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

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

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

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

Geological Time Scale

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

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

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

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

Prothrombin Thrombin Fibrinogen Fibrin monomer Tissue Factor VIIa VII VIIa/TF IXIXa X Xa Fibrin polymer Crosslinked FibrinV Va VIII VIIIa XIXIa XIIXIIa PK, HK HK XIIIXIIIa Ca ++ PL 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. 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. Coagulation

Platelet Activation Thrombus Injury Platelet Aggregation Thrombin Generation Thrombin Activity Coagulation

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

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

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

Medical Rx No Cath Cath PCI Surgery Medical Rx Delayed surgery Medical Rx No disease Delayed PCI Time Admission Cath PCI DischargeSurgery UA/NSTEMI Management

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

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

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

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

OASIS 5 OASIS 5 Investigators N Engl J Med. 2006;354: Patients w/ NSTE ACS Chest pain < 24 hours 2/3: Age > 60 ST-segment ∆ ↑ cardiac markers ASA, clopidogrel, IIb/IIIa, planned cath per local practice 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 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 PrimaryEfficacyDeath, MI, refractory ischemia at 9 days SafetyMajor bleeding at 9 days Risk/benefitDeath, MI, refractory ischemia and major bleeding at 9 days SecondaryAbove and each component separately at day 30 and 6 months Hypothesis:First test non-inferiority, then test superiority PCI < 6 h: no UFH PCI > 6h: IV UFH 100 U/kg w/o IIb/IIIa 60 U/kg w/ IIb/IIIa Outcomes

OASIS 5 OASIS 5 Investigators N Engl J Med. 2006;354: In-hospital procedures at 9 Days Cath LabNo Cath Lab Centers (n)420 (73%)156 (27%) Patients (n)14,028 (70%)6050 (30%) Angiography73.2%27.7% PCI39.6%12.5% CABG6.8%1.8% Revascularizatio n 46.1%14.1% Mean duration of therapy: Enoxaparin days Fondaparinux days

OASIS 5 OASIS 5 Investigators N Engl J Med. 2006;354:

OASIS 5 OASIS 5 Investigators N Engl J Med. 2006;354:

Abciximab (n=1,012) Abciximab (n=1,012) Placebo (n=1,010) 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 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 ISAR-REACT 2: Trial Design 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) 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)  ↑ troponin T or new ST ↓  Transient ( 0.1 mV  New BBB  ↑ troponin T or new ST ↓  Transient ( 0.1 mV  New BBB  Significant lesion in native vessel or bypass graft  Amenable to and requiring PCI  Significant lesion in native vessel or bypass graft  Amenable to and requiring PCI 2,022 patients with ACS and new angina episode within past 48 hours Kastrati A, et al. JAMA. 2006; 295:

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

ISAR-REACT 2: Bleeding 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) In-hospital Major and Minor Bleeding (%) P=NS Kastrati A, et al. JAMA. 2006; 295:

Moderate- high risk ACS ACUITY Angiography within 72h Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,800) Medical management PCI CABG 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. ASA in all clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R

Moderate- high risk ACS ACUITY Angiography within 72h Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,800) Medical management PCI CABG 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. ASA in all clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R Ischemic Composite Bleeding Net Clinical Outcome 7.3 %5.7 %11.7 % 7.7 %5.3 %11.8 % 7.8 %3.0 %10.1 %

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

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

Mehta SR, et al. JAMA. 2005;293: Routine vs Selective Invasive Strategy Summary of Odds Ratios for All Major Outcomes Routine vs Selective Invasive Strategy: Summary of Odds Ratios for All Major Outcomes

Routine vs Selective Invasive Strategies in ACS Adapted from Mehta S, et al. JAMA. 2005;293; Composite of Death or Myocardial Infarction No./Total (%) SourceRoutine Invasive Selective Invasive TIMI IIIB86/740 (11.6)101/733 (13.8) VANQWISH152/462 (32.9)139/458 (30.3) MATE16/111 (14.4)11/90 (12.2) FRISC II127/1222 (10.4)174/1235 (14.1) TACTICS81/1114 (7.3)105/1106 (9.5) VINO4/64 (6.3)15/67 (22.4) RITA 395/895 (10.6)118/915 (12.9) Total561/4608 (12.2)663/4604 (14.4) Odds Ratio (95% CI) Favors Routine Invasive Favors Selective Invasive OR % CI, P < 0.001

ICTUS N Engl J Med 2005; 353: 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 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

Early Invasive Selective Invasive Death2.2 %2.0 % MI14.6 %9.4 % Rehospitalization7.0 %10.9 % Total21.7 %20.4 % ICTUS N Engl J Med 2005; 353:

22.7 % 21.2 % [ RR 1.07, 95 % CI ; p=0.33 ] ICTUS N Engl J Med 2005; 353:

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 ICTUS N Engl J Med 2005; 353:

FRISC II MI - CK-MB > ULN for spontaneous MI, > 1.5X ULN following PCI TACTICS MI - CK-MB > ULN for spontaneous MI, > 3X ULN following PCI ICTUS N Engl J Med 2005; 353:

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

Comparative Revascularization Rates ICTUS N Engl J Med 2005; 353:

Routine vs Selective Invasive Strategies in ACS Adapted from Mehta S, et al. JAMA. 2005;293; Composite of Death or Myocardial Infarction No./Total (%) SourceRoutine Invasive Selective Invasive TIMI IIIB86/740 (11.6)101/733 (13.8) VANQWISH152/462 (32.9)139/458 (30.3) MATE16/111 (14.4)11/90 (12.2) FRISC II127/1222 (10.4)174/1235 (14.1) TACTICS81/1114 (7.3)105/1106 (9.5) VINO4/64 (6.3)15/67 (22.4) RITA 395/895 (10.6)118/915 (12.9) Total561/4608 (12.2)663/4604 (14.4) Odds Ratio (95% CI) Favors Routine Invasive Favors Selective Invasive OR, % CI, P<.001

 Optimize supply / demand Acute  Treat underlying atherosclerosis  Prevent recurrent events Stabilize the plaques Enhance endothelial function Chronic anti-thrombotic Rx  Treat underlying atherosclerosis  Prevent recurrent events Stabilize the plaques Enhance endothelial function Chronic anti-thrombotic Rx Long - term Statins ASA Clopidogrel ASA / Clopidogrel Warfarin Risk factor ↓ Other things not to forget BP control Glucose control Smoking cessation ACE inhibitors And don’t forget... O 2 Nitrates  -blockers

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

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

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

Lessons Learned 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 UA / NSTEMI

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

Lessons Learned 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 StatinsACE Inhibitors Antiplatelet RxAntithrombotic Rx UA / NSTEMI

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

ASA IIb/IIIa antagonists EPISTEN T PURSUIT 2001 ESPRIT GUSTO ISAR REACT Clopidogrel CURE 2000 Anti-platelet agents UFH LMWH TIMI 11B 2004 SYNERGY Bivalirudin 2003 REPLACE Anti-thrombotic agents ISAR REACT 2 Fondaparinux ACUITY ? ? ?OASIS 5 Our Evolving Anticoagulant Armamentarium

 The predictive value of a diagnostic test  is a function not only of sensitivity and specificity,  but also the prevalence of the disease  in the population being tested.  The predictive value of a diagnostic test  is a function not only of sensitivity and specificity,  but also the prevalence of the disease  in the population being tested. Bayes’ Theorem

 Stuff you do works best  in people who really need it.  Stuff you do works best  in people who really need it. Bubba’s Theorem

 Age  (+) Biomarkers  (+) ST-segment Δs  Diabetes  Refractory symptoms Acute Risk Stratifiers Extent of disease Extent of damage Ongoing thrombosis

F Age F (+) Biomarkers  (+) ST-segment Δs F Diabetes F Refractory symptoms Acute Risk Stratifiers Extent of damage EF, CK, CKMB, troponin Extent of homeostatic derangement CRP, CD40L, BNP, IL-6, Fibrinogen, P-selectin Extent of disease EF, DM

 Age  Lipid status  Diabetes  Extent of disease  Prior revascularization  Pro-thrombotic tendencies  Endothelial homeostasis  CRP Long-term Risk Stratifiers Progression Thrombosis Stability

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

Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together Therapeutic epochs Building on what has gone before Changing it Adding to it

Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together Plaque rupture Homeostatic forces Dynamic balance Multiple interlocking mechanisms

Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together OASIS 5, ISAR-REACT 2, ACUITY ICTUS Stay tuned... more to come

Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together Open vessels Keep them open Adjunctive therapy important Perfusion rather than patency

Evolutionary perspectives Evolving physiology Evolving data Evolving messages Putting it together Look at the big picture Evaluate the data yourself Risk stratification is key Don’t just do... think

ACS Patients Invasive Strategy Conservative Strategy Angio No Angio Medical RxPCISurgery

ACS Patients Invasive Strategy Conservative Strategy Angio No Angio Medical RxPCISurgery Higher risk IIb/IIIa (eptifibatide or tirofiban) or clopidogrel (with load) Enoxaparin Fondaparinux UFH Bivalirudin Evidence of myocardial damage Delay to angio Recurrent ischemia Poor LV function IIb/IIIa plus clopidogrel (with load) Class I Class IIa Class IIb Class III ASA Alternative - Clopidogrel

ACS Patients Invasive Strategy Conservative Strategy Angio No Angio Medical RxPCISurgery Higher risk Lower risk IIb/IIIa (eptifibatide or tirofiban) or clopidogrel (with load) Enoxaparin Fondaparinux UFH Bivalirudin Evidence of myocardial damage Delay to angio Recurrent ischemia Poor LV function IIb/IIIa plus clopidogrel (with load) IIb/IIIa or clopidogrel (with load) or both Class I Class IIa Class IIb Class III ASA Alternative - Clopidogrel

ACS Patients Invasive Strategy Conservative Strategy Angio No Angio Medical RxPCISurgery Class I Class IIa Class IIb Class III

ACS Patients Invasive Strategy Conservative Strategy Angio No Angio Medical RxPCISurgery ASA Alternative - Clopidogrel Enoxaparin Fondaparinux UFH Clopidogrel (with load) added to ASA Continue for at least 1 year Recurrent symptoms/ischemia Heart failure Serious arrhythmias Enoxaparin, Fondaparinux preferable to UFH (unless CABG planned within 24 hrs) Add IIb/IIIa (eptifibatide, tirofiban) Fibrinolytic Rx Abciximab (if no PCI) Class I Class IIa Class IIb Class III Not low riskLow risk Consider IIb/IIIa