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A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction – 30 Day Results – Gregg W. Stone MD For the HORIZONS AMI Investigators. Disclosures. Gregg W. Stone MD

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  1. A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction – 30 Day Results – Gregg W. Stone MD For the HORIZONS AMI Investigators

  2. Disclosures Gregg W. Stone MD Research support from The Medicines Company and Boston Scientific Honoraria from Eli Lilly Co.

  3. Background In addition to suppressing periprocedural ischemia, prevention of hemorrhagic complications has emerged as a priority in patients undergoing PCI In patients with stable angina and NSTEMI, the direct thrombin inhibitor bivalirudin has been shown to result in similar rates of composite ischemia as heparin plus GP IIb/IIIa inhibitors, while significantly reducing major bleeding Whether bivalirudin has comparable safety and efficacy in patients with STEMI undergoing primary PCI is unknown

  4. Harmonizing Outcomes with Revascularization and Stents in AMI ≥3400* 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 1:3 CABG – – Primary PCI Medical Rx 3000 pts eligible for stent randomization TAXUS paclitaxel-eluting stent Bare metal stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years *To rand 3000 stent pts

  5. Harmonizing Outcomes with Revascularization and Stents in AMI ≥3400* pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Pharmacology Arm Primary Endpoints* 30 Day Intention to Treat Population R 1:1 * All stent randomization results are still blinded

  6. 30 Day Study Objectives • In patients with STEMI undergoing a primary PCI strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy will result in: • Similar or reduced rates of net adverse clinical events (the composite of major adverse cardiovascular events and major bleeding) at 30 days • Similar or reduced rates of major bleeding at 30 days

  7. Inclusion Criteria STEMI >20 mins and <12 hours in duration ST-segment elevation of 1 mm in 2 contiguous leads; or Presumably new left bundle branch block; or True posterior MI with ST depression of 1 mm in 2 contiguous anterior leads Patients with cardiogenic shock, left main disease, etc., were not excluded Age ≥18 years Written, informed consent

  8. Principal Exclusion Criteria Contraindication to any of the study medications Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed) Current use of coumadin History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm3 or hgb <10 g/dL Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment

  9. Study Medications (i) • Unfractionated heparin • 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed • Bivalirudin • Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) • Glycoprotein IIb/IIIa inhibitors • Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm • Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abcx) or 12-18 (eptif) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus

  10. Study Medications (ii) • Aspirin • 324 mg chewed non enteric coated or 500 mg IV in the ER, followed by 300-325 mg/day in-hospital and 75-81 mg/day as out patient indefinitely • Thienopyridines • Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended) • Ticlopidine load + daily dose permissible if clopiodgrel is unavailable or patient is allergic • Other • Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF <40%;Statinif LDL >100 mg/dl

  11. 2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events and 2) Major Bleeding (non CABG) • Intracranial bleeding • intraocular bleeding • Retroperitoneal bleeding • Access site bleed requiring • intervention/surgery • Hematoma ≥5 cm • Hgb ≥3g/dL with an overt source • Hgb ≥4g/dL w/o overt source • Reoperation for bleeding • Blood product transfusion

  12. 2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events = 2) Major Bleeding (non CABG) or Major adverse cardiovascular events (major secondary endpoint) • All cause death • Reinfarction • Ischemic TVR • Stroke

  13. Statistical Methodology • Randomization stratification • Administration of non protocol pre-procedural heparin • Planned administration of 300 or 600 mg of clopidogrel or 500 mg of ticlopidine prior to cardiac catheterization • Whether the patient will receive abciximab or eptifibatide • U.S. vs. non-U.S. site • Primary analysis is by ITT among all randomized pts; secondary analysis is ITT among primary PCI cohort • Sequential noninferiority and superiority testing • NI for net adverse clinical events  NI for major bleeding  Sup for major bleeding  Sup for adverse clinical net events • One-sided α=0.025 for NI; Two-sided α=0.05 for Sup • Primary analyses conducted using binomial proportions

  14. Horizons Enrollment - Centers 3,602 pts randomized at 123 centers in 11 countries between March 25th, 2005 and May 7th, 2007 (2) Norway (3) Netherlands Poland (9) (6) UK Germany (16) Austria (5) USA (57) Israel (10) (1) Spain Italy (2) Argentina (12)

  15. Horizons Enrollment - Patients 3,602 pts randomized at 123 centers in 11 countries between March 25th, 2005 and May 7th, 2007 (79, 2.2%) Norway (133, 3.7%) Netherlands Poland (582, 16.2%) (102, 2.8%) UK Germany (791, 22%) USA (814, 22.6%) Austria (143, 4.0%) Israel (526, 14.6%) (6, 0.2%) Spain Italy (219, 6.1%) Argentina (207, 5.7%)

  16. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin Monotherapy N=1800 Randomized 9 15 • • • Withdrew • • • • • • Lost to FU • • • 10 13 N=1778 (98.7%) N=1777 (98.7%) 30 day FU* ITT population N=1802 N=1800 * Range ±7 days

  17. Baseline Characteristics (i) * *P=0.04

  18. Baseline Characteristics (ii)

  19. Study Drugs * For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory

  20. Primary Management Strategy* UFH + GP IIb/IIIa Inhibitor N=1802 Bivalirudin Monotherapy N=1800 Primary PCI CABG Deferred PCI Medical Rx *Primary ITT analysis includes all pts regardless of treatment

  21. Primary Outcome Measures (ITT) Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ 0.0001 Psup = 0.006 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] Psup = 1.00 1 endpoint 1 endpoint • *Not related to CABG • **MACE = All cause death, reinfarction, ischemic TVR or stroke

  22. 30 Day Net Adverse Clinical Events Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 12.2% 9.3% Primary Endpoint Net adverse clinical events (%)* HR [95%CI] = 0.75 [0.62, 0.92] P=0.006 Time in Days Number at risk Bivalirudin 1800 1660 1633 1626 1620 1607 1544 Heparin + GPIIb/IIIa 1802 1635 1591 1578 1569 1552 1482 • *MACE or major bleeding (non CABG)

  23. 30 Day Major Bleeding (non-CABG) Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 8.4% Primary Endpoint Major Bleeding (%) 5.0% HR [95%CI] = 0.59 [0.45, 0.76] P<0.0001 Time in Days Number at risk Bivalirudin 1800 1697 1675 1668 1664 1653 1590 Heparin + GPIIb/IIIa 1802 1651 1617 1606 1598 1581 1511

  24. 30 Day Major Bleeding Components *CEC adjudicated

  25. 30 Day Bleeding Endpoints (CEC Adjudicated) *Primary endpoint; **Life threatening

  26. Thrombocytopenia P = 0.002 P = 0.04 P = 0.04 <100,000 cells/mm3 <50,000 cells/mm3 <20,000 cells/mm3

  27. 30 Day Major Adverse CV Events Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 5.5% 5.5% Major adverse CV events (%)* HR [95%CI] = 1.00 [0.75, 1.32] P=0.98 Time in Days Number at risk Bivalirudin 1800 1716 1701 1695 1689 1673 1608 Heparin + GPIIb/IIIa 1802 1744 1712 1699 1688 1668 1590 • *MACE = All cause death, reinfarction, ischemic TVR or stroke

  28. 30 Day MACE Components* *CEC adjudicated

  29. 30 Day Mortality Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 3.1% Death (%) 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Time in Days Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630

  30. 30 Day Mortality: Cardiac and Non Cardiac Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 2.9% Death (%) Cardiac 1.8% Non cardiac 0.3% 0.2% Time in Days Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630

  31. new Impact of Peak ACT on Control Arm Event Rates P = 0.10 P = 0.12 P = 0.35 P = 0.30 [231,357] [239,332] [232,338] [2134,329] [228,320] [228,320] [227,319] [227,320] N=210 N=1528 N=144 N=1594 N=96 N=1642 N=54 N=1684 • *Not related to CABG • **MACE = All cause death, reinfarction, ischemic TVR or stroke

  32. Primary PCI Procedure (N=3,340; 92.7%) IA = infarct artery; * For giant thrombus or refractory no reflow

  33. Primary PCI Cohort (N=3,340; 92.7%) Diff = -3.0% [-5.2, -2.9] RR = 0.75 [0.62, 0.92] PNI ≤ 0.0001 Psup = 0.005 Diff = -3.5% [-5.2, -1.7] RR = 0.59 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = -0.1% [-1.6, 1.5] RR = 0.99 [0.75, 1.32] Psup = 1.00 • *Not related to CABG • **MACE = All cause death, reinfarction, ischemic TVR or stroke

  34. 30 Day Net Clinical Events: PCI Cohort Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) 12.3% 9.2% Net Adverse Clinical Events (%)* HR [95%CI] = 0.74 [0.60, 0.92] P=0.005 Time in Days Number at risk Bivalirudin 1678 1554 1528 1521 1516 1505 1448 Heparin + GPIIb/IIIa 1662 1510 1467 1456 1448 1436 1372 • *MACE or major bleeding (non CABG)

  35. 30 Day Major Bleeding: PCI Cohort Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) 8.6% Major Bleeding (Non-CABG) (%) 5.1% HR [95%CI] = 0.58 [0.44, 0.76] P<0.0001 Time in Days Number at risk Bivalirudin 1678 1590 1568 1561 1558 1548 1490 Heparin + GPIIb/IIIa 1662 1525 1492 1482 1475 1463 1399

  36. 30 Day Major Adverse CV Events: PCI Cohort Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) 5.5% 5.4% Major Adverse CV Events (%)* HR [95%CI] = 1.00 [0.74, 1.33] P=0.98 Time in Days Number at risk Bivalirudin 1678 1606 1592 1585 1581 1567 1509 Heparin + GPIIb/IIIa 1662 1613 1581 1570 1561 1546 1474 • *MACE = All cause death, reinfarction, ischemic TVR or stroke

  37. 30 Day Stent Thrombosis (N=3,124) *Protocol definition of stent thrombosis, CEC adjudicated

  38. 30 Day Mortality: PCI Cohort Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) HR [95%CI] = 0.63 [0.40, 0.99] P=0.049 2.8% Death (%) Cardiac 1.8% Non cardiac 0.2% 0.1% Time in days Number at risk Bivalirudin 1678 1647 1640 1635 1632 1620 1563 Heparin + GPIIb/IIIa1662 1631 1615 1604 1598 1583 1512

  39. Impact of Definite Stent Thrombosis and Major Bleeding* on Mortality Major bleed No major bleed Stent thrombosis No stent thrombosis 9.5% 8.8% Death (%) 1.6% 1.2% Time in Days Number at risk Stent thrombosis 57 54 53 52 52 52 51 No stent thrombosis 3067 3023 3008 2998 2991 2969 2848 Major bleed 195 183 181 177 176 171 161 No major bleed 2929 2894 2880 2873 2867 2850 2738 • *Not related to CABG

  40. Impact of Definite Stent Thrombosis and Major Bleeding* on Mortality • *Not related to CABG

  41. Limitations • Open label design • Potential bias was mitigated by high protocol procedure compliance and use of blinded clinical event adjudication committees and core laboratories • Underpowered for MACE and low frequency safety endpoints • The virtually identical rates of MACE in the bivalirudin and UFH plus GP IIb/IIIa inhibitor arms makes it unlikely major differences favoring control exist, especially given the lower cardiac mortality with bivalirudin

  42. Conclusions • In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy with GP IIb/IIIa inhibitors reserved for suboptimal PCI outcomes resulted in: • A significant 24% reduction in the 30 day primary endpoint of net adverse clinical events • A significant 40% reduction in the 30 day primary endpoint of major bleeding

  43. Conclusions • The long-term impact of treatment with bivalirudin monotherapy rather than heparin plus GP IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI will be determined by the ongoing 5 year follow-up of patients randomized in this trial • The primary endpoint results of the second randomized arm of the HORIZONS AMI trial (paclitaxel-eluting vs. bare metal stents) will be available for presentation at TCT 2008

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