1. Two-Year Follow-up from a Prospective, Randomized Trial of Heparin Plus Glycoprotein IIb/IIIa Inhibitors vs. Bivalirudin and Paclitaxel-Eluting vs. Bare-Metal Stents in STEMI Gregg W. Stone MD For the HORIZONS-AMI Investigators

2. Disclosures Gregg W. Stone MD Gregg W. Stone MD –Advisory Board for Boston Scientific and Abbott Vascular –Research support from The Medicines Company

3. Background At 1-year in the 2x2 factorial prospective, randomized HORIZONS-AMI trial: 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 at 2 years has not been reported Whether these findings are sustained at 2 years has not been reported

4. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 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 1:1 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 Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years; angio FU at 13 months

5. 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 2-Year FU N=1672 (94.4%)N=1693 (95.6%) N=1772N=1771 Withdrew Withdrew Lost to FU Lost to FU 26132219 3602 pts with STEMI Not true MI* Not true MI* 3029 1-Year FU N=1733 (97.8%)N=1730 (97.7%) Withdrew Withdrew Lost to FU Lost to FU 13481225

6. 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% 87.1% 87.7% 65.6% 67.8% All P = NS Pharmacology Randomization: Aspirin and Thienopyridine Use 35.8% 32.7% 95.2% Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

7. Two-Year Major Bleeding (non-CABG)* *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 18001603157115401290 18021535150514531218 p<0.001 HR [95%CI]= 0.64 [0.51, 0.81] 6.4% 6.4% 9.6% 9.6% Major Bleeding (%) 0 2 4 6 8 10 12 Months 03691215182124 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

8. Two-Year Major Adverse CV Events* *MACE = All cause death, reinfarction, ischemic TVR or stroke 18001584151314001159 18021577151813991142 p= 0.99 HR [95%CI]= 1.00 [0.86, 1.17] 18.7% 18.8% MACE (%) 0 4 8 12 16 20 24 Months 03691215182124 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

9. Two-Year All-Cause Mortality 18001690165816271359 18021669163715791324 p= 0.049 HR [95%CI]= 0.75 [0.56, 1.00] 4.6% 4.6% 6.1% 6.1% All-Cause Mortality (%) 0 1 2 3 4 5 6 7 8 03691215182124 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months 3.1% 2.1% 1 month P=0.049 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

10. 18001690165816271359 18021669163715791324 p= 0.005 HR [95% CI]= 0.59 [0.41, 0.86] 2.5% 2.5% 4.2% 4.2% Cardiac Mortality 0 1 2 3 4 5 Months 03691215182124 Two-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Mortality (%) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 180016901658 1627 1359 180216691637 1579 1324 p= 0.69 HR [95% CI]= 1.10 [0.69, 1.76] 2.2% 2.2% 2.0% 2.0% Non Cardiac Mortality 0 1 2 3 4 5 Months 03691215182124

11. Two-Year Reinfarction 18001644160315541298 18021621157615001244 p= 0.038 HR [95%CI]= 0.75 [0.56, 0.98] 5.1% 5.1% 6.9% 6.9% Reinfarction (%) 0 1 2 3 4 5 6 7 8 9 10 03691215182124 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

12. Two-Year Death or Reinfarction 18001644160315541298 18021621157615001244 p= 0.007 HR [95%CI]= 0.75 [0.61, 0.93] 9.1% 9.1% 12.0% Death or reinfarction (%) 0 3 6 9 12 15 03691215182124 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

13. Two-Year MACE Components* UFH + GPI (N=1802)Bivalirudin(N=1800) HR [95%CI] P Value Death6.1%4.6% 0.75 [0.56,1.00] 0.049 - Cardiac - Cardiac4.2%2.5% 0.59 [0.41,0.86] 0.005 - Non cardiac - Non cardiac2.0%2.2% 1.10 [0.69,1.76] 0.69 Reinfarction6.9%5.1% 0.75 [0.56,0.98] 0.038 - Q-wave - Q-wave3.4%3.1% 0.92 [0.63,1.34] 0.67 - Non Q-wave - Non Q-wave3.9%2.2% 0.56 [0.37,0.83] 0.004 Death or reinfarction 12.0%9.1% 0.75 [0.61,0.93] 0.007 Ischemic TVR 11.0%12.7% 1.17 [0.96,1.42] 0.12 - Ischemic TLR - Ischemic TLR8.7%10.2% 1.19 [0.95,1.49] 0.12 - Ischemic remote TVR - Ischemic remote TVR3.8%4.5% 1.19 [0.85,1.66] 0.31 Stroke1.7%1.5% 0.88 [0.52,1.52] 0.65 *All Kaplan-Meier estimates, CEC adjudicated

14. Adverse Events Between 30 Days and 2-Years UFH + GPI (N=1802)Bivalirudin(N=1800) P Value Death3.1%2.6%0.41 - Cardiac - Cardiac1.3%0.7%0.08 - Non cardiac - Non cardiac1.8%1.9%0.76 Reinfarction5.2%3.2%0.005 Death or reinfarction 7.9%5.5%0.006 Ischemic TVR 9.5%10.2%0.53 Stroke1.0%0.7%0.41 MACE14.7%13.9%0.53 Major bleeding (non CABG) 1.0%1.3%0.55 NACE15.2%14.6%0.63 *Kaplan-Meier estimates, landmark analysis, CEC adjudicated

15. 2-Year Stent Thrombosis (ARC Definite/Probable) 16111509147514441206 15911482144913861153 p= 0.73 HR [95%CI]= 0.94 [0.67, 1.32] 4.3% 4.3% 4.6% 4.6% Stent Thrombosis (%) 0 1 2 3 4 5 6 03691215182124 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

16. 2-Year Stent Thrombosis* (N=3,202) UFH + GPI (N=1591)Bivalirudin(N=1611)PValue ARC definite or probable, 24 hours 0.3%1.5%<0.001 - definite, 24 hours - definite, 24 hours0.2%1.5%<0.001 - probable, 24 hours - probable, 24 hours0.1%0.0%0.32 ARC definite or probable, >24h – 2y 4.4%2.9%0.03 - definite, >24 hours – 2 year - definite, >24 hours – 2 year3.6%2.6%0.11 - probable, >24 hours – 2 year - probable, >24 hours – 2 year0.8%0.3%0.08 ARC definite or probable, 2 years 4.6%4.3%0.73 - definite, 2-year - definite, 2-year3.8%3.9%0.71 - probable, 2-year - probable, 2-year0.8%0.3%0.05 *All Kaplan-Meier estimates; all CEC adjudicated

17. TAXUS DES N=2257 EXPRESS BMS N=749 Randomized 1 year FU N=2223 (98.5%)N=729 (97.3%) Withdrew Withdrew Lost to FU Lost to FU 1816713 R 3:1 3006 pts eligible for stent rand. Primary Medical Rx193 Primary CABG 62 Deferred PCI 2 Index PCI, not eligible - PTCA only119 - Stented220 UFH + GPI (n=1802) Bivalirudin (n=1800) R 1:1 3602 pts with STEMI 93.1% of all stented pts were randomized 2 year FU N=2157 (95.6%)N=715 (95.5%) Withdrew Withdrew Lost to FU Lost to FU 125468 13 month angiographic FU 942 307 Harmonizing Outcomes with Revascularization and Stents in AMI

18. Stent Randomization: Aspirin and Thienopyridine Use Antiplatelet agent use (%) Regular* aspirin use (%) Regular* thieno. use (%) *Taken >50% of days since last visit 99.1% 98.6% 98.5% 98.3% 97.5% 98.3% 97.1% 97.5% 99.4% 98.9% 98.7% 97.8% 94.6% 87.5% 72.8% 63.8% P<0.001 P<0.001 97.5% 96.2% P=0.004 36.8% 30.7% All P=NS TAXUS DES (n=2257) EXPRESS BMS (n=749)

19. Primary Efficacy Endpoint: Ischemic TLR P<0.001 HR [95%CI]= 0.58 [0.44, 0.76] 6.8% 6.8% 11.6% Ischemic TLR (%) 0 3 6 9 12 15 TAXUS DES (n=2257) EXPRESS BMS (n=749) 22572105204119491618 749677654611507 03691215182124 Number at risk TAXUS DES EXPRESS BMS Months

20. Primary Efficacy Endpoint: Ischemic TLR 22572105204119491618 749677654611507 P<0.001 HR [95%CI]= 0.58 [0.44, 0.76] 6.8% 6.8% 11.6% Ischemic TLR (%) 0 3 6 9 12 15 03691215182124 TAXUS DES (n=2257) EXPRESS BMS (n=749) Number at risk TAXUS DES EXPRESS BMS Months p= 0.002 1-yr HR [95%CI]= 0.60 [0.43, 0.84] 13 mo angio FU

21. Secondary Efficacy Endpoint: Ischemic TVR

22. Primary Safety Endpoint: Safety MACE* * Safety MACE = death, reinfarction, stroke, or stent thrombosis

23. Two-Year All-Cause Mortality

24. Two-Year Cardiac Mortality

25. Two-Year Reinfarction

26. Two-Year Stent Thrombosis (ARC Definite or Probable) p= 0.99 HR [95%CI]= 1.00 [0.66, 1.51] 4.1% 4.1% Stent Thrombosis (%) 0 1 2 3 4 5 6 TAXUS DES (n=2257) EXPRESS BMS (n=749) 03691215182124 22382108206119981661 744696681661547 Number at risk TAXUS DES EXPRESS BMS Months

27. 2-Year Stent Thrombosis* TAXUS(N=2238)EXPRESS(N=744)PValue ARC definite or probable, 30 days 2.2%2.7%0.45 - definite, 30 days - definite, 30 days1.8%2.3%0.45 - probable, 30 days - probable, 30 days0.4%0.4%0.86 ARC definite or probable, >30d - 1y 1.0%0.7%0.45 - definite, >30 days – 1-year - definite, >30 days – 1-year0.9%0.7%0.58 - probable, >30 days – 1-year - probable, >30 days – 1-year0.1%0.0%0.42 ARC definite or probable, 1y - 2y 1.1%0.7%0.40 - definite, 1-year – 2-year - definite, 1-year – 2-year1.1%0.6%0.27 - probable, 1-year – 2-year - probable, 1-year – 2-year0.0%0.1%0.41 ARC definite or probable, 2 years 4.1%4.1%0.99 - definite, 2-year - definite, 2-year3.7%3.6%0.96 - probable, 2-year - probable, 2-year0.5%0.6%0.88 *All Kaplan-Meier estimates; all CEC adjudicated

28. Two Year Composite Safety Endpoints* TAXUS(N=2257)EXPRESS(N=749) HR [95%CI] P Value Safety MACE 11.0%11.2% 0.98 [0.77,1.26] 0.89 Death, all-cause 4.3%5.2% 0.83 [0.57,1.20] 0.32 - Cardiac - Cardiac2.7%3.3% 0.83 [0.52,1.33] 0.43 - Non cardiac - Non cardiac1.6%2.0% 0.82 [0.44,1.52] 0.53 Reinfarction5.7%6.1% 0.92 [0.65,1.30] 0.64 - Q-wave - Q-wave3.1%2.9% 1.06 [0.65,1.72] 0.83 - Non Q-wave - Non Q-wave3.0%3.2% 0.91 [0.57,1.47] 0.71 Stent thrombosis 4.1%4.1% 1.00 [0.66,1.51] 0.99 - ARC definite - ARC definite3.7%3.6% 1.01 [0.65,1.57] 0.96 - ARC probable - ARC probable0.6%0.5% 0.91 [0.29,2.87] 0.88 Stroke1.4%1.1% 1.24 [0.57,2.70] 0.59 *Kaplan-Meier estimates

29. Adverse Events Between 1 and 2 Years* TAXUS(N=2257)EXPRESS(N=749) HR [95%CI] P Value Safety MACE 3.4%3.5% 0.96 [0.60,1.53] 0.86 Death, all-cause 0.8%1.8% 0.46 [0.22,0.97] 0.04 - Cardiac - Cardiac0.3%0.6% 0.49 [0.14,1.74] 0.26 - Non cardiac - Non cardiac0.5%1.2% 0.45 [0.18,1.12] 0.08 Reinfarction2.3%1.5% 1.58 [0.80,3.12] 0.19 - Q-wave - Q-wave1.1%0.9% 1.20 [0.49,2.97] 0.69 - Non Q-wave - Non Q-wave1.4%0.6% 2.30 [0.81,6.55] 0.11 Stent thrombosis 1.1%0.7% 1.51 [0.58,3.98] 0.40 - ARC definite - ARC definite1.1%0.6% 1.81 [0.62,5.25] 0.27 - ARC probable - ARC probable0.05%0.14% 0.33 [0.02,5.24] 0.41 Stroke0.4%0.5% 0.87 [0.23,3.29] 0.84 Ischemic TLR 2.6%4.7% 0.55 [0.35,0.85] 0.006 Ischemic TVR 3.4%5.2% 0.65 [0.43,0.97] 0.03 *Kaplan-Meier estimates

30. Two-Year Mortality (All-Cause)

31. Conclusions: Pharmacology Randomization In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, at 2 years initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in: In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, at 2 years initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in: –A significant 36% reduction in major bleeding and a significant 25% reduction in reinfarction, with comparable rates of stent thrombosis, TVR and stroke –A significant 41% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 15 lives saved per 1000 patients treated with bivalirudin (NNT = 67 to save 1 life)

32. Conclusions: Stent Randomization Among pts with STEMI undergoing primary PCI, at 2 years the implantation of TAXUS paclitaxel-eluting EXPRESS stents compared to EXPRESS bare metal stents resulted in: Among pts with STEMI undergoing primary PCI, at 2 years the implantation of TAXUS paclitaxel-eluting EXPRESS stents compared to EXPRESS bare metal stents resulted in: –Significant 42% and 34% reductions in ischemic TLR and TVR respectively, with no evidence of late catch-up –Comparable rates of all-cause and cardiac mortality, reinfarction and stent thrombosis, with no safety concerns apparent TLR, TVR and mortality were reduced between 1 and 2 years in pts treated with TAXUS EXPRESS compared to EXPRESS BMS, observations that should be considered hypothesis generating given their borderline significance and possible influence of routine angiographic follow-up TLR, TVR and mortality were reduced between 1 and 2 years in pts treated with TAXUS EXPRESS compared to EXPRESS BMS, observations that should be considered hypothesis generating given their borderline significance and possible influence of routine angiographic follow-up