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HORIZONS –AMI

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. Stone GW et al. Lancet 2011: Published online June 13, DOI:10.1016/S0140-6736(11)60764-2. Background.

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HORIZONS –AMI

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  1. HORIZONS –AMI A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors vs. BivalirudiinSTEMI: Final 3-year results from the HORIZONS-AMI Trial Stone GW et al. Lancet 2011: Published online June 13, DOI:10.1016/S0140-6736(11)60764-2

  2. 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

  3. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… R 1:1 R 3:1 CABG – – Primary PCI Medical Rx 3006 pts eligible for stent randomization Paclitaxel-eluting TAXUS stent Bare metal EXPRESS 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.

  4. 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 • • • Not true MI* • • • 28 29 1-Year FU Eligible N=1774 N=1771 22 53 26 46 • • • Withdrew • • • • • • Lost to FU • • • N=1696 1-Year FU N=1702 • • • Withdrew • • • • • • Lost to FU • • • 17 57 18 44 3-Year FU N=1628 N=1634 * 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

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

  6. 3-Year Major Bleeding (non-CABG)* Bivalirudin alone (n=1800) 12 Heparin + GPIIb/IIIa (n=1802) 10.5% 10 9.4% 8 6.9% Major Bleeding (%) 6 6.0% 3-yr HR (95%CI) 4 0.64 (0.51, 0.80) P=0.0001 2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months * 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

  7. Time in Months 3-Year Cardiac Mortality ' Time in Months Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) 3-yr HR (95%CI) 6 0.56 (0.40, 0.80) 5.1% P=0.001 5 4 3.8% Cardiac Mortality (%) 3 2.9% 2 2.1% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  8. 3-Year Cardiac MortalityLandmark analysis Heparin + GP IIb/IIIa (n=1802) 5 Bivalirudin (n=1800) 30 day HR (95% CI) 0.62(0.40 – 0.96) p=0.03 4 3 year HR (95% CI) 0.490.28 –0.86 p=0.01 3 2.9% Cardiac mortality (%) 2.2% 2 1.8% 1.1% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  9. 3-Year Reinfarction Bivalirudin alone (n=1800) 10 Heparin + GPIIb/IIIa (n=1802) 9 8.2% 8 7 6.2% 6 Reinfarction (%) 5 4.4% 4 3 3.6% 2 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 3-yr HR (95%CI) 0.76 (0.59, 0.99) P=0.04 Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  10. 3-Year ReinfarctionLandmark analysis 10 Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 9 30-day HR (95% CI) 1.07 (0.66 – 1.73) p=0.79 3-year HR (95% CI) 0.66(0.49 – 0.90) p=0.007 8 7 6.5% 6 Reinfarction (%) 5 4.4% 4 3 1.9% 2 1.8% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  11. 3-Year All-Cause Mortality or Reinfarction Landmark analysis Heparin + GPIIb/IIIa (n=1802) 5 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 4 10.6% 3 7.8% All-cause mortality or reinfarction (%) 2 4.5% 3.8% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  12. 3-year MACE Components* *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

  13. 3-year Bleeding Endpoints Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  14. 3-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) 3 Stent Thrombosis (%) 0.89 (0.65, 1.23) 3.0% p=0.49 2 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months ARC= Academic Research Consortium Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  15. 3-Year Stent Thrombosis*(N=3202) *All Kaplan-Meier estimates; all CEC adjudicated ARC= Academic Research Consortium Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

  16. 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

  17. 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

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