A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction – One Year Results – Roxana Mehran MD For the HORIZONS-AMI Investigators

Background Numerous studies have demonstrated a strong association between hemorrhagic complications and subsequent mortality in pts with ACS and after PCI Numerous studies have demonstrated a strong association between hemorrhagic complications and subsequent mortality in pts with ACS and after PCI In the HORIZONS-AMI trial, among high risk pts with STEMI undergoing primary PCI, randomization to bivalirudin monotherapy compared to UFH + GPI resulted in reduced rates of bleeding, thrombo- cytopenia, and blood transfusions; non significantly different rates of reinfarction, stent thrombosis and TVR; and improved survival at 30 days In the HORIZONS-AMI trial, among high risk pts with STEMI undergoing primary PCI, randomization to bivalirudin monotherapy compared to UFH + GPI resulted in reduced rates of bleeding, thrombo- cytopenia, and blood transfusions; non significantly different rates of reinfarction, stent thrombosis and TVR; and improved survival at 30 days Whether these benefits are maintained at 1-year is unknown Whether these benefits are maintained at 1-year is unknown

Harmonizing Outcomes with Revascularization and Stents in AMI 3602 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 or medical therapy 3006 pts eligible for stent randomization R 3:1 Bare metal EXPRESS stent Paclitaxel-eluting TAXUS stent 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 3602 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 Pharmacology Arm Primary and Secondary Endpoints 1-Year Intention to Treat Population Outcomes in the 4 randomized groups

Study Medications (i) Unfractionated heparin Unfractionated heparin –60 U/kg IV*; subsequent boluses titrated by nomogram to ACT secs; terminated at procedure end unless prolonged antithrombin needed Bivalirudin Bivalirudin –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 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 (abcx) or (eptif) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30 after last bolus

2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events 2) Major Bleeding (non CABG) Intracranial bleeding intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma 5 cm Hgb 3g/dL with an overt source Hgb 4g/dL w/o overt source Reoperation for bleeding Blood product transfusion and

2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events 2) Major Bleeding (non CABG) = or All cause death Reinfarction Ischemic TVR Stroke Major adverse cardiovascular events (major secondary endpoint)

Harmonizing Outcomes with Revascularization and Stents in AMI UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 R 1:1 Randomized * Biomarkers WNL and no DS >50% by core lab determination 30 day FU only 1-Year FU Eligible 30 Day FU N=1791 (99.4%)N=1787 (99.3%) N=1774N=1771 Withdrew Withdrew Lost to FU Lost to FU pts with STEMI Not true MI* Not true MI* Year FU N=1702 (95.9%)N=1696 (95.8%)

Baseline Characteristics (i) UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) Age (years) 60.7 [52.9, 70.1] 59.8 [51.9, 69.5] Male76.1%77.1% Diabetes17.3%15.6% Hypertension55.2%51.8% Hyperlipidemia42.7%43.4% Current smoking 45.0%47.2% Prior MI 11.4%10.4% Prior PCI 11.0%10.5% Prior CABG 2.6%3.3% *P=0.04 * Stone GW et al. NEJM 2008;358:

Baseline Characteristics (ii) UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) Weight (kg) 80 [71, 90] Chest pain – ER, hrs 2.1 [1.3, 3.9] 2.2 [1.3, 4.0] Killip class %8.5% Anterior MI 43.9%41.2% LVEF 50 [41, 59] 50 [45, 60] Femoral a. access 93.6%93.9% Venous access 8.4%9.3% Closure device 27.7%28.3% Aspiration catheter 11.1%11.9% Stone GW et al. NEJM 2008;358:

Study Drugs UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) UFH pre randomization 65.6%65.6% Antithrombin in CCL - UFH - UFH98.9%2.6% - Bivalirudin - Bivalirudin0.2%96.9% - Peak ACT - Peak ACT 264 [228, 320] 357 [300, 402] GP IIb/IIIa in CCL 94.5%*7.2%* - Bail-out per protocol** - Bail-out per protocol**-4.4% - Abciximab - Abciximab49.9%4.0% - Eptifibatide - Eptifibatide44.4%3.1% - Tirofiban - Tirofiban0.2%0.1% *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory

Primary Management Strategy* UFH + GP IIb/IIIa Inhibitor N=1802 Bivalirudin Monotherapy N=1800 Primary PCI Deferred PCI CABG Medical Rx *Primary ITT analysis includes all pts regardless of treatment

Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99 RR = 0.99 [0.76, 1.30] P sup = 0.95 Primary Endpoints at 30 Days 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 Stone GW et al. NEJM 2008;358: Major 2 endpoint

Aspirin and Thienopyridine Use Antiplatelet agent use (%) Regular* aspirin use (%) Regular* thieno. use (%) *Taken >50% of days since last visit 97.1% 98.1% 96.7% 97.3% 96.3% 97.0% 95.7% 96.1% 92.7% 93.7% 92.9% 93.3% 87.2% 87.8% 65.8% 68.0% All P = NS

1-Year Net Adverse Clinical Events* *MACE or major bleeding (non CABG) 18.3% 15.7% Diff [95%CI] = -2.6% [-5.1, -0.1] HR [95%CI] = 0.84 [0.71, 0.98] P=0.03 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

9.2% 5.8% Diff [95%CI] = -3.4% [-5.2, -1.7] 2 HR [95%CI] = 0.61 [0.48, 0.78] P< Year Major Bleeding (non-CABG) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

1-Year Bleeding Endpoints* UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Protocol Major, non CABG** 9.2%5.8%< Protocol Major, All 11.8%7.7%< Protocol Minor 16.5%9.1%< Blood transfusion 4.0%2.7%0.02 TIMI Major 5.5%3.6%0.005 TIMI Minor 4.8%3.0%0.008 TIMI Major or Minor 10.2%6.5%< GUSTO LT*** or Severe 0.7%0.8%0.70 GUSTO Moderate 5.4%3.7%0.01 GUSTO LT or Sev or Mod 6.0%4.4%0.02 *Kaplan-Meier estimates; all CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

1-Year Major Adverse CV Events* Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) MACE (%) Time in Months % 11.9% Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21] P=0.98 *MACE = All cause death, reinfarction, ischemic TVR or stroke

1-Year All-Cause Mortality Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Mortality (%) Time in Months Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 4.8% 3.4% Diff [95%CI] = -1.5% [-2.8,-0.1] HR [95%CI] = 0.69 [0.50, 0.97] P= % 2.1% Δ = 1.0% P=0.049 Δ = 1.4%

1-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Cardiac Non Cardiac Mortality (%) Time in Months % 2.1% 1.3% 1.1% HR [95%CI] = 0.57 [0.38, 0.84] P= % 1.8% Δ = 1.1% P=0.03 Δ = 1.7%

1-Year Death or Reinfarction Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Death or MI (%) Time in Months % 6.6% HR [95%CI] = 0.77 [0.61, 0.98] P= % 3.8% Δ = 0.7% P=0.30 Δ = 1.9% Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

1-Year MACE Components* UFH + GPI (N=1802)Bivalirudin(N=1800) HR [95%CI] P Value Death4.8%3.4% 0.69 [0.50,0.97] Cardiac - Cardiac3.8%2.1% 0.57 [0.38,0.84] Non cardiac - Non cardiac1.1%1.3% 1.14 [0.62,2.11] 0.67 Reinfarction4.4%3.6% 0.81 [0.58,1.14] Q-wave - Q-wave2.1%2.2% 1.06 [0.67,1.67] Non Q-wave - Non Q-wave2.7%1.4% 0.53 [0.32,0.86] 0.01 Death or reinfarction 8.5%6.6% 0.77 [0.61,0.98] 0.04 Ischemic TVR 5.9%7.2% 1.23 [0.94,1.60] Ischemic TLR - Ischemic TLR4.5%6.0% 1.34 [1.00,1.80] Ischemic remote TVR - Ischemic remote TVR2.0%2.3% 1.13 [0.71,1.79] 0.60 Stroke1.2%1.1% 1.00 [0.54,1.85] 0.99 *All Kaplan-Meier estimates, CEC adjudicated

Adverse Events Between 30 Days and 1-Year UFH + GPI (N=1802)Bivalirudin(N=1800) P Value Death1.8%1.4% Cardiac - Cardiac0.9%0.4% Non cardiac - Non cardiac0.9%1.0%0.75 Reinfarction2.8%1.7%0.04 Death or reinfarction 4.4%3.0%0.02 Ischemic TVR 4.3%4.7%0.57 Stroke0.5%0.4%0.77 MACE7.3%6.8%0.52 Major bleeding (non CABG) 0.7%0.8%0.71 NACE7.8%7.3%0.52 *Kaplan-Meier estimates, landmark analysis, CEC adjudicated

1-Year Stent Thrombosis (ARC Definite/Probable) 3.5% 3.2% HR [95%CI] = 1.11 [0.76, 1.63] P= % 2.2% Δ = 0.5% P=0.31 Δ = 0.3%

1-Year Stent Thrombosis* (N=3,202) UFH + GPI (N=1591)Bivalirudin(N=1611)PValue ARC definite or probable, 24 hrs 0.3%1.5% definite, 24 hours - definite, 24 hours0.2%1.4%< probable, 24 hours - probable, 24 hours0.1%0.1%1.0 ARC definite or probable, >1 - 30d 1.9%1.3% definite, >1 day - 30 days - definite, >1 day - 30 days1.3%1.1% probable, >1 day - 30 days - probable, >1 day - 30 days0.6%0.2%0.049 ARC definite or probable, >30d – 1y 1.1%0.9% definite, >30 days – 1-year - definite, >30 days – 1-year1.0%0.9% probable, >30 days – 1-year - probable, >30 days – 1-year0.1%0.1%0.55 ARC definite or probable, 1-year 3.2%3.5% definite, 1-year - definite, 1-year 2.4%3.2% probable, 1-year - probable, 1-year0.8%0.3%0.06 *All Kaplan-Meier estimates except 24 hours; all CEC adjudicated

Harmonizing Outcomes with Revascularization and Stents in AMI R 1: pts with STEMI Stent rand. eligible UFH + GP IIb/IIIa N=1802 N=1479 TAXUS N=1111 EXPRESS N=368 Bivalirudin N=1800 N=1527 TAXUS N=1146 EXPRESS N=381 R 3:1 R 3:1 Stratified by 1 st rand.

Interaction Between Drug and Stent Randomization 30 Day Pharmacology Endpoints (N=3006) Kaplan-Meier estimates UFH + GPI (N=1479)Bivalirudin(N=1527) HR [95%CI] P int NACE, all* 11.3%8.7% 0.76 [0.60,0.95] - - TAXUS subgroup - TAXUS subgroup 11.5%9.1% 0.78 [0.60,1.01] EXPRESS subgroup - EXPRESS subgroup10.6%7.4% 0.69 [0.42,1.11] Major bleeding, all** 8.4%5.1% 0.59 [0.44,0.78] - - TAXUS subgroup - TAXUS subgroup8.9%5.4% 0.59 [0.43,0.81] EXPRESS subgroup - EXPRESS subgroup7.1%4.2% 0.58 [0.31,1.09] MACE, all*** 4.7%4.9% 1.05 [0.75,1.45] - - TAXUS subgroup - TAXUS subgroup4.6%5.1% 1.11 [0.76,1.62] EXPRESS subgroup - EXPRESS subgroup4.9%4.2% 0.86 [0.44,1.69] *MACE or major bleeding; **Protocol defined (non CABG); ***Death, reinfarction, stroke or ischemic TVR

Interaction Between Drug and Stent Randomization 1-Year Stent Endpoints (N=3006) Kaplan-Meier estimates TAXUS(N=2257)EXPRESS(N=749) HR [95%CI] P int Ischemic TLR, all 4.5%7.5% 0.59 [0.43,0.83] - - UFH + GPI subgroup - UFH + GPI subgroup3.3%7.9% 0.42 [0.25,0.68] Bivalirudin subgroup - Bivalirudin subgroup5.6%7.1% 0.78 [0.50,1.24] Safety MACE, all* 8.1%8.0% 1.02 [0.76, 1.36] - - UFH + GPI subgroup - UFH + GPI subgroup8.2%8.8% 0.92 [0.66,1.27] Bivalirudin subgroup - Bivalirudin subgroup8.0%7.2% 1.17 [0.83,1.64] Binary restenosis, all** 10.0%22.9% 0.44 [0.33, 0.57] - - UFH + GPI subgroup - UFH + GPI subgroup10.9%19.2% 0.57 [0.38,0.84] Bivalirudin subgroup - Bivalirudin subgroup9.2%26.7% 0.34 [0.24,0.49] *Death, reinfarction, stroke or stent thrombosis **1081 lesions in the TAXUS group, 332 in the EXPRESS group

1-Year Mortality (All-Cause) Heparin + GPI / TAXUS (n=1111) Heparin + GPI / EXPRESS (n=368) Bivalirudin / TAXUS (n=1146) Bivalirudin / EXPRESS (n=381) 4.0% 3.0% P int = % 2.6% Mortality (%) Time in Months

Limitations Open label design Open label design –Potential bias was mitigated by high protocol procedure compliance and use of blinded clinical event adjudication committees and core laboratories Underpowered for low frequency safety endpoints and subgroup interactions Underpowered for low frequency safety endpoints and subgroup interactions –All such observations should be considered hypothesis-generating

Conclusions In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: –A significant 16% reduction in the 1-year rate of composite net adverse clinical events –A significant 39% reduction in the 1-year rate of major bleeding

Conclusions In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: –Significant 31% and 43% reductions in the 1-year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year

Clinical Implications HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival –Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies