1. Interventional Pharmacology: The Basics Michael J. Cowley, FACC,FSCAI Nothing to Disclose

2. Heparin (UFH) GP IIb/IIIa Receptor Antagonists Low Molecular Weight Heparins Direct Thrombin Inhibitors Thienopyridines Heparin (UFH) GP IIb/IIIa Receptor Antagonists Low Molecular Weight Heparins Direct Thrombin Inhibitors Thienopyridines Interventional Pharmacology

3. GP IIb/IIIa Receptor Antagonists Low Molecular Weight Heparins Direct Thrombin Inhibitors Thienopyridines GP IIb/IIIa Receptor Antagonists Low Molecular Weight Heparins Direct Thrombin Inhibitors Thienopyridines Interventional Pharmacology

4. Adjunctive Therapy for ACS / PCI GP 2b3a Agents Abciximab Eptifibatide Tirofiban + Clopidogrel pre-treatment how early? how much? Anti Thrombins Heparin LMWH Bivalirudin

5. Adjunctive Therapy for PCI GP 2b3a Agents Abciximab Eptifibatide Tirofiban + Clopidogrel pre-treatment Anti Thrombins Heparin LMWH DTI

6. UFH: Clinical Experience, Non-inferiority GP2b3a: Numerous studies (vs UFH alone) LMWH: ESSENCE, TIMI 11, INTERACT SYNERGY, STEEPLE Clopdiogrel: CURE, PCI-CURE, CREDO Bivalirudin: BAT, REPLACE 2, ACUITY Beneficial Agents Interventional Pharmacology

7. UFH: Clinical Experience, Non-inferiority GP2b3a: Numerous studies (vs UFH alone) LMWH: ESSENCE, TIMI 11, INTERACT SYNERGY, STEEPLE Clopdiogrel: CURE, PCI-CURE, CREDO, CLARITY,COMMIT Bivalirudin: BAT, REPLACE 2, ACUITY Beneficial Agents Interventional Pharmacology

8. UFH: Clinical Experience, Non-inferiority GP2b3a: Numerous studies (vs UFH alone) LMWH: INTERACT, SYNERGY, STEEPLE Clopdiogrel: CURE, PCI-CURE, CREDO Bivalirudin: BAT, REPLACE 2, ACUITY Beneficial Agents Interventional Pharmacology

9. Anti-Thrombin Effects Platelet Effects UFHXa / IIaAggregation GP 2b/3a---Inhibition ADP inhibitor---Inhibition LMWHXa / IIaMinimal effect BivalirudinIIa (direct)Inhibition

10. Interventional Pharmacology Anti-thrombinPlatelet Effects UFHXa / IIaAggregation GP 2b/3aInhibition ADP inhibitorInhibition LMWHXa / IIaMinimal effect BivalirudinIIa (direct)Inhibition

11. Unfractionated Heparin

12. UFH with PCI

13. Unfractionated Heparin  Indirect thrombin inhibitor (does not inhibit clot-bound thrombin)  Nonspecific binding to: ―Plasma proteins ―Endothelial cells (variable anticoagulation level)  Inhibited by platelet factor 4 ―reduced effect in ACS  Causes platelet aggregation  Risk of HIT Disadvantages  Multiple sites of action in coagulation cascade (IIa,Xa)  Long history of successful clinical use  Readily monitored by aPTT and ACT  Very inexpensive Advantages Hirsh J, et al. Circulation. 2001;103:2994-3018

14. ACC/AHA/SCAI PCI Guidelines UFH should be given to pts under- going PCI (Level of Evidence: C) Unfractionated Heparin Class I:

15. GP IIb / IIIa Receptor Antagonists

16. GP IIb/IIIa Receptor Inhibition EPIC CAPTURE SPEED RAPPORT EPILOG PRISM TIMI 14 ADMIRAL RESTORE PRISM PLUS GUSTO 5 ISAR 2 IMPACT PURSUIT ASSENT 3 CADILLAC IMPACT 2 GUSTO 4 Impact AMI ACE EPISTENT ESPRIT TARGET STEMI PCI ACS Lysis PCI

17. GPIIb/IIIa Antagonists in PCI Risk Ratio & 95% CI EPIC IMPACT-II EPILOG CAPTURE Trial 9.6% 8.5% 9.1% 9.0% 6.3% RESTORE Placebo II b/ III a 6.6% 7.0% 4.0% 4.8% 5.1% 2,099 4,010 2,792 1,265 2,141 N 10.2% EPISTENT 5.2% 2,399 Placebo Better II b/ III a Antag Better 0.62 (0.55, 0.71) p < 0.000000001 8.8% Pooled 5.6% 16,770 00.511.52 ESPRIT 2,064 10.2%6.3% 30 Day Death / MI

18. % p=.047 30 day Events (D, MI, uTVR): EPIC and EPILOG Abciximab in PCI: Complex Lesions p=.001 p=.078 p=.001 Ellis: JACC 1998; 32:1619 365 452 761 961 380 799 2994 2312 1896

19. % Abciximab for Complex Lesions: EPISTENT 30 day D, MI, uTVR p=0.17 p<0.001 230 267 517 468

21. Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials Newby KL: Circulation 2001;103:2891-2896 TnT-NegativeTnT-Positive PARAGON-B PRISM CAPTURE Combined 0.125120.50.125120.5 GP IIb/IIIa Better GP IIb/IIIa Worse GP IIb/IIIa Better GP IIb/IIIa Worse

22. ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets With and Without Elevated Troponin Levels (>0.03 µg/L) 20 15 10 5 0 05 15202530 Days After Randomization Placebo Group (N=1010) Abciximab Group (N=1012) Troponin >0.03 µg/L Log-Rank p = 0.02 Troponin <0.03 µg/L Log-Rank p =.98 Adapted from Kastrati A: JAMA 2006; 295:1531-1538 %

23. % GP IIb/IIIa in Acute MI Abciximab PCI in Acute MI Trials 30 Day Endpoint (D, Re-MI, Urg TVR) p=0.023 p<0.05 p=0.005 PTCA N = 483 Stent N = 401 Stent N = 301 PTCA or Stent N = 2082 Stent N = 400 p=0.038 p=0.01

24. Anti-Platelet Therapy

25. 10.1 5.0* Placebo 158 ASA 178 0 4 8 12 Patients (%) 11.9 3.3* Placebo 118 ASA 121 0 5 10 15 12.9 6.2* Placebo 279 ASA 276 0 5 10 15 Lewis HD Jr: NEJM 1983 309:396-403 Theroux P: NEJM 1988 319:1105-1111 Cairns JA: NEJM 1985 313:1369-1375 17.1 6.5* Placebo 397 ASA 399 0 5 10 15 20 The RISC Group: Lancet 1990 336:827-830 Death or MI *p =.0005*p =.012*p =.008* p<.0001 ASA in UA/NSTEMI

26. CURE Primary End Point: MI/Stroke/CV Death Months of Follow-up Clopidogrel + Aspirin * (n=6259) Placebo + Aspirin * (n=6303) p < 0.001 N=12,562 369012 20% Relative Risk Reduction 0.12 0.14 0.10 0.06 0.08 0.00 0.04 0.02 Cumulative Hazard Rate * In addition to other standard therapies Yusuf S: N Engl J Med 2001;345:494-502

27. Clopidogrel 100200300 Placebo p = 0.002 Days of Follow-Up CURE PCI Substudy 0 400 PCI - 31% RRR The CURE Investigators: Lancet August 2001 N = 2,658 0.00 0.02 0.04 0.06 0.08 0.10 Cumulative Hazard Rates

28. Months 036912 8.5% 11.5% 0 5 15 10 Clopidogrel N=1053 Placebo N=1063 Death, MI or Stroke 27% RRR p = 0.02 CREDO: 1 Year Primary Outcome %

29. RRR 19.7% p=NS 5.5 6.9 RRR 37.4% p=0.04 2.9 4.6 RRR 26.9% p=0.02 8.5 11.5 0 4 8 12 Day 28Day 29 to 1 year Composite Death, MI, Stroke % Timing of Benefit

30. Clopidogrel Loading Dose for PCI 300 mg 600 mg 900 mg A fistful The whole bottle 300 mg 600 mg 900 mg A fistful The whole bottle

31. Circulation 2005; 112:2946-2950

32. ADP 5 ADP 20 Beckerath: Circ Nov 2005 Clopidogrel Loading Doses ISAR-CHOICE

33. Circles represent single measurements; bars denote mean ± SD von Beckerath N, et al: Circulation 2005;112:2946-2950 120 100 80 60 40 20 0 300 mg600 mg900 mg n = 20 p =.01p =.59 p = 0.001 A ADP (5 µmol/L)-Induced Aggregation (%) 120 100 80 60 40 20 0 300 mg600 mg900 mg n = 20 p = 0.01p =.59 p = 0.001 B ADP (20 µmol/L)-Induced Aggregation (%) 5 µmol/L ADP 20 µmol/L ADP Platelet Aggregation 4h after Clopidogrel Loading

34. ARMYDA-2 Trial Primary Endpoint: death, MI, or TVR at 30 days 4% 0% 2% 4% 6% 8% 10% 12% 14% High DoseStandard Dose 12% Clopidogrel Loading Dose 600 mg Pre-PCI Clopidogrel Loading Dose 300 mg Pre-PCI 255 patients with stable CAD or NSTEMI prior to PCI 13% GP IIb/IIIa inhibitors 20% DES Randomized 4-8 hrs Pre-PCI p=0.041 Patti G et al:. Circulation 2005;111:2099-2106

35. 0.40.60.81.01.2 Hazard Ratio (95% CI) RRR: –13.4% p=0.60 RRR: 38.6% p=0.05 RRR: 18.5% P=.23 CREDO Overall Steinhubl SR, et al: JAMA. 2002;288:2411-2420 CREDO Study: Timing of Loading Dose and 28-Day Endpoint TimingNPretreatNo Pretreat 3–<6 h8937.97.0 ≥ 6–24h8515.89.4

36. Clopidogrel No TrialPretreatmentPretreatment PCI-CURE3.65.1 CREDOn/an/a PCI-CLARITY4.06.1 Overall3.75.5 Meta-analysis of Clopidogrel Pretreatment CV Death or MI after PCI (%) MI before PCI (%) 1.0 0.25 2.0 0.5 1.00.252.00.5 OR (95% CI) OR: 0.67 p=0.005 Favors Pretreatment Favors No Pretreatment OR: 0.71 p=0.004 Adapted with permission from Sabatine MS, et al. JAMA. 2005;294:1224-1232 ClopidogrelNo TrialPretreatmentPretreatment PCI-CURE2.94.4 CREDO6.07.1 PCI-CLARITY3.35.4 Overall3.95.5

37. Clopidogrel with PCI Pre-treatment effective if started > 6 hr before PCI No advantage to load dose >600 mg Beneficial effects evident out to 1 yr Optimal duration with DES unknown Pre-treatment effective if started > 6 hr before PCI No advantage to load dose >600 mg Beneficial effects evident out to 1 yr Optimal duration with DES unknown Summary

38. LMWH with PCI

39. Low-Molecular-Weight Heparin  Indirect thrombin inhibitor  Less reversible than UFH  Long half-life  Renal clearance  Risk of HIT Disadvantages  Increased anti-Xa to anti-IIa activity  inhibits thrombin generation more effectively  Induces ↑ TFPI release vs UFH  Not neutralized by platelet factor 4  Less binding to plasma proteins:  more consistent anticoagulation  Lower rate of HIT vs UFH  Easy SC administration  Long history of clinical studies and experience, FDA-approved indications  Monitoring typically unnecessary Advantages Hirsh J, et a:. Circulation 2001;103:2994-3018

40. Antman EM: Circulation 1996; 94: 911; Théroux P: N Engl J Med 1992; 327: 141; Cohen M: Circulation 1994; 89:81 Limitations of UFH Unpredictable anticoagulant effect Non-specific protein binding and saturable clearance mechanism Inactivation by platelet factor 4 Platelet activation and aggregation Unpredictable anticoagulant effect Non-specific protein binding and saturable clearance mechanism Inactivation by platelet factor 4 Platelet activation and aggregation

41. Advantages of LMWH vs UFH No platelet activation Inhibits von Willebrand factor release Augments TFPI release Inhibits thrombin generation No rebound hypercoagulability No platelet activation Inhibits von Willebrand factor release Augments TFPI release Inhibits thrombin generation No rebound hypercoagulability

42. UFH Therapy Does not provide Predictable Anticoagulation

43. Advantages of LMWH vs UFH No platelet activation Inhibits von Willebrand factor release Augments TFPI release Inhibits thrombin generation No rebound hypercoagulability No platelet activation Inhibits von Willebrand factor release Augments TFPI release Inhibits thrombin generation No rebound hypercoagulability

44. Enoxaparin in the Cath Lab In Cath LabTransition to Cath Lab NICE 1 NICE 4 ELECT Choussat Carnendran STEEPLE NICE 1 NICE 4 ELECT Choussat Carnendran STEEPLE Collet PEPCI PK study NICE 3 SYNERGY Collet PEPCI PK study NICE 3 SYNERGY

45. Enoxaparin in PCI PCI-12 hr12 hr-8 hr Last dose of SQ Enox pre-PCI (none) Enox IV at PCI 0.3 mg/kg (none) 0.3 mg/kg (none) 1.0 mg/kg 0.75 mg/kg GP 2b/3a PEPCI NICE-3 Collet NICE-1 NICE-4 Trial Adapted from Ferguson: J Invasive Cardiol 2000;12 (Suppl E):E10-3 Yes (none) 0.5 mg/kg Choussat STEEPLE (none) 0.5 or 0.75

46. Enoxaparin in PCI PCI-12 hr12 hr-8 hr Last dose of SQ Enox pre-PCI (none) Enox IV at PCI 0.3 mg/kg (none) 0.3 mg/kg (none) 1.0 mg/kg 0.75 mg/kg GP 2b/3a PEPCI NICE-3 Collet NICE-1 NICE-4 Trial Adapted from Ferguson: J Invasive Cardiol 2000;12 (Suppl E):E10-3 Yes (none)0.5 mg/kg Choussat

47. Peterson JL: JAMA 2004; 292:89-96

48. LMWH vs UFH in PCI Trials LMWH n=3787 UFH studies n=978 p Efficacy EP5.8%7.6%0.03 Major Bleed0.6%1.8%0.0001 Minor Bleed3.1% ns Pooled Results (15 studies) Borentain, Montalescot: ESC 2003

49. Enoxaparin in PCI Trials Enox 0.5 n=798 Enox 0.75 n=1051 Enox 1.0 n=1226 p Efficacy EP1.8%6.9%6.6%0.0001 All Bleed2.3%4.8%3.9%0.02 Pooled Results Borentain, Montalescot: ESC 2003

50. Low Dose IV Enoxaparin for PCI 242 pts with elective PCI Single IV bolus of 0.5 mg/kg 26% (n=64) given eptifibatide Peak anti-Xa level >0.5 IU/mL in 97.5% Immed sheath removal (4h after eptifibatide) 30 day MACE: 2.5% ; Minor bleed: 1.6% Major bleed: 0.4% (82 yo F hematoma/PxA on eptifibatide) 242 pts with elective PCI Single IV bolus of 0.5 mg/kg 26% (n=64) given eptifibatide Peak anti-Xa level >0.5 IU/mL in 97.5% Immed sheath removal (4h after eptifibatide) 30 day MACE: 2.5% ; Minor bleed: 1.6% Major bleed: 0.4% (82 yo F hematoma/PxA on eptifibatide) Choussat, Montalescot: JACC; 2002; 40: 1943-50

51. PCI Low Dose Enoxaparin with PCI Choussat, Montalescot: JACC; 2002; 40: 1943-50 Enox Enox + Eptifib

52. IV enoxaparin 0.5 mg/kg n=1070 IV enoxaparin 0.5 mg/kg n=1070 STEEPLE Trial IV enoxaparin 0.75 mg/kg n=1228 IV enoxaparin 0.75 mg/kg n=1228 3528 pts with non-emergent single or multi-vessel PCI ACT – adjusted UFH Target ACT 200-300 With GP IIb/IIIa Target ACT 300-350 if no GP IIb/IIIa n=1230 ACT – adjusted UFH Target ACT 200-300 With GP IIb/IIIa Target ACT 300-350 if no GP IIb/IIIa n=1230 Montalescot: NEJM 2006;355:1006-1017 Primary Endpoint: Major / minor bleeding (non-CABG) at 48 hrs post-PCI Secondary Endpoints: - Percent reaching target anticoagulation levels at start and end of PCI - Composite of major bleed (48 hrs), mortality, MI, Urg TVR at 30 days

53. STEEPLE Trial: Primary Endpoint Non-CABG Major or Minor Bleeding at 48 hrs Lower bleeding rate was observed overall and in the GP IIb/IIIa subgroup p=0.014 vs UFH p=0.052 vs UFH Montalescot: NEJM 2006;355:1006-1017

54. Analysis of Major Bleeding STEEPLE Trial 57% lower with Enoxaparin Montalescot: NEJM 2006;355:1006-1017 p=0.007 vs UFH p=0.005 vs UFH

55. Patients reaching target anticoagulation levels at the start and end of procedure STEEPLE Trial: Secondary Endpoint p<0.001 vs Enox Montalescot: NEJM 2006;355:1006-1017

56. Composite: Major Bleed (non-CABG) at 48 hrs and 30 day incidence of Death, MI, or urgent TVR STEEPLE Trial: Secondary Endpoint p = ns No difference in Death or MI among groups Montalescot: NEJM 2006;355:1006-1017

57. STEEPLE Trial Reduced dose enoxaparin had less major or minor bleeding at 48 hrs than UFH Lower dose IV enoxaparin for PCI offers a safety advantage over ACT-guided UFH Reduced dose enoxaparin had less major or minor bleeding at 48 hrs than UFH Lower dose IV enoxaparin for PCI offers a safety advantage over ACT-guided UFH Summary

58. 10,027 ACS patients with 2 out of 3 high-risk criteria: Age > 60 (+) biomarkers (+) ECG  s Randomized to enoxaparin vs UFH Invasive management strategy GP IIb/IIIa antagonists encouraged Primary endpoint : Death / MI at 30 days 10,027 ACS patients with 2 out of 3 high-risk criteria: Age > 60 (+) biomarkers (+) ECG  s Randomized to enoxaparin vs UFH Invasive management strategy GP IIb/IIIa antagonists encouraged Primary endpoint : Death / MI at 30 days Superior Yield of the New strategy of Enoxaparin, Revascularization & GlYcoprotein IIb/IIIa Inhibitors The Synergy Investigators: JAMA 2004; 292: 45-54

59. SYNERGY p=0.705 p=0.135 p=0.396 % Efficacy at 30 days The Synergy Investigators: JAMA 2004; 292: 45-54

60. SYNERGY EnoxaparinUFH (n = 4993)(n = 4985) Cath during Hosp (%)92.192.0 Time to cath (hrs)* 21.721.5 (6.3, 43.6)*(6.3, 42.6) Coronary Intervention (%)46.547.4 Time to PCI (hrs)*22.722.5 (6.4, 48.8)(6.3, 48.1) CABG (%)19.318.0 EnoxaparinUFH (n = 4993)(n = 4985) Cath during Hosp (%)92.192.0 Time to cath (hrs)* 21.721.5 (6.3, 43.6)*(6.3, 42.6) Coronary Intervention (%)46.547.4 Time to PCI (hrs)*22.722.5 (6.4, 48.8)(6.3, 48.1) CABG (%)19.318.0 *Median (25th, 75th) p=NS In Hospital Procedures The Synergy Investigators: JAMA 2004; 292: 45-54

61. p=0.0029 RRR = 17.9% p=0.0039 RRR = 16.4% SYNERGY Outcomes with Consistent Therapy* Per ProtocolIntent-to-treat n=3398n=2740n=2627n=3010 *Consistent therapy = no pre-randomized therapy, or randomized to the same therapy they had been receiving % p=ns The Synergy Investigators: JAMA 2004; 292: 45-54

62. ACC/AHA/SCAI PCI Guidelines Class IIa: LMWH is a reasonable alternative to UFH in pts with UA/NSTEMI undergoing PCI (Level of Evidence: B) Class IIb: LMWH may be considered as an alternative to UFH in pts with STEMI undergoing PCI (Level of Evidence: B) Class IIa: LMWH is a reasonable alternative to UFH in pts with UA/NSTEMI undergoing PCI (Level of Evidence: B) Class IIb: LMWH may be considered as an alternative to UFH in pts with STEMI undergoing PCI (Level of Evidence: B) LMWH

63. Bivalirudin

64. IIa S C Direct antithrombin LMWH AT Xa AT Xa Pentasaccharide Bivalirudin = saccharide unit. Konkle BA, Schafer AI. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. 7th ed, vol 2. Philadelphia: Elsevier Saunders; 2005:2067-2092. UFH

65. Direct Thrombin Inhibitors  Predictable anticoagulant response  Inhibits soluble and fibrin- bound thrombin  Inhibits thrombin-induced platelet aggregation  No HIT  Needs continuous infusion  No antidote  Cost DisadvantagesAdvantages Xiao Z, Theroux P: Circulation 1998;97:251-256

66. Direct Thrombin Inhibitors BAT REPLACE – 2 ACUITY Bivalirudin

67. Direct Thrombin Inhibitors REPLACE – 2 ACUITY Bivalirudin

68. REPLACE – 2 Trial Design

69. REPLACE - 2 % Primary Endpoint p=0.324 p=0.255 p=0.43 p=0.435 p<0.001

70. REPLACE - 2 % Outcomes p=ns p<0.001 cytopenia

71. REPLACE - 2 Non-inferior to heparin + GP 2b3a receptor inhibitors Superior to heparin Reduced bleeding, transfusion, and thrombocytopenia Reduced time of treatment Non-inferior to heparin + GP 2b3a receptor inhibitors Superior to heparin Reduced bleeding, transfusion, and thrombocytopenia Reduced time of treatment Conclusions

72. ACC/AHA/SCAI PCI Guidelines Class I: For pts with HIT, it is recommended that bivalirudin or argatroban be used (Level of Evidence: B) Class IIa: It is reasonable to use bivalirudin as an alternative to UFH +GPI in low-risk pts having elective PCI (Level of Evidence: B) Class I: For pts with HIT, it is recommended that bivalirudin or argatroban be used (Level of Evidence: B) Class IIa: It is reasonable to use bivalirudin as an alternative to UFH +GPI in low-risk pts having elective PCI (Level of Evidence: B) Bivalirudin

73. Moderate- to high- risk ACS ACUITY Study Design: First Randomization Angiography within 72 h Aspirin in all; Clopidogrel dosing and timing per local practice UFH or enox + GP IIb/IIIa n=4603 Bivalirudin + GP IIb/IIIa n=4604 Bivalirudin alone n=4,612 R* Moderate- to high-risk patients with UA or NSTEMI undergoing an invasive strategy (N = 13,819) Medical management PCI CABG Stone GW, et al: Am Heart J 2004; 148:764–775 *Stratified by pre-angiography thienopyridine treatment

74. Moderate- to high- risk ACS ACUITY Study Design: Second Randomization Moderate- to high-risk patients with unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Aspirin in all; Clopidogrel dosing and timing per local practice Bivalirudin alone N=4612 UFH or Enoxaparin Routine upstream GPI in all pts (2294) GPI started in CCL for PCI only (2309) R Bivalirudin R Routine upstream GPI in all pts (2311) GPI started in CCL for PCI only (2293) UFH, Enoxaparin, or Bivalirudin Routine upstream GPI in all pts n=4603 Deferred GPI for PCI only N=4604 vs Primary analysis Secondary analysis Stone GW, et al: Am Heart J 2004; 148:764–775

75. 11.7%11.8%1.01 (0.90-1.12) <.001.93 Risk ratio ±95% CI Risk ratio ±95% CI Primary end point ACUITY: Primary End Point Measures* UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin + GP IIb/IIIa Net clinical outcome Ischemic composite Major bleeding Bivalirudin + GP IIb/IIIa better UFH/Enox + GP IIb/IIIa better Bival + IIb/IIIa UFH/Enox + IIb/IIIa RR (95% CI) P value (noninferior) (superior) 7.3%7.7%1.07 (0.92-1.23).015.39 5.7%5.3%0.93 (0.78-1.10) <.001.38 Upper boundary non-inferiority Stone GW, et al: Presented at: 55 th ACC Annual Meeting March 2006 *ITT population

76. ACUITY: Primary End Point Measures* Bivalirudin alone better UFH/Enox + IIb/IIIa better Risk ratio ±95% CI Risk ratio ±95% CI Primary end point Bival alone UFH/Enox + IIb/IIIa RR (95% CI) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.7%10.1%0.86 (0.77-0.97) <.001.015 7.3%7.8%1.08 (0.93-1.24).02.32 5.7%3.0%0.53 (0.43-0.65) <.001 P value (noninferior) (superior) UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone Stone GW et al: Presented at: 55 th ACC Annual Meeting March 2006 *ITT population

77. Management Strategy (N=13,819) 56.4% 11.4% 32.2% CABG (n=1,539) Medical Rx (n=4,491) PCI (n=7,789) Heparin + IIb/IIIa N = 2,561 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619

78. ACUITY-PCI Net Clinical Outcomes 0 5 10 15 05101520253035 Days from Randomization Estimate p (log rank) 13.5% Heparin* + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) 0.10 15.1% Bivalirudin alone (N=2619) 0.049 11.7% p=0.001 Stone GW: Presented at TCT; October 2006 %

79. ACUITY- PCI Composite Ischemia 0 5 10 15 05101520253035 Days from Randomization Estimate p (log rank) 8.4% Heparin* + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) 0.15 9.4% Bivalirudin alone (N=2619) 0.45 8.9% p=0.36 Stone GW. Presented at TCT; October 2006 %

80. Conclusions and Clinical Implications In patients with moderate and high risk ACS undergoing PCI Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone results in similar rates of ischemia with markedly reduced hemorrhagic complications, thereby improving overall event- free survival In patients with moderate and high risk ACS undergoing PCI Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone results in similar rates of ischemia with markedly reduced hemorrhagic complications, thereby improving overall event- free survival

81. Conclusions and Clinical Implications In patients with moderate and high risk ACS undergoing PCI Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone (with provisional IIb/IIIa inhibitor use in <10% of pts) results in similar rates of ischemia with markedly reduced hemorrhagic complications, thereby improving overall event- free survival In patients with moderate and high risk ACS undergoing PCI Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone (with provisional IIb/IIIa inhibitor use in <10% of pts) results in similar rates of ischemia with markedly reduced hemorrhagic complications, thereby improving overall event- free survival

82. 11.7% 1.00 (0.89-1.11) <.001.93 Risk ratio ±95% CI Risk ratio ±95% CI Primary end point ACUITY Timing: Primary End Point* Net clinical outcome Ischemic composite Major bleeding Upstream IIb/IIIa Deferred IIb/IIIa RR (95% CI) P value (non inferior) (superior) 7.9%7.1%1.12 (0.97-1.29).06.13 4.9%6.1%0.80 (0.67-0.95) <.001.01 Upper boundary non-inferiority Deferred PCI GPI better Routine Upstream GPI better Routine Upstream GP IIb/IIIa vs Deferred PCI GP IIb/IIIa *ITT population Stone GW et al: Presented at: 55 th ACC Annual Meeting March 2006

83. ACC/AHA/SCAI PCI Guidelines Class I: UFH should be given to pts undergoing PCI (Level of Evidence: C) For pts with HIT, it is recommended that bivalirudin or argatroban be used (Level of Evidence: B) Class I: UFH should be given to pts undergoing PCI (Level of Evidence: C) For pts with HIT, it is recommended that bivalirudin or argatroban be used (Level of Evidence: B) Anti-thrombin Therapy

84. ACC/AHA/SCAI PCI Guidelines Class IIa: It is reasonable to use bivalirudin as an alternative to UFH +GPI in low-risk pts having elective PCI (Level of Evidence: B) LMWH is a reasonable alternative to UFH in pts with UA/NSTEMI under-going PCI (Level of Evidence: B) Class IIa: It is reasonable to use bivalirudin as an alternative to UFH +GPI in low-risk pts having elective PCI (Level of Evidence: B) LMWH is a reasonable alternative to UFH in pts with UA/NSTEMI under-going PCI (Level of Evidence: B) Anti-thrombin Therapy

85. ACC/AHA/SCAI PCI Guidelines Class IIb: LMWH may be considered as an alternative to UFH in pts with STEMI undergoing PCI (Level of Evidence: B) Class IIb: LMWH may be considered as an alternative to UFH in pts with STEMI undergoing PCI (Level of Evidence: B) Anti-thrombin Therapy

86. Anti-Thrombins for PCI UFH is effective for PCI, especially when used with GP2b3a inhibition LMWH (enoxaparin) is safe and effective with PCI Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx UFH is effective for PCI, especially when used with GP2b3a inhibition LMWH (enoxaparin) is safe and effective with PCI Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx Summary

87. Anti-Thrombins for PCI UFH is effective for PCI, especially when used with GP2b3a inhibition LMWH (enoxaparin) is safe and effective with PCI Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx UFH is effective for PCI, especially when used with GP2b3a inhibition LMWH (enoxaparin) is safe and effective with PCI Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx Summary