For the HORIZONS-AMI Investigators 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 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

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

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

Inclusion Criteria STEMI >20 mins and <12 hours in duration ST-segment elevation of 1 mm in 2 contiguous leads; or Presumably new left bundle branch block; or True posterior MI with ST depression of 1 mm in 2 contiguous anterior leads Patients with cardiogenic shock, left main disease, etc., were not excluded Age ≥18 years Written, informed consent

Principal Exclusion Criteria Contraindication to any of the study medications Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed) Current use of coumadin History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm3 or hgb <10 g/dL Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment

Study Medications (i) Unfractionated heparin Bivalirudin 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed 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 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 12-18 (eptif) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus

Study Medications (ii) Aspirin 324 mg chewed non enteric coated or 500 mg IV in the ER, followed by 300-325 mg/day in-hospital and 75-81 mg/day as out patient indefinitely Thienopyridines Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended) Ticlopidine load + daily dose permissible if clopidogrel is unavailable or patient is allergic Other Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF <40%; Statin if LDL >100 mg/dl

2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events and 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

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

Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 Randomized 30 Day FU N=1791 (99.4%) N=1787 (99.3%) 28 • • • Not true MI* • • • 29 1-Year FU Eligible N=1774 N=1771 26 46 • • • Withdrew • • • • • • Lost to FU • • • 22 53 1-Year FU N=1702 (95.9%) N=1696 (95.8%) * Biomarkers WNL and no DS >50% by core lab determination → 30 day FU only

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] Male 76.1% 77.1% Diabetes 17.3% 15.6% Hypertension 55.2% 51.8% Hyperlipidemia 42.7% 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;358:2218-30

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 2-4 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;358:2218-30

Study Drugs UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) UFH pre randomization 65.6% Antithrombin in CCL - UFH 98.9% 2.6% - Bivalirudin 0.2% 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 0.1% *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

Primary Endpoints at 30 Days 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 Major 2 endpoint Stone GW et al. NEJM 2008;358:2218-30

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

1-Year Net Adverse Clinical Events* *MACE or major bleeding (non CABG) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 1800 1559 1514 1483 1343 1802 1499 1459 1427 1281 NACE (%) 2 4 6 8 10 12 14 16 18 20 Time in Months 1 3 5 7 9 11 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 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 *MACE or major bleeding (non CABG)

1-Year Major Bleeding (non-CABG) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 1800 1621 1601 1586 1448 1802 1544 1532 1515 1368 Major Bleeding (%) 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months 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<0.0001

1-Year Bleeding Endpoints* UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) P Value Protocol Major, non CABG** 9.2% 5.8% <0.0001 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% *Kaplan-Meier estimates; all CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

1-Year Major Adverse CV Events* 15 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 14 11.9% 13 12 11.9% 11 10 9 8 Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21] P=0.98 MACE (%) 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk Bivalirudin alone 1800 1627 1579 1544 1394 Heparin+GPIIb/IIIa 1802 1619 1573 1540 1380 *MACE = All cause death, reinfarction, ischemic TVR or stroke

1-Year All-Cause Mortality 5 Bivalirudin alone (n=1800) 4.8% Heparin + GPIIb/IIIa (n=1802) Δ = 1.4% 4 3.4% 3.1% 3 Mortality (%) Diff [95%CI] = -1.5% [-2.8,-0.1] HR [95%CI] = 0.69 [0.50, 0.97] P=0.029 2 2.1% Δ = 1.0% P=0.049 1 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk Bivalirudin alone 1800 1705 1684 1669 1520 Heparin+GPIIb/IIIa 1802 1678 1663 1646 1486

1-Year Mortality: Cardiac and Non Cardiac Bivalirudin alone (n=1800) HR [95%CI] = 0.57 [0.38, 0.84] P=0.005 5 Heparin + GPIIb/IIIa (n=1802) 4 3.8% 3 Δ = 1.7% 2.9% Cardiac Mortality (%) 2.1% 2 1.8% Δ = 1.1% P=0.03 1 Non Cardiac 1.3% 1.1% 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk Bivalirudin alone 1800 1705 1684 1669 1520 Heparin+GPIIb/IIIa 1802 1678 1663 1646 1486

1-Year Death or Reinfarction 10 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 9 8.5% 8 7 6.6% 6 4.5% Δ = 1.9% Death or MI (%) 5 4 HR [95%CI] = 0.77 [0.61, 0.98] P=0.04 3.8% 3 Δ = 0.7% P=0.30 2 1 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk Bivalirudin alone 1800 1670 1638 1617 1469 Heparin+GPIIb/IIIa 1802 1648 1617 1593 1431

1-Year MACE Components* UFH + GPI (N=1802) Bivalirudin (N=1800) HR [95%CI] P Value Death 4.8% 3.4% 0.69 [0.50,0.97] 0.029 - Cardiac 3.8% 2.1% 0.57 [0.38,0.84] 0.005 - Non cardiac 1.1% 1.3% 1.14 [0.62,2.11] 0.67 Reinfarction 4.4% 3.6% 0.81 [0.58,1.14] 0.22 - Q-wave 2.2% 1.06 [0.67,1.67] 0.81 - Non Q-wave 2.7% 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] 0.12 - Ischemic TLR 4.5% 6.0% 1.34 [1.00,1.80] 0.051 - Ischemic remote TVR 2.0% 2.3% 1.13 [0.71,1.79] 0.60 Stroke 1.2% 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 Death 1.8% 1.4% 0.31 - Cardiac 0.9% 0.4% 0.046 - Non cardiac 1.0% 0.75 Reinfarction 2.8% 1.7% 0.04 Death or reinfarction 4.4% 3.0% 0.02 Ischemic TVR 4.3% 4.7% 0.57 Stroke 0.5% 0.77 MACE 7.3% 6.8% 0.52 Major bleeding (non CABG) 0.7% 0.8% 0.71 NACE 7.8% *Kaplan-Meier estimates, landmark analysis, CEC adjudicated

1-Year Stent Thrombosis (ARC Definite/Probable) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 1611 1525 1504 1486 1356 1591 1495 1475 1457 1315 Stent Thrombosis (%) 1 2 3 4 5 Time in Months 6 7 8 9 10 11 12 Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591) Δ = 0.3% 3.5% 3.2% 2.7% HR [95%CI] = 1.11 [0.76, 1.63] P=0.59 2.2% Δ = 0.5% P=0.31

1-Year Stent Thrombosis* (N=3,202) UFH + GPI (N=1591) Bivalirudin (N=1611) P Value ARC definite or probable, ≤24 hrs 0.3% 1.5% 0.0002 - definite, ≤24 hours 0.2% 1.4% <0.0001 - probable, ≤24 hours 0.1% 1.0 ARC definite or probable, >1 - ≤30d 1.9% 1.3% 0.14 - definite, >1 day - ≤30 days 1.1% 0.60 - probable, >1 day - ≤30 days 0.6% 0.049 ARC definite or probable, >30d – 1y 0.9% 0.53 - definite, >30 days – 1-year 1.0% 0.65 - probable, >30 days – 1-year 0.55 ARC definite or probable, ≤1-year 3.2% 3.5% 0.59 - definite, ≤1-year 2.4% 0.15 - probable, ≤1-year 0.8% 0.06 *All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated

Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 Stent rand. eligible N=1479 N=1527 R 3:1 R 3:1 Stratified by 1st rand. TAXUS N=1111 EXPRESS N=368 TAXUS N=1146 EXPRESS N=381

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] Pint NACE, all* 11.3% 8.7% 0.76 [0.60,0.95] - - TAXUS subgroup 11.5% 9.1% 0.78 [0.60,1.01] 0.95 - EXPRESS subgroup 10.6% 7.4% 0.69 [0.42,1.11] Major bleeding, all** 8.4% 5.1% 0.59 [0.44,0.78] 8.9% 5.4% 0.59 [0.43,0.81] 1.0 7.1% 4.2% 0.58 [0.31,1.09] MACE, all*** 4.7% 4.9% 1.05 [0.75,1.45] 4.6% 1.11 [0.76,1.62] 0.89 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] Pint Ischemic TLR, all 4.5% 7.5% 0.59 [0.43,0.83] - - UFH + GPI subgroup 3.3% 7.9% 0.42 [0.25,0.68] 0.17 - Bivalirudin subgroup 5.6% 7.1% 0.78 [0.50,1.24] Safety MACE, all* 8.1% 8.0% 1.02 [0.76, 1.36] 8.2% 8.8% 0.92 [0.66,1.27] 0.89 7.2% 1.17 [0.83,1.64] Binary restenosis, all** 10.0% 22.9% 0.44 [0.33, 0.57] 10.9% 19.2% 0.57 [0.38,0.84] 0.18 9.2% 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) 5 4.6% 4.0% 4 3.0% 3 2.6% Mortality (%) 2 Pint = 0.75 1 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months

Limitations 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 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: 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: 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 Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies