New Horizons for Patients with ST-Elevation Myocardial Infarction

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:  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

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. Impact of Major Bleed and MI after Elective and Urgent PCI1-Year Mortality (N=6,012) With major bleed 8.8% 5.7% With MI Cumulative % Mortality 2.0% Without major bleed 1.9% Without MI Time from Randomization in Days Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

5. Predictors of 1-year Mortality after Elective and Urgent PCI Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

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

7. Major Bleed only (without MI) (N=551) 12.5% MI only (without Major Bleed) (N=611) 8.6% No MI or Major Bleed (N=12,557) Both MI and Major Bleed (N=94) 28.9% 3.4% Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 1 yearEstimate 30 25 20 Mortality (%) 15 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization 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 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 HR ± 95% CI HR (95% CI) P-value 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

9. 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 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

10. ACUITY: Early and Late MortalityLandmark analysis 30 day P (log rank) Estimate UFH/Enoxaparin + IIb/IIIa 1.4% — Bivalirudin + IIb/IIIa 0.53 1.6% Bivalirudin alone 0.39 1.6% 30d - 1 year P (log rank) Estimate 3.1% — 0.54 2.7% 0.21 2.3% 4 3 Mortality (%) 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 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 Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… R 1:1 R 1:3 CABG – – Primary PCI Medical Rx 3000 pts eligible for stent randomization TAXUS paclitaxel-eluting stent Bare metal stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years *To rand 3000 stent pts

12. 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.

13. 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

14. 30 Day Bleeding Endpoints* *CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

15. Thrombocytopenia P = 0.002 P = 0.04 P = 0.02 <100,000 cells/mm3 <50,000 cells/mm3 <20,000 cells/mm3 Stone GW et al. In press.

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

17. 30 Day Mortality 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.

18. 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.

19. 30 Day Stent Thrombosis (N=3,124) *Protocol definition of stent thrombosis, CEC adjudicated

20. 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/IIIa1662 1631 1615 1604 1598 1583 1512 Stone GW et al. In press.

21. Predictors of 30 Day Mortality32 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

22. Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Attributable Ischemic EventsHR (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** - any10.71 [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

23. Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Attributable Bleeding EventsHR (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/mm33.89 [2.22, 6.84] <0.001 11.1 [8.2,12.8] 0.78 - <50,000 cells/mm36.44 [2.93,14.18] <0.001 5.9 [4.6,6.5] 0.78 - <20,000 cells/mm34.98 [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

24. 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 <0.001 Major bleeding (non CABG) 4.66 [2.84, 7.63] Ischemic TVR 1.11 [0.29, 4.21] 0.88 2.64 [0.71, 9.75] 0.15 Stroke 0.01 0.1 1 10 100 Hazard Ratio [95% CI] C-statistic = 0.87.

25. 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 *9.7% of 93 total deaths **21.9% of 93 total deaths 0.01 0.1 1 10 100 Hazard Ratio [95% CI] C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

26. 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 *8.3% of 54 total deaths **28.0% of 54 total deaths 0.01 0.1 1 10 100 Hazard Ratio [95% CI] C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

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.