James J. Ferguson, MD

1. James J. Ferguson, MD The Evolving Standard of Care for Acute Coronary Syndromes 2006

2. How do we sort out this mess ? CAPTURE PROTECT EPILOG EPIC ISAR-SWEET GUSTO IIA SYNERGY ISAR-REACT IMPACT 2 ACE RESTORE GUSTO IV TACTICS CAPRIE FRIC BAT PURSUIT CADILLAC ESPRIT TIMI 8 CREDO FRISC 2 EPISTENT FRAXIS GUSTO IIB PRISM OASIS Pilot PRISM-PLUS CURE RITA 3 TIMI 7 INTERACT TIMI 11B FRISC OASIS 2 ACUTE 2 FRISC 2 REPLACE 2 HELVETICA A to Z TARGET ESSENCE The Evolving Standard of Care for Acute Coronary Syndromes 2006

3. The Evolving Standard of Care for Acute Coronary Syndromes 2006 Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together

4. The Evolving Standard of Care for Acute Coronary Syndromes 2006 Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together

5. Geological Time Scale

6. Understand the biology Harmonize therapies Open the vessel Treat the thrombus Reduce demand Palliative Epoch Antithrombotic Epoch Interventional Epoch Synergistic Epoch Mechanistic Epoch ACS Time Scale

7. The Evolving Standard of Care for Acute Coronary Syndromes 2006 Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together

8. Inflammation and repair STABLE PLAQUE Luminal factors Extra-luminal factors Systemic factors UNSTABLE PLAQUE MYOCARDIAL INFARCTION DETERMINANTS OF Rupture Thrombosis Healing Fibrous tissue Cap thickness Atheromatous material(lipid-rich) Core size Thrombus Plaque hemorrhage Macrophage Smooth muscle cell “Vulnerable” Plaque and Acute Coronary Syndromes

9. Reduce thrombus burden Limit thrombus progression Promote healing / homeostasis Open the occluded vessel Limit the extent of the damage Rx UA Rx MI Rupture Thrombosis Occlusion

10. Crosslinked Fibrin Thrombin Coagulation XIII XIIIa PK, HK VIII Fibrin polymer XII XIIa V HK Fibrin monomer VIIIa XI XIa Va IX IXa Ca++ PL Ca++ PL Xa Fibrinogen Tissue Factor VIIa/TF X VIIa Prothrombin VII

11. Coagulation Question: What do we really need to know about coagulation? Answer: How to treat it when it happens. How to prevent it in the first place.

12. Platelet Activation Thrombus Injury Platelet Aggregation Thrombin Activity Thrombin Generation Coagulation

13. Aspirin Ticlopidine Clopidogrel Platelet Activation Injury Platelet Aggregation IIb/IIIa blockers Heparin LMW heparin Xa inhibitors Thrombin Generation LMW heparin Heparin Antithrombins Thrombin Activity Thrombus Fibrinolytic Rx

14. The Evolving Standard of Care for Acute Coronary Syndromes 2006 Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together

15. BAT (original) STARS FANTASTIC MATTIS TIMI 11B ISAR-COOL ISAR-COOL ACE P-S stent DE stent A to Z CAPTURE EPISTENT 1990 1993 1996 1999 2002 2005 ESSENCE ISAR-REACT Interventional Issues Eptifibatide Bivalirudin Enoxaparin Dalteparin Enox ACS Dalt ACS GUSTO IV Thienopyridines REDUCE Clopidogrel Clopidogrel ACS REPLACE 2 OASIS 2 ACUTE 2 TAXUS IV ISAR-REACT STRESS BENESTENT GP IIb/IIIa antagonists LMW Heparins CAPRIE ISAR SIRIUS FRISC 2 CURE CREDO ERA FRISC 2 CLASSICS RAVEL EPILOG PURSUIT EPIC ESPRIT TACTICS FRISC INTERACT SYNERGY OASIS Pilot Thrombin Inhibitors Abciximab TARGET CADILLAC ISAR-SWEET ISAR-SWEET PROTECT Wallstent restenosis HELVETICA BAT (revised) TIMI 8 RITA 3 ICTUS Lepirudin FRAXIS FRIC IMPACT 2 PRISM RITA 3 TACTICS PROTECT GUSTO IIB PROTECT GUSTO IIA TIMI 7 Tirofiban Argatroban Desirudin PRISM-PLUS RESTORE ARMYDA 2 ISAR-REACT 2 CHARISMA ACUITY [ OASIS 5 ] UA / NSTEMI Trials

16. Discharge PCI Surgery Admission Cath Cath Surgery Delayed surgery Medical Rx Delayed PCI Medical Rx Time No disease Medical Rx PCI No Cath UA/NSTEMI Management

17. Surgery Discharge PCI Admission Cath Cath Surgery Delayed surgery Medical Rx Delayed PCI Medical Rx Time No disease Medical Rx PCI No Cath UA/NSTEMI Management Patient X

18. PCI 63 % < 48 hrs Surgery Discharge Cath Admission 40 % < 48 hrs CRUSADE Registry 10/05-9/05 n=35,897 Cath Surgery Delayed surgery Medical Rx (12 %) Delayed PCI Medical Rx 12 % > 48 hrs 19 % > 48 hrs Time No disease Medical Rx Medical Rx PCI (82 %) (52 %) No Cath (18 %) UA/NSTEMI Management Patient X

19. Important Data UA / NSTEMI IIb/IIIa antagonists Clopidogrel ISAR - COOL PROTECT CURE Invasive Strategy LMW Heparin FRISC II TACTICS / TIMI 18 RITA 3 ICTUS INTERACT A to Z SYNERGY

20. Very Recent Data UA / NSTEMI OASIS 5 ISAR-REACT 2 ACUITY ICTUS

21. Patients w/ NSTE ACS Chest pain < 24 hours 2/3: Age > 60 ST-segment ∆ ↑ cardiac markers Exclude Age < 21 Contraindication to enox Hemorrhagic stroke < 12 mo Creat > 3 mg/dL (265 umol/L) Randomize n = 20,000 Fondaparinux 2.5 mg sc qd Enoxaparin 1 mg/kg sc bid ASA, clopidogrel, IIb/IIIa, planned cath per local practice PCI < 6 h: IV fondaparinux 2.5 mg w/o IIb/IIIa, 0 w/ IIb/IIIa PCI > 6h: IV fondaparinux 5 mg w/o IIb/IIIa, 2.5 mg w/ IIb/IIIa PCI < 6 h: no UFH PCI > 6h: IV UFH 100 U/kg w/o IIb/IIIa 60 U/kg w/ IIb/IIIa Outcomes Primary Efficacy Death, MI, refractory ischemia at 9 days Safety Major bleeding at 9 days Risk/benefit Death, MI, refractory ischemia and major bleeding at 9 days Secondary Above and each component separately at day 30 and 6 months Hypothesis: First test non-inferiority, then test superiority

22. Cath Lab No Cath Lab Centers (n) 420 (73%) 156 (27%) Patients (n) 14,028 (70%) 6050 (30%) Angiography 73.2% 27.7% PCI 39.6% 12.5% CABG 6.8% 1.8% Revascularization 46.1% 14.1% In-hospital procedures at 9 Days Mean duration of therapy: Enoxaparin 5.2 + 2.3 days Fondaparinux 5.4 + 2.4 days

25. ISAR-REACT 2: Trial Design 2,022 patients with ACS and new angina episode within past 48 hours • ↑ troponin T or new ST ↓ • Transient (<20 min) ST ↑ of > 0.1 mV • New BBB • Significant lesion in native vessel or bypass graft • Amenable to and requiring PCI Clopidogrel (Pre-treatment high-dose 600 mg loading dose for at least 2 hour pre-procedure, 2 x 75 mg/d through discharge, 75 mg/d for 4 weeks) Abciximab (n=1,012) Placebo (n=1,010) Endpoints: Primary Endpoint: Composite of death, MI, and urgent TVR due to myocardial ischemia within 30 days Secondary Endpoint: In-hospital major and minor bleeding Kastrati A, et al. JAMA. 2006; 295: 1531-8

26. ISAR-REACT 2: Primary Endpoint Primary Endpoint By Troponin Status Primary Endpoint Death, MI, or urgent TVR in 30 days p = .03 p = .02 p = .98 Kastrati A, et al. JAMA. 2006; 295: 1531-8

27. ISAR-REACT 2: Bleeding In-hospital Major and Minor Bleeding (%) P=NS • There was no difference between the abciximab and placebo groups in in-hospital major and minor bleeding (p=NS for both). • There was one intracranial bleed in each group. • 2.5% of patients received transfusions in the abciximab group compared with 2.0% in the placebo group (RR 1.25) Kastrati A, et al. JAMA. 2006; 295: 1531-8

28. R UFH or Enoxaparin + GP IIb/IIIa ACUITY Medical management Angiography within 72h Moderate- high risk ACS PCI Bivalirudin + GP IIb/IIIa Bivalirudin Alone CABG Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,800) ASA in all clopidogrel dosing and timing per local practice Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30-days); composite of the above (30-days) Stone G. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

29. Ischemic Composite R UFH or Enoxaparin + GP IIb/IIIa Bleeding Net Clinical Outcome ACUITY Medical management Angiography within 72h Moderate- high risk ACS 7.3 % 5.7 % 11.7 % PCI Bivalirudin + GP IIb/IIIa 7.7 % 5.3 % 11.8 % Bivalirudin Alone 7.8 % 3.0 % 10.1 % CABG Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,800) ASA in all clopidogrel dosing and timing per local practice Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30-days); composite of the above (30-days) Stone G. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

30. R ACUITY Second Randomization – GP IIb/IIIa Inhibitor Timing Routine upstream GPI in all pts (4,605) Moderate- high risk ACS (n=13,819) UFH, Enoxaparin, or Bivalirudin VS R Deferred GPI for PCI only (n=4,602) Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,819) UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only Bivalirudin Routine upstream GPI in all pts GPI started in CCL for PCI only Aspirin in all Clopidogrel dosing and timing per local practice Bivalirudin Alone (n=4,612) Bivalirudin Alone (n=4,612) Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30-days); composite of the above (30-days) Stone G. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

31. Ischemic Composite R Bleeding Net Clinical Outcome ACUITY Second Randomization – GP IIb/IIIa Inhibitor Timing Routine upstream GPI in all pts (4,605) Moderate- high risk ACS (n=13,819) 7.1 % 6.1 % 11.7 UFH, Enoxaparin, or Bivalirudin VS R Deferred GPI for PCI only (n=4,602) 7.9 % 4.9 % 11.7 % 7.8 % 3.0 % 10.1 % Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,819) UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only Bivalirudin Routine upstream GPI in all pts GPI started in CCL for PCI only Aspirin in all Clopidogrel dosing and timing per local practice Bivalirudin Alone (n=4,612) Bivalirudin Alone (n=4,612) Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30-days); composite of the above (30-days) Stone G. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

32. No./Total (%) Routine vs Selective Invasive Strategy:Summary of Odds Ratios for All Major Outcomes Outcome Routine Selective Odds Ratio (95% CI) P Value Randomization to Hospital Discharge Death 82/4608 (1.8) 51/4604 (1.1) 1.60 (1.14 – 2.25) .007 Nonfatal MI 171/4608 (3.7) 139/4604 (3.0) 1.24 (0.99 – 1.56) .07 Death or MI 238/4608 (5.2) 177/4604 (3.8) 1.36 (1.12 – 1.66) .002 After Hospital Discharge to End of Follow-up Death 172/4526 (3.8) 223/4552 (4.9) 0.76 (0.62 – 0.94) .01 Nonfatal MI 164/4370 (3.8) 294/4430 (6.6) 0.56 (0.46 – 0.67) <.001 Death or MI 323/4370 (7.4) 486/4430 (11.0) 0.64 (0.56 – 0.75) <.001 Randomization to End of Follow-up Death 254/4608 (5.5) 274/4604 (6.0) 0.92 (0.77 – 1.09) .33 Nonfatal MI 335/4608 (7.3) 433/4604 (9.4) 0.75 (0.65 – 0.88) <.001 Death or MI 561/4608 (12.2) 663/4604 (14.4) 0.82 (0.72 – 0.93) .001 Mehta SR, et al. JAMA. 2005;293:2908-2917.

33. Composite of Death or Myocardial Infarction No./Total (%) Routine vs Selective Invasive Strategies in ACS Source Routine Invasive Selective Invasive TIMI IIIB 86/740 (11.6) 101/733 (13.8) VANQWISH 152/462 (32.9) 139/458 (30.3) MATE 16/111 (14.4) 11/90 (12.2) FRISC II 127/1222 (10.4) 174/1235 (14.1) TACTICS 81/1114 (7.3) 105/1106 (9.5) VINO 4/64 (6.3) 15/67 (22.4) RITA 3 95/895 (10.6) 118/915 (12.9) Total 561/4608 (12.2) 663/4604 (14.4) Favors Routine Invasive Favors Selective Invasive OR - 0.82 95% CI, 0.72-0.93 P < 0.001 0.1 1.0 10 Odds Ratio (95% CI) Adapted from Mehta S, et al. JAMA. 2005;293;2908-2917.

34. ICTUS N Engl J Med 2005; 353: 1095-1104 • 1200 ACS patients • Presenting within 1 day of onset of chest pain • 42 Dutch hospitals (12 were high-volume PCI centers) • ↑ Troponin T (≥ 0.03 μg/L) • Either ECG evidence of ischemia or documented Hx CAD • Randomized • Early invasive (n=604) • Angio within 24-48 hours • PCI within 48 hours, CABG as soon as possible • Selective invasive (n=596) • Angio for refractory angina, provocable ischemia Primary Endpoint: Death / MI / rehospitalization at 1 year

35. Early Invasive Selective Invasive Death 2.2 % 2.0 % MI 14.6 % 9.4 % Rehospitalization 7.0 % 10.9 % Total 21.7 % 20.4 % ICTUS N Engl J Med 2005; 353: 1095-1104

36. ICTUS N Engl J Med 2005; 353: 1095-1104 22 .7 % 21.2 % [ RR 1.07, 95 % CI 0.87 - 1.33; p=0.33 ]

37. ICTUS N Engl J Med 2005; 353: 1095-1104 Median time to PCI 23 hours (25th to 75th percentile, 15 to 44) with early invasive Rx 283 hours (25th to 75th percentile, 142 to 647) with selective invasive Rx

38. Even after ICTUS ... All-Cause Mortality Bavry et al. J Am Coll Cardiol 2006; 48: 1319-25

39. Even after ICTUS ... All-cause mortality as a function of time of angio and extent of revascularization Bavry et al. J Am Coll Cardiol 2006; 48: 1319-25

40. Acute Long - term O2 Nitrates β-blockers BP control Glucose control Smoking cessation ACE inhibitors Statins ASA Clopidogrel ASA / Clopidogrel Warfarin Other things not to forget Risk factor ↓ And don’t forget . . . Optimize supply / demand Treat underlying atherosclerosis Prevent recurrent events Stabilize the plaques Enhance endothelial function Chronic anti-thrombotic Rx

41. The Evolving Standard of Care for Acute Coronary Syndromes 2006 Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together

42. FRISC II TACTICS / TIMI 18 RITA 3 ?? ICTUS ?? Lessons Learned UA / NSTEMI Invasive is better than conservative in high and medium risk patients

43. Clopidogrel is beneficial IIb/IIIa blockers are beneficial Earlier is better in high risk “Standard” is more than ASA Lessons Learned UA / NSTEMI Invasive is better than conservative in high and medium risk patients Antiplatelet therapy is important

44. Lessons Learned UA / NSTEMI Invasive is better than conservative in high and medium risk patients Antiplatelet therapy is important Antithrombin therapy is important Enoxaparin - SYNERGY Bivalirudin - ACUITY Fondaparinux - OASIS 5 “Standard” moving beyond UFH Challenges of multiple management pathways

45. Interaction among agents Interaction with treatment strategies Lessons Learned UA / NSTEMI Invasive is better than conservative in high and medium risk patients Antiplatelet therapy is important Antithrombin therapy is important How you put them together is important

46. Statins ACE Inhibitors Antiplatelet Rx Antithrombotic Rx Lessons Learned UA / NSTEMI Invasive is better than conservative in high and medium risk patients Antiplatelet therapy is important Antithrombin therapy is important How you put them together is important Long term therapy is important

47. The Evolving Standard of Care for Acute Coronary Syndromes 2006 Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together

50. 1992 1995 1998 2001 2004 2007 Our Evolving Anticoagulant Armamentarium UFH 2004 ACUITY 1997 1999 SYNERGY LMWH TIMI 11B 2006 2001 2003 Bivalirudin REPLACE 2 ACUITY Anti-thrombotic agents Fondaparinux OASIS 5 ? ? ? ASA 2004 2006 EPISTENT ESPRIT ACUITY IIb/IIIa antagonists PURSUIT GUSTO 4 ISAR REACT ISAR REACT 2 1995 1998 2000 2001 CURE Clopidogrel Anti-platelet agents