1. Angiomax (bivalirudin) in Peripheral Vascular Disease (PVD)

2. 2 Anticoagulation in PVD ► Thrombus occurs in 100% of peripheral percutaneous intervention (PPI) cases ► Bleeding risks are greater in PPI than PCI ► PPI and PCI are different ► PPI requires superior anticoagulation

3. 3 Clinical Differences in PVD vs. PCI ► Longer length diseased vessel ► Larger sheath size requirement ► Longer PTA/stented segments ► Larger acute and chronic thrombus burden ► Longer procedural times (sheath dwell times) ► Multiple catheter, guidewire, devices, etc exchanges (oftentimes crossover techniques)

4. 4 Clinical Differences in PVD vs. PCI (con’t) ► “Low flow” state in peripheral versus coronary flow beds ► Increased incidence of CRF (renal insufficiency) ► Postprocedural anticoagulation (infrainguinal, limb salvage, ALI, etc.) ► PVD- > 50-60% Diabetes: PCI- 20-30% Diabetes ► PVD patients are hypercoaguable

5. 5 Peripheral interventions ► Percutaneous peripheral interventions (PPI) require predictable and reliable anticoagulation that also minimizes risk of bleeding  Large sheaths  Renal dysfunction  Long interventions ► Strategies needed to improve throughput  Reduce time to sheath removal  Reduce time to ambulation ► Heparin is typically used in PPI, but no data exist on the optimal level of anticoagulation ► The limitations of heparin persist in PPI…

6. 6 Bivalirudin in peripheral interventions ► Bivalirudin: a thrombin-specific anticoagulant, superior efficacy, significantly less bleeding vs heparin in PTCA 1 ► Bivalirudin used in PPI registries: St Joseph’s, Naples Endovascular, Cardiovascular Institute of the South, Cardiovascular Research Foundation/Lenox Hill ► Based on these limited data, bivalirudin may be an attractive alternative to heparin in peripheral interventions ► May offer decreased vascular complications, earlier sheath removal time, earlier ambulation and decreased length of stay ► Further studies are warranted 1 Bittl et al AJC 2001

7. 7 Overview Peripheral experience St Joseph’s Hospital Registry Naples Endovascular Cardiovascular Research Foundation & Lenox Hill Cardiovascular Inst of the South Angiomax clinical programAPPROVE trial

8. 8 St. Joseph’s Hospital Registry ► 72 Patients, elective procedures ► 88 Lesions (4 with concomitant PCI) ► Mean Age 65.8 yrs (Range 43-84) ► 60% Male ► 73% HTN ► 23% Diabetes ► Prior MI 25% ► Prior PCI 62% ► Prior CABG 27% ► Prior CVA 10% Knopf et al, TCT 2002 Demographics

9. 9 St. Joseph’s Hospital Registry ► Bivalirudin bolus 0.75mg/kg in 100% ► Infusion 1.75 mg/kg/hr used in 50% of cases ► Mean ACT 286.6 (224-389) ► Sheath 6F-11F ► Mean creatinine pre 1.17 (0.7-2.7) ► Plavix 99% ► GP IIb/IIIa 0% ► Closure devices 20% Knopf et al, TCT 2002 Methods

10. 10 Location of the 88 lesions ► Iliac 33 ► Renal 26 ► Femoral 12 ► Carotid 16 ► Distal Aorta 1 ► Subclavian 1 Knopf et al, TCT 2002 St. Joseph’s Hospital Registry

11. 11 Results ► Success 100% ► Bleeding 0% ► Mortality 0% ► Subacute closure 0% ► Vascular repair 0% ► CVA 0% ► Post-procedure creatinine increase > 0.5 0% ► Mean sheath removal 108 minutes ► LOS 0.6 days (0-2) Knopf et al, TCT 2002 St. Joseph’s Hospital Registry

12. Naples Endovascular Registry Grubbs, CRT 2003 TypeN casesBivalirudin RxSuccess rate Arterial lysis12bolus+ inf100% Endovascular AAA 8bolus+ inf100% Carotid art. stent 3bolus+ inf100% Venous interventions13bolus 94% Arterial interventions16bolus100% Venous dialysis Graft declots w/lytic 13bolus100% Venous dialysis Graft declots w/mech device 4bolus100% 69 procedures Bivalirudin bolus 0.75mg/kg Infusion 1.75 mg/kg/hr

13. Naples Endovascular Registry Grubbs, CRT 2003 Bivalirudin provided adequate anticoagulation for all peripheral interventions Achieved ACT targets immediately No adverse events (bleeding, procedural failure, acute thrombosis, or death) were seen. Historical analysis of usual complication rates for this composite set of procedures w/ heparin= 6% >1200 interventions. Bivalirudin procedural success rate of 100% on 12 consecutive arterial lysis cases is of note, historical complete lysis rate of 78% in >100 cases using tPA alone during the past 4 years. Conclusions

14. 14 Cardiovascular Research Fdn& LHH ► 59 consecutive pts with bivalirudin (bolus 75mg/kg, 1.75 mg/kg/hr infusion throughout the procedure) ► 83 case-matched controls with UFH (5,000U), same timeframe ► mean age = 72 + 9 yrs ► 60.4% male ► No GP IIb/IIIa inhibitors ► Neurological events, bleeding and vascular complications were recorded and adjudicated by an independent committee Adamyan et al, ACC 2003 Carotid Stenting

15. 15 Cardiovascular Research Fdn& LHH Adamyan et al, ACC 2003 Clinical Outcomes Bivalirudin n=59 UFH n=83 P value Death, n% 0 (/59) 0 (0/83) NS Major stroke, n% 0 (0/59) 1.2 (1/83) 1.00 Minor stroke, n% 0 (0/59) 0 (0/83) NS Hematoma > 5cm (%) 1.7 (1/59) 3.6(3/83) 0.64 Pseudoaneurysm(%) 0 (0/59) 2.4 (2/83) 0.51 Transfusion (%) 0 (0/59) 8.6 (7/81) 0.02 Vascular complication 1.7 (1/59) 4.9 (4/81) 0.39 Results

16. 16 Bivalirudin in peripheral interventions ► Based on these limited data, bivalirudin may be an attractive alternative to heparin in peripheral interventions ► May offer decreased vascular complications, earlier sheath removal time, earlier ambulation and decreased length of stay ► Further studies are warranted

17. 17 Direct Thrombin Inhibition in PVD Bivalirudin as Sole Anticoagulant in Peripheral Vascular Disease: A Safety and Feasible Alternative in Renal and Iliac Interventions David E. Allie, Mitchell D. Lirtzman, V. Antoine Keller, Mohamed H. Khan, Muhammad A. Khan, Peter S. Fail, Chris J. Hebert, Adam A. Allie, Craig M. Walker, Cardiovascular Institute of the South, LA, HCA, LA Allie et al ACC 2003

18. 18 Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA Design/ Methods Retrospective, consecutive review of 180 renal, 75 iliac Bivalirudin: 0.75 mg/kg bolus with 1.75 mg/kg/hr infusion for procedural duration Variables: Sheath removal time (SRT), access complication (AC), time to ambulate (TA), and length of stay (LOS). Follow up: 6 month renal and iliac duplex ultrasound and ankle-brachial index Matched historical control with UFH Allie, ACC 2003

19. 19 Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA Results: Allie, ACC 2003 Variables Bivalirudin Renal, n=180 Historical C ontrol Renal, n=180 P- value PPI Success, n (%) 180 (100) 179 (99) 0.3173 AC (Major1), n (%) 2(1.1) 6 (3.3) 0.1532 AC (Minor2), n(%) 5(2.7) 8 (4.4) 0.3974 SRT <60 min, n (%) 152 (84) 106 (59) <0.0001 SRT >60 min, n (%) 28 (16) 74 (41) <0.0001 LOS <24 hrs, n (%) 154(85.5) 130 (72) 0.002 LOS >24 hrs, n (%) 26(14.5) 50 (28) 0.002 TA <6 hrs, n (%) 136(75.5) 105 (58) 0.0005 TA >6 hrs, n (%) 44(24.5) 75 (42) 0.0005 1="Major’ = any surgery, > 5 cm hematoma, or > 2u transfusion 2="Minor’ = all other non-intracranial or retroperitoneal bleeding RT, LOS and TA all significantly shorter with bivalirudin

20. 20 Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA Results Allie, ACC 2003 1="Major’ = any surgery, > 5 cm hematoma, or > 2u transfusion 2="Minor’ = all other non-intracranial or retroperitoneal bleeding Variables Bivalirudin Iliac n=75 Historicalcontrol Iliac n=75 P-value PPI Success, n (%) 75 (100) 74 (98.6) 0.3173 AC (Major1), n (%) 2(2.5) 3 (4) 0.6503 AC (Minor2), n(%) 3(4) 5 (6.6) 0.4689 SRT <60 min, n (%) 36 (48) 21 (28) 0.0119 SRT >60 min, n (%) 39 (52) 54 (72) 0.0119 LOS <24 hrs, n (%) 42(56) 32 (43) 0.1036 LOS >24 hrs, n (%) 33(44) 43 (57) 0.1036 TA <6 hrs, n (%) 31(41) 19 (25) 0.0383 TA >6 hrs, n (%) 44(59) 56 (75) 0.0383

21. 21 ► Procedural success and clinical outcomes similar in both PVD groups with bivalirudin and UFH ► Fewer access site complications in all groups RenalIliac Bivalirudin UFHBivalirudinUFH Overall 3.9%7.7%6.5% 10.6% Major 1.1%3.3%2.5%4.0% Minor 2.7% 4.4%4.0%6.6% Overall Access Site Complications Bivalirudin = 3.8% UFH = 6.6% Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA

22. 22 Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA ► No thrombotic events, intracranial bleeding, or major surgical complications occurred in bivalirudin group ► Sheath removal time, time to ambulation and length of stay were reduced compared to historical control ► 6 month repeat PPI:  Renal 7/180 (3.9%) bivalirudin 8/180 (5%) UFH  Iliac and 3/75 (4%) bivalirudin 4/75 (5.3%) UFH Allie, ACC 2003

23. Principal Investigators: David Allie MD Cardiovascular Institute of the South Patrick Hall MD South Carolina Heart Center Direct Thrombin Inhibition in PVD

24. 24  To demonstrate that Angiomax can safely replace unfractionated heparin as the primary anticoagulant in patients undergoing peripheral interventions, including outpatient interventions (<23hour)  Open label trial of Angiomax anticoagulation in renal, femoral, and Iliac lesions  505 patients  26 sites Study Objective and Design

25. 25  Angiomax 0.75 mg/kg IV bolus + 1.75 mg/kg-hr IV infusion for duration of procedure  GP IIb/IIIa’s at physician discretion  Bivalirudin post-procedural infusion 0.25 mg/kg/hr at physician discretion Study Drug Administration

26. 26  Primary: Procedural success defined as ≤ 20% residual stenosis as determined by the treating physician.  Secondary: · Activated clotting times (ACTs) · Health economics (sheath size, time to sheath removal, time to ambulation, time to discharge, use of closure devices) · Death · Bleeding · Myocardial infarction (MI) · Unplanned revasc or surgical intervention for ischemia · Amputation · Renal function (relation to ischemic and bleeding outcomes). Endpoints

27. 27 Primary lesion/vessel Renal n/N (%) 173/505 (34.3) Iliac n/N (%) 140/505 (27.7) Femoral n/N (%) 184/505 (36.4) Other n/N (%) 8/505 (1.6)

28. 28 ► Clopidogrel pretreatment 95% ► Aspirin 96.8% ► GP IIb/IIIa inhibitors4.4% ► Procedural success95% Procedural characteristics

29. 29 Patient demographics Characteristic Age (mean)69 Age > 65 yrs n/N (%)320/505 (63.4) Age > 75 yrs n/N (%) 164/505 (32.5) Female n (%)231 (45.7) Male n (%)274 (54.3) Angina History n/N (%)178/504 (35.3) Prior MI n/N (%)124/505 (24.6) Prior Vascular Surgery n/N (%)175/505 (34.7) Current Smoker (<6 mos) n/N (%)152/505 (30.1) Hyperlipidemia n/N (%)400/505 (72.9) Hypertension n/N (%)450/504 (89.3) Congestive Heart Failure n/N (%)79/505 (15.6) Diabetes (insulin-dependent) n/N (%)63/505 (12.5) Diabetes (non insulin-dependent n/N (%)120/505 (23.8)

30. 30 Ischemic outcomes: 30 days RenalIliacFemoralTotal n/N (%) Death0/173 (0.0)0/139 (0.0)0/184 (0.0)0/505 (0.0) Unplanned revasc0/173 (0.0)0/139 (0.0)4/184 (2.2)4/504 (0.8) Amputation0/173 (0.0)0/139 (0.0)2/184 (1.1)2/504 (0.4) Myocardial infarction 0/173 (0.0)0/139 (0.0)1/184 (0.5)1/505 (0.2) New Q- wave*0/173 (0.0)0/139 (0.0)0/184 (0.0)0/505 (0.0) CK-MB>3XULN0/173 (0.0)0/139 (0.0)1/184 (0.5)1/505 (0.2) * New Q-wave >0.04 sec duration in 2 or more contiguous leads

31. 31 Hemorrhagic outcomes: 30 days RenalIliacFemoralTotal n/N (%) Major (protocol)7/173 (4.0)5/140 (3.6)7/184 (3.8)19/505 (3.8) Tfx ≥2 U3/173 (1.7)5/140 (3.6)3/184 (1.6)11/505 (2.2) Intracranial0/173 (0.0)0/139 (0.0)1/184 (0.5)1/504 (0.2) Retroperitoneal0/173 (0.0)1/139 (0.7)1/184 (0.5)2/504 (0.4) Fall in Hgb >4g/dL w/no site 2/173 (1.2)3/140 (2.1)4/183 (2.2)9/505 (1.8) Fall in Hgb >3g/dL overt 2/173 (1.2)0/139 (0.0)1/184 (0.5)3/504 (0.6) Minor (protocol)13/173 (7.5)14/139(10.1)21/184 (11.4)48/504 (9.5) Major (TIMI)1/168 (0.6)1/137 (0.7)4/177 (2.3)6/490 (1.2) Minor (TIMI)4/172 (2.3)4/139 (2.9)7/181 (3.9)15/500 (3.0)

32. 32 ► Bivalirudin, as the sole procedural anticoagulant, provided similar outcomes in all vessel types treated ► Consistent anticoagulation at the dose tested ► Major & minor hemorrhagic complications were low ► Times to sheath removal, ambulation, and discharge were favorable and appear to increase the potential for same-day discharge without compromising efficacy or safety Summary: APPROVE 30-day outcomes