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

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

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

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: 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

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 pts with STEMI Not true MI* Not true MI* Year FU N=1733 (97.8%)N=1730 (97.7%) Withdrew Withdrew Lost to FU Lost to FU

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)

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 p<0.001 HR [95%CI]= 0.64 [0.51, 0.81] 6.4% 6.4% 9.6% 9.6% Major Bleeding (%) Months Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

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

Two-Year All-Cause Mortality p= HR [95%CI]= 0.75 [0.56, 1.00] 4.6% 4.6% 6.1% 6.1% All-Cause Mortality (%) 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

p= HR [95% CI]= 0.59 [0.41, 0.86] 2.5% 2.5% 4.2% 4.2% Cardiac Mortality Months 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) p= 0.69 HR [95% CI]= 1.10 [0.69, 1.76] 2.2% 2.2% 2.0% 2.0% Non Cardiac Mortality Months

Two-Year Reinfarction p= HR [95%CI]= 0.75 [0.56, 0.98] 5.1% 5.1% 6.9% 6.9% Reinfarction (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

Two-Year Death or Reinfarction p= HR [95%CI]= 0.75 [0.61, 0.93] 9.1% 9.1% 12.0% Death or reinfarction (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

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] Cardiac - Cardiac4.2%2.5% 0.59 [0.41,0.86] 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] Q-wave - Q-wave3.4%3.1% 0.92 [0.63,1.34] Non Q-wave - Non Q-wave3.9%2.2% 0.56 [0.37,0.83] Death or reinfarction 12.0%9.1% 0.75 [0.61,0.93] Ischemic TVR 11.0%12.7% 1.17 [0.96,1.42] Ischemic TLR - Ischemic TLR8.7%10.2% 1.19 [0.95,1.49] 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

Adverse Events Between 30 Days and 2-Years UFH + GPI (N=1802)Bivalirudin(N=1800) P Value Death3.1%2.6% Cardiac - Cardiac1.3%0.7% 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

2-Year Stent Thrombosis (ARC Definite/Probable) p= 0.73 HR [95%CI]= 0.94 [0.67, 1.32] 4.3% 4.3% 4.6% 4.6% Stent Thrombosis (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

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%< definite, 24 hours - definite, 24 hours0.2%1.5%< probable, 24 hours - probable, 24 hours0.1%0.0%0.32 ARC definite or probable, >24h – 2y 4.4%2.9% definite, >24 hours – 2 year - definite, >24 hours – 2 year3.6%2.6% 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% definite, 2-year - definite, 2-year3.8%3.9% probable, 2-year - probable, 2-year0.8%0.3%0.05 *All Kaplan-Meier estimates; all CEC adjudicated

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 R 3: 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: 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 month angiographic FU Harmonizing Outcomes with Revascularization and Stents in AMI

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< % 96.2% P= % 30.7% All P=NS TAXUS DES (n=2257) EXPRESS BMS (n=749)

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 (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) Number at risk TAXUS DES EXPRESS BMS Months

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 (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) Number at risk TAXUS DES EXPRESS BMS Months p= yr HR [95%CI]= 0.60 [0.43, 0.84] 13 mo angio FU

Secondary Efficacy Endpoint: Ischemic TVR

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

Two-Year All-Cause Mortality

Two-Year Cardiac Mortality

Two-Year Reinfarction

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 (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) Number at risk TAXUS DES EXPRESS BMS Months

2-Year Stent Thrombosis* TAXUS(N=2238)EXPRESS(N=744)PValue ARC definite or probable, 30 days 2.2%2.7% definite, 30 days - definite, 30 days1.8%2.3% probable, 30 days - probable, 30 days0.4%0.4%0.86 ARC definite or probable, >30d - 1y 1.0%0.7% definite, >30 days – 1-year - definite, >30 days – 1-year0.9%0.7% 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% definite, 1-year – 2-year - definite, 1-year – 2-year1.1%0.6% 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% definite, 2-year - definite, 2-year3.7%3.6% probable, 2-year - probable, 2-year0.5%0.6%0.88 *All Kaplan-Meier estimates; all CEC adjudicated

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] Cardiac - Cardiac2.7%3.3% 0.83 [0.52,1.33] 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] Q-wave - Q-wave3.1%2.9% 1.06 [0.65,1.72] 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] ARC definite - ARC definite3.7%3.6% 1.01 [0.65,1.57] 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

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] Cardiac - Cardiac0.3%0.6% 0.49 [0.14,1.74] 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] Q-wave - Q-wave1.1%0.9% 1.20 [0.49,2.97] 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] ARC definite - ARC definite1.1%0.6% 1.81 [0.62,5.25] 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] Ischemic TVR 3.4%5.2% 0.65 [0.43,0.97] 0.03 *Kaplan-Meier estimates

Two-Year Mortality (All-Cause)

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)

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