Introduction and Objectives Issues and challenges in ACS High Risk Patients with ACS — EuroPCR 2008, Barcelona, Spain Introduction and Objectives Issues and challenges in ACS Philippe Gabriel Steg INSERM U-698 Hôpital Bichat – Claude Bernard Université Paris VII – Denis Diderot

Disclosures Speaker’s name: Philippe Gabriel Steg  I have the following potential conflicts of interest to report:  Consulting/Advisory Board: AstraZeneca, Boehringer-Ingelheim, BMS, GSK, MSD, Nycomed, sanofi-aventis, Servier, Takeda, The Medicines Company  Research Grant: sanofi-aventis  Speaker’s Bureau: Boehringer-Ingelheim, BMS, GSK, Nycomed, sanofi-aventis, Servier, ZLB-Behring  I do not have any potential conflict of interest

The Landscape A changing pattern of care for all high-risk ACS

Trends in Management of STEMI in the GRACE Registry Fox KAA et al. JAMA 2007;297:1892-1900

The Landscape A changing pattern of care for all high-risk ACS …and outcomes which are improving

In-Hospital and 6-Month Outcomes in Patients With STEMI or LBBB Fox KAA et al. JAMA 2007;297:1892-1900.

CRUSADE In-Hospital Outcomes: Data from 2006 Death 3.6% (Re)-Infarction 1.8% CHF 6.6% Cardiogenic Shock 2.2% Stroke 0.7% RBC Transfusion* 9.1% *Excluding CABG-related transfusions CRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)

The Landscape A changing pattern of care for all high-risk ACS …and outcomes which are improving A growing level of complexity

Antithrombotics for ACS More and More Choices (and Combinations) Fonda Direct TIs Lytics Clopidogrel GP IIb/IIIa inhibitors LMWH Heparin Aspirin

Choices Impacting Antithrombotic Therapy Anticoagulants: UFH LMWH Fonda Bival Antiplatelets: ASA (dose) Clopidogrel (time/dose) IV antiplatelets: None Abcix Ept/Tiro (timing) Cath strategy: Early Delayed Never 72 Different Combinations!

Treatment of ACS is a Jungle ! Anticoagulant Rx UFH Enoxaparin Bivalirudin Fondaparinux Warfarin ? Anti X ? Anti II Timing Antiplatelet Rx ASA Clopidogrel ? Prasugrel ? AZD 6140 GpIIb/IIIA IV blockers ? Cangrelor ? TRA Revascularization PCI BMS DES CABG Patient Bleeding risk Comorbidities Risk of thrombotic event

The Landscape A changing pattern of care for all high-risk ACS …and outcomes which are improving A growing level of complexity Use and timing of interventions impact therapeutic choices

The Landscape A changing pattern of care for all high-risk ACS …and outcomes which are improving A growing level of complexity Use and timing of interventions impact therapeutic choices Fortunately, we have guidelines to assist us !

Objectives Know the current guidelines for the management of STEMI and NSTE ACS Understand their implications for patient management

New Horizons for Patients with ST-Elevation Myocardial Infarction Gregg W. Stone MD Columbia University Medical Center Cardiovascular Research Foundation 16

Potential Conflicts of Interest Speaker’s name: Gregg W. Stone, MD  I have the following potential conflicts of interest to report:  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Grant/Research Support: The Medicines Company and Boston Scientific  I do not have any potential conflict of interest 17

FACT Major bleeding (with or without blood product transfusions) has emerged as a powerful independent predictor of early and late mortality in pts with NSTEMI, STEMI and in those undergoing PCI Ndrepepa et al. JACC 2008;51:690–7

Cumulative % Mortality Time from Randomization in Days Impact of Major Bleed and MI after Elective and Urgent PCI 1-Year Mortality (N=6,012) With major bleed 8.8% With MI 5.7% Cumulative % Mortality Without major bleed 2.0% 1.9% Without MI Time from Randomization in Days Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

Predictors of 1-year Mortality after Elective and Urgent PCI Variable Groups O.R. (95% CI) p-value Creatinine clear. <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) CHF Yes 4.38 (2.83–6.78) Major Bleeding 3.26 (1.78–5.96) 0.0001 MI @30day 2.77 (1.62–4.75) 0.0002 Urg Revasc @30d (1.15–6.71) .024 Hx angina 2.18 (1.25–3.81) 0.006 Prior MI 1.81 (1.09–3.03) 0.023 Diabetes 1.64 (1.10–2.44) 0.015 Stone GW. J Inv Cardiol 2004;16(suppl G):12–17. 20

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

Days from Randomization Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 1 year Estimate 28.9% Both MI and Major Bleed (N=94) Major Bleed only (without MI) (N=551) 12.5% MI only (without Major Bleed) (N=611) 8.6% 30 3.4% No MI or Major Bleed (N=12,557) 25 20 Mortality (%) 15 10 5 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007

Influence of Major Bleeding and MI in the First 30 Days on the Risk of Death within 30 Days Of 13,819 enrolled pts, 704 (5.1%) had a MI, 644 (4.7%) had a major bleed (non CABG), and 206 (1.5%) died within 30 days Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates Attributable deaths HR ± 95% CI HR (95% CI) P-value Myocardial infarction 5.25 (3.72-7.43) <0.0001 Major bleeding without or before transfusion 3.04 (1.66-5.55) Major bleeding after transfusion 5.45 (3.54-8.38) 42.0* 38.2** *20.4% of all deaths **18.5% of all deaths Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR Stone GW. ACC 2008

Of 13,819 enrolled pts, 524 (3.8%) died within 1 year Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year Of 13,819 enrolled pts, 524 (3.8%) died within 1 year Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates Attributable deaths HR ± 95% CI HR (95% CI) P-value Myocardial infarction 2.51 (1.95-3.25) <0.0001 Major bleeding without or before transfusion 2.00 (1.30-3.06) Major bleeding after transfusion 3.93 (2.95-5.24) 51.5* 66.5** *9.8% of all deaths **12.7% of all deaths Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR Mehran RM et al. Submitted

ACUITY: Early and Late Mortality Landmark analysis 4 30 day Estimate P (log rank) 1.4% 0.53 1.6% 0.39 — Estimate P (log rank) 3.1% 0.54 2.7% 0.21 2.3% 30d - 1 year — UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 3 Mortality (%) 2 1 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. JAMA 2007;298:2497-506

Harmonizing Outcomes with Revascularization and Stents in AMI ≥3400* pts with STEMI with symptom onset ≤12 hours UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Aspirin, thienopyridine R 1:1 Emergent angiography, followed by triage to… Primary PCI CABG – Medical Rx 3000 pts eligible for stent randomization R 1:3 Bare metal stent TAXUS paclitaxel-eluting stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years *To rand 3000 stent pts

Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin Monotherapy N=1800 Randomized 9 15 • • • Withdrew • • • • • • Lost to FU • • • 10 13 N=1778 (98.7%) N=1777 (98.7%) 30 day FU* ITT population N=1802 N=1800 * Range ±7 days Stone GW et al. In press.

Primary Outcome Measures (ITT) Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ 0.0001 Psup = 0.005 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] Psup = 0.95 1 endpoint 1 endpoint *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke

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% Protocol Minor 15.4% 8.6% 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% GUSTO LT*** or Severe 0.6% 0.4% 0.49 GUSTO Moderate GUSTO LT or Sev or Mod 5.6% *CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

Thrombocytopenia P = 0.002 P = 0.04 P = 0.02 <100,000 cells/mm3 Stone GW et al. In press.

30 Day MACE Components* UFH + GP IIb/IIIa (N=1802) Bivalirudin P Value Death 3.1% 2.1% 0.047 - Cardiac 2.9% 1.8% 0.028 - Non cardiac 0.2% 0.3% 0.75 Reinfarction 0.90 - Q-wave 1.2% 1.4% 0.66 - Non Q-wave 0.7% 0.4% 0.37 Ischemic TVR 1.9% 2.6% 0.18 - Ischemic TLR 2.5% 0.13 - Ischemic remote TVR 1.0 Stroke 0.6% 0.68 *CEC adjudicated Stone GW et al. In press.

30 Day Mortality 3.1% Death (%) 2.1% P=0.048 Time in Days Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 3.1% Death (%) 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Time in Days Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630 Stone GW et al. In press.

30 Day Mortality: Cardiac and Non Cardiac Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 2.9% Death (%) Cardiac 1.8% Non cardiac 0.3% 0.2% Time in Days Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630 Stone GW et al. In press.

30 Day Stent Thrombosis (N=3,124) UFH + GP IIb/IIIa (N=1553) Bivalirudin (N=1571) P Value ARC 30d definite or probable stent thrombosis* 1.9% 2.5% 0.30 - definite 1.4% 2.2% 0.09 - probable 0.5% 0.3% 0.24 - acute (≤24 hrs) 1.3% 0.0007 - subacute (>24 hrs – 30d) 1.7% 1.2% 0.28 *Protocol definition of stent thrombosis, CEC adjudicated

30 Day Mortality: PCI Cohort Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) HR [95%CI] = 0.63 [0.40, 0.99] P=0.049 2.8% Death (%) Cardiac 1.8% Non cardiac 0.2% 0.1% Time in days Number at risk Bivalirudin 1678 1647 1640 1635 1632 1620 1563 Heparin + GPIIb/IIIa 1662 1631 1615 1604 1598 1583 1512 Stone GW et al. In press.

Predictors of 30 Day Mortality 32 Candidate Baseline Variables* Demographic: Age; sex; race; US vs. OUS; HTN, hyperlipidemia, smoking, diabetes, diabetes on insulin, MI, PCI, CABG, CAD, angina, CHF, major cardiac rhythm/rate disturbances, PVD Medication use at home previous 5 days: aspirin, beta blocker, thienopyridines, calcium channel blocker, ACE/ARB, diuretic Time from symptom onset to hospital ER Physical exam: BMI; KILLIP class Baseline labs: Estimated CrCl, anemia, platelet count Medications in hospital prior to angiography: Randomized treatment (bivalirudin vs. heparin + GPI; pre-procedure heparin; clopidogrel load * Angiographic variables not yet available; - treatment related variables not used

Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Attributable Ischemic Events HR (95% CI) P 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 10.71 [3.93,29.18] <0.001 4.5 [3.7,4.8] 0.83 - acute (<24 hours) 5.88 [0.78,44.30] 0.09 0.8 [-0.3,1] 0.82 Stroke 5.44 [1.67,17.69] 0.005 2.4 [1.2,2.8] 0.82 * 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

Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Attributable Bleeding Events HR (95% CI) P 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/mm3 3.89 [2.22, 6.84] <0.001 11.1 [8.2,12.8] 0.78 - <50,000 cells/mm3 6.44 [2.93,14.18] <0.001 5.9 [4.6,6.5] 0.78 - <20,000 cells/mm3 4.98 [1.20,20.66] 0.03 1.6 [0.3,1.9] 0.77 * 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

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

Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality - Complete model with MACE components and major bleeding - Attributable Deaths Risk Factor HR [95% CI] P-value Reinfarction Incidence 69 (2.2%) 10 deaths with event 9.75 [2.72,34.91] 9.0* [6.3, 9.7] <0.001 Major bleeding (Non CABG) Incidence 238 (6.8%) 26 deaths with event 4.66 [2.84, 7.63] 20.4** [16.8, 22.6] <0.001 Hazard Ratio [95% CI] 0.01 0.1 1 10 100 *9.7% of 93 total deaths **21.9% of 93 total deaths C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality - Complete model in 3,124 pts with successfully implanted stents - Attributable Deaths Risk Factor HR [95% CI] P-value Stent thrombosis (definite) Incidence 57 (1.8%) 5 deaths with event 10.62 [3.96, 28.48] 4.5* [3.7, 4.8] <0.001 Major bleeding (non CABG) Incidence 195 (6.2%) 18 deaths with event 6.22 [3.33, 11.60] 15.1** [12.6, 16.4] <0.001 Hazard Ratio [95% CI] 0.01 0.1 1 10 100 *8.3% of 54 total deaths **28.0% of 54 total deaths C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

Conclusions 1. Major bleeding is a powerful independent determinant of mortality in ACS, STEMI, and in pts undergoing PCI, at least as important as MI/reinfarction. 2. In high risk pts with STEMI undergoing primary PCI, treatment with bivalirudin compared to heparin + GPI results in a significant reduction in bleeding, thrombocytopenia and transfusions, with similar rates of reinfarction, stent thrombosis, iTVR and stroke. 3. This favorable balance of adverse events results in lower 30-day mortality in primary PCI pts treated with bivalirudin rather than heparin + GPI, representing a new standard of care for pts with STEMI.

SWITCH Changing Anticoagulants in Midstream — What Are the Benefits and Risks? Harvey White Green Lane Cardiovascular Service and Cardiovascular Research Unit Auckland City Hospital; Auckland, New Zealand Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

Potential conflicts of interest Speaker’s name: Harvey D. White  I have the following potential conflicts of interest to report:  Research Grants: Sanofi Aventis, The Medicines company, Eli Lilly, Roche,Schering Plough, Pfizer, Johnson and Johnson, Astra Zenica, Merck Sharpe and Dohme and NIH  Consulting Fees: The Medicines Company  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  I do not have any potential conflict of interest

Background ACS patients Published studies and perceptions 87% of patients receive either UFH or Enox within 24 hours after admission1 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin2,3 Published studies and perceptions Patients in SYNERGY who crossed over between UFH and Enox had an increase in bleeding complications2 This activity occurred at various times through the study period: At times in response to clinical or clinician perception Consistent therapy is better4 Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ 1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al, NEJM 2006; 4 Cohen et al, JACC 2006;

Switching Concern about switching antithrombins in patients with ACS (lessons from SYNERGY) European guidelines Why should switching to bivalirudin monotherapy be reasonable? Mechanistic rationale for switching SWITCH REPLACE 2 ACUITY Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ 46

ESC Non-STEACS 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) Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ EHJ 2007;28:1598-60

SWITCH Definitions Switch: Protocol mandated change in antithrombotic therapy at randomization Crossover : Post randomization change in antithrombotic therapy due to physician choice Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

Is it better to switch to bivalirudin or remain on consistent therapy? ACUITY — SWITCH 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 Is it better to switch to bivalirudin or remain on consistent therapy? Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ White HD. In Press JACC 49

ACUITY – Primary Results UFH/Enoxaparin + GPI vs. Bivalirudin Alone UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612) PNI <0.0001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PNI <0.0001 PSup <0.0001 30 day events (%) 11.7% 10.1% 7.3% 7.8% 5.7% 3.0% Net clinical outcome Ischemic composite Major bleeding

ACUITY — Switch Analysis Study Methods Patients on prior antithrombin 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 From Enoxaparin → Bivalirudin or UFH → Bivalirudin Event rates at 30-days Net clinical outcome Ischemic composite Major bleeding White HD, et al. J Am Coll Cardiol 2008;51:1734–41 51

ACUITY – Switch Consort CONSISTENT UFH/Enox N = 2137 SWITCH Bivalirudin N = 2078 UFH→UFH N = 1294 Enox→Enox N = 843 UFH→Biv N = 1313 Enox→Biv N = 765 Pts on Prior AT N = 4215 ╪ ╪ excludes Arm B and pts. with multiple crossovers, missing data Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

Consistent vs. Switch Comparing Consistent therapy on Enox + GPIIb/IIIa Inhibition vs. Switch to Bivalirudin Alone Consistent Enox + GPIIb/IIIa Inhibition (N = 843) Switch to Bivalirudin alone (N = 765) 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% 20 15 30 day events (%) 10 5 Net clinical outcome Ischemic composite Major bleeding Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ White HD, et al. J Am Coll Cardiol 2008;51:1734–41

ACUITY – Switch Consistent vs. Switch High Risk High Risk Patients Comparing Consistent UFH/Enox vs Switch Bivalirudin Consistent UFH/Enox N = 1581 Switch Bivalirudin N = 1496 RR Net Clinical Outcome 13.0% 10.6% 0.82 [0.67-0.99] Ischemia 8.2% 7.7% 0.94 [0.74-1.20] Major Bleeding 6.5% 3.5% 0.51 [0.39-0.75] Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

ACUITY – SWITCH Consistent vs. Switch Patients Undergoing PCI PCI Patients Comparing Consistent UFH/Enox vs Switch Bivalirudin Consistent UFH/Enox N = 1236 Switch Bivalirudin N = 1292 RR Net Clinical Outcome 13.2% 11.8% 0.90 [0.73 -1.10] Ischemia 8.2% 9.0% 1.10 [0.85 -1.42] Major Bleeding 6.7% 3.5% 0.52 [0.36-0.74] Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

Prior Antithrombin Therapy ACUITY: Switch 30 Days Prior Antithrombin Therapy Relative Risk ± 95% CI RR (95% CI) Composite Ischemia 0.93 (0.75-1.16) Major Bleeding 0.49 (0.36-0.66) Net Clinical Outcome 0.77 (0.65-0.92) 1 2 Switch to Bivalirudin Better Consistent UFH/Enox + IIb/IIIa Better Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ White HD, et al. J Am Coll Cardiol 2008;51:1734–41

Naïve to Antithrombin Therapy ACUITY — Switch 30 Days Naïve to Antithrombin Therapy Relative Risk ± 95% CI RR (95% CI) Composite Ischemia 1.11 (0.83-1.49) Major Bleeding 0.52 (0.35-0.77) Net Clinical Outcome 0.85 (0.67-1.07) 1 2 Randomization to Bivalirudin Better Randomization to UFH/Enox + IIb/IIIa Better Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ White HD, et al. J Am Coll Cardiol 2008;51:1734–41

ACUITY – Switch ACUITY PCI: Switch from Prior Antithrombin 30-Day Results 1-Year Results Risk Ratio ± 95% CI Hazard Ratio ± 95% CI RR (95% CI) HR (95% CI) PCI (n=2528) PCI (n=2528) Composite ischemia 1.10 (0.85-1.42) Mortality 0.93 (0.58-1.48) Major bleeding 0.52 (0.36-0.74) PCI HIGH RISK* (n=1988) PCI HIGH RISK* (n=1988) Composite ischemia 1.14 (0.86-1.52) Mortality 0.99 (0.60-1.63) Major bleeding 0.56 (0.38-0.81) Switch to Bivalirudin better Consistent UFH/Enox + IIb/IIIa better * High risk = ↑Tn, CKMB or ECG Δ’s 0.1 1 10 0.1 1 10 White HD. In Press JACC 58

Naïve to Antithrombin Therapy Randomized to Enox + GPIIb/IIIa Inhibition (N = 842) Randomized to Bivalirudin (N = 1427) 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] 20 9.5% 8.0% 5.8% 6.2% 5.0% 2.5% 15 30 day events (%) 10 5 Net clinical Ischemic Major outcome composite bleeding Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

ACUITY – Switch Limitations Post-hoc subgroup analysis Pre-randomization use of anti-thrombin was not stratified Timing and dose of last UFH and Enox was not collected in the CRF Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

REPLACE-2: SWITCH Analysis Overall population: Urgent or elective PCI patients (N=6,002)1 Randomize Bivalirudin 0.75 mg/kg bolus/1.75 mg/kg/h infusion with “provisional” GP IIb/IIIa (n=2,994)1 UFH 65 U/kg with planned GP IIb/IIIa (n=3,008)1 Naïve – no prior AT (n=2,345)2 Prior UFH (n=287)2 Prior LMWH (n=258)2 Naïve – no prior AT (n=2,325)2 Prior UFH (n=349)2 Prior LMWH (n=313)2 Key Message: SWITCH Retrospective Post-hoc Analysis: Among the patients who received ANGIOMAX, 2,345 patients had not received an AT agent during that hospitalization before randomization, 287 had received UFH, and 258 patients had received LMWH. Of the patients who received GP IIb/IIIa and UFH during PCI, 2,325 patients were AT-naïve, 349 had received UFH, and 313 had received LMWH. Outcomes for patients in each randomized arm were analyzed according to whether they had received UFH, LMWH within 48 hours of randomization or no AT (naïve) before randomization. Reference Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99:1687-1690. Protocol major/minor bleeding, TIMI bleeding, transfusion, mortality AT=antithrombin. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ 1. Lincoff ML et al. JAMA. 2004;292:696-703. 2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690. 61

Protocol Major/Minor Bleeding by SWITCH and Randomized Therapy 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 34.8% 35% 33.8% † 30% 28.6% 25% * Protocol major/minor bleed 20% 16.7% 15.6% 15.3% 15% Key Message: Regardless of receiving prior heparin or not, patients administered ANGIOMAX experienced fewer bleeding events. In contrast, there was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy. Reference Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99:1687-1690. 10% 5% 0% Naïve→ Bivalirudin‡ (n=2,345) LMWH→ Bivalirudin (n=258) UFH→ Bivalirudin (n=287) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→ UFH + GP IIb/IIIa‡ (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) *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. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

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 administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins 6% 5.4% 5% 4.3% 4% 3.5% TIMI major/minor bleed 3% * 1.9% 1.9% 2% 1.4% Key Message: Patients switched from UFH or LMWH 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. Reference Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99:1687-1690. 1% 0% Naïve→ Bivalirudin† (n=2,345) LMWH → Bivalirudin (n=258) UFH→ Bivalirudin (n=287) LMWH→UFH+ GP IIb/IIIa (n=313) Naïve→UFH + GP IIb/IIIa† (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) *P=NS for all 3-way comparisons versus bivalirudin alone; †naïve=no prior AT therapy in preceding 48 hours. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

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

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

From UFH to Bivalirudin How to Switch From UFH to Bivalirudin Discontinue UFH for 30 minutes before starting bivalirudin From LMWH to Bivalirudin • Discontinue LMWH for 8 hours before starting bivalirudin Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ 66

Conclusions Switching to bivalirudin is safe Furthermore Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events Furthermore Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

Role of Bleeding Reduction in ACS The Role and Implications of Bleeding in ACS Role of Bleeding Reduction in ACS Impact on Outcomes and Costs Keith A A Fox Edinburgh Centre for Cardiovascular Science

Potential conflicts of interest Speaker’s name: Keith A A Fox  I have the following potential conflicts of interest to report:  Consulting  Research grants/speaker honoraria: sanofi-aventis, Bristol-Myers Squibb, and GlaxoSmithKline  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest .

How common is major bleeding in ACS? What are the risk factors for bleeding? The impact of anti-thrombotic therapy? What are the consequences of bleeding? Net clinical outcome Costs

Factors Contributing to the Balance of Risks Reduced Thrombotic and Embolic Events Cerebral and Systemic Bleeding Events Anticoagulants Anti-platelets Anti-thrombins ACE / ARB Hypertension & lipid control Smoking cessation Anticoagulants Anti-platelets Anti-thrombins Renal dysfunction Poor hypertension control

Hierarchy of Bleeding Risk A consistent definition of bleeding is required Fatal bleed Intra-cerebral bleed Life-threatening bleed Bleed with hemodynamic disturbance or requiring transfusion or prolonging hospital stay Minor bleeds TIMI “ Major Bleed”: >5gm Hb drop or 5U transfusion or ICH GUSTO “ severe/life threatening”: ICH or hemodynamic compromise requiring treatment

Major Bleeding in ACS: GRACE Registry 6 3.9 2.3 4.7 4.8 5 4 Overall ACS Unstable angina Patients % 3 Non-ST MI 2 ST-MI 1 Major bleeding Life threatening bleeding requiring a transfusion of 2+ units Bleeding resulting in an absolute decrease in hematocrit of ≥ 10% Bleeding resulting in death n= 24,045 patients Definition of bleeding: European Heart Journal (2003) 24, 1815–1823

Multivariate Risk (Non-ST MI) Major Bleeding (1) Hosomer-Lemeshow p value 0.70, C statistic 0.73 Odds Ratio (95% CI) Thrombolytic + IIb/IIIa 4.19 1.68-10.0 IIb/IIIa 1.86 1.43-2.43 History of Bleeding 2.18 1.17-4.08 Renal Insufficiency 1.53 1.13-2.08 Moscucci et al Eur Heart J 2003

Multivariate Risk (Non-ST MI) Major Bleeding Hosomer-Lemeshow p value 0.70, C statistic 0.73 Odds Ratio (95% CI) Age (10yr) 1.22 1.10-1.35 Female 1.36 1.07-1.73 Inotropes (iv) 1.88 1.35-2.62 Renal Insufficiency 2.01 1.38-2.91 Diuretics 1.91 1.46-2.49 Mean Arterial Pressure (20mm ) 1.04 1.14-1.27 Moscucci et al Eur Heart J 2003

GUSTO I Predictors of Bleeding Variable Odds Ratio 95% CI 2 Patients treated in US 1.76 (1.08, 2.85) 521 Age (60 v 50y) 1.30 (1.26, 1.35) 222 Weight (75 v 85kg) 1.23 (1.18, 1.28) 164 Female 1.42 (1.31, 1.53) 73 African Ancestry 1.33 (1.12, 1.57) 10 Berkowitz, Circulation 1997;95:2508-2516 12

The Role and Implications of Bleeding in ACS Bleeding and Outcome?

Bleeding and Outcomes in ACS Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT 1.00 0.95 0.90 0.85 0.80 0.75 0.70 None Mild Moderate Severe Data from clinical trial populations corroborates findings from the GRACE Registry. This analysis of 26,452 NSTEACS patients from 4 large international randomized clinical trials shows a relationship between bleeding severity and worsening 30day mortality; however, this is a post-hoc analysis and could be confounded by differences among patients that suffered varying bleed severity. 0 5 10 15 20 25 30 Days to Death log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6.

6-month Death/MI (Adjusted) According to Severity of Bleeding 1.3 GUSTO Mild 2.0 GUSTO Moderate 5.1 GUSTO Severe 1.0 5.0 Odds ratio Rao SV, et. al., ACC 2005

30 Day Death According to Bleeding OASIS Registry, OASIS-2, CURE 14 12 10 Bleeding Cumulative Events, % 8 6 4 2 No Bleeding 5 10 15 20 25 30 Days No. at Risk No Bleeding 33676 33419 33157 32990 32879 32769 32710 Bleeding 470 459 440 430 420 410 408 J Eikelboom et al Circulation 2006

The impact of renal dysfunction The Role and Implications of Bleeding in ACS The impact of renal dysfunction

SYNERGY: Clinical Outcomes and Procedures Creatinine Clearance (CrCl) p-value 30-Day Outcomes Death/MI 24.4% 17.3% 12.7% <0.0001 Death 15.4% 5.7% 1.8% Cardiac Cath 80.1% 88.8% 93.7% PCI 35.0% 42.4% 51.5% CSBG 17.1% 20.0% 20.2% 0.84 In-Hospital Bleeding GUSTO Severe 7.7% 3.7% P-value from logistic regression with CrCl as continuous variable * in-hospital

Increased Risks Associated with Transfusion The Role and Implications of Bleeding in ACS Increased Risks Associated with Transfusion

CRUSADE Bleeding Risks Transfusion by Age 14.9% overall 10.3% non-CABG 20 18.5 17.9 14.1 15 10.3 9.7 % RBC Transfusion 10 4.5 5 <65 yrs 65-75 yrs > 75 yrs Through Q2 2004 (n=74,271) Non-CABG Overall -- Yang, J Am Coll Cardiol 2005;46:1490-5

Transfusion and 30-day Mortality 3.8 Adjusted for transfusion propensity 3.5 Adjusted for baseline characteristics Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, & nadir HCT 3.9 0.1 1.0 10 Odds Ratio Cox model, transfusion = time-dependent covariate -- Rao SV, et. al., JAMA 2004

Does Prevention of Bleeding Improve Long-term Outcome? The Role and Implications of Bleeding in ACS Does Prevention of Bleeding Improve Long-term Outcome?

Multivariate Logistic Model 1-Year Mortality Multivariate Logistic Model Predictor Odds Ratio 95%Confidence Interval p-value CrCl <30 ml/min 7.9 2.7-22.4 <0.001 CrCl 30-60 ml/min 3.8 2.2-6.6 CrCl 60-90 ml/min 1.7 1.0-2.7 Major Bleed 3.67 2.1-6.5 Non-Q MI 2.58 1.5-4.4 0.004 Diabetes 1.74 1.3-2.6 0.005

Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year Of 13,819 enrolled pts, 524 (3.8%) died within 1 year Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates Attributable deaths HR ± 95% CI HR (95% CI) P-value Myocardial infarction 2.51 (1.95-3.25) <0.0001 Major bleeding without or before transfusion 2.00 (1.30-3.06) Major bleeding after transfusion 3.93 (2.95-5.24) 51.5* 66.5** *9.8% of all deaths **12.7% of all deaths Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR Mehran RM et al. Submitted

Predictors of Major Bleeding Results: The ACUITY Trial — PCI Population Risk ratio ± 95% CI RR (95% CI) P-value 1 2 3 Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension No prior PCI Prior antithrombotic therapy Heparin(s) + GPI (vs. Bivalirudin) 1.56 (1.19-2.04) 0.0009 1.89 (1.48-2.41) <0.0001 1.68 (1.29-2.18) 1.30 (1.03-1.63) 0.0248 2.08 (1.68-2.57) 1.42 (1.06-1.90) 0.0178 1.33 (1.03-1.70) 0.0287 1.47 (1.15-1.88) 0.0019 1.23 (0.98-1.55) 0.0768 2.08 (1.56-2.76) These data from patients undergoing PCI in the ACUITY randomized trial confirm the findings from the GRACE Registry and also identify “novel” risk factors such as diabetes and anemia. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

UFH/Enox versus Fondaparinux Major Bleeding at 30 Days UFH/Enox versus Fondaparinux OASIS 5 & 6 UFH/Enoxaparin 0.04 0.03 Fondaparinux Cumulative Hazard 0.02 HR 0.67 95% CI 0.59-0.76 P<0.00001 0.01 0.0 5 10 15 20 25 30 Days

Mortality: Day 30 Enoxaparin Fondaparinux OASIS 5 HR 0.83 0.03 Fondaparinux 0.02 Cumulative Hazard HR 0.83 95% CI 0.71-0.97 P=0.022 0.01 0.0 3 6 9 12 15 18 21 24 27 30 Yusuf et al NEJM 2006 Days

Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality OASIS 5 Crude Odds Ratio for Death (95% CI) 30 Days 30 to 180 Days 180 Days Nonfatal MI 9.9 (8.0-12.3) 2.3 (1.6-3.3) 5.7 (4.7-6.9) Refractory Ischemia 4.1 (3.0-5.7) 1.4 (0.8-2.4) 2.7 (2.0-3.6) Major Bleeds 6.6 (5.2-8.3) 2.2 (1.6-3.2) 4.2 (3.5-5.1) Minor Bleeds 3.0 (2.1-4.3) 1.6 (1.0-2.5) 2.2 (1.7-3.0)

Minimizing the Risks of Bleeding? The Role and Implications of Bleeding in ACS Minimizing the Risks of Bleeding?

Excessive Dosing of Anticoagulants by Age 70 64.5 60 50 38.5 40 37 % Excessive Dose 33.1 28.7 30 20 16.5 12.5 12.5 8.5 10 LMW Heparin UF Heparin GP IIb/IIIa < 65 yrs 65-75 yrs >75 yrs

Dosing Combinations and Transfusions Heparin + GP IIb-IIIa Inhibitors* 20 18.5 18 16 14 12 % RBC Transfusions 10 9 8 6 4.1 4 2 Both Right 1 Excessive Both Excessive * Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors

Bleeding and Resource Use Predictors of Total Costs 14,000 $12,409 12,000 10,000 8,000 $7,188 $ 6,000 $5,255 4,000 $3,370 $2,488 $2,436 $2,164 2,000 $1,158 $1,336 Mod/Sev UA Cath PCI CABG Pacemaker IABP ICU day Non-ICU Bld day N=1235 pts from GUSTO IIb Model C-index=0.87 Adjusted for patient characteristics Rao SV, et. al. AHJ 2008.

Conclusions In ACS bleeding is important as it is a harbinger of adverse outcomes, including death Major bleeding and recurrent MI have a similar risk of death Older age, chronic kidney disease, female gender, anemia, diabetes: consistently associated with bleeding and blood transfusion Major bleeding is associated with adverse outcomes and increased costs Both ESC and ACC/AHA Guidelines in ACS highlight the importance of bleeding reduction in ACS care

The Science and Medicine of ACS Translating Advances in NSTEMI and STEMI into Real World Institutional Practice Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Fletcher Allen Health Care 99

Potential conflicts of interest Speaker’s name: Harold L. Dauerman, MD  I have the following potential conflicts of interest to report:  Consulting: The Medicines Company, Abbott Vascular  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest

University of Vermont Post-PCI Bleeding and Vascular Complication Rates 4 Introduction of Bivalirudin to Cath Lab 3.5 3 NNE Rate: 2.0% in 2006 2.5 Bleeding Complication, % 2 1.5 Introduction of Upstream Bivalirudin 1 0.5 2001 2002 2003 2004 2005 2006 2007 Any Transfusion, RPH or Repair = Bleeding Complication 101

Incorporation of Bivalirudin in Cath Lab for NSTEMI in 2003—A Cautious Beginning GP IIb/IIIa Inhibitor UFH alone

Signs of Hope Since 2004 P < 0.001 for temporal trend 3.37 3.5 3.2 3 2.51 2.5 2.11 1.96 Major Vascular Complications, %* 2 1.5 1 0.5 2002 2003 2004 2005 2006 Arterial injury and/or arterial injury related bleeding N= 36,631 Patients Undergoing PCI, NNE Registry Dauerman, Applegate and Cohen, JACC 2007 103

How We Introduced Upstream and Downstream Bivalirudin: The UVMC Time Line 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI 2007: Educational programs for fellows, floor staff and attendings We did not remove GPI option We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and don’t overdose patients. 2008: A standardized STEMI bivalirudin approach For upstream AMI utilization, bivalirudin ordered from pharmacy In collaboration with ED (EDICT for ACS Strategy)

NSTEMI Transfers, Upstream Strategies, and Results of Clinical Trials Non ST-Elevation Myocardial Infarction NSTEMI Transfers, Upstream Strategies, and Results of Clinical Trials 105

What We Really Do With Transfers? September 24, 2007 email from me To: Sullivan, Claudia A. Cc: Ades, Philip A. Subject: Transfer of John XXXXX, DOB 11/08/25 81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center. Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable). Thanks, Harry

Protocol Major/Minor Bleed by SWITCH and Randomized Therapy 15.6% 15.3% 16.7% 28.6% 33.8% 34.8% 0% 5% 10% 15% 20% 25% 30% 35% † Protocol major/minor bleed * Key Message: Regardless of receiving prior heparin or not, patients administered bivalirudin experienced fewer bleeding events. In contrast, there was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy. Reference Gibson CM, Ten Y, Murphy SA. Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol. 2007;99:1687-1690. Naïve→ Bivalirudin‡ (n=2,345) UFH→ Bivalirudin (n=287) LMWH→ Bivalirudin (n=258) Naïve→ UFH + GP IIb/IIIa‡ (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) LMWH→UFH + GP IIb/IIIa (n=313) *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. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

Transfer to Cardiology Floor Enoxaparin held—wait 8 hours from community hospital last dose. Then, start upstream bivalirudin Patient pain free—1st case next A.M DES, no eptifibatide, closure device, 150 mg clopidogrel Ambulate at 6 hours D/C following 0900 A.M.

If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions? 11.8% 7.5% 5.7% 3.5% 12.7% 10.3% Net clinical outcomes Ischemic composite Major bleeding UFH/Enoxaparin + IIb/IIIa (N=1722) UFH/Enoxaparin + IIb/IIIa (N=811) Bivalirudin Alone (N=1789) Bivalirudin Alone (N=804) RR [95%CI] 0.81 (0.68-0.96) RR [95%CI] 0.96 (0.77-1.20) RR [95%CI] 0.50 (0.37-0.67) RR [95%CI] 1.07 (0.83-1.39) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 0.61 (0.39-0.97) 13.8% 11.1% 8.4% 8.1% 7.2% One of the most hotly debated aspects of the study is the potential interaction with clopidogrel. In patients who were not exposed to clopidogrel before PCI (defined as any pre-procedural exposure, regardless of dose or timing) there was a significantly higher incidence of ischemic composite events in patients in the bivalirudin monotherapy group, in contrast to patients who had been exposed to clopidogrel, where no such difference existed. A number of issues are worth noting. The differences in ischemic events in the patients not treated with clopidogrel stem not only from worse outcomes with bivalirudin, but BETTER outcomes in the heparin group, at least in comparison to the thienopyridine exposed patients. Mechanistically, this COULD relate to the fact that patients undergoing PCI may benefit from more than just ASA as an antiplatelet foundation, and that in patients not pre-loaded with clopidogrel, that critical time window may not be covered in patients not treated with a IIb/IIIa antagonist, and that what you are really comparing is potent early platelet inhibition with no potent early platelet inhibition, emphasizing the need for clopidogrel pretreatment in ACS patients coming forward to intervention. It could, always represent the play of chance as well, given the multiple comparisons and subgroups involved in the study. Nevertheless, the observation is there, and for now reinforces the need for more than ASA therapy in ACS patients coming forward to PCI - in clopidogrel-loaded patients, incremental Iib/IIIa provides no additional benefit, and bivalirudin alone provides comparable (identical, actually) ischemic outcomes, and significantly less major bleeding. 3.6% Net clinical Ischemic Major bleeding outcomes composite Not Thienopyridine Exposed Thienopyridine Exposed Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16 109

Timing of Clopidogrel Administration and 30-Day Risk of Ischemic Outcomes Risk ratio (RR) ±95% CI for the triple ischemic endpoint (death, MI, unplanned revascularization) Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15] Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92] pinteraction = 0.35 Post-PCI Clopidgrel (> 30 minutes After PCI) N=519 RR 1.48 [95% CI 0.89, 2.47] Angiomax was found to be superior to heparin and as effective as heparin plus GP IIb/IIIa with respect to the quadruple endpoint of death, MI, urgent revascularization and major bleeding. No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72] 1 2 3 4 5 6 7 8 Bivalirudin alone better Heparin + GPIIb/IIIa better S. Steinhubl TCT 2007

Does Periprocedural Infarct Increase With Upstream and Downstream Bivalirudin? No! ACS PCI Outcomes 2005 Bival 61% N=373 2007 Bival 91% N=361 P value Any Transfusion (%) 2.0 1.0 NS Death (%) 3.0 0.08 Urgent revascularization (%) MI, 50% CK-MB Rise (%) 4.0 0.02 Mechanical Complication (%) 8.0 6.0 Submitted, TCT 2008 Clopidogrel preload in approx 60% of PCI patients CK-MB on all patients the day after PCI (University of Vermont data)

STEMI Switching, Clopidogrel and Stent Thrombosis ST-Elevation Myocardial Infarction STEMI Switching, Clopidogrel and Stent Thrombosis 112

The Standard of Care for STEMI PCI in 2005: National Registry of Myocardial Infarction-5 Primary PCI for STEMI N= 7,629 Bivalirudin and GPIIbIIIa PCI N=177 (55%) No N= 7,309 Clopidogrel N=171 (97%) GP IIbIIIa Inhibitor use N=6,873 (94%) Prior to PCI N=37 (21%) Not Prior to PCI N= 140 (79%) N=2,489 (36%) N= 4,384 (64%) Abciximab N=64 (36%) Eptifibatide N=93 (52%) Tirofiban N=1 (1%) Unkown N=19 (11%) N=2,283 (33%) N=3,551 (52%) N=154 (2%) Unknown N= 885 (13%) N=8 (22%) N=27 (73%) N=1 (3%) Unknown N=1 (2%) N=622 (25%) N=1621 (65%) N=99 (4%) Unknown N=147 (6%) N=56 (40%) N=66 (47%) N=0 (0%) Unknown N=18 (13%) N=1661 (38%) N=1930 (44%) N=55 (1%) Unknown N=738 (17%) Alone N=143 (45%) N=41 (24%) N=137 (96%) N=31 (23%) N=6878 (94%) Prior to PCI N=1466 (21%) N=320 (4%) Dauerman and French, Coronary Artery Disease, 2006 113

Implementation of HORIZONS AMI PCI Pharmacologic Aspects of Management Unfractionated heparin 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) Glycoprotein IIb/IIIa inhibitors Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abciximab) or 12-18 (eptifibatide) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus

Primary PCI for STEMI: Community Hospital Algorithm ASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVM 27 miles, on interstate highway Time from ED Presentation at NWMC to Open Artery at FAHC: 88 Minutes

Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab? The HORIZONS AMI Switching Perspective UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) UFH pre randomization 65.6% Antithrombin in CCL UFH 98.9% 4.1% 0.4% 96.9% Peak ACT 264 [228, 320] 357 [300, 402] GP IIb/IIIa in CCL 94.5%* 7.2%* Bail-out per protocol** - 4.4% Abciximab 49.9% 4.0% Eptifibatide 44.4% 3.1% Tirofiban 0.2% 0.1% *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory G Stone TCT 2007

Bivalirudin Improves Mortality in STEMI Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 3.1% Death (%) 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Time in Days G Stone TCT 2007

The UVM STEMI Order Sheet One Pathway for Primary PCI and ED Collaboration TESTS AND MEDICATIONS EKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required. LABORATORY: 7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately on arrival: STAT 8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin 9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one 11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from Pharmacy) 12. Saline Lock with routine flushes every 8 hours OPTIONAL: 13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV Titrate to chest pain, keep systolic BP >90. 14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140

The Bivalirudin Strategy for STEMI PCI ASA, clopidogrel 600 po x 1, bivalirudin and stent

What About The Stent Thrombosis Risk? UFH + GP IIb/IIIa (N=1553) Bivalirudin (N=1571) P Value ARC definite or probable* 1.9% 2.5% 0.33 Definite 1.4% 2.2% 0.11 Probable 0.5% 0.3% 0.26 Acute (≤24 hrs) 1.3% 0.0009 Subacute (>24 hrs – 30d) 1.7% 1.2% 0.30 G Stone TCT 2007 *Protocol definition of stent thrombosis, CEC adjudicated

Risk Stratification For STEMI Stent Thrombosis The Importance of Thrombus Burden Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583 Large thrombus burden (LTB), defined as thrombus burden >  2 vessel diameters: Approx 25% of STEMI

Increased Risk of 30 Day Stent Thrombosis Drug Eluting Stent Thrombosis and Large Thrombus Burden: Modifying Strategy In Highest Risk Patients 15 12 9 6 3 Large Thrombus Burden> 5 fold Increased Risk of 30 Day Stent Thrombosis LTB vs. STB, p<0.001 8.2% LTB Cumulative IRA-ST Rate (%) 5.8% 3.2% Total Population 2.7% 2.1% 3.2% Thrombectomy Prolonged Bivalirudin GPI 1.1% 1.4% STB 1.3% 0.7% 0.5% 0.7% 0 1 3 6 9 12 15 18 21 24 Months of follow-up Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583

ACUITY and Large Thrombus Data The Rationale for Selective Adjunctive GPI Heparin + IIb/IIIa (N=222) Bivalirudin + IIb/IIIa (N=241) Bivalirudin alone (N=249) P value 3-way Any thrombotic complication post PCI 8.6% 3.7% 5.6% 0.09 Final TIMI flow 3 90.5% 93.7% 90.7% 0.37 Final blush grade 3 81.5% 79.0% 79.5% 0.78 * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization G. Stone AHA 2006

Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients 4.9 5.2 8.3 1 2 3 4 5 6 7 8 9 Major Bleeding, % Bival + UFH + GPI P < 0.001 Still P < 0.001 UVM Implemented HORIZONS—25% HORIZONS 7% Assumes Bival + GPI bleeding rate of 6.8%

Incorporation of HORIZONS AMI and Large Thrombus Data—STEMI Algorithm ED STEMI—25% of Patients ASA/clopidogrel 600 mg po load and bivalirudin Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden Angiojet and Bare Metal Stent 150 mg clopidogrel and 18 hours of eptifibatide No ambulation until eptifibatide off (18 hours) D/C on Day 3 post MI

STEMI: Within 24 Hours CP Transfer PCI Capability or < 60 minute Transfer Time No PCI Capability and > 60 minute Transfer Time ASA 325 po UFH or Bivalirudin: GPI Optional: Avoid if High Bleed Risk B Blockers ONLY if HTN UFH (60 U/Kg) Beta Blockers only if HTN Clopidogrel 600 po Clopidogrel 300 po 90 minutes To Open Artery Emergent Transfer Lytic Contraindicated Primary PCI with Stenting: GPI/Thrombectomy if Large Thrombus or as Bailout; Otherwise, Bivalirudin Alone Rescue PCI: Class I Indication Continue bivalirudin for 2 hours after PCI If Reperfusion Fails, Emergent PCI with stent TNK and UFH ASA/Clopidogrel Statin Groin Closure Cardiac Rehab Lopressor 12.5 bid Transfer If no CP and less than 50% ST Elevations, PCI at 12-24 Hours with Stent Transfer from Community ER To PCI Site The NSTEMI Paradigm of 4-48 Hours

Conclusions Key Implementation Points Bivalirudin can be safely instituted across the spectrum of PCI patients, including those with NSTE-ACS and STEMI. Clopidogrel 600 mg po load may be done in ED or immediately after PCI. Community referring hospitals may use antithrombotic therapy of choice—then switch to bivalirudin on arrival to PCI institution. STEMI requires an algorithm for care and bivalirudin is the baseline strategy. But, bivalirudin may be instituted in the ED or the cath lab, depending upon local issues. Enhanced management of large thrombus burden should be considered especially during the most “vulnerable” 2 hours after PCI. 127

Questions for the Panel Does a consistent, unified upstream strategy for anticoagulation across the STEMI and NSTE-ACS risk spectrum make sense? When does it? When doesn’t it? Given that bleeding appears to be a driver of MACE events, including mortality, in ACS and STEMI, and since switching to bivalirudin appears to decrease bleeding, should this switching strategy be promulgated in patients undergoing PCI? What are the best ways, from an institutional/process-of-care perspective, to establish a consistent antithrombotic strategy for this patient population? Other issues? We’ll answer your questions! 128