The HORIZONS-AMI Trial One Year Outcomes of Primary Angioplasty in Acute Anterior Myocardial Infarction with Bivalirudin Compared to Unfractionated Heparin plus GP IIb/IIIa Inhibitors: The HORIZONS-AMI Trial For the HORIZONS AMI Investigators Jochen Wöhrle, Bernhard Witzenbichler, Giulio Guagliumi, Bruce R. Brodie, Dariusz Dudek, Ran Kornowski, Franz Hartmann, Helen Parise, Alexandra J. Lansky, Roxana Mehran, Brendon Ryan, Alison Kellock, Carol Moore, Gregg W. Stone

Disclosures Jochen Wöhrle None Bernhard Witzenbichler None Giulio Guagliumi Grant support: LightLab, Medtronic Vasc., Boston Scientific; Research grant: Boston Scientific Bruce R. Brodie None Dariusz Dudek None Ran Kornowski None Franz Hartmann None Helen Parise None Alexandra J. Lansky Grant support: The Medicines Company Roxana Mehran Grant support and Lecture Fees: The Medicines Company Brendon Ryan None Alison Kellock None Carol Moore None Gregg W. Stone Advisory Board: Boston Scientific; Abbott

Background STEMI patients undergoing primary PCI of LAD compared to non-LAD lesions have a higher rate of major adverse cardiac events. In the HORIZONS-AMI trial, including STEMI patients undergoing primary PCI, randomization to bivalirudin compared to UFH + GPI resulted in a significant reduction of major bleeding; non significantly different rates of reinfarction, stent thrombosis, stroke and TVR; and significant reduction of all-cause and cardiac mortality at 1 year. Whether these benefits are also present in STEMI patients with primary PCI of LAD, is unknown.

Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Pharmacology Arm One year results Intention to Treat Population

Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) PCI cohort: LAD 1445 pts Non-LAD 1884 pts

Baseline Characteristics LAD (N=1445) Non-LAD (N=1884) Age (years) 61.0 [53.0, 70.7]* 59.5 [52.1, 68.8] Male 77.9% 76.6% Diabetes 17.3% 15.5% Hypertension 52.1% 52.8% Hyperlipidemia 41.4% 44.0% Current smoking 42.1%* 50.9% Prior MI 8.1%* 12.3% Prior PCI 9.0%* 11.6% Prior CABG 1.3% 3.5% Weight (kg) 80 [70, 90]* 80 [71, 91] * P<0.05

Study Drugs LAD (N=1445) Non-LAD (N=1884) UFH pre randomization 64.9% 66.1% Antithrombin in CCL - UFH 52.6% 49.5% - Bivalirudin 47.8%* 51.4% - Peak ACT 306 [251, 384] 317 [253, 391] GP IIb/IIIa any 54.0% 51.3% - Bail-out per protocol** 8.2% - Abciximab 27.6% 28.5% - Eptifibatide 26.3%* 22.7% - Tirofiban 0.1% 0.2% ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory * P<0.05

Primary Outcome Measures (ITT) LAD (N=1445) Non-LAD (N=1884) Diff = 3.9% [1.2, 6.5] RR = 1.27 [1.08, 1.50] P = 0.004 Diff = 1.1% [-0.8, 2.9] RR = 1.15 [0.90, 1.47] P = 0.27 Diff = 3.8% [1.6, 6.1] RR = 1.40 [1.15, 1.71] P = 0.0007 19.3 15.4 14.1 10.3 8.4 7.3 *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke

One Year Bleeding Endpoints LAD (N=1445) Non-LAD (N=1884) P Value Protocol Major, non CABG 8.4% 7.3% 0.27 Protocol Major, All 9.4% 8.8% 0.60 Blood transfusion 3.7% 3.2% 0.50 TIMI Major 3.9% 3.7% 0.80 TIMI Minor 3.9% 3.9% 0.99 TIMI Major or Minor 7.7% 7.5% 0.88 GUSTO LT* or Severe 1.0% 0.5% 0.09 GUSTO Moderate 3.7% 4.1% 0.54 GUSTO LT* or Sev or Mod 5.1% 4.7% 0.66 *Life threatening

One Year MACE Components* LAD (N=1445) Non-LAD (N=1884) P Value Death 5.6% 2.8% 0.0001 - Cardiac 4.2% 1.9% - Non cardiac 1.5% 0.9% 0.13 Reinfarction 4.5% 3.7% 0.25 - Q-wave 2.0% 2.3% 0.59 - Non Q-wave 2.6% 1.6% 0.04 Ischemic TVR 7.7% 6.2% 0.09 - Ischemic TLR 6.3% 4.9% 0.10 - Ischemic remote TVR 2.5% 2.2% 0.53 Stroke 1.0% 0.89 *CEC adjudicated

One Year Stent Thrombosis LAD (N=1445) Non-LAD (N=1884) P Value ARC definite or probable* 3.4% 0.95 - definite 2.8% 2.9% 0.86 - probable 0.7% 0.5% 0.58 Late (>30d-1<r), def/prob 1.1% 1.0% 0.97 *Protocol definition of stent thrombosis, CEC adjudicated

Harmonizing Outcomes with Revascularization and Stents in AMI 1445 pts with STEMI and primary PCI of LAD UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) N=746 Bivalirudin monotherapy (± provisional GP IIb/IIIa) N=699 Pharmacology Arm One year results Intention to Treat Population

Baseline Characteristics (i) Bivalirudin (N=699) UFH+GP IIb/IIIa (N=746) Age (years) 60.7 [52.4, 70.8] 61.1 [53.0, 70.7] Male 77.4% 78.3% Diabetes 16.2% 18.4% Hypertension 51.1% 53.1% Hyperlipidemia 41.5% 40.3% Current smoking 44.5% 39.8% Prior MI 8.3% 7.9% Prior PCI 9.6% 8.5% Prior CABG 1.6% 1.1% Weight (kg) 80 [70, 90] * P<0.05

Baseline Characteristics (ii) Bivalirudin (N=699) UFH+GP IIb/IIIa (N=746) Chest pain – balloon 221 [165, 337] 220 [160, 346] Chest pain – SH, min 129 [75, 240] 120 [75, 235] SH – Cath lab, min 47 [30, 72] 46 [28, 70] Killip class 2-4 12.9% 12.8% LVEF 45 [38, 55] 45 [37, 52] Femoral a. access 93.3% 93.8% Venous access 6.7% 4.4% Aspiration catheter 9.5% 8.8% Closure device 27.5% 28.0%

TIMI Flow pre and post PCI Bivalirudin (N=699) UFH+GP IIb/IIIa (N=746) TIMI flow pre PCI - TIMI 0/1 60.6% 61.1% - TIMI 2 18.6% 18.2% - TIMI 3 20.9% 20.7% TIMI flow after PCI 2.3% 1.9% 7.4% 6.8% 90.3% 91.3%

Study Drugs Bivalirudin (N=699) UFH+GP IIb/IIIa (N=746) UFH pre randomization 66.8% 63.2% Antithrombin in CCL - UFH 2.1%* 99.9% - Bivalirudin 98.4%* 0.0% - Peak ACT 360 [300, 407]* 265 [229, 317] GP IIb/IIIa any in CCL 7.5%* 97.6% - Bail-out per protocol** 8.2% --- - Abciximab 4.4%* 49.2% - Eptifibatide 3.0%* 48.1% - Tirofiban 0.3% ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory * P<0.01

Primary Outcome Measures (ITT) UFH+GP IIb/IIIa (N=746) Bivalirudin (N=699) Diff = -2.0% [-6.0, 2.1] RR = 0.89 [0.70, 1.12] P = 0.31 Diff = -3.6% [-6.5, -0.7] RR = 0.63 [0.43, 0.91] P = 0.01 Diff = -0.2% [-3.8, 3.4] RR = 0.98 [0.75, 1.29] P = 0.90 20.2 18.3 14.2 14.0 10.1 6.5 *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke

One Year Net Adverse Clinical Events Bivalirudin Alone (n=699) UFH+GP IIb/IIIa (n=746) 22 Bivalirudin Alone (n=699) 20 18 16 14 NACE (%) 12 10 8 6 P (interaction) = 0.40 4 2 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk UFH+GPI 746 623 605 588 528 Bivalirudin 699 607 589 576 519

One Year Major Bleeding (non-CABG) Bivalirudin Alone (n=699) UFH+GP IIb/IIIa (n=746) 12 Bivalirudin Alone (n=699) 11 10 9 8 7 Major Bleeding (%) 6 5 4 P (interaction) = 0.77 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk UFH+GPI 746 641 637 631 567 Bivalirudin 699 634 629 624 567

One Year Major Adverse CV Events Bivalirudin Alone (n=699) UFH+GP IIb/IIIa (n=746) 16 Bivalirudin Alone (n=699) 14 12 10 MACE (%) 8 6 P (interaction) = 0.84 4 2 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk UFH+GPI 746 673 652 634 570 Bivalirudin 699 638 620 606 546

One Year Bleeding Endpoints Bivalirudin (N=699) UFH+GP IIb/IIIa (N=746) P Value Protocol Major, non CABG 6.5% 10.1% 0.01 Protocol Major, All 7.4% 11.2% 0.01 Blood transfusion 2.6% 4.6% 0.04 TIMI Major 3.1% 4.8% 0.10 TIMI Minor 2.9% 4.7% 0.07 TIMI Major or Minor 6.0% 9.3% 0.02 GUSTO LT* or Severe 1.3% 0.7% 0.24 GUSTO Moderate 2.5% 4.7% 0.02 GUSTO LT* or Sev or Mod 3.8% 5.4% 0.13 *LT=Life threatening

One Year MACE Components* Bivalirudin (N=699) UFH+GP IIb/IIIa (N=746) P Value Death 4.8% 6.3% 0.19 - Cardiac 3.0% 5.3% 0.04 - Non cardiac 1.8% 1.1% 0.32 Reinfarction 3.7% 0.15 - Q-wave 2.0% 1.9% 0.87 - Non Q-wave 1.6% 3.6% 0.03 Ischemic TVR 8.5% 7.1% - Ischemic TLR 6.8% 5.8% 0.41 - Ischemic remote TVR 2.8% 2.1% Stroke 1.0% 0.8% 0.71 *CEC adjudicated

One Year Stent Thrombosis Bivalirudin (N=699) UFH+GP IIb/IIIa (N=746) P Value ARC definite or probable* 3.3% 3.6% 0.81 - definite 3.0% 2.6% 0.62 - probable 0.3% 1.0% 0.11 Late (>30d-1<r), def/prob 1.1% 0.96 *Protocol definition of stent thrombosis, CEC adjudicated

Conclusions (i) In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, analysis of patients with primary PCI of LAD compared to patients with primary PCI of non-LAD resulted at one year in: Significantly higher rates of net adverse clinical events and major adverse cardiovascular events Significantly higher rates of all-cause and cardiac mortality No difference in rate of stent thrombosis Similar rate of major bleeding

Conclusions (ii) In patients undergoing primary PCI of LAD lesions, anticoagulation with bivalirudin monotherapy as compared to UFH + GP IIb/IIIa inhibitor resulted in Similar rates of net adverse clinical events, major adverse cardiac events and stent thrombosis Significantly lower rates of major bleeding and cardiac death