding outcomes ACUITY analysis (White) –Data in ACS patients undergoing PCI –Switching to ANGIOMAX yielded improved bleeding outcomes

23. 23 PTCA Stratify Randomize Measure death, MI, revascularization, bleeding in hospital 2 Prespecified analysis: Patients on UFH infusion (n=1,006) 1 Non post-MI (n=765) 2 Post-MI (n=241) 2 Switch to ANGIOMAX ® (bivalirudin) Heparin Switch to ANGIOMAX Heparin UA patients without UFH infusion (n=3,306) 1 1. Henry TD. J Invasive Cardiol. 2002;14(suppl B):19B-29B. 2. Data on file. The Medicines Company, Parsippany, NJ. Overall population: Patients with new onset severe, accelerating or rest angina (N=4,312) 1 PTCA=percutaneous transluminal coronary angiography. Bivalirudin Angioplasty Trial (BAT): Switch BAT

24. 24 BAT: Switch Analysis Among 4,312 patients, there were 1,2 –1,006 patients who had a UFH infusion during the hour prior to randomization and were switched to ANGIOMAX ® (bivalirudin) or continued on UFH –241 in the post-MI patient group (<2 weeks) who received UFH during the hour prior to randomization and were switched to ANGIOMAX or continued on UFH In patients receiving UFH prior to PTCA, infusion was discontinued at least 30 minutes prior to switching 1. Bittl J. Circulation. 2000;102(suppl 2):813. Abstract 3927. 2. Henry TD. J Invasive Cardiol. 2002;14(suppl B):19B-29B. BAT

25. 25 Death/MI/revascularization Heparin ANGIOMAX Heparin ANGIOMAX UA/UFH prior to PTCA & <14 days post-MI 1,2 (n=241) In patients receiving UFH prior to PTCA, infusion was discontinued at least 30 minutes prior to switching. Hemorrhage BAT: Outcomes for ACS Patients With Prior Heparin Patients in prestratified high-risk groups switched to ANGIOMAX ® (bivalirudin) 1. Henry TD. J Invasive Cardiol. 2002;14(suppl B):19B-29B. 2. Data on File. The Medicines Company, Parsippany, NJ. UA/UFH prior to PTCA 1,2 (n=1,006) UA/UFH prior to PTCA non post-MI 2 (n=765) BAT

26. 26 31 30 Primary end point: major bleeding 91 ACS patients undergoing PCI (3 US sites) Open-label, prospective, 3-arm study LMWH 1 mg/kg SC 0-4 h before PCI LMWH 1 mg/kg SC 4-8 h before PCI LMWH 1 mg/kg SC 8-12 h before PCI ANGIOMAX ® (bivalirudin) during PCI 0.75 mg/kg bolus 1.75 mg/kg/h IV infusion Arms switched SWITCH: Study Design Waksman R et al. J Invasive Cardiol. 2006;18:370-375. IV=intravenous; LMWH=low-molecular-weight heparin; SC=subcutaneous.

27. 27 EVENT All (N=91) SWITCH 0-4 h (n=30) SWITCH 4-8 h (n=30) SWITCH 8-12 h (n=31) P value All major bleeding8% (7)13% (4)*3% (1)7% (2)*.39 Transfusion ≥2 units4% (4)3% (1) 7% (2)1.00 Intracranial bleed0000-- Retroperitoneal bleed0000-- Drop in Hg >4 g/dL, no site2% (2)7% (2)00.21 All transfusions4% (4)7% (2)0% (0)7% (2)1.00 Minor bleeding4% (4)7% (2) 0 (0).39 *One patient received postprocedural enoxaparin and/or heparin. Hg=hemoglobin. SWITCH: Bleeding Outcomes in Patients Switched to ANGIOMAX ® (bivalirudin) Reproduced with permission. Waksman R et al. J Invasive Cardiol. 2006;18:370-375. ©2006 The Journal of Invasive Cardiology.

28. 28 SWITCH: Conclusions There were no significant differences in major bleeding between the various enoxaparin pretreatment groups when switched over to ANGIOMAX ® (bivalirudin) for PCI For patients on LMWH, ANGIOMAX can be started 8 hours after the last LMWH dose Waksman R et al. J Invasive Cardiol. 2006;18:370-375.

29. 29 REPLACE-2: SWITCH Analysis The goal of this analysis was to evaluate whether a hazard existed when UFH or LMWH was administered prior to ANGIOMAX ® (bivalirudin) This analysis compared bleeding among patients treated with or without UFH or LMWH in the 48 hours before study treatment Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

30. 30 Randomize Protocol major/minor bleeding, TIMI bleeding, transfusion, mortality ANGIOMAX ® (bivalirudin) 0.75 mg/kg bolus/1.75 mg/kg/h infusion with “provisional” GP IIb/IIIa (n=2,994) 1 Prior UFH (n=287) 2 Naïve – no prior AT (n=2,345) 2 Overall population: Urgent or elective PCI patients (N=6,002) 1 UFH 65 U/kg with planned GP IIb/IIIa (n=3,008) 1 Prior LMWH (n=258) 2 Naïve – no prior AT (n=2,325) 2 Prior UFH (n=349) 2 Prior LMWH (n=313) 2 REPLACE-2: SWITCH Analysis AT=antithrombin. 1. Lincoff ML et al. JAMA. 2004;292:696-703. 2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

31. 31 Protocol Major/Minor Bleed by SWITCH and Randomized Therapy Regardless of prior heparin or not, patients administered ANGIOMAX ® (bivalirudin) had decreased bleeding There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy *P=NS for all 3-way comparisons versus ANGIOMAX alone; † P<.05 vs prior treatment with UFH or enoxaparin; ‡ naïve=no prior AT therapy in preceding 48 hours. Protocol major/minor bleed Naïve→ ANGIOMAX ‡ (n=2,345) LMWH→ ANGIOMAX (n=258) UFH→ ANGIOMAX (n=287) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→ UFH + GP IIb/IIIa ‡ (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) * † Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

32. 32 TIMI Major/Minor Bleed by SWITCH and Randomized Therapy Patients switched from UFH or enoxaparin to ANGIOMAX ® (bivalirudin) had the lowest rates of TIMI bleeding Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins TIMI major/minor bleed Naïve→ ANGIOMAX † (n=2,345) LMWH → ANGIOMAX (n=258) UFH→ ANGIOMAX (n=287) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→UFH + GP IIb/IIIa † (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) * *P=NS for all 3-way comparisons versus ANGIOMAX alone; † naïve=no prior AT therapy in preceding 48 hours. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

33. 33 Transfusion by SWITCH and Randomized Therapy Patients switched to ANGIOMAX ® (bivalirudin) had lower rates of transfusions UFH continued on UFH + GP IIb/IIIa had twice the rate of transfusions than naïve  UFH group Enoxaparin switched to UFH + GP IIb/IIIa had 3 times the rate of transfusions than naïve  UFH group Non-CABG transfusion ≥2 units Naïve→ ANGIOMAX ‡ (n=2,345) UFH→ ANGIOMAX (n=287) UFH→UFH + GP IIb/IIIa (n=349) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→ UFH + GP IIb/IIIa ‡ (n=2,325) LMWH → ANGIOMAX (n=258) * † *P=NS for all 3-way comparisons versus ANGIOMAX alone; † P<.05 versus prior treatment with UFH or enoxaparin; ‡ naïve= no prior AT therapy in preceding 48 hours. CABG=coronary artery bypass graft surgery. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

34. 34 1-Year Mortality: Prior UFH or LMWH Patients switched to ANGIOMAX ® (bivalirudin) with “provisional” GP IIb/IIIa experienced a 33%-57% relative risk reduction in mortality at 1 year Lincoff AM et al. JAMA 2004;292:696-703. Data on file. The Medicines Company, Parsippany, NJ. Cumulative deaths at 12 months *Pretreatment within prior 48 hours. P=.38P=.07 33% 57%45%

35. 35 Moderate- and high-risk UA or NSTEMI patients undergoing an early invasive strategy Prospective, randomized, active-controlled trial ACUITY Study Design *Stratified by preangiography thienopyridine use or administration. † UFH or enoxaparin. ‡ ANGIOMAX alone = ANGIOMAX monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. NSTEMI=non-ST–segment elevation myocardial infarction; R=randomized. The safety and effectiveness of ANGIOMAX have not been established in patients with ACS who are not undergoing PCI. CABG Moderate- and high- risk ACS (N=13,819) Angiography within 72 h Aspirin in all; clopidogrel dosing and timing per local practice Heparin(s) † + GP IIb/IIIa (n=4,603) ANGIOMAX ® (bivalirudin) + GP IIb/IIIa (n=4,604) ANGIOMAX alone ‡ (n=4,612) R* Medical management PCI Stone GW et al. N Engl J Med. 2006;355:2203-2216.

36. 36 *ANGIOMAX monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. P =.47 P <.001 48% Adverse events (%) 30-day 9.0% 3.5% 8.2% 6.7% 0 5 10 15 Composite ischemiaNon-CABG major bleeding P =.75 Adverse events (%) 1-year 2.7% 2.9% 0 1 2 3 4 5 Mortality Data on file. The Medicines Company, Parsippany, NJ. Switch to ANGIOMAX* vs consistent heparin + GP IIb/IIIa outcomes Switching to ANGIOMAX ® (bivalirudin) Improves Bleeding Outcomes Ischemic suppression was maintained and bleeding significantly reduced at 30 days Long-term efficacy in both groups was consistent at 1 year ANGIOMAX* (n=1,292) switch arm UFH/enoxaparin + GP IIb/IIIa (n=1,236) consistent arm PCI Subgroup

37. 37 ANGIOMAX* (n=1,014) switch arm P =.36 P =.003 45% *ANGIOMAX monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. † 76% of ACUITY PCI patients had raised cardiac biomarkers and/or ST-segment deviation at baseline. 9.3% 3.9% 8.1% 7.1% UFH/enoxaparin + GP IIb/IIIa (n=974) consistent arm 0 5 10 15 P =.97 3.1% 0 1 2 3 4 5 30-day Composite ischemiaNon-CABG major bleeding 1-year Mortality Adverse events (%) Data on file. The Medicines Company, Parsippany, NJ. In High-Risk Patient Subset, Switching to ANGIOMAX ® (bivalirudin) Improves Bleeding Outcomes Ischemic suppression was maintained and major bleeding significantly reduced at 30 days Long-term efficacy in both groups was consistent at 1 year Switch to ANGIOMAX* vs consistent heparin + GP IIb/IIIa outcomes † PCI Subgroup

38. 38 How to Switch from Heparin(s) to ANGIOMAX ® (bivalirudin) for PCI Reed MD et al. Pharmacotherapy. 2002;22(6 pt 2):105S-111S. UFH LMWH From UFH to ANGIOMAX, discontinue UFH for 30 minutes before starting ANGIOMAX for PCI From LMWH to ANGIOMAX, discontinue LMWH for 8 hours before starting ANGIOMAX for PCI

39. 39 ACUITY PCI Subgroup Analysis: 1-Year Mortality Results PCI Subgroup

40. 40 56% of Patients in ACUITY Underwent PCI 56.4% 11.1% 32.5% CABG (n=1,539) Medical management (n=4,491) Heparin(s) + GP IIb/IIIa (n=2,561) Heparin(s) + GP IIb/IIIa (n=2,561) ANGIOMAX ® (bivalirudin) + GP IIb/IIIa (n=2,609) ANGIOMAX ® (bivalirudin) + GP IIb/IIIa (n=2,609) ANGIOMAX alone (n=2,619) ANGIOMAX alone (n=2,619) Stone GW et al. N Engl J Med. 2006;355:2203-2216. PCI (n=7,789)

41. 41 Baseline Characteristics ANGIOMAX ® (bivalirudin) alone (n=2,619) Heparin(s) + GP IIb/IIIa (n=2,561) Age (median [range], y)63 [30-92]63 [25-91] Male73% Weight (median [IQR], kg)84 [75,95]84 [73,96] Diabetes28% - Insulin requiring9%8% Hypertension66% Hyperlipidemia56% Current smoker31% Prior MI31%30% Prior PCI40%38% Prior CABG18%17% Renal insufficiency (CrCl <60 mL/min)18%19% P=NS for all values. Stone GW et al. Lancet. 2007;369:907-919. PCI Subgroup

42. 42 Baseline High-Risk Features 77% of the PCI patients had elevated cardiac biomarkers or ST- segment changes ANGIOMAX ® (bivalirudin) alone (n=2,619) Heparin(s) + GP IIb/IIIa (n=2,561)  Cardiac biomarker  (MB or troponin) 66%65%  - Troponin  66%65% ST-segment  ≥1 mm 35%  Cardiac biomarker  or ST-segment  77% Stone GW et al. Lancet. 2007;369:907-919. PCI Subgroup

43. 43 ACUITY Patients Undergoing PCI 30-Day Outcomes Supplement to: Stone GW et al. N Engl J Med. 2006;355:2203-2216. http://content.nejm.org. Accessed December 21, 2006. Stone GW et al. Lancet. 2007;369(9565):907-919. P=.45P<.001P=.057 30-day PCI results *In the ANGIOMAX-alone group: 91% of PCI patients received ANGIOMAX monotherapy. ® PCI Subgroup

44. 44 Results at 1 Year HR ±95% CI HR (95% CI) ANGIOMAX ® (bivalirudin) alone better UFH/enoxaparin + GP IIb/IIIa better Composite ischemia1.09 (0.96–1.23) Mortality0.95 (0.70–1.30) Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

45. 45 Mortality (%) Days from randomization Early and Late Mortality UFH/Enoxaparin + GP IIb/IIIa vs ANGIOMAX ® (bivalirudin) Alone 30-day estimate P (log rank) estimate P (log rank) ANGIOMAX alone.63 1.1%.48 2.2% 1-year UFH/enoxaparin + IIb/IIIa 0.9%—3.1%— P=.78 Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

46. 46 Age ≥75 years 2.63 (1.92-3.60) <.001 Anemia 1.45 (1.07-1.96).016 Baseline CrCl <60 mL/min 1.43 (1.03-1.99).033 Diabetes mellitus 1.74 (1.35-2.25) <.001 Male 1.46 (1.07-1.98).017 History of CAD 1.97 (1.46-2.65) <.001 Baseline ST- deviation ≥1 mm1.42 (1.08-1.86).011 Baseline cardiac biomarker ↑ 2.05 (1.49-2.81) <.001 Revascularization within 30 days 1.70 (1.03-2.81).039 MI within 30 days 2.31 (1.58-3.39) <.001 Major bleeding 3.20 (2.28-4.50) <.001 HR ±95% CIP valueHR (95% CI) Predictors of 1-Year Mortality Major bleeding was associated with the highest risk followed by age ≥75 years and MI within 30 days Cox model with major bleeding, MI, and revascularization as time-updated covariates Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

47. 47 Influence of 30-Day Major Bleeding and MI on Late Mortality HR ±95% CI 30-day major bleeding3.16 (2.25-4.42)<.001 HR (95% CI) Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates. 30-day MI2.30 (1.57-3.36)<.001 P value Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

48. 48 Impact of Bleeding on Length of Stay Patients with a bleeding event had a significant increase of 2 days in their length of stay Patients with bleeding event (n=459) Patients without bleeding event (n=7,318) P value Hospital length of stay, median days 5.03.0<.001 Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

49. 49 In High-risk Patients With Elevated Troponin Levels and/or ST-segment Changes Risk Ratio ±95% CI RR (95% CI) HR ±95% CI HR (95% CI) UFH/enoxaparin + GP IIb/IIIa better ANGIOMAX ® (bivalirudin) alone better ANGIOMAX alone better 30-Day Results1-Year Results Composite ischemia 1.08 (0.88-1.32) Major bleeding 0.55 (0.42-0.72) Mortality0.94 (0.67-1.31) UFH/enoxaparin + GP IIb/IIIa better Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

50. 50 Impact of Clopidogrel at 1 Year PCI patients 1-year mortality HR ±95% CI HR (95% CI) ANGIOMAX ® (bivalirudin) alone better UFH/enoxaparin + GP IIb/IIIa better Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine. Pre-PCI clopidogrel (n=3,429) 1.02 (0.69-1.50) Peri-PCI clopidogrel (n=1,044) 1.14 (0.59-2.22) Post-PCI clopidogrel (n=519) 0.43 (0.17-1.11) No clopidogrel (n=88) 3.24 (0.34-31.1) Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

51. 51 Impact of Clopidogrel at 1 Year: Troponin-Positive Patients PCI troponin-positive patients 1-year mortality HR ±95% CI HR (95% CI) ANGIOMAX ® (bivalirudin) alone better UFH/enoxaparin + GP IIb/IIIa better Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine. Pre-PCI clopidogrel (n=1,891) 1.07 (0.66-1.73) Peri-PCI clopidogrel (n=649) 1.09 (0.46-2.58) Post-PCI clopidogrel (n=307) 0.56 (0.17-1.93) No clopidogrel (n=51) 3.07 (0.32-29.49) Data on file. The Medicines Company, Parsippany, NJ. PCI Subgroup

52. 52 Additional Considerations ANGIOMAX ® (bivalirudin) Important Safety Information, Dosing and Administration

53. 53 Important Safety Information ANGIOMAX ® (bivalirudin) with provisional use of GP IIb/IIIa inhibitor is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), and in patients with or at risk for heparin- induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI ANGIOMAX is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin ANGIOMAX is contraindicated in patients with active major bleeding or hypersensitivity to ANGIOMAX or its components The most common (≥10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache, and hypotension An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of ANGIOMAX administration ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

54. 54 Dosing and Administration The recommended dose for ANGIOMAX ® (bivalirudin) is an intravenous (IV) bolus of 0.75 mg/kg This should be followed by an infusion of 1.75 mg/kg/hour for the duration of the PCI procedure or up to 4 hours per physician discretion After the 4 hours of the initial infusion, an additional infusion may be initiated at a rate of 0.2 mg/kg/hour for up to 20 hours, if needed If the low-rate infusion is used after the initial infusion, a lower concentration bag of 0.5 mg/mL should be prepared. See Prescribing information for diluting instructions Special precaution: It is important to note that the pre-PCI ANGIOMAX dose for patients with acute coronary syndromes in the ACUITY trial is not an approved dose and is much lower than the approved PCI dose discussed in these instructions ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

55. 55 Special Population: Patients With Renal Impairment No reduction in the bolus dose of ANGIOMAX ® (bivalirudin) is needed The infusion dose may need to be reduced –Severe renal impairment (CrCl <30 mL/minute): reduction in the infusion rate to 1.0 mg/kg/hour should be considered –On hemodialysis: infusion should be reduced to 0.25 mg/kg/hour Standard infusion dose for patients with normal to moderate renal impairment (CrCl ≥30 mL/minute) Anticoagulation status should be monitored in patients with renal impairment ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

56. 56 ANGIOMAX ® (bivalirudin) in PCI ANGIOMAX improves bleeding outcomes while preserving ischemic suppression for UA/NSTEMI patients undergoing PCI even if the patients are switched from UFH or enoxaparin to ANGIOMAX Consistent results in low-, moderate-, and high-risk patients For more information about ANGIOMAX, please see the representative for full ANGIOMAX Prescribing Information.