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

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

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

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.

VariableGroupsO.R. (95% CI) p-value Creatinine clear. <30 mL/min 7.21(2.53–20.51)< –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) < Major Bleeding Yes3.26(1.78–5.96) Yes2.77(1.62–4.75) Urg Yes2.77 (1.15–6.71).024 Hx angina Yes2.18 (1.25–3.81) Prior MI Yes1.81 (1.09–3.03) DiabetesYes1.64 (1.10–2.44) Predictors of 1-year Mortality after Elective and Urgent PCI Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

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

Mortality (%) Days from Randomization 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

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 ( )< Major bleeding without or before transfusion 3.04 ( ) < Major bleeding after transfusion 5.45 ( ) < 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

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 ( )< Major bleeding without or before transfusion 2.00 ( ) < Major bleeding after transfusion 3.93 ( ) < HR ± 95% CIP-valueHR (95% CI) Attributable deaths 51.5* 66.5** *9.8% of all deaths **12.7% of all deaths

ACUITY: Early and Late Mortality Landmark analysis UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 30 day Estimate P (log rank) 1.4% % % — Estimate P (log rank) 3.1% % % 30d - 1 year — Mortality (%) Days from Randomization Stone GW. JAMA 2007;298:

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: 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

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 pts with STEMI Stone GW et al. In press.

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 ≤ P sup ≤ Diff = Diff = -2.9% [-4.9, -0.8] RR = RR = 0.76 [0.63, 0.92] P NI ≤ P sup =  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%< 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 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

Thrombocytopenia P = 0.02 P = 0.04 P = <100,000 cells/mm 3 <20,000 cells/mm 3 <50,000 cells/mm 3 Stone GW et al. In press.

30 Day MACE Components* UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Death3.1%2.1% Cardiac - Cardiac2.9%1.8% Non cardiac - Non cardiac0.2%0.3%0.75 Reinfarction1.8%1.8% Q-wave - Q-wave1.2%1.4% Non Q-wave - Non Q-wave0.7%0.4%0.37 Ischemic TVR 1.9%2.6% Ischemic TLR - Ischemic TLR1.8%2.5% 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.

30 Day Mortality Number at risk Bivalirudin Heparin + GPIIb/IIIa 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.

30 Day Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin Heparin + GPIIb/IIIa 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.

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% definite1.4%2.2% probable0.5%0.3% acute (≤24 hrs)0.3%1.3% subacute (>24 hrs – 30d)1.7%1.2%0.28 *Protocol definition of stent thrombosis, CEC adjudicated

Number at risk Bivalirudin Heparin + GPIIb/IIIa 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.

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

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< Reinfarction [5.44,22.59] < [8.2,9.6] 0.83 Ischemic TVR< Ischemic TVR 6.91 [3.36,14.18] < [6.3,8.4] 0.83 Stent thrombosis, definite** - any< any [3.93,29.18] < [3.7,4.8] acute (<24 hours) acute (<24 hours) 5.88 [0.78,44.30] [-0.3,1] 0.82 Stroke Stroke 5.44 [1.67,17.69] [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

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) < Major bleed (non-CABG) 4.43 [2.67, 7.33] < [16.3,22.5] 0.85 Major bleed (all)< Major bleed (all) 5.92 [3.73, 9.41] < [25.6,31.3] 0.86 Transfusion< Transfusion 3.88 [2.09, 7.20] < [ 8.4,13.8] 0.83Thrombocytopenia** - <100,000 cells/mm 3 < <100,000 cells/mm [2.22, 6.84] < [8.2,12.8] <50,000 cells/mm 3 < <50,000 cells/mm [2.93,14.18] < [4.6,6.5] <20,000 cells/mm <20,000 cells/mm [1.20,20.66] [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

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] C-statistic = 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

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] C-statistic = 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] < ** [16.8, 22.6] Reinfarction Incidence 69 (2.2%) 10 deaths with event 9.75 [2.72,34.91] < * [6.3, 9.7]

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] C-statistic = 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] < ** [12.6, 16.4] Stent thrombosis (definite) Incidence 57 (1.8%) 5 deaths with event [3.96, 28.48] < * [3.7, 4.8]

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.