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Landmark Practice Advances In ST-Elevation Myocardial Infarction (STEMI) and Acute Coronary Syndrome (ACS) Consistent and Unified Management Strategies.

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Presentation on theme: "Landmark Practice Advances In ST-Elevation Myocardial Infarction (STEMI) and Acute Coronary Syndrome (ACS) Consistent and Unified Management Strategies."— Presentation transcript:

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2 Landmark Practice Advances In ST-Elevation Myocardial Infarction (STEMI) and Acute Coronary Syndrome (ACS) Consistent and Unified Management Strategies for 2008 and BeyondWhat Do New Trials Tell Us About Care for High Risk ACS? Landmark Practice Advances In ST-Elevation Myocardial Infarction (STEMI) and Acute Coronary Syndrome (ACS) Consistent and Unified Management Strategies for 2008 and BeyondWhat Do New Trials Tell Us About Care for High Risk ACS? A Year 2008 Update Stefano Savonitto, MD, FESC Prima Divisione di Cardiologia Dipartimento Cardiologico Angelo De Gasperis Ospedale Niguarda Ca Granda Milano, Italy Carlo Di Mario, MD, PhD, FESC, FACC, FRCP Professor of Clinical Cardiology Imperial College of Sciences, Medicine & Technology Technology Consultant in Interventional Cardiology Royal Brompton Hospital London, UK Program Co-Chairmen

3 CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from The Medicines Company Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

4 Program Educational Objectives As a result of this educational activity, physicians will: Learn how recently issued ESC and AHA/ACC guidelines for UA/Non ST-elevation myocardial infarction and STEMI are best applied to appropriately risk-stratified patients with high risk ACS and STEMI. Learn to understand the implications of recent clinical data, trials, and recommendations on upstream and catheterization laboratory- based management of STEMI and NSTEMI. Learn to apply guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with high risk ACS. As a result of this educational activity, physicians will: Learn how recently issued ESC and AHA/ACC guidelines for UA/Non ST-elevation myocardial infarction and STEMI are best applied to appropriately risk-stratified patients with high risk ACS and STEMI. Learn to understand the implications of recent clinical data, trials, and recommendations on upstream and catheterization laboratory- based management of STEMI and NSTEMI. Learn to apply guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with high risk ACS.

5 Program Faculty Program Co-Chairmen Carlo Di Mario, MD, PhD, FESC, FACC, FRCP Professor of Clinical Cardiology Imperial College of Sciences, Medicine & Technology Technology Consultant in Interventional Cardiology Royal Brompton Hospital London, UK Stefano Savonitto, MD, FESC Prima Divisione di Cardiologia Dipartimento Cardiologico Angelo De Gasperis Ospedale Niguarda Ca Granda Milano, Italy Distinguished Faculty Presenters Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Chief of Cardiology VA Boston Healthcare System Director of the Integrated Cardiovascular Intervention Program Intervention Program Brigham and Womens Hospital and the VA Boston Healthcare System VA Boston Healthcare System Harvard Medical School Boston, Massachusetts Michael M. Hirschl, MD Associate Professor Head of the Emergency Room Medical Department of Cardiology and Intensive Care Medicine Care Medicine Landesklinikum St. Pölten A-3100 St. Pölten, Austria

6 Faculty COI Disclosures Carlo Di Mario, MD, PhD, FESC, FACC, FRCP Research Grants: Eli Lilly, Cordis Johnson and Johnson, Biotronik, Biosensors, Medtronic Consulting or Speakers Fees: Boston Scientific, Abbott, The Medicines Company, Biosensors Stefano Savonitto, MD, FESC Speakers Honoraria: sanofi-aventis, Eli Lilly, The Medicines Company Consultant Fees: Eli Lilly Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Consultant Fees: Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, The Medicines Company, tns Healthcare, Vertex. Honoraria are donated to NPOs. PI and/or on steering committees of several potentially related trials. This presentation discusses off-label and/or investigational uses of antithrombotic drugs and interventional devices. Michael M. Hirschl, MD Speakers Honoraria: Takeda-Austria, Merck Sharp&Dome, Actelion and Servier Austria. Research grant: Actelion-Austria

7 Issues and Challenges in Acute Coronary Syndromes A Review of Critical Advances and Current Controversies in STEMI and High Risk ACS Landmark Practice Advances in STEMI and ACS Stefano Savonitto, MD, FESC Program Co-Chairman Prima Divisione di Cardiologia Dipartimento Cardiologico Angelo De Gasperis Ospedale Niguarda Ca Granda Milano, Italy

8 NSTE-ACS STEMI TROPONIN SK Landmark Practice Advances in Acute Coronary Syndromes SK+ASPIRIN r-tPA TNK Pre-H lysis Morrison PRIMARY PCI ABCIXIMAB CLOPIDOGREL REACT BIVALIRUDIN VIENNA REGISTRY CARESS ASPIRIN + HEPARIN1983-88 CLOPIDOGREL UPSTREAM GP IIb/IIIa EARLY INVASIVE ABCIXIMAB IN CATH LAB FONDAPARINUX BIVALIRUDIN ENOXAPARIN 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

9 ACC/AHA ESC 1990AMI R. Gunnar 1994 Unstable Angina^ E. Braunwald 2000UA/NSTEMIRevised 2002UA/NSTEMIUpdated 2007UA/NSTEMIRevised J. Anderson 2000 ACS w/o STE M. Bertrand 2002 ACS w/o STE Updated M. Bertrand 2007NSTEACS JP. Bassand Development of ESC and ACC/AHA ACS Guidelines (modified from Ohman EM) ^AHCPR: Agency for Health Care Policy and Research. 1999 AMI upd. T. Ryan 2004 STEMI Revised E. Antman 2007STEMI Focused upd. E. Antman 1996AMI T. Ryan 2003STEMI F. Van de Werf 2008STEMI 2005PCI SC Smith 2005 PCI upd SC Smith 2005PCI S. Silber 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

10 Reperfusion by Time Proportion % Uppsala Clinical Research Centre 2005 1995 - 2004

11 30-day AMI Mortality Over Time 1995 - 2004 Mortality % >= 75 yr 65 – 74 yr < 65 yr Women<65 Women 65-75 Women >75 Men<65 Men 65-75 Men >75 Uppsala Clinical Research Centre 2005

12 Prehospital ECG and Time to Reperfusion Based on NRMI 4, 2000 to 2002 Lytic cohort PCI cohort % of pts with door to needle <30 N= 35,370 4.5% with Pre-H ECG N= 21,277 8.0% with Pre-H ECG Curtis JP, JACC 2006;47:1544 % of pts with door to balloon <90

13 Impact of Direct Access to Cath Lab on Hospital Mortality for STEMI Ortolani P. Eur Heart J 2006;27:1550 Thrombolysis Primary PCI with direct access via 118 Policlinico S.Orsola, Bologna - Italy Mortality reduction over time = 43% %

14 Pre-hospitalthrombolysis Rescue PCI Facilitated PPCI ? Primaryangioplasty In-hospitalthrombolysis GOAL 75% early reperfusion Implementation of Reperfusion Therapy in STEMI ESC Policy Statement Bassand JP et al, Eur Heart J 2005;26:2733 All forms of reperfusion, depending on local facilities, need to be available to patients with STEMI

15 R-PCI: 93.8% ( CI 89.8%-97.7%) R-Lysis: 87.3% (CI 81.9%-92.8%) Conservative: 87.2% (CI 81.7%-92.7%) REACT: Survival at 6 months Gershlick AH, N Engl J Med 2005;353:2758 0 20 40 60 80 100 120 140 160 180 200 Number of Days Survival Distribution Function 1.00.90.80.70.60

16 Time Trends of Primary and Rescue PCI for STEMI in Italy: The GISE Registry Giornale Italiano di Cardiologia Invasiva 2008;(2) suppl 1

17 Primary Endpoint p=0.55 Ellis S, NEJM 2008;358:2205

18 Primary Outcome at 30 Days 4.1% 11.1% Death, re-MI, refractory ischaemia OR 0.34 (95%CI 0.17-0.68) P=0.001 Di Mario C et al. Lancet 2008; 371: 559 + EF 15 mm STE or new LBB, + Killip >2, + EF <0.35 0 5 10 15 20 25 30 0.150.100.050 Proportion of Patients Having an Event Time Since Randomisation (Days) Medical Treatment/Rescue Group Facilitated PCI Group

19 Kaplan-Meier Curves for Survival Kaplan-Meier Curves for Survival Krakow STEMI Registry 1 Year Follow-Up PRIMARY Dudek D, EuroPCR 2005 Zone I Zone II FACILITATED 0 8 16 24 32 40 48 1,000,950,900,850,80 P=NS (log rank)

20 Abciximab for Primary PCI in STEMI Significant Mortality Reduction -29% De Luca G, et al. JAMA 2005;293:1759 Abciximab Control Abciximab Control Control (n-14,145) Abciximab (n=12,297) Better Better P Value RAPPORT11/242(4.5)10/241(4.1).83 ISAR-217/200(8.5)12/201(6.0).33 ADMIRAL11/151(7.3)5/149(3.4).13 CADILLAC45/103044/1052(4.2).83 Petronio et al6/45(13.3)2/44(4.5).15 Zorman et al7/51(13.7)5/112(4.5).04 ACE21/197(10.5)10/197(5.0).04 Primary PCI118/1916(6.2)88/1996(4.4).01 No. of Deaths/Total (%) 0.1 1.0 10.0

21 HORIZONS AMI 30 Day Mortality Number at risk Bivalirudin 1800175817511746174217291666 Heparin + GPIIb/IIIa 1802176417481736172817071630 Death (%) Time in Days 3.1% 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

22 Adjudicated Cases of Myocardial Infarction Ospedale Niguarda: Year 2003 12 136 216 264 MI ST MI no ST Cardiology Medicine 228 (36%) 400 (64%) 148 480 628

23 Lagerqvist B, JACC 2002;40:1902-14 High risk (FRISC score 4-7) 30% Invasive Non-Inv. RR (95% CI) 32.7% 41.6% 0.79 (0.64-0.97) Medium risk (FRISC score 2-3) 53% Invasive Non-Inv. RR (95% CI) 14.6% 20.4% 0.72 (0.55-1.13) Death or MI During 5 Years and Risk Low risk (FRISC score 0-1) 17% Invasive Non-Inv. RR (95% CI) 10.3% 8.2% 1.26 (0.66-2.40) FRISC score (sum of): Age > 65 years Age > 65 years Male gender Male gender Diabetes mellitus Diabetes mellitus Previous MI Previous MI ST-depression ST-depression Elevated troponin Elevated troponin Elevated II-6/CRP Elevated II-6/CRP 0 1 2 3 4 5 Time since randomisation (years) 403020100 Death or myocardial infarction (%)

24 Impact of Abciximab on Top of ASA and Clopidogrel Depends on Patients Baseline Risk Death or MI at 30 days Kastrati A, NEJM 2004, JAMA 2006 ISAR REACT 1 Stable patients ISAR REACT 2 NSTEACS TnT - ISAR REACT 2 NSTEACS TnT + P=0.98 P=0.91 P=0.02

25 Common Key Points of the Year 2007 ESC and ACC/AHA Editions Both guidelines indicate a grading for urgency at angiography Patients with refractory ischemia, haemodynamic or arrhythmic instability must undergo urgent angiograhy with the intent of revascularization (IC ESC, IB ACC/AHA) Patients with refractory ischemia, haemodynamic or arrhythmic instability must undergo urgent angiograhy with the intent of revascularization (IC ESC, IB ACC/AHA) Patients with intermediate and high risk characteristics, but without urgent characteristics, should undergo angiography, within 72 hours according to ESC, without indication on timing according to ACC/AHA. (IA both) Patients with intermediate and high risk characteristics, but without urgent characteristics, should undergo angiography, within 72 hours according to ESC, without indication on timing according to ACC/AHA. (IA both) Both guidelines recommend that, in conjunction with either management strategy, great care should be taken in considering the risk vs benefit ratio of antithrombotic therapy Both guidelines recommend that, in conjunction with either management strategy, great care should be taken in considering the risk vs benefit ratio of antithrombotic therapy

26 ACUITY: Primary Endpoint Measures Bivalirudin alone better UFH/Enox + IIb/IIIa better Risk ratio ±95% CI Risk ratio ±95% CI PrimaryendpointBivalalone 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) <0.0010.015 7.3%7.8% 1.08 (0.93-1.24) 0.020.32 5.7%3.0% 0.53 (0.43-0.65) <0.001<0.001 p value (non-inferior) (superior) UFH/Enoxaparin + GPI vs. Bivalirudin Alone UFH/Enoxaparin + GPI vs. Bivalirudin Alone Stone GW et al. NEJM 2006;355:2203-16

27 ACUITY: Early and Late Mortality Landmark Analysis Stone GW. JAMA 2007;298:2497-506 0306090120150180210240270300330360390 0 3 4 2 1 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 30 day Estimate P (log rank) 1.4% 0.53 1.6% 0.39 1.6% Estimate P (log rank) 3.1% 0.54 2.7% 0.21 2.3% 30d - 1 year Mortality (%) Days from Randomization

28 Mortality (%) Days from Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 1 year Estimate Major Bleed only (without MI) (N=551)12.5% 28.9%Both MI and Major Bleed (N=94) 3.4%No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611)8.6% ACUITY Trial: Impact of MI and Major Bleeding (non- CABG) in the First 30 Days on Risk of Death Over 1 Year Stone GW, et al. JAMA 2007; 298:2497-2506.

29 Common Key Points of the 2007 ESC and ACC/AHA Editions Risk stratification in relation to bleeding and the prevention of bleedingare considered of utmost importance in both GLs, and particularly, in the ESC GLs. The validation and introduction in the GLs of newer antithrombotic agents (particularly bivalirudin and fondaparinux), characterized by lower bleeding risk, based upon large scale RCTs, is one of the most important new features of both ESC and ACC/AHA GLs. Risk stratification in relation to bleeding and the prevention of bleeding are considered of utmost importance in both GLs, and particularly, in the ESC GLs. The validation and introduction in the GLs of newer antithrombotic agents (particularly bivalirudin and fondaparinux), characterized by lower bleeding risk, based upon large scale RCTs, is one of the most important new features of both ESC and ACC/AHA GLs. Recommendations about a restrictive approach to transfusionsand instructions for continuing antithrombotic therapies in the case of bleeding in order to avoid rebound phenomena are similar and bear important clinical implications. Recommendations about a restrictive approach to transfusions and instructions for continuing antithrombotic therapies in the case of bleeding in order to avoid rebound phenomena are similar and bear important clinical implications. Bleeding and Transfusions

30 Both GLs note special care required in frail/high risk populations Common Key Points of the 2007 ESC and ACC/AHA Guidelines ELDERLY 30% of the NSTEACSPopulation >75 y.o. WOMEN 30% of the population in ACUITY Trial; 40% in OASIS 5 DIABETICS 25-30% of the NSTE-ACSpopulationCKD 10% of the NSTE-ACS population with eGFR<60ml

31 Randomized Trials of Early Invasive Treatment in Elderly Patients with NSTE-ACS Trial Average age % pts >75y Outcome TIMI IIIB 593 Benefit only >65 y VANQWISH618 No difference FRISC II 65Excluded Benefit only >65 y RITA 3 63 No age classes reported Not reported by age TACTICS6212.5 39% RR >65 56% RR >75 56% RR >75 ICTUS61 Not reported Trend towards > benefit >65y

32 Patients with CKD with CrCl < 60 ml/min are at high risk of further ischaemic events, and therefore, should be submitted to invasive evaluation and revascularisation whenever possible (IIa-B). Chronic Kidney Disease ESC Recommendations for Special Populations Chronic kidney disease carries a far worse prognosis, but unlike in several other high-risk subsets, the value of aggressive therapeutic interventions is less certain and should be further studied. Chronic Kidney Disease ACC/AHA

33 CrCl and/or GFR should be calculated for every patient hospitalised for NSTE-ACS (I-B). Elderly people, women and low body weight patients merit special attention as near normal serum creatinine levels may be associated with lower than expected CrCl and GFR levels (I-B). CrCl and/or GFR should be calculated for every patient hospitalised for NSTE-ACS (I-B). Elderly people, women and low body weight patients merit special attention as near normal serum creatinine levels may be associated with lower than expected CrCl and GFR levels (I-B). Patients with CKD should receive the same first-line treatment as any other patient, in the absence of contraindications (I-B). Patients with CKD should receive the same first-line treatment as any other patient, in the absence of contraindications (I-B). Anticoagulants should be carefully dosed. In patients with CrCl < 30ml/min or GFR <30ml/min/1.73m 2 bivalirudin should be used at reduced doses, whereas fondaparinux, enoxaparin and other LMWHs are contraindicated (I-B). Anticoagulants should be carefully dosed. In patients with CrCl < 30ml/min or GFR <30ml/min/1.73m 2 bivalirudin should be used at reduced doses, whereas fondaparinux, enoxaparin and other LMWHs are contraindicated (I-B). CrCl and/or GFR should be calculated for every patient hospitalised for NSTE-ACS (I-B). Elderly people, women and low body weight patients merit special attention as near normal serum creatinine levels may be associated with lower than expected CrCl and GFR levels (I-B). CrCl and/or GFR should be calculated for every patient hospitalised for NSTE-ACS (I-B). Elderly people, women and low body weight patients merit special attention as near normal serum creatinine levels may be associated with lower than expected CrCl and GFR levels (I-B). Patients with CKD should receive the same first-line treatment as any other patient, in the absence of contraindications (I-B). Patients with CKD should receive the same first-line treatment as any other patient, in the absence of contraindications (I-B). Anticoagulants should be carefully dosed. In patients with CrCl < 30ml/min or GFR <30ml/min/1.73m 2 bivalirudin should be used at reduced doses, whereas fondaparinux, enoxaparin and other LMWHs are contraindicated (I-B). Anticoagulants should be carefully dosed. In patients with CrCl < 30ml/min or GFR <30ml/min/1.73m 2 bivalirudin should be used at reduced doses, whereas fondaparinux, enoxaparin and other LMWHs are contraindicated (I-B). Chronic Kidney Disease ESC Recommendations for Special Populations

34 Reducing Residual Risk in Primary PCI of STEMI Patients Approaches to Reducing Mortality in High Risk ACSWhat Do the Trials Teach Us? Deepak L. Bhatt MD, FACC, FSCAI, FESC, FAHA Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program at Brigham and Womens Hospital and the VA Boston Healthcare System Senior Investigator, TIMI Group Landmark Practice Advances in STEMI and ACSYear 2008 Update

35 Bhatt DL et al. Circulation 2005; 112:906-923. ARTERIAL INFLAMMATION Atheroma Burden Atheroma Burden Plaque Vulnerability Plaque Vulnerability Statins Statins ARTERIAL INFLAMMATION Atheroma Burden Atheroma Burden Plaque Vulnerability Plaque Vulnerability Statins Statins ASPIRINRESISTANCE Antihrombotics Antihrombotics Clopidogrel Clopidogrel GP IIb/IIIa GP IIb/IIIa Enoxaparin Enoxaparin Bivalirudin BivalirudinASPIRINRESISTANCE Antihrombotics Antihrombotics Clopidogrel Clopidogrel GP IIb/IIIa GP IIb/IIIa Enoxaparin Enoxaparin Bivalirudin Bivalirudin INTERVENTIONALDEVICE Atherectomy Atherectomy EPD EPD Catheter aspiration Catheter aspirationINTERVENTIONALDEVICE Atherectomy Atherectomy EPD EPD Catheter aspiration Catheter aspiration Periprocedural Myonecrosis Cardiovascular Morbidity and Mortality Mechanisms Behind Periprocedural MI

36 Major Bleeding TransfusionHypotension Cessation of ASA/Clop Mortality Ischemia Stent Thrombosis Inflammation Bhatt DL et al. In Braunwald: Harrisons Online 2005. Potential Relationship Between Bleeding and Mortality

37 Impact of Major Bleed and MI after Elective and Urgent PCI Stone GW. J Inv Cardiol 2004;16(suppl G):12–17. Time from Randomization in Days Cumulative % Mortality With MI 5.7% Without major bleed 2.0% Without MI 1.9% With major bleed8.8% 1-Year Mortality (N=6,012)

38 VariableGroupsO.R. (95% CI) p-value Creatinine clearance <30 mL/min 7.21(2.53–20.51) <0.0001 30–60 mL/min 3.34(1.92–5.78) 60–90 mL/min 1.57(0.96–2.57) CHFYes4.38(2.83–6.78)<0.0001 Major Bleeding Yes3.26(1.78–5.96)0.0001 MI @30day Yes2.77(1.62–4.75)0.0002 Urg Revasc @30d Yes2.77(1.15–6.71).024 Hx angina Yes2.18(1.25–3.81)0.006 Prior MI Yes1.81(1.09–3.03)0.023 DiabetesYes1.64(1.10–2.44)0.015 Predictors of 1-year Mortality after Elective and Urgent PCI Predictors of 1-year Mortality after Elective and Urgent PCI Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

39 1-year Mortality All 6,012 Patients (ITT) P value = 0.16 Cumulative Deaths Days 2.5% 1.9% Lincoff AM et al. JAMA 2004;292:696–703

40 Relation of Various MI and Bleeding Definitions Used in REPLACE-2 CK-MB elevation 10x 1x 2x 3x 4x 5x 6x 7x 8x 9x 5g/dl 4g/dl 3g/dl 2g/dl 1g/dl Intracranial hemorrhage (n=3) Transfusion 2 Units Mls by CK-MB elevation occurring 48 h Mls occuring > 48 h (n=29) Change in haemoglobin CK > 1 ULN (n=940) CK > 2 ULN (n=532) CK > 3 ULN (n=388) CK > 5 ULN (n=190) CK > 10 ULN (n=47) TIMI major n=35 TIMI major/minor n=157 Protocol major n=173 Protocol major/minor n=1321 AB Chew DP et al. Heart 2006;92:945–50. Bleeding definitions MI threshold definitions

41 Attributable Risk: Apportions Deaths at 12 Months Associated with 30-d Events Stringent definition: Affects a small proportion of the population with high overall relative risk of late mortality Liberal definition: Affects a large proportion of the population with low overall relative risk of late mortality Relative risk of late mortality associated with event Absolute proportion of patients experiencing the event Spectrum of possible clinical event definitionsEvent definitions with high sensitivity Event definitions with high specificity Chew DP et al. Heart 2006;92:945–50. Effects of various endpoint definitions

42 OR and Attributable Risk for Baseline Factors Associated with Death by 12 Months Percentage attributable fraction 20 Myocardial infarction definitions and late mortality > 1 x ULN A 15 10 5 0 20 15 10 5 1 > 2 x ULN> 3 x ULN> 5 x ULN> 10 x ULN Percentage attributable fraction Odds Ratio 2.0 2.8 3.5 5.3 7.6 11.6% 13.2%13.4% 13.7% 4.6% B 20 15 10 05 0 Percentage attributable fraction 20 15 10 5 1 Bleeding definitions and late mortality Odds Ratio Protocol major/ minor bleed Protocol major bleed TIMI major/ minor bleed TIMI major bleed 1.6 2.2 4.0% 3.9% 2.3 3.5% 6.1 12.0% Chew DP et al. Heart 2006;92:945–50. Odds ratio is represented by dotted lines; attributable risk by shaded area

43 Mortality (%) Days from Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 1 year Estimate Major Bleed only (without MI) (N=551)12.5% 28.9%Both MI and Major Bleed (N=94) 3.4%No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611)8.6% Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4% Stone GW, et al. JAMA 2007; 298:2497-2506

44 Harmonizing Outcomes with Revascularization and Stents in AMI 3400* pts with STEMI with symptom onset 12 hours Emergent angiography, followed by triage to… Primary PCI Strategy UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Aspirin, thienopyridine R 1:1 3000 pts eligible for stent randomization R 1:3 Bare metal stent TAXUS paclitaxel-eluting stent *To rand 3000 stent pts Clinical FU at 30 days, 1 year, and then yearly through 5 years HORIZONS-AMI Trial Mehran R et al. Am Heart J. 2008 Jul;156(1):44-56.

45 Harmonizing Outcomes with Revascularization and Stents in AMI UFH + GP IIb/IIIa N=1802 Bivalirudin Monotherapy N=1800 R 1:1 Randomized 30 day FU* * Range ±7 days ITT population N=1778 (98.7%) N=1777 (98.7%) N=1802N=1800 Withdrew Withdrew Lost to FU Lost to FU 9151013 3602 pts with STEMI HORIZONS-AMI Trial Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

46 RR = 0.99 [0.76, 1.30] P sup = 0.95 Primary Outcome Measures (ITT) RR = 0.60 [0.46, 0.77] P sup 0.0001 RR = 0.76 [0.63, 0.92] P sup = 0.005 1 endpoint *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke ischemic TVR or stroke Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

47 30-Day Bleeding Endpoints* *CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Protocol Major, non CABG** 8.3%4.9%<0.0001 Protocol Major, All 10.8%6.8%<0.0001 Protocol Minor 15.4%8.6%<0.0001 Blood transfusion 3.5%2.1%0.009 TIMI Major 5.0%3.1%0.002 TIMI Minor 4.6%2.8%0.006 TIMI Major or Minor 9.6%5.9%<0.0001 GUSTO LT*** or Severe 0.6%0.4%0.49 GUSTO Moderate 5.0%3.1%0.002 GUSTO LT or Severe or Moderate 5.6%3.5%0.002 Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

48 Thrombocytopenia in HORIZONS-AMI P = 0.02 P = 0.04 P = 0.002 <100,000 cells/mm 3 <20,000 cells/mm 3 <50,000 cells/mm 3 Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

49 30-Day MACE Components* *CEC adjudicated UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Death3.1%2.1%0.047 - Cardiac - Cardiac2.9%1.8%0.028 - Non cardiac - Non cardiac0.2%0.3%0.75 Reinfarction1.8%1.8%0.90 - Q-wave - Q-wave1.2%1.4%0.66 - Non Q-wave - Non Q-wave0.7%0.4%0.37 Ischemic TVR 1.9%2.6%0.18 - Ischemic TLR - Ischemic TLR1.8%2.5%0.13 - Ischemic remote TVR - Ischemic remote TVR0.3%0.3%1.0 Stroke0.6%0.7%0.68 Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

50 30-Day Mortality Number at risk Bivalirudin 1800175817511746174217291666 Heparin + GPIIb/IIIa 1802176417481736172817071630 Death (%) Time in Days 3.1% 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

51 30-Day Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin 1800175817511746174217291666 Heparin + GPIIb/IIIa 1802176417481736172817071630 Death (%) Time in Days 2.9% 1.8% Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 0.3% 0.2% Cardiac Non cardiac HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

52 30-Day Stent Thrombosis (N=3,124) *Protocol definition of stent thrombosis, CEC adjudicated UFH + GP IIb/IIIa (N=1553)Bivalirudin(N=1571)PValue ARC 30d definite or probable stent thrombosis* 1.9%2.5%0.30 - definite - definite1.4%2.2%0.09 - probable - probable0.5%0.3%0.24 - acute (24 hrs) - acute (24 hrs)0.3%1.3%0.0007 - subacute (>24 hrs – 30d) - subacute (>24 hrs – 30d)1.7%1.2%0.28

53 Number at risk Bivalirudin 1678164716401635163216201563 Heparin + GPIIb/IIIa 1662163116151604159815831512 Death (%) Time in days 1.8% Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) 0.2% 0.1% Cardiac Non cardiac 30-Day Mortality: PCI Cohort 2.8% HR [95%CI] = 0.63 [0.40, 0.99] P=0.049 Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

54 Time-updated Covariate Adjusted Cox Model Relating Single 30-Day Adverse Events to 30-Day Mortality * Of 93 total deaths; ** in 3,124 successfully stented pts ***Only 2 pts with acute stent thrombosis died within 30 days, 1 in each randomized group Ischemic Events HR (95% CI) P Attributable deaths* C-stat Reinfarction 11.09 [5.44,22.59]<0.001 9.1 [8.2,9.6]0.83 Ischemic TVR 6.91 [3.36,14.18]<0.001 7.7 [6.3,8.4]0.83 Stent thrombosis, definite** - any - any - acute (<24 hours) - acute (<24 hours) 10.71 [3.93,29.18] 5.88 [0.78,44.30]<0.0010.09 4.5 [3.7,4.8] 0.8 [-0.3,1]0.830.82 Stroke 5.44 [1.67,17.69]0.005 2.4 [1.2,2.8]0.82

55 Time-updated Covariate Adjusted Cox Model Relating Single 30-Day Adverse Events to 30-Day Mortality * Of 93 total deaths; ** * Of 93 total deaths; ** 88 deaths in 3550 patients Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR Bleeding Events HR (95% CI) P Attributable deaths* Attributable deaths*C-stat Major bleed (non-CABG) 4.43 [2.67, 7.33]<0.001 20.1 [16.3,22.5]0.85 Major bleed (all) 5.92 [3.73, 9.41]<0.001 29.1 [25.6,31.3]0.86 Transfusion 3.88 [2.09, 7.20]<0.001 11.9 [8.4,13.8]0.83 Thrombocytopenia** - <100,000 cells/mm 3 - <100,000 cells/mm 3 - <50,000 cells/mm 3 - <50,000 cells/mm 3 - <20,000 cells/mm 3 - <20,000 cells/mm 3 3.89 [2.22, 6.84] 6.44 [2.93,14.18] 4.98 [1.20,20.66]<0.001<0.0010.03 11.1 [8.2,12.8] 5.9 [4.6,6.5] 1.6 [0.3,1.9]0.780.780.77

56 HR [95% CI] P-value Risk Factor Time-updated Covariate Adjusted Cox Model Relating 30-Day Events to 30-Day Mortality Hazard Ratio [95% CI] 0.01 0.1 1 1 10 100 C-statistic = 0.87. Reinfarction 9.75 [2.72,34.91] 9.75 [2.72,34.91] <0.001 Major bleeding (non CABG) 4.66 [2.84, 7.63] 4.66 [2.84, 7.63] <0.001 Ischemic TVR 1.11 [0.29, 4.21] 1.11 [0.29, 4.21] 0.88 Stroke 2.64 [0.71, 9.75] 2.64 [0.71, 9.75] 0.15 Complete model with MACE components and major bleeding

57 Meadows TA, Bhatt DL. Circ Res. 2007;100:1261

58 Bhatt DL. N Engl J Med 2007;357:2078-81. Role of Platelet Activation and Aggregation

59 Stent Thrombosis (ARC Definite + Probable) 0 1 2 3 0306090180270360450 HR 0.48 P <0.0001 Prasugrel Clopidogrel 2.4 (142) NNT= 77 1.1 (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844 Wiviott SD et al NEJM 2007;357: 2001. Slide courtesy of Dr. Elliott Antman

60 PLATO Can PLATelet Inhibition be Optimized to Prevent Vascular Events At least 2 inclusion criteria: 1. ST segment changes biomarkers 2. At least 1: - >60 yo - Previous MI/CABG - Known > 1 Vessel CAD - AODM - PVD -Renal dysfunction -Renal dysfunction Double-blind, double-dummy Mean f/u ~12.5 months. Range 6-24 AODM, adult-onset diabetes mellitus; PVD, peripheral vascular disease. Wallentin L, et al., for the PLATO study. A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome. Washington, DC. US Food and Drug Administration. Available at: http://clinicaltrials.gov. ~18,000 patients within 24 hours of an index ACS (STEMI or NSTEMI) Primary Endpoint: Time to first occurrence of the composite of death, MI or stroke. Primary Safety Endpoint: Major bleeding ASA 75-100mg QD AZD6140 90mg BID Clopidogrel 75mg QID

61 Cangrelor (AR-C69931MX) Parenteral ADP-P2Y12 receptor antagonist ATP analogue Molecular weight 800 Daltons Plasma half-life of 5-9 minutes 20 minutes for return to normal platelet function Parenteral ADP-P2Y12 receptor antagonist ATP analogue Molecular weight 800 Daltons Plasma half-life of 5-9 minutes 20 minutes for return to normal platelet function N N N N NH S CF 3 OH OH O O P O O P P O O O Cl O O O S 4Na +

62 CHAMPION Program Phase III program underway Phase III program underway 1 O Endpoint – Superiority for ischemic events vs. clopidogrel 600 mg at the start of PCI vs. clopidogrel 600 mg at the end of PCI N = 9,000 pts N = 6,300 pts

63 Filter Protection During Acute Infarction Bhatt DL et al. Circulation 2005; 112:906-923.

64 TAPAS Trial Good myocardial blush: 46% with aspiration and 32% with standard PCI (p<0.001) Good myocardial blush: 46% with aspiration and 32% with standard PCI (p<0.001) ST-segment resolution: 57% and 44%, respectively (p<0.001) ST-segment resolution: 57% and 44%, respectively (p<0.001) Death: 2.1% and 4.0%, respectively (p=0.07) Death: 2.1% and 4.0%, respectively (p=0.07) Trial design: Patients with ST-elevation myocardial infarction were randomized to thrombus aspiration prior to PCI (n=535) or standard PCI without aspiration (n=536) Results Conclusions In STEMI, thrombus aspiration prior to PCI is superior to standard PCI without aspiration In STEMI, thrombus aspiration prior to PCI is superior to standard PCI without aspiration Thrombus aspiration improves myocardial blush and ST-segment resolution Thrombus aspiration improves myocardial blush and ST-segment resolution Thrombus aspiration may improve adverse Thrombus aspiration may improve adverse events including survival Svilaas T et al. N Engl J Med 2008;358:557-567 Good myocardial blush p < 0.001 Mortality p = 0.07 % Thrombus aspiration and PCI n = 535 PCI alone n = 536 3246 2.14 www.cardiosource.com

65 Vlaar PJ, et al. Lancet. 2008 Jun 7;371(9628):1915-20. 1071 STEMI patients randomized 530 complete follow-up at 1 year TAPAS Trial Design 33 did not undergo PCI 502 underwent primary PCI - 295 underwent TA followed by direct stenting - 153 underwent TA with additional balloon dilation - 54 had crossover to conventional PCI 33 did not undergo PCI 503 underwent primary PCI - 485 underwent balloon dilation followed by stening - 12 underwent conventional PCI with additional TA - 6 had crossover to TA 535 were assigned to thrombus aspiration 536 were assigned to conventional PCI

66 Mortality at 1 Year Log-Rank p = 0.040 Vlaar PJ, et al. Lancet. 2008 Jun 7;371(9628):1915-20. 0 100200 300 400 121086420 Time (days) Mortality (%) Conventional PCI Thrombus-Aspiration

67 Conclusions: Optimizing STEMI Care Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI, at least as important as MI and reinfarction Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI, at least as important as MI and reinfarction Bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and transfusions Bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and transfusions In primary PCI for STEMI, a lower 30-day mortality rate is observed with bivalirudin versus heparin + GPI In primary PCI for STEMI, a lower 30-day mortality rate is observed with bivalirudin versus heparin + GPI Novel antiplatelet agents may potentially further reduce ischemic events Novel antiplatelet agents may potentially further reduce ischemic events Simple manual thrombus aspiration also appears to reduce mortality Simple manual thrombus aspiration also appears to reduce mortality Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI, at least as important as MI and reinfarction Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI, at least as important as MI and reinfarction Bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and transfusions Bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and transfusions In primary PCI for STEMI, a lower 30-day mortality rate is observed with bivalirudin versus heparin + GPI In primary PCI for STEMI, a lower 30-day mortality rate is observed with bivalirudin versus heparin + GPI Novel antiplatelet agents may potentially further reduce ischemic events Novel antiplatelet agents may potentially further reduce ischemic events Simple manual thrombus aspiration also appears to reduce mortality Simple manual thrombus aspiration also appears to reduce mortality

68 Changing Anticoagulants in Midstream Strategies for Optimizing Outcomes in STEMI and High Risk ACS: To Switch or Not to Switch? Why? When? How? Landmark Practice Advances in STEMI and ACS Carlo Di Mario, MD, PhD, FESC, FACC, FRCP Professor of Clinical Cardiology Imperial College of Sciences, Medicine & Technology Consultant in Interventional Cardiology Royal Brompton Hospital London, UK

69 What is the Problem? We Always Mix Antiplatelet Agents Thrombin Thromboxane A 2 5HT P2Y 12 ADPADPADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR1 PAR4 Dense granule Thrombingeneration Shapechange a IIb b 3 a b 3 Fibrinogen a b 3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP a Coagulation GPVI Collagen ATPATP P2X 1 ASPIRIN x TICLOPIDINECLOPIDOGRELPRASUGREL ACTIVEMETABOLITE x AZD6140CANGRELOR GP IIb/IIIa ANTAGONISTS x Storey RF. Curr Pharm Des. 2006;12:1255-59.

70 Yes, But: All Antithrombotic Drugs Act on Thrombin Activity In ACS patients In ACS patients 87% of patients receive either UFH or Enoxaparin within 24 hours after admission 1 87% of patients receive either UFH or Enoxaparin within 24 hours after admission 1 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 In ACS patients In ACS patients 87% of patients receive either UFH or Enoxaparin within 24 hours after admission 1 87% of patients receive either UFH or Enoxaparin within 24 hours after admission 1 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al, NEJM 2006; 4 Cohen et al, JACC 2006; Anti-platelet Agents act on different mechanisms, with synergistic effects; some inhibit only the aggregation of platelets Anti-platelet Agents act on different mechanisms, with synergistic effects; some inhibit only the aggregation of platelets In most cases, we dont need antithrombotic agents to produce prolonged anticoagulation (unlike antiaggregation) In most cases, we dont need antithrombotic agents to produce prolonged anticoagulation (unlike antiaggregation)

71 Potential Risks of Combining Different Antithrombotic Drugs Potential Risks of Combining Different Antithrombotic Drugs Unfractionated Heparin (UHF) Low Molecular Weight Heparin (Enoxaparin sc) FondaparinuxBivalirudinHalf-Life 3 Hrs 6 Hrs 4 Hrs 0.3 Hrs Dose/Kg 30-120 mg/Kg 1 mg/Kg 2.5 mg sc STEMI: 0.75 mg/kg bolus followed by infusion 1.75 mg/kg/h NSTE-ACS: 0.1 mg/kg bolus followed by infusion 0.25 mg/kg/h (if PCI, additional 0.5 mg/kg IV bolus followed by infusion 1.75 mg/kg/h) MonitoringACT/aPTT Factor X (not required) Not required ACT (not required) Inactivation Protamine Sulphate n.a.n.a.n.a.

72 Randomize (n = 10,000) 60 U/kg 12 U/kg/h (aPTT 50 – 70 sec) 1 mg/kg SC Q12 h SYNERGY Trial Investigators. JAMA 2004;292:45-54 Primary Endpoint: Death or MI at 30 Days Early Invasive Strategy Other Therapy per ACC/AHA Guidelines (ASA, ß-blocker, ACE, Clopidogrel, GP IIb/IIIa) Enoxaparin IV UFH High-Risk ACS Patients SYNERGY Study Design At Least 2 of 3 Required: Age > 60 Age > 60 ST (transient) or ST (transient) or (+) CK-MB or Troponin (+) CK-MB or Troponin

73 0.811.2 Hazard Ratio (95% CI) EnoxaparinUFH BetterBetter 30-day Death/MI HR 0.96 (0.86 – 1.06) SYNERGY: Death and MI at 30 Days 051015202530 0.8 0.9 0.951.0 Freedom from Death / MI Days from Randomization 0.85 Enoxaparin UFH SYNERGY Trial Investigators. JAMA 2004;292:45-54

74 SYNERGY Bleeding Events GUSTO severe2.7%2.2%0.08 TIMI major (clinical): 9.1%7.6%0.008 CABG-related6.8%5.9%0.08 Non-CABG-related2.4%1.8%0.03 Hb/HCT drop (algorithm)15.2%12.5%< 0.001 Any RBC transfusion17.0%16.0%0.16 ICH< 0.1%< 0.1%NS EnoxaparinUFHP value EnoxaparinUFHP value (n = 4,993) (n = 4,985) (n = 4,993) (n = 4,985) SYNERGY Trial Investigators. JAMA 2004;292:45-54

75 SYNERGY: Relation of Heparin Crossover to Bleeding GUSTO Severe (%) TIMI Major (%) n=9978 n=9180 n=798 Enoxaparin Unfractionated Heparin SYNERGY Trial Investigators. JAMA 2004;292:45-54

76 OASIS-6: Fondaparinux Synthetic Factor Xa Inhibitor Yusuf S, et al. JAMA. 2006;295:1519-1530 STEMI24h12h N=12092 STRATUM 1: no indication for UFH STRATUM 2: indication for UFH Fondaparinux 2.5 mg sc od 8days or discharge Placebo Fondaparinux IV sc UFH bolus + infusion 24 to 48 hours Reduction in Death/MI: Stratum 2 (UFH Indicated) P=NS p=0.9 7 14% 12% 10% 8% 6% 4% 2% 0% FondaparinuxUFH 8.3% 8.7% 31% 1ary PCI Do NOT use as sole anticoagulant DURING PCI 2007 Focused Update of ACC/AHA STEMI Guidelines 2008 15% PrimaryEnd Point:Death/Reinfarction (%) P=.008P=.003P=.008 Frequency 12% 9% 6% 3% 0% 9.7% 11.2% 7.4% 8.9% 13.4% 14.8% 30 days9 days3-6 months Fondaparinux (n=6036 ) Control (n=6056)

77 ESC NSTE-ACS Guidelines At PCI procedures, the initial anticoagulant should also be maintained during the procedure regardless of whether this treatment is UFH (I- C), enoxaparin (IIb-B), or bivalirudin (I-B) At PCI procedures, the initial anticoagulant should also be maintained during the procedure regardless of whether this treatment is UFH (I- C), enoxaparin (IIb-B), or bivalirudin (I-B) EHJ 2007;28:1598-60

78 Is It Safe Switching to Bivalirudin? Why should switching to bivalirudin monotherapy be reasonable? Why should switching to bivalirudin monotherapy be reasonable? Mechanistic rationale for switching Mechanistic rationale for switching SWITCH SWITCH REPLACE 2 REPLACE 2 ACUITY ACUITY Why should switching to bivalirudin monotherapy be reasonable? Why should switching to bivalirudin monotherapy be reasonable? Mechanistic rationale for switching Mechanistic rationale for switching SWITCH SWITCH REPLACE 2 REPLACE 2 ACUITY ACUITY

79 Switch: Protocol-mandated change in antithrombotic therapy at randomization Switch: Protocol-mandated change in antithrombotic therapy at randomization Crossover: Post-randomization change in antithrombotic therapy due to physician choice Crossover: Post-randomization change in antithrombotic therapy due to physician choice Switch: Protocol-mandated change in antithrombotic therapy at randomization Switch: Protocol-mandated change in antithrombotic therapy at randomization Crossover: Post-randomization change in antithrombotic therapy due to physician choice Crossover: Post-randomization change in antithrombotic therapy due to physician choice SWITCH Definitions

80 ACUITY SWITCH Hypothesis Hypothesis Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation Is it better to switch to bivalirudin or remain on consistent therapy? Is it better to switch to bivalirudin or remain on consistent therapy? White HD, et al. J Am Coll Cardiol 2008;51:1734–41

81 ACUITY – Primary Results UFH/Enoxaparin + GPI vs. Bivalirudin Alone P NI <0.0001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.0001 P Sup <0.0001 Stone GW et al. NEJM 2006;355:2203-16

82 ACUITY Switch Analysis Study Methods Study Methods Patients on prior antithrombin therapy Patients on prior antithrombin therapy Consistent: No switching from pre-randomization antithrombin agent to randomized therapy: Consistent: No switching from pre-randomization antithrombin agent to randomized therapy: –Enoxaparin Enoxaparin or UFH UFH Switch: Single switch to bivalirudin determined by randomization code Switch: Single switch to bivalirudin determined by randomization code –From Enoxaparin Bivalirudin or UFH Bivalirudin Event rates at 30-days Event rates at 30-days Net clinical outcome Net clinical outcome Ischemic composite Ischemic composite Major bleeding Major bleeding White HD, et al. J Am Coll Cardiol 2008;51:1734–41

83 ACUITY – Switch Consort ACUITY 13819 CONSISTENT UFH/Enox N = 2137 SWITCH Bivalirudin N = 2078 UFHUFH N = 1294 EnoxEnox N = 843 UFHBiv N = 1313 EnoxBiv N = 765 Pts on Prior AT N = 4215 Pts on Prior AT N = 4215 excludes Arm B and pts. with multiple crossovers, missing data excludes Arm B and pts. with multiple crossovers, missing data

84 Consistent vs. Switch Comparing Consistent therapy on Enox + GPIIb/IIIa Inhibition vs. Switch to Bivalirudin Alone P=0.15 0.80 [0.60 – 1.81] P=0.43 0.86 [0.60 – 1.25] P=0.03 0.58 [0.35 – 0.96] 11.0% 8.9% 7.0% 6.1% 5.0% 2.9% 0 5 10 15 20 Net clinical outcomeIschemic compositeMajor bleeding 30 day events (%) Consistent Enox + GPIIb/IIIa Inhibition (N = 843) Switch to Bivalirudin alone (N = 765) White HD, et al. J Am Coll Cardiol 2008;51:1734–41

85 ACUITY – Switch Consistent vs. Switch High Risk Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin High Risk Patients ConsistentUFH/Enox N = 1581 SwitchBivalirudin N = 1496 RR Net Clinical Outcome 13.0%10.6% 0.82 [0.67-0.99] Ischemia8.2%7.7% 0.94 [0.74-1.20] Major Bleeding 6.5%3.5% 0.51 [0.39-0.75] White HD, et al. J Am Coll Cardiol 2008;51:1734–41

86 ACUITY – SWITCH Consistent vs. Switch Patients Undergoing PCI Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin ConsistentUFH/Enox N = 1236 SwitchBivalirudin N = 1292 RR Net Clinical Outcome 13.2%11.8% 0.90 [0.73 -1.10] Ischemia8.2%9.0% 1.10 [0.85 -1.42] Major Bleeding 6.7%3.5% 0.52 [0.36-0.74] PCI Patients White HD, et al. J Am Coll Cardiol 2008;51:1734–41

87 Relative Risk ± 95% CI RR (95% CI) Prior Antithrombin Therapy Prior Antithrombin Therapy 0.49 (0.36-0.66) Major Bleeding 0.77 (0.65-0.92) Net Clinical Outcome 0.93 (0.75-1.16) Composite Ischemia Switch to Bivalirudin Better Consistent UFH/Enox + IIb/IIIa Better ACUITY: Switch 30 Days 30 Days 012 White HD, et al. J Am Coll Cardiol 2008;51:1734–41

88 ACUITY Switch 30 Days Relative Risk ± 95% CI 0.52 (0.35-0.77) Major Bleeding 0.85 (0.67-1.07) Net Clinical Outcome 1.11 (0.83-1.49) Composite Ischemia Randomization to Bivalirudin Better Randomization to UFH/Enox + IIb/IIIa Better Naïve to Antithrombin Therapy Naïve to Antithrombin Therapy RR (95% CI) 012 White HD, et al. J Am Coll Cardiol 2008;51:1734–41

89 PCI (n=2528) Composite ischemia 1.10 (0.85-1.42) Major bleeding 0.52 (0.36-0.74) Switch to Bivalirudin better Consistent UFH/Enox + IIb/IIIa better + IIb/IIIa better Switch to Bivalirudin better Consistent UFH/Enox + IIb/IIIa better + IIb/IIIa better * High risk = Tn, CKMB or ECG Δs Risk Ratio ± 95% CI RR (95% CI) Hazard Ratio ± 95% CI HR (95% CI) 30-Day Results 1-Year Results PCI HIGH RISK* (n=1988) Composite ischemia 1.14 (0.86-1.52) Major bleeding 0.56 (0.38-0.81) PCI ( n=2528 ) Mortality 0.93 (0.58-1.48) PCI HIGH RISK* ( n=1988 ) Mortality 0.99 (0.60-1.63) ACUITY – SWITCH ACUITY PCI: Switch from Prior Antithrombin 0.11100.1110 White HD, et al. J Am Coll Cardiol 2008;51:1734–41

90 Naïve to Antithrombin Therapy 9.5%8.0% 5.8% 6.2% 5.0% 2.5% P=0.18 0.83 [0.63 – 1.09 P=0.74 1.06 [0.76 – 1.49] P<0.01 0.51 [0.33 – 0.78] 0 5 10 15 20 Net clinical outcome Ischemic composite Major bleeding 30 day events (%) Randomized to Enox + GPIIb/IIIa Inhibition (N = 842) Randomized to Bivalirudin (N = 1427) White HD, et al. J Am Coll Cardiol 2008;51:1734–41

91 ACUITY – Switch Limitations Post-hoc subgroup analysis Post-hoc subgroup analysis Pre-randomization use of antithrombin was not stratified Pre-randomization use of antithrombin was not stratified Timing and dose of last UFH and enoxaparin was not collected in the CRF Timing and dose of last UFH and enoxaparin was not collected in the CRF Post-hoc subgroup analysis Post-hoc subgroup analysis Pre-randomization use of antithrombin was not stratified Pre-randomization use of antithrombin was not stratified Timing and dose of last UFH and enoxaparin was not collected in the CRF Timing and dose of last UFH and enoxaparin was not collected in the CRF

92 Randomize Protocol major/minor bleeding, TIMI bleeding, transfusion, mortality 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 (N=6,002) 1 Overall population: Urgent or elective PCI patients (N=6,002) 1 (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 1. Lincoff ML et al. JAMA. 2004;292:696-703. 2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690. AT=antithrombin.

93 Protocol Major/Minor Bleeding by SWITCH and Randomized Therapy Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy 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 bivalirudin alone; P<.05 vs prior treatment with UFH or enoxaparin; naïve=no prior AT therapy in preceding 48 hours. Protocol major/minor bleed Naïve Bivalirudin Naïve Bivalirudin (n=2,345) LMWH Bivalirudin (n=258) UFH Bivalirudin (n=287) LMWHUFH + GP IIb/IIIa (n=313) Naïve UFH + GP IIb/IIIa (n=2,325) UFHUFH + GP IIb/IIIa (n=349) * Gibson CM et al. Am J Cardiol. 2007;99:1687-1690. 15.6% 15.3% 16.7% 28.6% 33.8% 34.8% 0% 5% 10% 15% 20% 25% 30% 35%

94 TIMI Major/Minor Bleeding by SWITCH and Randomized Therapy Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins TIMI major/minor bleed Naïve Bivalirudin (n=2,345) LMWH Bivalirudin (n=258) UFH Bivalirudin (n=287) LMWHUFH + GP IIb/IIIa (n=313) NaïveUFH + GP IIb/IIIa (n=2,325) UFHUFH + GP IIb/IIIa (n=349) * *P=NS for all 3-way comparisons versus bivalirudin alone; naïve=no prior AT therapy in preceding 48 hours. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690. 1.9% 1.4% 4.3% 5.4% 1.9% 3.5% 0% 1% 2% 3% 4% 5% 6%

95 SWITCH Waksman et al. J Invasive Cardiol 2006;18:370 p = 0.39 n = 30 n = 31 n = 30 13% 3% 7% 0% 5% 10% 15% GPI (0 - 4 hr) GPII (4 - 8 hr) GPIII (8 - 12 hr) Time from last enoxaparin dose Major Bleeding %

96 4.8% 5.2% 8.5% 7.5% 0% 2% 4% 6% 8% 10% UFH pretreatment (n=2,553) No UFH pretreatment (n=1,042) 30-Day Major Bleeding 4.6% 7.2% 5.2% 5.6% 0% 2% 4% 6% 8% 10% UFH pretreatment (n=2,553) No UFH pretreatment (n=1,042) 30-Day MACE Bivalirudin with "provisional" GP IIb/IIIa Heparin + GP IIb/IIIa P int =0.08 P int =0.47 HORIZONS AMI Trial Switching Data UFH pre-procedure was administered to 65.8% of bivalirudin pts and 76.3% of heparin + GPIIb/IIIa pts RR [95%CI]= 0.81 [0.58,1.14] RR [95%CI]= 1.39 [0.85,2.28] RR [95%CI]= 0.57 [0.42,0.77] RR [95%CI]= 0.69 [0.43,1.12]

97 Which Protocol Should We Follow? From UFH to Bivalirudin From UFH to Bivalirudin Discontinue LMWH for 8 hours before Discontinue LMWH for 8 hours before starting bivalirudin starting bivalirudin Discontinue UFH for 30 minutes beforeDiscontinue UFH for 30 minutes before starting bivalirudin starting bivalirudin From LMWH to Bivalirudin

98 Conclusions Switching to bivalirudin is safe Switching to bivalirudin is safe Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events Furthermore Furthermore Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin Switching to bivalirudin is safe Switching to bivalirudin is safe Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events Furthermore Furthermore Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin Risks of Combining Different Antithrombotic Drugs

99 Guidelines and the Role of Bleeding Reduction to Optimize Outcomes and Upstream Antithrombotic Care for STEMI and NSTEMI Stefano Savonitto, MD, FESC Prima Divisione di Cardiologia Dipartimento Cardiologico Angelo De Gasperis Ospedale Niguarda Ca Granda Milano, Italy Landmark Practice Advances in STEMI and ACS

100 Minimizing infarct size Clinical Stabilization Prevention of early (re)infarction Protection of microcirculation Procedural MI Bleeding Renal damage Benefit Risk Impact of Pharmacoinvasive Therapy in PCI and ACS Reduction of death+MI in high-risk patients Increased mortality?

101 Emphasis on Bleeding Prevention in the 2007 ESC and ACC/AHA NSTE-ACS Guidelines Risk stratification in relation to bleeding and the prevention of bleeding are considered of utmost importance in both GLs, and particularly in the ESC guidelines. Risk stratification in relation to bleeding and the prevention of bleeding are considered of utmost importance in both GLs, and particularly in the ESC guidelines. The validation and introduction in the GLs of newer antithrombotic agents characterised by lower bleeding risk is one of the most important novelties of both guidelines. The validation and introduction in the GLs of newer antithrombotic agents characterised by lower bleeding risk is one of the most important novelties of both guidelines. Recommendations about a restrictive approach to transfusions and instructions for continuing antithrombotic therapies in the case of bleeding in order to avoid rebound phenomena bear important clinical implications. Recommendations about a restrictive approach to transfusions and instructions for continuing antithrombotic therapies in the case of bleeding in order to avoid rebound phenomena bear important clinical implications.

102 Incidence of Bleeding in ACS Landmark Practice Advances inSTEMI and ACS

103 30-Day Bleeding Endpoints* UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Protocol Major, non CABG** 8.3%4.9%<0.0001 Protocol Major, All 10.8%6.8%<0.0001 Protocol Minor 15.4%8.6%<0.0001 Blood transfusion 3.5%2.1%0.009 TIMI Major 5.0%3.1%0.002 TIMI Minor 4.6%2.8%0.006 TIMI Major or Minor 9.6%5.9%<0.0001 GUSTO LT*** or Severe 0.6%0.4%0.49 GUSTO Moderate 5.0%3.1%0.002 GUSTO LT or Severe or Moderate 5.6%3.5%0.002 *CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening HORIZONS-AMI Trial Bleeding Incidence Depends on Definition

104 Major Bleeding in Italian Registries Same definition: life threatening, Hb -5 mg/dL or Ht -15%, transfusion. RegistryrefY N° centers N° patients (% con ACS) Inclusion Criteria Major Bleeding BLITZ-1 Eur Heart J 2003 2001296 1959 (100) Consecutive pts with MI 2.0% BLITZ-2 Eur Heart J 2006 2003275 1888 (100) Consecutive patients with NSTEACS 1.3% IDEA Ital Heart J 2005 200379 1517 (50) Consecutive patients with PCI Stable 0.5% ACS 1.3% STEMI 4.3%

105 ISAR-REACT 2 Trial (N=2020) Clopidogrel 600 mg and Abciximab in ACS Kastrati A. JAMA 2006 In-hospital Major and Minor Bleeding (%) p=NS

106 30-Day Death According to Bleeding OASIS Registry, OASIS-2, CURE J Eikelboom et al Circulation 2006 0 2 4 6 8 10 12 14 051015202530 Bleeding No Bleeding No. at Risk No Bleeding Bleeding 33676334193315732990328793276932710 470 (1.4%) 459440430420410408 Cumulative Events, % Days

107 Association Between Bleeding and Outcome in ACS and PCI Landmark Practice Advances in STEMI and ACS

108 Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS Patients Moscucci et al. Eur Heart J 2003;24:1815-23 GRACE Registry in 24,045 ACS patients *After adjustment for comorbidities, clinical presentation and hospital therapies **p<0.001 for differences in unadjusted death rates OR (95% CI) 1.64 (1.18 to 2.28*) 0 Overall ACS UA NSTEMISTEMI 10 20 3040** ** ** ** 5.1 18.6 3.0 16.1 5.3 15.3 7.0 22.8 Inhospital death (%) In hospital major bleeding Yes No

109 30 -Death According to Bleeding OASIS Registry, OASIS-2, CURE J Eikelboom et al Circulation 2006 0 2 4 6 8 10 12 14 051015202530 Bleeding No Bleeding No. at Risk No Bleeding Bleeding 33676334193315732990328793276932710 470 (1.4%) 459440430420410408 Cumulative Events, % Days

110 Bleeding is Associated with an Increased 30-Day Mortality in NSTEMI Patients Rao et al. Am J Cardiol 2005;96:1200-1206 N=26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & B Log-rank p values are 0.0001 for all 4 categories, 0.20 for no bleeding vs. mild bleeding, 0.0001 for mild vs. moderate bleeding, and 0.001 for moderate vs. severe bleeding. Adjusted HR (95% CI) % Death 2.9%1.0 3.5%1.6 (1.3-1.9) 5.9%2.7 (2.3-3.4) 25.7%10.6 (8.3-13.6) GUSTO bleeding NoneMildModerateSevere 051015202530 0.70 0.75 0.80 0.85 0.90 0.951.00 Days to Death Cumulative survival

111 Procedure- and Non-Procedure-Related Bleeds are Associated with an higher 30-Day Mortality in NSTEMI Procedure-related GUSTO bleeds Non-procedure-related GUSTO bleeds Risk of death (hazard Ratio) None 1.0 Mild 1.3 Severe 16.5 0 5 20 10 15 None 1.0 Mild 2.1 Moderate 2.5 Severe 10.9 Moderate 3.7 Rao et al. Am J Cardiol 2005;96:1200-1206 N=26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & B

112 Bleeding Within 30 Days is a Powerful and Independent Predictor of 1-year Death After PCI Ndrepepa G. JACC 2008;51:690-7 * Calculated for a 10-year increase in age. 5,384 patients from 4 RCT on the value of abciximab after pretreatment with 600 mg of clopidogrel: ISAR-REACT, SWEET, SMART-2 and REACT-2 Our study demonstrates a strong relationship between the 30-day frequency of bleeding and 1-year mortality after PCI and supports the inclusion of periprocedural bleeding in a 30-day quadruple endpoint for the assessment of outcome after PCI. Variable Hazard Ratio (95% CI) P Value Bleeding within 30 days 2.96(1.96-4.48)<0.001 Myocardial infarction within 30 days 2.29(1.52-3.46)<0.001 Urgent revascularization within 30 days 2.49(1.16-5.35)0.019 Age (years)* 2.27(1.78-2.89)<0.001 Diabetes1.47(1.11-1.96)0.008 Multivessel coronary disease 2.72(1.56-4.67)<0.001 Elevated troponin 1.77(1.27-2.47)<0.001 Left ventricular ejection fraction 0.71(0.60-0.85)<0.001 Creatinine level 1.10(1.06-1.14)<0.001

113 Potential Mechanisms for the Higher Morbidity/Mortality Associated with Bleeding 1. Cessation of antithrombotic therapies after bleeding may increase subsequent ischemic events 2. Patients who bleed may have an heightened inflammatory state 3. Adverse effects of hypotension 4. Adverse effects of transfusion 5. Common risk factors for bleeding and adverse outcome 1. Cessation of antithrombotic therapies after bleeding may increase subsequent ischemic events 2. Patients who bleed may have an heightened inflammatory state 3. Adverse effects of hypotension 4. Adverse effects of transfusion 5. Common risk factors for bleeding and adverse outcome 1. Gibbons & Fuster. N Engl J Med 2006;354:1524-7 2. Califf. JAMA 2006;295:1579-80 3. Jozic J. AJC 2006;98:36M

114 Blood Transfusion is Associated with an Increased 30-Day Mortality in NSTEMI Rao et al. JAMA 2004;292:1555-62 N=24,112 ACS patients from GUSTO IIb, PURSUIT and PARAGON *Adjusted for baseline characteristics, bleeding and transfusion propensity and nadir hematocrit HR=3.94*; 95%CI: 3.26 to 4.75 30-day death rate Transfusion No Transfusion Cumulative mortality Log-rank p<0.001 0 0.02 0.04 0.06 0.08 0.10 51015202530 Day 8.00% 3.08%

115 Transfusion and 30-day Mortality 1.0100.1 Cox model, transfusion = time-dependent covariate Adjusted for transfusion propensity Adjusted for baseline characteristics characteristics, bleeding propensity, transfusion propensity, and nadir HCT 3.8 3.5 3.9 Odds Ratio Rao SV, et. al., JAMA 2004

116 Bleeding is an independent predictor of outcome Reducing bleeding improves outcome The Therapeutic Theorem

117 OASIS-5Major Bleeding: 9 Days OASIS 5 Investigators. NEJM 2006;354:1464-76 0.00 0.01 0.02 0.030.04 Cumulative Hazard Days Hazard ratio 0.53 (95% CI, 0.45-0.62) BleedingBleeding0123456789Fondaparinux Enoxaparin

118 OASIS 5 Investigators. NEJM 2006;354:1464-76 OASIS-5Efficacy Outcomes at Day 9 5.9%5.8% Death/MI/RI 2.05%1.9% Refract Ischemia 2.7%2.7% MI 1.8%1.9% Death 4.1%4.1% Death/MI FondaEnox 0.811.2 Non-inferiority Margin=1.185 Hazard Ratio Fonda Better EnoxBetter

119 Death/Reinfarction/Stroke/Severe Bleeding HR95%CI No reperfusion therapy Thrombolytic therapy PCIOverall 0.810.69-0.960.016 0.830.73-0.950.007 1.120.90-1.390.29 0.880.80-0.970.007 1.0100.1 Fondaparinux better Placebo/UFH better Hazard Ratio (log scale) p value The OASIS-6 Trial Group. JAMA 2006;295:1519-30 OASIS-6Effect on PCI Patients: The Achilles Heel of Fondaparinux

120 OASIS 5 Investigators. NEJM 2006;354:1464-76 OASIS-5: Mortality at 6 Months Days Cumulative Hazard 0.0 0.02 0.04 0.06 020406080100120140160180 HR 0.89 95% CI 0.79 - - 0.99 0.99 P=0.037 P=0.037 Enoxaparin Fondaparinux

121 OASIS-6: Fondaparinux Reduced Mortality up to Day 180 Days UFH or placebo Fondaparinux HR: 0.88 95% CI: 0.79-0.99 p=0.03 0 0.02 0.04 0.06 0.08 0.10 0.12 0.140.160 Cumulative Hazard 306090120150180 The OASIS-6 Trial Group. JAMA 2006;295:1519-30

122 Principal Endpoint p = 0.324 p = 0.255 p = 0.430 p = 0.435 p < 0.001 Lincoff AM et al. JAMA. 2003; 289:853-863.

123 ACUITY: Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin Alone PNI <0.0001 PSup = 0.015 P NI = 0.011 P Sup = 0.32 PNI <0.0001 PSup <0.0001 11.7% 7.3% 5.7% 3.0% 10.1% 7.8% Net clinical outcome Ischemic composite Major bleeding 30 day events (%) UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612) Stone GW et al. NEJM 2006;355:2203-16

124 Primary Endpoint Major Bleeding (%) Time in Days 8.4% 5.0% HR [95%CI] = 0.59 [0.45, 0.76] P<0.0001 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) HORIZONS AMI30-Day Major Bleeding (non-CABG) Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

125 HORIZONS AMI30-Day Stent Thrombosis (N=3,124) UFH + GP IIb/IIIa (N=1553)Bivalirudin(N=1571)PValue ARC definite or probable* 1.9%2.5%0.33 Definite Definite1.4%2.2%0.11 Probable Probable0.5%0.3%0.26 Acute Acute (24 hrs) 0.3%1.3%0.0009 Subacute (>24 hrs – 30d) Subacute (>24 hrs – 30d)1.7%1.2%0.30 Stone GW, et al. N Engl J Med. 2008 May 22;358(21):2218-30

126 REPLACE-2N=6,002 Lincoff AM, JAMA 2005 ACUITYN=13,819 Stone GW, AHA 2007 HORIZONS AMI N=3,602 Stone GW, JAMA 2008 1-year mortality -24%p=0.16 -14%p=0.90 30-day mortality -32%p=0.048 Consistent Reduction in Mortality Across the Bivalirudin Trials

127 Net Clinical Benefit Death, MI, Stroke, Major Bleed (non CABG) 0 5 10 15 0306090180270360450 Days Endpoint (%) HR 0.87 P=0.004 13.9 12.2 Prasugrel Clopidogrel ITT= 13,608 Events per 1000 pts MI Major Bleed (non CABG) + All Cause Mortality Clop 3.2% Pras 3.0 % -6% P=0.64

128 Antiplatelet Therapy in ACS Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA ASA ASA + Clopidogrel ASA + Prasugrel - 22% - 20% - 19% + 60%+ 38%+ 32% Reduction in Ischemic Events Increase in Major Bleeds

129 Better Outcomes Observed with Newer Anticoagulants vs Antiplatelet Drugs Recent improvements in anticoagulant therapy have dramatically reduced acute bleeding at the expense of a slightly lower, but insignificant, anti-ischemic efficacy, particularly in PCI patients. This shift in the efficacy vs safety ratio translated into a mortality reduction at follow up. Recent improvements in anticoagulant therapy have dramatically reduced acute bleeding at the expense of a slightly lower, but insignificant, anti-ischemic efficacy, particularly in PCI patients. This shift in the efficacy vs safety ratio translated into a mortality reduction at follow up. Recent improvements in antiplatelet therapy have improved anti-ischemic protection, particularly in PCI patients, at the expense of a higher bleeding risk. This shift in the efficacy vs safety ratio translated into a prevention of acute and subsequent MI, however without a mortality reduction at follow up. Recent improvements in antiplatelet therapy have improved anti-ischemic protection, particularly in PCI patients, at the expense of a higher bleeding risk. This shift in the efficacy vs safety ratio translated into a prevention of acute and subsequent MI, however without a mortality reduction at follow up.

130 Ischemic Risk Bleeding risk 0 25 50 75 100% 100-80-60-40-20-0- Anti-ischemic effect Net clinical benefit Treatment effect The Relationships Among Baseline Risk, Bleeding Risk and Net Clinical Benefit for an Effective Treatment

131 NSTE-ACS ST depression ST depression Tn elevation Tn elevation Refractory ischemia Refractory ischemia LV dysfunction LV dysfunction Diabetes Diabetes Elderly Elderly Chronic Kidney Dysf. Chronic Kidney Dysf. STEMI Elderly Elderly High Killip High Killip Prior MI Prior MI Large MI Large MI Failed lysis Failed lysis Diabetes Diabetes CKD CKD Independent Predictors of Ischemic and Bleeding Events PCI PATIENTS Female Female Elderly Elderly Chronic Kidney Dysf. Chronic Kidney Dysf. Prior PCI Prior PCI Cardiogenic shock Cardiogenic shock NYHA >2 NYHA >2 Prior valve surgery Prior valve surgery ISCHEMIC EVENTS BLEEDING Mehta S, AHA 2007 Risk model from 302,152 pts In the NCDR database 2007 ESC and ACC/AHA NSTEACS Guidelines 2004 ACC/AHA STEMI Guidelines NSTE-ACS STEMI PCI PATIENTS

132 1997 2008 and Beyond 2008 and Beyond UrgentTVR Symptomatic MI CKMB GPI UrgentTVR CKMB Bivalirudin Majorbleeding Net Clinical Benefit of Pharmacological Intervention in PCI: Should We Move From a Triangle to a Square? Dauerman HL. JACC 2008;51:698 30-Day and 1-year Mortality Rates 30-DayMortality Bivalirudin

133 Translating Advances In STEMI And NSTEMI Into Real World Practice The Austrian ExperienceEarly Findings and Observations Landmark Practice Advances in STEMI and ACS Michael M. Hirschl, MD Michael M. Hirschl, MD Associate Professor Head of the Emergency Room Medical Department of Cardiology and Intensive Care Medicine Landesklinikum St. Pölten A-3100 St. Pölten, Austria

134 STEMI Advances in STEMI Management Logistic Pharmacological

135 Implementation of networks among cardiac catheterization centers (especially in urban areas) using a rotation principle Implementation of networks among cardiac catheterization centers (especially in urban areas) using a rotation principle Establishment of integrated systems of care among primary care hospitals without cardiac catheterization capability and a high-volume tertiary cardiac care center Establishment of integrated systems of care among primary care hospitals without cardiac catheterization capability and a high-volume tertiary cardiac care center Logistical Advances in STEMI Care

136 Concept of upstream treatment of STEMI patients Concept of upstream treatment of STEMI patients (Facilitated PCI) – A Pharmacoinvasive Concept (Facilitated PCI) – A Pharmacoinvasive Concept Pharmacological Advances

137 Upstream Treatment: Principles Early administration of antithrombotic and/or anticoagulation therapy seems to improve survival of STEMI patients. Early administration of antithrombotic and/or anticoagulation therapy seems to improve survival of STEMI patients. The optimal timing is still a matter of discussion: The optimal timing is still a matter of discussion: In the cath lab (data available) In the cath lab (data available) In the emergency department (data available) In the emergency department (data available) In the EMS (NO DATA) In the EMS (NO DATA) Early administration of antithrombotic and/or anticoagulation therapy seems to improve survival of STEMI patients. Early administration of antithrombotic and/or anticoagulation therapy seems to improve survival of STEMI patients. The optimal timing is still a matter of discussion: The optimal timing is still a matter of discussion: In the cath lab (data available) In the cath lab (data available) In the emergency department (data available) In the emergency department (data available) In the EMS (NO DATA) In the EMS (NO DATA)

138 How can we establish these advances in daily clinical practice? Landmark Practice Advances in STEMI and ACS

139 LAMI: The Network 6 primary care hospitals – STEMI referral 6 primary care hospitals – STEMI referral 1 STEMI-accepting hospital: 24 hours a day, 7 days a week 1 STEMI-accepting hospital: 24 hours a day, 7 days a week Affiliated Emergency Medical Services (EMS) – Ground transport Affiliated Emergency Medical Services (EMS) – Ground transport Affiliated rescue helicopters (2): Day- time operation Affiliated rescue helicopters (2): Day- time operation 6 primary care hospitals – STEMI referral 6 primary care hospitals – STEMI referral 1 STEMI-accepting hospital: 24 hours a day, 7 days a week 1 STEMI-accepting hospital: 24 hours a day, 7 days a week Affiliated Emergency Medical Services (EMS) – Ground transport Affiliated Emergency Medical Services (EMS) – Ground transport Affiliated rescue helicopters (2): Day- time operation Affiliated rescue helicopters (2): Day- time operation

140 Two-Step Program 2006: Assessment of the current logistic and treatment modalities in our network 2006: Assessment of the current logistic and treatment modalities in our network January 2007: Conference with the heads of the hospitals, the EMS, and air rescue service to implement uniform logistic and treatment guidelines. January 2007: Conference with the heads of the hospitals, the EMS, and air rescue service to implement uniform logistic and treatment guidelines. February 2007: Start of the uniform protocol February 2007: Start of the uniform protocol 2006: Assessment of the current logistic and treatment modalities in our network 2006: Assessment of the current logistic and treatment modalities in our network January 2007: Conference with the heads of the hospitals, the EMS, and air rescue service to implement uniform logistic and treatment guidelines. January 2007: Conference with the heads of the hospitals, the EMS, and air rescue service to implement uniform logistic and treatment guidelines. February 2007: Start of the uniform protocol February 2007: Start of the uniform protocol

141 Aim of the LAMI Study Evaluation of the uniform protocol with regard to: Evaluation of the uniform protocol with regard to: Interhospital transfer interval Interhospital transfer interval Intrahospital transfer time Intrahospital transfer time Total ischemic time Total ischemic time Adherence to treatment guidelines Adherence to treatment guidelines MORTALITY MORTALITY Evaluation of the uniform protocol with regard to: Evaluation of the uniform protocol with regard to: Interhospital transfer interval Interhospital transfer interval Intrahospital transfer time Intrahospital transfer time Total ischemic time Total ischemic time Adherence to treatment guidelines Adherence to treatment guidelines MORTALITY MORTALITY

142 The LAMI Protocol Application of treatment as early as possible, i.e. at the time of first medical contact – normally administered by the EMS-staff! Application of treatment as early as possible, i.e. at the time of first medical contact – normally administered by the EMS-staff! Aspirin 300 mg i.v. Aspirin 300 mg i.v. Clopidogrel 600 mg orally Clopidogrel 600 mg orally Heparin (UFH or LMWH) Heparin (UFH or LMWH) Thrombolysis if onset of symptoms < 2 hours Thrombolysis if onset of symptoms < 2 hours Primary PCI if onset of symptoms > 2 hours Primary PCI if onset of symptoms > 2 hours Until March 2008: Abciximab given in the EMS Until March 2008: Abciximab given in the EMS Since April 2008: Bivalirudin (bolus and continuous infusion ) Since April 2008: Bivalirudin (bolus and continuous infusion ) Application of treatment as early as possible, i.e. at the time of first medical contact – normally administered by the EMS-staff! Application of treatment as early as possible, i.e. at the time of first medical contact – normally administered by the EMS-staff! Aspirin 300 mg i.v. Aspirin 300 mg i.v. Clopidogrel 600 mg orally Clopidogrel 600 mg orally Heparin (UFH or LMWH) Heparin (UFH or LMWH) Thrombolysis if onset of symptoms < 2 hours Thrombolysis if onset of symptoms < 2 hours Primary PCI if onset of symptoms > 2 hours Primary PCI if onset of symptoms > 2 hours Until March 2008: Abciximab given in the EMS Until March 2008: Abciximab given in the EMS Since April 2008: Bivalirudin (bolus and continuous infusion ) Since April 2008: Bivalirudin (bolus and continuous infusion )

143 Transfer Intervals: Early Findings 0 100 200 300 400 1.ECG-EDED-PCI TOTAL TIME Minutes 2006 2007 p=0.038 p=0.042 n.s Decrease from 235 to 180 minutes

144 Reperfusion Strategies 20062007OverallN113130243 Primary PCI 69%69%69% Thrombolysis18%16%16% No Acute Intervention 13%15%15%

145 Adherence to Treatment Guidelines 20062007OverallNumber113130243 Aspirin90%89%89% Clopidogrel90%94%92% Heparin Heparin(UFH/LMWH)87%95%92% GPIIb/IIIa Antagonist 82%88%85%

146 30-Day Mortality: LAMI Relative RR: 36%

147 Change From Abciximab to Bivalirudin Percentage of bleeding complications Percentage of bleeding complications Easier Handling: One drug from initial ECG until 12 hours after intervention Easier Handling: One drug from initial ECG until 12 hours after intervention Percentage of bleeding complications Percentage of bleeding complications Easier Handling: One drug from initial ECG until 12 hours after intervention Easier Handling: One drug from initial ECG until 12 hours after intervention

148 Bleeding Complications: LAMI Protocol AbciximabN=243BivalirudinN=54 Major Complications 4.3%2.1% Overall9.2%5.8%

149 Bivalirudin in the Real World I Start of bivalirudin treatment after the 1st ECG: Start of bivalirudin treatment after the 1st ECG: EMS (out-of-hospital) EMS (out-of-hospital) Emergency department of the primary care hospital Emergency department of the primary care hospital Intravenous bolus: 0.1 mg/kg Intravenous bolus: 0.1 mg/kg Followed by continuous infusion with 0.25 mg/kg i.v. Followed by continuous infusion with 0.25 mg/kg i.v. Start of bivalirudin treatment after the 1st ECG: Start of bivalirudin treatment after the 1st ECG: EMS (out-of-hospital) EMS (out-of-hospital) Emergency department of the primary care hospital Emergency department of the primary care hospital Intravenous bolus: 0.1 mg/kg Intravenous bolus: 0.1 mg/kg Followed by continuous infusion with 0.25 mg/kg i.v. Followed by continuous infusion with 0.25 mg/kg i.v.

150 Bivalirudin in the Real World II Increase bivalirudin dose to 1.75 mg/kg i.v. in the cath lab in case of intervention Increase bivalirudin dose to 1.75 mg/kg i.v. in the cath lab in case of intervention Reduction of dose at the end of the intervention to 0.25 mg/kg i.v. Reduction of dose at the end of the intervention to 0.25 mg/kg i.v. End of continuous infusion 12 hours after intervention and switch to LMWH End of continuous infusion 12 hours after intervention and switch to LMWH Increase bivalirudin dose to 1.75 mg/kg i.v. in the cath lab in case of intervention Increase bivalirudin dose to 1.75 mg/kg i.v. in the cath lab in case of intervention Reduction of dose at the end of the intervention to 0.25 mg/kg i.v. Reduction of dose at the end of the intervention to 0.25 mg/kg i.v. End of continuous infusion 12 hours after intervention and switch to LMWH End of continuous infusion 12 hours after intervention and switch to LMWH

151 Adherence to Treatment Guidelines LAMI Protocol: 2008 20062007 March to June 2008 N11313054 Aspirin90%89%92% Clopidogrel90%94%94% Heparin (UFH/LMWH) 87%95% GPIIb/IIIa-Antag.82%88% Bivalirudin: 94%

152 Summary I Logistical guidelines contribute substantially to an improved survival of STEMI patients. However, the total ischemic time was significantly prolonged compared to current guidelines even after implementation (mean: 180 min. vs. 90 minutes recommended) in real world. Logistical guidelines contribute substantially to an improved survival of STEMI patients. However, the total ischemic time was significantly prolonged compared to current guidelines even after implementation (mean: 180 min. vs. 90 minutes recommended) in real world. Reasons for these delays are enviromental and infrastructural circumstances in rural areas such as those served by our (LAMI) network. Reasons for these delays are enviromental and infrastructural circumstances in rural areas such as those served by our (LAMI) network. Logistical guidelines contribute substantially to an improved survival of STEMI patients. However, the total ischemic time was significantly prolonged compared to current guidelines even after implementation (mean: 180 min. vs. 90 minutes recommended) in real world. Logistical guidelines contribute substantially to an improved survival of STEMI patients. However, the total ischemic time was significantly prolonged compared to current guidelines even after implementation (mean: 180 min. vs. 90 minutes recommended) in real world. Reasons for these delays are enviromental and infrastructural circumstances in rural areas such as those served by our (LAMI) network. Reasons for these delays are enviromental and infrastructural circumstances in rural areas such as those served by our (LAMI) network.

153 Summary II Optimal adherence to guidelines and a high percentage of PPCI are important factors to offset the negative impact of extended transfer intervals. Optimal adherence to guidelines and a high percentage of PPCI are important factors to offset the negative impact of extended transfer intervals. The start of treatment as early as possible, i.e. in the EMS, plays a key role in the establishment of a successful upstream strategy. The start of treatment as early as possible, i.e. in the EMS, plays a key role in the establishment of a successful upstream strategy.

154 Conclusions Transfer of scientific advances into real world is a time- consuming and never-ending process. Transfer of scientific advances into real world is a time- consuming and never-ending process. This process may reduce the gap between advances in the ideal scientific world and daily clinical practice. This process may reduce the gap between advances in the ideal scientific world and daily clinical practice. In the LAMI system, initial data suggests use of bivalirudin appears to decrease bleeding and is associated with high adherence to treatment guidelines. In the LAMI system, initial data suggests use of bivalirudin appears to decrease bleeding and is associated with high adherence to treatment guidelines. Transfer of scientific advances into real world is a time- consuming and never-ending process. Transfer of scientific advances into real world is a time- consuming and never-ending process. This process may reduce the gap between advances in the ideal scientific world and daily clinical practice. This process may reduce the gap between advances in the ideal scientific world and daily clinical practice. In the LAMI system, initial data suggests use of bivalirudin appears to decrease bleeding and is associated with high adherence to treatment guidelines. In the LAMI system, initial data suggests use of bivalirudin appears to decrease bleeding and is associated with high adherence to treatment guidelines.

155 Take Home Messages Landmark Practice Advances in STEMI and ACS Landmark Advances and Novel Perspectives on Management of STEMI and High Risk ACS Challenging the Conventional WisdomApplying Clinical Trials and GLs to the Front Lines of Interventional Cardiovascular Practice

156 Take Home Messages Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI and is at least as important as MI and myocardial reinfarction Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI and is at least as important as MI and myocardial reinfarction In STEMI, bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and transfusions In STEMI, bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and transfusions In primary PCI for STEMI, bivalirudin is associated with a lower 30-day mortality as compared to heparin plus GPI In primary PCI for STEMI, bivalirudin is associated with a lower 30-day mortality as compared to heparin plus GPI Novel antiplatelet agents may potentially further reduce ischemic events Novel antiplatelet agents may potentially further reduce ischemic events

157 Take Home Messages Simple manual thrombus aspiration also appears to reduce mortality in STEMI Simple manual thrombus aspiration also appears to reduce mortality in STEMI There are compelling studies to suggest that when assessing pharmacoinvasive strategies, net clinical benefit may be better assessed by a quadruple end point that includes bleeding, MI, urgent TVR, and ischemic biomarkers. There are compelling studies to suggest that when assessing pharmacoinvasive strategies, net clinical benefit may be better assessed by a quadruple end point that includes bleeding, MI, urgent TVR, and ischemic biomarkers. Risk stratification in relation to bleeding and the prevention of bleeding are considered of utmost importance in both GLs, especially those published by the ESC. Risk stratification in relation to bleeding and the prevention of bleeding are considered of utmost importance in both GLs, especially those published by the ESC.

158 Take Home Messages The validation and introduction in the ESC and AHA guidelines of newer antithrombotic agents (particularly fondaparinux and bivalirudin) is characterized by lower bleeding risk, based upon large scale RCTs, and is one of the most important new features of both GLs. The validation and introduction in the ESC and AHA guidelines of newer antithrombotic agents (particularly fondaparinux and bivalirudin) is characterized by lower bleeding risk, based upon large scale RCTs, and is one of the most important new features of both GLs. Therapeutic choices, especially as they relate to bleeding minimization, should be individualized for high risk subgroups including the elderly, patients with diabetes, and those with renal disease. Therapeutic choices, especially as they relate to bleeding minimization, should be individualized for high risk subgroups including the elderly, patients with diabetes, and those with renal disease. Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events. Furthermore, a switch to bivalirudin is associated with a 50% reduction in bleeding. Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events. Furthermore, a switch to bivalirudin is associated with a 50% reduction in bleeding.

159 Take Home Messages In one regional network for STEMI, the LAMI system, initial data suggests use of bivalirudin appears to decrease bleeding and is associated with high adherence to treatment guidelines for STEMI. In one regional network for STEMI, the LAMI system, initial data suggests use of bivalirudin appears to decrease bleeding and is associated with high adherence to treatment guidelines for STEMI. Initiation of treatment as early as possible, i.e. in the EMS, plays a key role in the establishment of a successful upstream strategy. Initiation of treatment as early as possible, i.e. in the EMS, plays a key role in the establishment of a successful upstream strategy. Mechanical thrombectomy in the select patients with STEMI appears to improve mortality outcome Mechanical thrombectomy in the select patients with STEMI appears to improve mortality outcome


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