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Background

A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Metal Stents During Primary Angioplasty in Acute Myocardial Infarction – One Year Results – Gregg W. Stone MD For the HORIZONS-AMI Investigators. Background.

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  1. A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Metal Stents During Primary Angioplasty in Acute Myocardial Infarction – One Year Results – Gregg W. Stone MD For the HORIZONS-AMI Investigators

  2. Background No consensus exists regarding the safety and efficacy of drug-eluting stents in pts with STEMI undergoing primary PCI TLR and restenosis rates tend to be lower in STEMI vs. elective PCI patients because of less plaque burden and non viable myocardium The safety of implanting DES in ruptured plaques with thrombus has been questioned Outcomes from registry studies of DES vs. BMS in STEMI have been conflicting, and no large-scale randomized trials have been performed

  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 3000 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 5 years; angio FU at 13 months

  4. Stent Randomization Hypotheses • In patients with STEMI undergoing primary PCI, the use of paclitaxel-eluting TAXUS stents rather than bare metal EXPRESS stents will be: • Efficacious, as evidenced by reduced rates of ischemia-driven target lesion revascularization at 1-year and angiographic binary restenosis at 13 months; and • Safe, with non-inferior rates of the composite measure of death, reinfarction, stent thrombosis or stroke at 1-year

  5. Clinical 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

  6. Principal Clinical 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

  7. Angiographic Inclusion Criteria The presence of least 1 acute infarct artery target vessel* in which: a) ALL significant lesions are eligible for stenting with study stents, and b) ALL such lesions have a visually estimated reference diameter ≥2.25 mm and ≤4.0 mm Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal tortuosity or severe calcification) Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked calcification) *Arteries containing multiple lesions may be randomized if all lesions are study stent eligible; multiple vessels may be randomized if all lesions in each vessel are study stent eligible

  8. Angiographic Exclusion Criteria Bifurcation lesion definitely requiring implantation of stents in both the main vessel + side branch Infarct related artery is an unprotected left main >100 mm of study stent length anticipated Infarction due to stent thrombosis, or infarct lesion at the site of a previously implanted stent High likelihood of CABG within 30 days anticipated

  9. 2 Primary Stent Endpoints (at 12 Months) 1) Ischemia-driven TLR* and 2) Composite Safety MACE = All cause death, reinfarction, stent thrombosis (ARC definite or probable)**, or stroke Major Secondary Endpoint (at 13 Months) Binary angiographic restenosis * Related to randomized stent lesions (whether study or non study stents were implanted); ** In randomized stent lesions with ≥1 stent implanted (whether study or non study stents)

  10. Statistical Methodology • Second randomization stratification • Results from the first randomization • Presence of medically treated diabetes mellitus • Presence of any lesion >26 mm in length (requiring overlapping stents by protocol) • U.S. vs. non-U.S. site • Primary analysis conducted in the ITT cohort using Kaplan-Meier methodology, with the groups compared by log-rank • 1-sided α=0.025 for NI; 2-sided α=0.05 for Sup

  11. Power Analysis With 2,850 pts randomized 3:1* With angiographic FU in 1,125 randomized pts (analyzable) * Assumed 5% withdrew or lost to FU at 1 year → 3000 randomized

  12. Study Organization • Sponsor: The Cardiovascular Research Foundation • Grant Support: Boston Scientific Corporation (unrestricted) The Medicines Company • Principal Investigator: Gregg W. Stone MD • Steering Committee: Gregg W. Stone (Chair), Bruce R. Brodie, David A. Cox, Cindy L. Grines, Barry D. Rutherford • European SteeringH Bonnier, A Colombo, Eulogio Garcia, Committee: E Grube, G Guagliumi, A Kastrati, P Serruys, H Suryapranata • Additional Country Y Almagor, A Banning, J Belardi, D Dudek, Leaders: L Grinfeld, K Huber, D Nilsen, G Olivecrona, L Rasmussen • PharmacologyDeepak Bhatt, George Dangas, Fred Feit, Committee:Magnus Ohman

  13. Study Organization • Data Management: CRF, Roxana Mehran (Director), Lynn Vandertie, Louise Gambone (Ops), Allison Kellock (Programming), Helen Parise (Stats) • Clinical Events Committee: CRF, S. Chiu Wong (Chair) • Site and Data Monitoring: J. Tyson and Associates (USA), Premier (Europe), Tango (S.A.) • Angiographic Core Lab: CRF, Alexandra Lansky (Director), Ecaterina Cristea (Ops) • ECG Core Lab: CRF, James Reiffel (Director) • IVUS Core lab: CRF, Akiko Maehara (Director) • DSMB: Bernhard Gersh (Chair), David Faxon, Spencer King, Stuart Pocock, David Williams

  14. The Cardiovascular Research Foundation (CRF) HORIZONS-AMI Team Sponsored by CRF

  15. 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)

  16. Top 20 Enrolling Sites

  17. Harmonizing Outcomes with Revascularization and Stents in AMI UFH + GPI (n=1802) Bivalirudin (n=1800) 3602 pts with STEMI Primary Medical Rx 193 Primary CABG 62 Deferred PCI 2 Index PCI, not eligible - PTCA only 119 - Stented 220 3006 pts eligible for stent rand. 93.1% of all stented pts were randomized R 1:1 R 3:1 TAXUS DES N=2257 EXPRESS BMS N=749 Randomized 18 53 • • • Withdrew • • • • • • Lost to FU • • • 7 27 N=2186 (96.9%) N=715 (95.5%) 1 year FU

  18. Baseline Characteristics (i) * *P=0.009

  19. Baseline Characteristics (ii)

  20. Study Drugs

  21. Procedural Data (Site Reported) * ** *P=0.002; **P<0.0001

  22. Quantitative Coronary Angiography † *Analysis segment, all lesions, whether stented or not; **stented lesions only; †P=0.006

  23. Aspirin and Thienopyridine Use Regular* aspirin use (%) Regular* thieno. use (%) 99.4% 98.7% 99.1% 98.5% 98.3% 97.5% 94.7% 98.9% 97.8% 98.6% 98.3% 97.5% 97.1% 73.1% 87.5% P<0.001 Antiplatelet agent use (%) 63.9% P<0.001 *Taken >50% of days since last visit

  24. Primary Efficacy Endpoint: Ischemic TLR 10 TAXUS DES (n=2257) Diff [95%CI] = -3.0% [-5.1, -0.9] HR [95%CI] = 0.59 [0.43, 0.83] P=0.002 EXPRESS BMS (n=749) 9 8 7.5% 7 6 Ischemic TLR (%) 5 4.5% 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk TAXUS DES 2257 2132 2098 2069 1868 EXPRESS BMS 749 697 675 658 603

  25. Secondary Efficacy Endpoint: Ischemic TVR 10 TAXUS DES (n=2257) Diff [95%CI] = -3.0% [-5.2, -0.7] HR [95%CI] = 0.65 [0.48, 0.89] P=0.006 8.7% EXPRESS BMS (n=749) 9 8 7 5.8% 6 Ischemic TVR (%) 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk TAXUS DES 2257 2119 2078 2045 1848 EXPRESS BMS 749 695 669 650 598

  26. Primary Safety Endpoint: Safety MACE* 10 TAXUS DES (n=2257) EXPRESS BMS (n=749) 8.1% 9 8 8.0% 7 6 Diff [95%CI] = 0.1% [-2.1, 2.4] HR [95%CI] = 1.02 [0.76, 1.36] PNI=0.01 PSup=0.92 Safety MACE (%) 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk TAXUS DES 2257 2115 2086 2057 1856 EXPRESS BMS 749 697 683 672 619 * Safety MACE = death, reinfarction, stroke, or stent thrombosis

  27. One-Year All-Cause Mortality 5 TAXUS DES (n=2257) EXPRESS BMS (n=749) 4 3.5% 3.5% 3 Mortality (%) HR [95%CI] = 0.99 [0.64,1.55] P=0.98 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk TAXUS DES 2257 2180 2161 2147 1949 EXPRESS BMS 749 716 712 702 648

  28. One-Year Death or Reinfarction TAXUS DES (n=2257) 8 7.0% EXPRESS BMS (n=749) 7 6.8% 6 5 HR [95%CI] = 0.97 [0.70,1.32] P=0.83 Death or MI (%) 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk TAXUS DES 2257 2140 2110 2083 1882 EXPRESS BMS 749 703 689 678 625

  29. Stent Thrombosis (ARC Definite or Probable) 4 TAXUS DES (n=2238) 3.4% EXPRESS BMS (n=744) 3.1% 3 Stent Thrombosis (%) HR [95%CI] = 0.92 [0.58,1.45] P=0.72 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk TAXUS DES 2238 2122 2098 2078 1884 EXPRESS BMS 744 701 694 683 629

  30. Stent Thrombosis Rates* *Kaplan-Meier estimates

  31. One Year Composite Safety Endpoints* *Kaplan-Meier estimates; **Primary safety endpoint; †ARC definite or probable

  32. Angiographic Follow-up 1800 consecutive eligible pts assigned to 13 month angiographic FU* TAXUS DES N=1348 EXPRESS BMS N=452 Randomized 40 11 • • • Died before angio FU • • • Eligible N=1308 N=441 366 134 • Angio FU not performed • N=942 (72.0%) N=307 (69.6%) Completed Angio FU • • Not received/analyzable • • • • • • Out of window • • • • 28 3 14 0 Analyzed N=911 N=293 1081 332 • • • Lesions • • • * Randomized in stent arm; stent procedure successful (DS <10%, TIMI-3 flow, ≤NHLBI type A peri-stent dissection); no stent thrombosis or CABG w/i 30 days

  33. Follow-up QCA

  34. Binary Analysis Segment Restenosis at 13 MonthsPatient and Lesion Level Analysis* RR [95%CI] = 0.44 [0.33, 0.57] P<0.0001 RR [95%CI] = 0.44 [0.33, 0.57] P<0.0001 Major 2 endpoint * ITT: Includes all stent randomized lesions, whether or not a stent was implanted, and whether or not non study stents were placed ** Any lesion with restenosis  per pt restenosis

  35. Angiographic Late Loss at 13 Month Lesions with Stents Implanted P<0.0001 ± 0.70 P<0.0001 ± 0.64 P = 0.07 ± 0.64 P = 0.18 ± 0.56 ± 0.50 ± 0.47 ± 0.54 ± 0.42

  36. Binary Angiographic Restenosis at 13 MonthsLesions with Stents Implanted RR [95%CI] = 0.39 [0.29, 0.52] P<0.0001 RR [95%CI] = 0.42 [0.32, 0.54] P<0.0001 P = 0.42 P = 0.13

  37. 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 stent thrombosis and death • The virtually identical rates of MACE in the TAXUS and EXPRESS groups makes it unlikely that major safety differences exist favoring either stent type at 1-year

  38. Conclusions • In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary stenting, the implantation of paclitaxel-eluting TAXUS stents compared to bare metal EXPRESS stents resulted in: • A significant 41% reduction in the 1-year primary efficacy endpoint of ischemia-driven TLR, and a significant 56% reduction in the 13 month major secondary efficacy endpoint of binary restenosis • Non inferior rates of the primary composite safety endpoint of all cause death, reinfarction, stent thrombosis or stroke at 1-year

  39. Conclusions • The long-term safety and efficacy profile of paclitaxel-eluting TAXUS stents compared to bare metal EXPRESS stents in STEMI will be determined by the ongoing 5 year follow-up of patients randomized in the HORIZONS-AMI trial

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