Stone p2203/Abstract/ Conclusions HORIZONS –AMI A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors vs. Bivalirudiin STEMI: Final 3-year results from the HORIZONS- AMI Trial Lincoff p853/Abstract/ Conclusions Key Message: HORIZONS AMI builds on a wealth of experience with bivalirudin across a spectrum of patients with acute coronary syndromes (ACS) undergoing PCI and supports the major landmark trials REPLACE-21 and ACUITY.2 References 1. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853-863. 2. Stone GW, McLaruin BT, Cox DA, for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-2216. Lincoff p853/Abstract/ Conclusions Stone p2203/Abstract/ Conclusions Stone GW et al. Lancet 2011: Published online June 13, DOI:10.1016/S0140-6736(11)60764-2 1

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) 3-year results are assessed in this report Prespecified endpoints in the pharmacology arm at 3 years included death, reinfarction, ischemia driven target lesion revascularization, stroke, and the composite of these (MACE); non-CABG major bleeding and the composite of all net adverse clinical events (NACE). Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

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 3 years; angio FU at 13 months Stone, GW N Engl J Med 2008;358:2218-30.

Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 N=1628 N=1634 N=1774 N=1771 N=1702 Randomized 28 • • • Not true MI* • • • 29 1-Year FU Eligible 26 46 • • • Withdrew • • • • • • Lost to FU • • • 22 53 1-Year FU N=1696 17 57 • • • Withdrew • • • • • • Lost to FU • • • 18 44 3-Year FU * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only) Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

Pharmacology Randomization: Aspirin and Thienopyridine Use Regular* aspirin use (%) Regular* thieno. use (%) Heparin + GPIIb/IIIa(n=1802) Bivalirudin alone (n=1800) 97% 97% 96% 96% 93.% 95% 94% 93% 87% 98% 97% 97% 96% 95% 95% 94% 93% 88% 66% 68% Antiplatelet agent use (%) All P = NS 33% 26% 36% All P = NS 27% *Taken >50% of days since last visit Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Major Bleeding (non-CABG)* 12 4 6 8 10 0.64 (0.51, 0.80) 2 15 18 21 24 27 30 33 36 P=0.0001 3-yr HR (95%CI) 6.9% 10.5% Major Bleeding (%) Months 3 9 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 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 Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Cardiac Mortality Time in Months ' Time in Months 3-Year Cardiac Mortality Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Cardiac Mortality (%) P=0.001 3-yr HR (95%CI) 0.56 (0.40, 0.80) 2.9% 12 15 18 21 24 27 30 33 36 Months 3 6 9 1 5 4 2 3.8% 2.1% 5.1% Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Cardiac Mortality Landmark analysis 5 4 3 2 1 6 9 12 15 18 21 24 27 30 33 36 Heparin + GP IIb/IIIa (n=1802) Bivalirudin (n=1800) 3 year HR (95% CI) 0.49 0.28 –0.86 p=0.01 30 day HR (95% CI) 0.62 (0.40 – 0.96) p=0.03 2.2% 1.1% Cardiac mortality (%) 1.8% 2.9% Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Reinfarction 8.2% 6.2% 3-yr HR (95%CI) 0.76 (0.59, 0.99) P=0.04 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, 0.99) 12 15 18 21 24 27 30 33 36 Months 4.4% 3.6% Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Reinfarction Landmark analysis 10 8 6 4 2 3 9 12 15 18 21 24 27 30 33 36 3-year HR (95% CI) 0.66 (0.49 – 0.90) p=0.007 30-day HR (95% CI) 1.07 (0.66 – 1.73) p=0.79 6.5% 4.4% Reinfarction (%) 1.8% 1.9% 7 5 1 Months Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year All-Cause Mortality or Reinfarction Landmark analysis 5 4 3 2 1 6 9 12 15 18 21 24 27 30 33 36 Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 3-year HR (95% CI) 0.72 (0.58 – 0.91) p=0.005 30-day HR (95% CI) 0.84 (0.61 – 1.16) p=0.30 10.6% 7.8% All-cause mortality or reinfarction (%) 3.8% 4.5% Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-year MACE Components* UFH + GPI (N=1802) Bivalirudin (N=1800) HR [95%CI] P Value Number needed to treat Death 7.7% 5.9% 0.75 (0.58,0.97) 0.03 54 - Cardiac 5.1% 2.9% 0.56 (0.40,0.80) 0.001 45 - Non cardiac 2.8% 3.1% 0.62 Reinfarction 8.2% 6.2% 0.76 (0.59,0.92) 0.04 52 - Q-wave 3.8% 3.4% 0.61 - Non Q-wave 4.9% 3.2% 0.009 58 Death or reinfarction 14.5% 11.3% 0.72 (0.58,0.91) 0.005 31 Ischemic TVR 12.1% 14.2% 0.06 Stroke 2.0% 1.7% 0.50 *Kaplan-Meier estimates, CEC adjudicated MACE= death, reinfarction, ischemia-driven target vessel revascularization, stroke Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-year Bleeding Endpoints UFH + GPI (N=1802) Bivalirudin (N=1800) HR (95% CI) P Value Number needed to treat Major bleeding, non-CABG 10.5% 6.9% 0.64 (0.51-0.80) 0.0001 28 Major bleeding, including CABG 12.8% 8.9% <0.0001 25 Blood transfusion 5.1% 3.5% 0.01 61 TIMI Major or Minor 10.9% 7.0% 26 TIMI Major 6.1% 4.1% 0.007 51 TIMI Minor 5.0% 3.2% 56 GUSTO (any) 12.7% 8.8% GUSTO severe/life-threatening 0.9% 1.0% 0.74 GUSTO moderate 6.3% 4.7% 0.03 63 GUSTO mild 6.2% 4.0% 0.003 Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Stent Thrombosis (ARC Definite/Probable) 6 2 3 4 5 0.89 (0.65, 1.23) 1 12 15 18 21 24 27 30 33 36 p=0.49 HR (95%CI) 4.5% 5.1% Stent Thrombosis (%) Months 9 Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591) 3.5% 3.0% ARC= Academic Research Consortium Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Stent Thrombosis* (N=3202) UFH + GPI (N=1591) Bivalirudin (N=1611) P Value ARC definite 4.1% 4.2% 0.87 ARC probable 1.0% 0.3% 0.02 ARC definite or probable 5.1% 4.5% 0.49 Early <30 days 2.1% 2.6% 0.31 Late (30 days to 1 year) 0.9% 0.64 Very late (> 1 year) 2.2% 1.1% <24 hours 1.5% 0.0002 24 hours to 3 years 4.8% 3.1% 0.01 ARC= Academic Research Consortium *All Kaplan-Meier estimates; all CEC adjudicated Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

Limitations Open label design, but high compliance to study processes Study applicable to patients enrolled, although there were few exclusions Slight imbalances between baseline groups and outpatient thienopyridine use, but none of the results were altered in multivariable adjustment Results were not adjusted for multiple comparisons and should be regarded as hypothesis-generating 8.0% of patients in the pharmacology randomization were not available for 3-year follow-up The impact of a comparison with heparin alone, or with higher use of radial access are not known Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

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 = 54 to save 1 life) Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2