For the HORIZONS-AMI Investigators A Prospective, Multicenter Randomized Trial of Heparin Plus Glycoprotein IIb/IIIa Inhibitors vs. Bivalirudin, and Drug-eluting vs. Bare Metal Stents in ST-Segment Elevation Myocardial Infarction: Final Report from the HORIZONS-AMI Trial Gregg W. Stone MD For the HORIZONS-AMI Investigators

Disclosures Gregg W. Stone MD Advisory Board for and honoraria from Boston Scientific and Abbott Vascular Consultant to the The Medicines Company

Background At 1-year in the 2x2 factorial prospective, randomized HORIZONS-AMI trial: Bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in comparable rates of MI and stent thrombosis, with significantly reduced rates of major bleeding and mortality (all-cause and cardiac) TAXUS PES compared to EXPRESS BMS reduced clinical and angiographic restenosis, with comparable rates of death, reinfarction and stent thrombosis Whether these findings are sustained with long- term follow-up has not been reported

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 – Medical Rx 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; angio FU at 13 months

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 • • • Not true MI* • • • 29 1-Year FU Eligible N=1772 N=1771 26 13 • • • Withdrew • • • • • • Lost to FU • • • 22 19 1-Year FU N=1733 (97.8%) N=1730 (97.7%) 17 90 • • • Withdrew • • • • • • Lost to FU • • • 18 78 3-Year FU N=1626 (91.7%) N=1634 (92.3%) * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)

Pharmacology Randomization: Aspirin and Thienopyridine Use Regular* aspirin use (%) Regular* thieno. use (%) Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) 98.1% 97.3% 97.0% 96.2% 95.4% 94.9% 93.7% 93.3% 87.7% 97.1% 96.7% 96.3% 95.7% 95.3% 92.7% 92.9% 94.0% 87.1% 67.7% Antiplatelet agent use (%) 65.6% 35.5% All P = NS All P = NS 27.4% 32.7% 25.6% *Taken >50% of days since last visit

Three-Year Major Bleeding (non-CABG)* 1523 1442 1572 1601 1534 12 1800 Bivalirudin alone 4 6 8 10 0.64 [0.51, 0.80] 2 15 18 21 24 27 30 33 36 1039 1802 1509 957 P<0.001 3-yr HR [95%CI]= 6.9% 10.5% Major Bleeding (%) Months 3 9 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Number at risk Heparin+GPIIb/IIIa 1544 1465 0.62 [0.49, 0.79] 1-yr HR [95%CI]= 1485 1402 9.4% 6.0% * Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion

Three-Year All-Cause Mortality P=0.03 3-yr HR [95%CI]= 0.75 [0.58, 0.97] 5.9% 7.7% All-Cause Mortality (%) 1 2 3 4 5 6 9 10 1611 1568 1660 1689 1670 1800 Bivalirudin alone 12 15 18 21 24 27 30 33 36 1098 1802 1643 Months Number at risk Heparin+GPIIb/IIIa 1633 1593 1574 1525 1043 0.71 [0.51, 0.98] P=0.04 1-yr HR [95%CI]= Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 7 8 4.8% 3.4%

3-Year Mortality: Cardiac and Non Cardiac Time in Months ' Time in Months 3-Year Mortality: Cardiac and Non Cardiac Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 3-yr HR [95%CI]= 1 6 5 4 3 2 0.56 [0.40, 0.80] 1 6 5 4 3 2 1-yr HR [95%CI]= P=0.001 5.1% 3-yr HR [95%CI]= 0.57 [0.38, 0.84] 1.11 [0.74, 1.65] P=0.004 P=0.62 3.8% 1-yr HR [95%CI]= 3.1% Cardiac Mortality (%) Non-Cardiac Mortality (%) 1.20 [0.65, 2.20] 2.9% 2.8% P=0.56 2.1% 1.3% 1.1% 3 6 9 12 15 18 21 24 27 30 33 36 3 6 9 12 15 18 21 24 27 30 33 36 Months Months Number at risk Number at risk Bival 1800 1689 1660 1633 1611 1574 1098 Bival 1800 1689 1660 1633 1611 1574 1098 H + GPI 1802 1670 1643 1593 1568 1525 1043 H + GPI 1802 1670 1643 1593 1568 1525 1043

Three-Year Reinfarction Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 6.2% 8.2% Reinfarction (%) 1 2 3 4 5 6 7 8 9 10 P=0.04 3-yr HR [95%CI]= 0.76 [0.59, 0.92] 0.81 [0.58, 1.14] P=0.22 1-yr HR [95%CI]= 1536 1474 1605 1643 1623 1800 Bivalirudin alone 12 15 18 21 24 27 30 33 36 1032 1802 1581 Months Number at risk Heparin+GPIIb/IIIa 1560 1513 1494 1425 965 4.4% 3.6%

Three-Year MACE Components* UFH + GPI (N=1802) Bivalirudin (N=1800) HR [95%CI] P Value Death 7.7% 5.9% 0.75 [0.58,0.97] 0.03 - Cardiac 5.1% 2.9% 0.56 [0.40,0.80] 0.001 - Non cardiac 2.8% 3.1% 1.11 [0.74,1.65] 0.62 Reinfarction 8.2% 6.2% 0.76 [0.59,0.99] 0.04 - Q-wave 3.8% 3.4% 0.91 [0.64,1.30] 0.61 - Non Q-wave 4.9% 3.2% 0.63 [0.45,0.90] 0.009 Death or reinfarction 14.5% 11.3% 0.77 [0.64,0.92] 0.005 Ischemic TVR 12.1% 14.2% 1.19 [0.99,1.44] 0.06 - Ischemic TLR 9.7% 1.18 [0.96,1.46] 0.11 - Ischemic remote TVR 4.1% 5.2% 1.25 [0.91,1.71] 0.17 Stroke 2.0% 1.7% 0.84 [0.51,1.38] 0.50 *Kaplan-Meier estimates, CEC adjudicated

Adverse Events Between 30 Days and 3-Years UFH + GPI (N=1802) Bivalirudin (N=1800) P Value Death 4.8% 3.9% 0.22 - Cardiac 2.1% 1.1% 0.01 - Non cardiac 2.6% 2.8% 0.67 Reinfarction 6.5% 4.4% 0.007 Death or reinfarction 10.6% 7.8% 0.005 Ischemic TVR 11.7% 0.31 Stroke 1.4% 1.0% 0.29 MACE 17.8% 17.3% 0.65 Major bleeding (non CABG) 1.9% NACE 18.7% 18.2% 0.73 *Kaplan-Meier estimates, landmark analysis, CEC adjudicated

Three-Year Stent Thrombosis (ARC Definite/Probable) Bivalirudin alone (n=1611) 6 Heparin + GPIIb/IIIa (n=1591) 5.1% 5 4.5% 3.5% 4 HR [95%CI]= Stent Thrombosis (%) 3 3.0% 0.89 [0.65, 1.23] p=0.49 2 HR [95%CI]= 1.16 [0.79, 1.71] 1 p=0.45 3 6 9 12 15 18 21 24 27 30 33 36 Months Number at risk Bivalirudin 1611 1509 1478 1453 1432 1398 971 Heparin+GPIIb/IIIa 1591 1484 1456 1401 1373 1335 906

Three-Year Stent Thrombosis* (N=3,202) UFH + GPI (N=1591) Bivalirudin (N=1611) P Value ARC definite or probable, ≤24 hours 0.3% 1.5% <0.001 - definite, ≤24 hours 0.2% - probable, ≤24 hours 0.1% 0.0% 0.32 ARC definite or probable, >24h – 3y 4.8% 3.1% 0.01 - definite, >24 hours – 3 years 4.0% 2.8% 0.08 - probable, >24 hours – 3 years 0.9% 0.03 ARC definite or probable, ≤3 years 5.1% 4.5% 0.49 - definite, ≤3 years 4.1% 4.2% 0.87 - probable, ≤3 years 1.0% 0.02 *All Kaplan-Meier estimates; all CEC adjudicated

Harmonizing Outcomes with Revascularization and Stents in AMI UFH + GPI (n=1802) Bivalirudin (n=1800) Primary Medical Rx 193 Primary CABG 62 Deferred PCI 2 Index PCI, not eligible - PTCA only 119 - Stented 220 3602 pts with STEMI R 1:1 3006 pts eligible for stent rand. 93.1% of all stented pts were randomized R 3:1 TAXUS DES N=2257 EXPRESS BMS N=749 Randomized 18 16 • • • Withdrew • • • • • • Lost to FU • • • 7 13 1 year FU N=2225 (98.6%) N=730 (97.5%) 13 month angiographic FU 942 23 97 • • • Withdrew • • • • • • Lost to FU • • • 8 34 307 3 year FU N=2103 (93.2%) N=687 (91.7%)

Stent Randomization: Aspirin and Thienopyridine Use Regular* aspirin use (%) Regular* thieno. use (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) 99.1% 98.3% 98.3% 99.4% 97.5% 98.7% 97.5% 95.8% 94.6% 98.9% 98.6% 98.5% 97.4% 97.1% 97.8% 96.3% 95.7% 72.8% 87.5% P<0.001 Antiplatelet agent use (%) 63.6% All P=NS P<0.001 36.7% 28.3% 30.5% P=0.004 22.5% P=0.003 *Taken >50% of days since last visit

Primary Efficacy Endpoint: Ischemic TLR 3-yr HR [95%CI]= 0.60 [0.48, 0.76] 9.4% 15.1% Ischemic TLR (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) 2 4 6 8 10 12 14 18 P=0.003 1-yr HR [95%CI]= 0.61 [0.44, 0.85] 1902 587 2042 2104 676 2257 TAXUS DES 15 21 24 27 30 33 36 749 655 Months 3 9 Number at risk EXPRESS BMS 1942 598 1846 567 372 1277 16 7.4% 4.6%

Primary Efficacy Endpoint: Ischemic TLR Routine angiographic FU No routine angiographic FU TAXUS DES (n=911) TAXUS DES (n=1346) EXPRESS BMS (n=293) EXPRESS BMS (n=456) 2 24 22 18 16 14 12 8 6 20 10 4 2 24 22 18 16 14 12 8 6 20 10 4 1-yr HR [95%CI]= 0.58 [0.32, 1.04] 18.3% P=0.06 1-yr HR [95%CI]= 0.64 [0.43, 0.95] 12.7% Ischemic TLR (%) Ischemic TLR (%) P=0.02 10.3% 8.7% 3-yr HR [95%CI]= 3-yr HR [95%CI]= 0.53 [0.38, 0.75] 0.67 [0.48, 0.93] P=0.001 P=0.01 3 6 9 12 15 18 21 24 27 30 33 36 3 6 9 12 15 18 21 24 27 30 33 36 Months Months Number at risk Number at risk PES 911 896 878 830 812 795 596 PES 1346 1208 1164 1112 1090 1051 681 BMS 293 282 274 237 234 229 157 BMS 456 394 381 361 353 338 215

Primary Safety Endpoint: Safety MACE* 1928 634 2037 2094 684 2257 TAXUS DES 12 15 18 21 24 27 30 33 36 749 669 Months 3 6 9 Number at risk EXPRESS BMS 1971 648 1875 615 412 1289 P=0.66 3-yr HR [95%CI]= 1.05 [0.84, 1.33] 12.9% 13.6% Safety MACE (%) 2 4 8 10 14 16 TAXUS DES (n=2257) EXPRESS BMS (n=749) P=0.92 1-yr HR [95%CI]= 1.02 [0.76, 1.36] 8.1% 8.0% * Safety MACE = death, reinfarction, stroke, or stent thrombosis

Three-Year Composite Safety Endpoints* TAXUS (N=2257) EXPRESS (N=749) HR [95%CI] P Value Safety MACE 13.6% 12.9% 1.05 [0.84,1.33] 0.66 Death, all-cause 5.6% 6.6% 0.84 [0.60,1.17] 0.31 - Cardiac 3.2% 3.8% 0.84 [0.54,1.30] 0.42 - Non cardiac 2.4% 2.9% 0.85 [0.51,1.42] 0.53 Reinfarction 7.0% 1.05 [0.76,1.46] 0.77 - Q-wave 3.5% 2.8% 1.24 [0.76,2.03] 0.39 - Non Q-wave 4.0% 1.02 [0.66,1.57] 0.94 Stent thrombosis 4.8% 4.3% 1.10 [0.74,1.65] 0.63 - ARC definite 4.2% 3.7% 1.12 [0.73,1.72] 0.61 - ARC probable 0.6% 1.00 [0.32,3.09] 0.99 Stroke 1.6% 1.4% 1.15 [0.57,2.32] 0.70 *Kaplan-Meier estimates

Three-Year Stent Thrombosis (ARC Definite or Probable) 6 TAXUS DES (n=2238) EXPRESS BMS (n=744) 5 4.8% 4.3% 4 3.4% Stent Thrombosis (%) 3-yr HR [95%CI]= 3 3.1% 1.10 [0.74, 1.65] 2 P=0.63 1-yr HR [95%CI]= 0.92 [0.58, 1.45] 1 P=0.72 3 6 9 12 15 18 21 24 27 30 33 36 Months Number at risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425

Three-Year Reinfarction P=0.77 3-yr HR [95%CI]= 1.05 [0.76, 1.46] 6.6% 7.0% Reinfarction (%) 1 2 3 4 5 6 7 8 9 10 TAXUS DES (n=2257) EXPRESS BMS (n=749) 1961 643 2066 2118 690 2257 TAXUS DES 12 15 18 21 24 27 30 33 36 749 676 Months Number at risk EXPRESS BMS 2002 654 1910 624 419 1316 P=0.31 1-yr HR [95%CI]= 0.81 [0.54, 1.21] 4.5% 3.7%

Three-Year All-Cause Mortality P=0.31 3-yr HR [95%CI]= 0.84 [0.60, 1.17] 5.6% 6.6% All-Cause Mortality (%) 1 2 3 4 5 6 7 8 TAXUS DES (n=2257) EXPRESS BMS (n=749) P=0.97 1-yr HR [95%CI]= 0.99 [0.64, 1.55] 2072 674 2138 2170 713 2257 TAXUS DES 12 15 18 21 24 27 30 33 36 749 702 Months 9 Number at risk EXPRESS BMS 2097 683 2026 657 443 1409 3.5%

Three-Year Mortality (All-Cause) ' All-Cause Mortality (%) 1 2 3 4 5 8 12 15 18 21 24 27 30 33 36 6 9 Months 7 Pint = 0.89 Heparin + GPI / TAXUS (n=1111) Heparin + GPI / EXPRESS (n=368) Bivalirudin / TAXUS (n=1146) Bivalirudin / EXPRESS (n=381) 6.3% 7.3% 4.9% 6.0%

Conclusions: Pharmacology Randomization In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in: A significant 36% reduction in major bleeding and a significant 24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 56 to save 1 life)

Conclusions: Stent Randomization Among pts with STEMI undergoing primary PCI, at 3 years the implantation of TAXUS EXPRESS PES compared to EXPRESS BMS resulted in: A significant 40% reduction in ischemic TLR, with no evidence of late catch-up In pts without routine angiographic follow-up, the absolute reduction in TLR was 4.0% at 3 years (NNT = 25) Non significantly different rates of all-cause and cardiac mortality, reinfarction and stent thrombosis