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

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

3. 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 FACT Ndrepepa et al. JACC 2008;51:690–7

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

5. VariableGroupsO.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) 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 Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

6. 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

7. 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 Stone GW. ACC 2007

8. Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates Influence of Major Bleeding and MI in the First 30 Days on the Risk of Death within 30 Days Myocardial infarction5.25 (3.72-7.43)<0.0001 Major bleeding without or before transfusion 3.04 (1.66-5.55) <0.0001 Major bleeding after transfusion 5.45 (3.54-8.38) <0.0001 HR ± 95% CIP-valueHR (95% CI) Stone GW. ACC 2008 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 Attributable deaths 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

9. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR Mehran RM et al. Submitted Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates Of 13,819 enrolled pts, 524 (3.8%) died within 1 year Myocardial infarction2.51 (1.95-3.25)<0.0001 Major bleeding without or before transfusion 2.00 (1.30-3.06) <0.0001 Major bleeding after transfusion 3.93 (2.95-5.24) <0.0001 HR ± 95% CIP-valueHR (95% CI) Attributable deaths 51.5* 66.5** *9.8% of all deaths **12.7% of all deaths

10. ACUITY: Early and Late Mortality Landmark analysis 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 Stone GW. JAMA 2007;298:2497-506

11. 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 CABG– Medical Rx – 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, 6 months, 1 year, and then yearly through 5 years Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years

12. 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 Stone GW et al. In press.

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

14. 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 Sev or Mod 5.6%3.5%0.002 *CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

15. Thrombocytopenia 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. In press.

16. 30 Day MACE Components* 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 *CEC adjudicated Stone GW et al. In press.

17. 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. In press.

18. 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. In press.

19. 30 Day Stent Thrombosis (N=3,124) UFH + GP IIb/IIIa (N=1553)Bivalirudin(N=1571)PValue ARC 30d definite or probable stent thrombosis*1.9%2.5%0.30 - definite1.4%2.2%0.09 - probable0.5%0.3%0.24 - acute (≤24 hrs)0.3%1.3%0.0007 - subacute (>24 hrs – 30d)1.7%1.2%0.28 *Protocol definition of stent thrombosis, CEC adjudicated

20. 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. In press.

21. 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 - treatment related variables not used

22. Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Ischemic EventsHR (95% CI)P deaths*C-stat Reinfarction<0.0010.83 Reinfarction 11.09 [5.44,22.59] <0.001 9.1 [8.2,9.6] 0.83 Ischemic TVR<0.0010.83 Ischemic TVR 6.91 [3.36,14.18] <0.001 7.7 [6.3,8.4] 0.83 Stent thrombosis, definite** - any<0.0010.83 - any 10.71 [3.93,29.18] <0.001 4.5 [3.7,4.8] 0.83 - acute (<24 hours)0.090.82 - acute (<24 hours) 5.88 [0.78,44.30] 0.09 0.8 [-0.3,1] 0.82 Stroke0.0050.82 Stroke 5.44 [1.67,17.69] 0.005 2.4 [1.2,2.8] 0.82 Attributable * 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

23. Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Bleeding EventsHR (95% CI)P deaths*C-stat Major bleed (non-CABG) <0.0010.85 Major bleed (non-CABG) 4.43 [2.67, 7.33] <0.001 20.1 [16.3,22.5] 0.85 Major bleed (all)<0.0010.86 Major bleed (all) 5.92 [3.73, 9.41] <0.001 29.1 [25.6,31.3] 0.86 Transfusion<0.0010.83 Transfusion 3.88 [2.09, 7.20] <0.001 11.9 [ 8.4,13.8] 0.83Thrombocytopenia** - <100,000 cells/mm 3 <0.0010.78 - <100,000 cells/mm 3 3.89 [2.22, 6.84] <0.001 11.1 [8.2,12.8] 0.78 - <50,000 cells/mm 3 <0.0010.78 - <50,000 cells/mm 3 6.44 [2.93,14.18] <0.001 5.9 [4.6,6.5] 0.78 - <20,000 cells/mm 3 0.030.77 - <20,000 cells/mm 3 4.98 [1.20,20.66] 0.03 1.6 [0.3,1.9] 0.77 Attributable * 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

24. HR [95% CI]P-valueRisk Factor Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality - Complete model with MACE components and major bleeding - Hazard Ratio [95% CI] 0.010.1110100 C-statistic = 0.87. 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

25. HR [95% CI]P-value Attributable Deaths Risk Factor Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality - Complete model with MACE components and major bleeding - Hazard Ratio [95% CI] 0.010.1110100 C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR *9.7% of 93 total deaths **21.9% of 93 total deaths Major bleeding (Non CABG) Incidence 238 (6.8%) 26 deaths with event 4.66 [2.84, 7.63] <0.001 20.4** [16.8, 22.6] Reinfarction Incidence 69 (2.2%) 10 deaths with event 9.75 [2.72,34.91] <0.001 9.0* [6.3, 9.7]

26. HR [95% CI]P-value Attributable Deaths Risk Factor Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality - Complete model in 3,124 pts with successfully implanted stents - Hazard Ratio [95% CI] 0.010.1110100 C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR *8.3% of 54 total deaths **28.0% of 54 total deaths Major bleeding (non CABG) Incidence 195 (6.2%) 18 deaths with event 6.22 [3.33, 11.60] <0.001 15.1** [12.6, 16.4] Stent thrombosis (definite) Incidence 57 (1.8%) 5 deaths with event 10.62 [3.96, 28.48] <0.001 4.5* [3.7, 4.8]

27. 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. Conclusions 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.