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A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Metal Stents During Primary Angioplasty in Acute Myocardial Infarction.

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Presentation on theme: "A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Metal Stents During Primary Angioplasty in Acute Myocardial Infarction."— Presentation transcript:

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 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 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 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

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: 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) 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 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/mm 3 or hgb <10 g/dL 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/mm 3 or hgb <10 g/dL Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment 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: 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 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) 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 Bifurcation lesion definitely requiring implantation of stents in both the main vessel + side branch Infarct related artery is an unprotected left main Infarct related artery is an unprotected left main >100 mm of study stent length anticipated >100 mm of study stent length anticipated Infarction due to stent thrombosis, or infarct lesion at the site of a previously implanted stent Infarction due to stent thrombosis, or infarct lesion at the site of a previously implanted stent High likelihood of CABG within 30 days anticipated High likelihood of CABG within 30 days anticipated

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

10 Statistical Methodology Second randomization stratification Second randomization stratification i.Results from the first randomization ii.Presence of medically treated diabetes mellitus iii.Presence of any lesion >26 mm in length (requiring overlapping stents by protocol) iv.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 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 1-sided α=0.025 for NI; 2-sided α=0.05 for Sup

11 Power Analysis Assumed event rates One Year TestEXPRESSTAXUSPower Ischemic TLR Superiority9.0%5.0%-95% Composite Safety MACE Noninferiority7.5%7.5%3.0%80% With 2,850 pts randomized 3:1* Assumed event rates 13 Months TestEXPRESSTAXUSPower RestenosisSuperiority26.0%15.6%-96% 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 Sponsor:The Cardiovascular Research Foundation Grant Support:Boston Scientific Corporation (unrestricted) The Medicines Company Grant Support:Boston Scientific Corporation (unrestricted) The Medicines Company Principal Investigator:Gregg W. Stone MD Principal Investigator:Gregg W. Stone MD Steering Committee:Gregg W. Stone (Chair), Bruce R. Brodie, David A. Cox, Cindy L. Grines, Barry D. Rutherford 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 European SteeringH Bonnier, A Colombo, Eulogio Garcia, Committee: E Grube, G Guagliumi, A Kastrati, P Serruys, H Suryapranata Additional CountryY Almagor, A Banning, J Belardi, D Dudek, Leaders:L Grinfeld, K Huber, D Nilsen, G Olivecrona, L Rasmussen Additional CountryY 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 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) 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) Clinical Events Committee:CRF, S. Chiu Wong (Chair) Site and Data Monitoring:J. Tyson and Associates (USA), Premier (Europe), Tango (S.A.) Site and Data Monitoring:J. Tyson and Associates (USA), Premier (Europe), Tango (S.A.) Angiographic Core Lab:CRF, Alexandra Lansky (Director), Ecaterina Cristea (Ops) Angiographic Core Lab:CRF, Alexandra Lansky (Director), Ecaterina Cristea (Ops) ECG Core Lab:CRF, James Reiffel (Director) ECG Core Lab:CRF, James Reiffel (Director) IVUS Core lab:CRF, Akiko Maehara (Director) IVUS Core lab:CRF, Akiko Maehara (Director) DSMB:Bernhard Gersh (Chair), David Faxon, Spencer King, Stuart Pocock, David Williams 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 USA (57) (1) Spain (6) UK (2) Norway (2) Norway Poland (9) Germany (16) Austria (5) (3) Netherlands Italy (2) Argentina (12) Israel (10) 3,602 pts randomized at 123 centers in 11 countries between March 25 th, 2005 and May 7 th, 2007

16 Top 20 Enrolling Sites 1. B. Witzenbichler, Germany 2. G. Guagliumi, Italy 3. J. Peruga, Poland 4. B. Brodie, USA 5. R. Kornowski, Israel 6. F. Hartmann, Germany 7. M. Moeckel, Germany 8. A. Ochala, Poland 9. W. Ruzyllo, Poland 10. V. Guetta, Israel 11. H. Suryapranata, Netherlands 12. K. Huber, Austria 13. J. Wöehrle, Germany 14. C. Metzger, USA 15. M. Desaga, Germany 16. K. Zmudka, Poland 17. J. Kochman, Poland 18. D. Nilsen, Norway 19. D. Dudek, Poland 20. A. Finkelstein, Israel

17 TAXUS DES N=2257 EXPRESS BMS N=749 Randomized 1 year FU N=2186 (96.9%) N=715 (95.5%) Withdrew Withdrew Lost to FU Lost to FU R 3:1 Harmonizing Outcomes with Revascularization and Stents in AMI 3006 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

18 Baseline Characteristics (i) TAXUS(N=2257)EXPRESS(N=749) Age (years) 59.9 [52.4, 69.4] 59.3 [51.8, 69.2] Male77.0%76.0% Diabetes16.1%15.2% Hypertension51.2%51.9% Hyperlipidemia42.2%41.1% Current smoking 46.3%51.9% Prior MI 9.1%10.9% Prior PCI 9.5%7.7% Prior CABG 2.2%1.9% *P=0.009 *

19 Baseline Characteristics (ii) TAXUS(N=2257)EXPRESS(N=749) Weight (kg) 80 [71, 90] Killip class %8.0% Anterior MI 42.2%44.7% LVEF (%), site 50 [44, 59] 50 [43, 58] Symptoms – PCI, hrs 3.7 [2.7, 5.5] 3.8 [2.7, 5.8] Femoral a. access 93.6%92.9% Venous access 8.5%8.0% Closure device 30.1%28.8% Aspiration catheter 11.4%10.7%

20 Study Drugs TAXUS(N=2257)EXPRESS(N=749) Aspirin at home 22.7%20.5% Aspirin load pre PCI 97.0%97.2% Thienopyridine at home 2.1%2.5% Thienopyridine loading dose 98.9%98.3% - clopidogrel 300 mg - clopidogrel 300 mg34.2%35.5% - clopidogrel 600 mg - clopidogrel 600 mg63.3%61.3% - clopidogrel other - clopidogrel other1.2%1.3% - ticlopidine - ticlopidine0.5%0.3% UFH pre randomization UFH pre randomization65.2%65.8% UFH as the procedural antithrombin UFH as the procedural antithrombin49.8%50.1% Bivalirudin administered Bivalirudin administered50.7%50.9% GP IIb/IIIa inhibitor administered 52.0%51.5%

21 Procedural Data (Site Reported) TAXUS (N=2257, L=2495) EXPRESS (N=749, L=815) N lesions treated 1.1 ± lesions treated - 2 lesions treated11.1%9.0% - 2 vessels treated - 2 vessels treated4.5%3.1% Direct stenting attempted 30.4%33.7% Stent target lesion: LAD, LCX, RCA, LM, SVG 40.1%, 14.6%, 45.1%, 0.3%, 0.3% 42.4%, 15.9%, 41.3%, 0.4%, 0.4% N stents implanted 1.5 ± ± 0.7 Total stent length** 30.8 ± ± 14.9 Max balloon dia. (mm) 3.00 [2.75, 3.50] 3.00 [2.90, 3.50] Max pressure (atm.) 14.0 [12.0, 16.0] *P=0.002; **P< * **

22 Quantitative Coronary Angiography TAXUS (L=2642, V=2353) EXPRESS (L=857, V=771) Pre RVD (mm) 2.89 ± ± 0.50 Pre MLD (mm) 0.35 ± 0.45 Pre %DS 87.6 ± ± 15.4 Pre lesion length (mm) 17.5 ± ± 8.8 Pre TIMI 0/1, 2, %, 13.6%, 25.7% 57.4%, 15.2%, 27.4% Post RVD (mm) 2.93 ± ± 0.50 Post MLD (mm)* 2.36 ± ± 0.52 Post %DS* 19.9 ± ± 11.1 Acute gain (mm)** 2.04 ± ± 0.62 Post TIMI 0/1, 2, 3 1.7%, 10.7%, 87.6% 0.9%, 9.3%, 89.8% *Analysis segment, all lesions, whether stented or not; **stented lesions only; P=0.006

23 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% 94.7% 87.5% 73.1% 63.9% P<0.001 P<0.001

24 Number at risk TAXUS DES EXPRESS BMS Primary Efficacy Endpoint: Ischemic TLR Ischemic TLR (%) Time in Months % 4.5% Diff [95%CI] = -3.0% [-5.1, -0.9] HR [95%CI] = 0.59 [0.43, 0.83] P=0.002 TAXUS DES (n=2257) EXPRESS BMS (n=749)

25 Ischemic TVR (%) Time in Months Number at risk TAXUS DES EXPRESS BMS 8.7% 5.8% Diff [95%CI] = -3.0% [-5.2, -0.7] HR [95%CI] = 0.65 [0.48, 0.89] P=0.006 TAXUS DES (n=2257) EXPRESS BMS (n=749) Secondary Efficacy Endpoint: Ischemic TVR

26 Primary Safety Endpoint: Safety MACE* Safety MACE (%) Time in Months Number at risk TAXUS DES EXPRESS BMS TAXUS DES (n=2257) EXPRESS BMS (n=749) 8.1% 8.0% Diff [95%CI] = 0.1% [-2.1, 2.4] HR [95%CI] = 1.02 [0.76, 1.36] P NI =0.01 P Sup =0.92 * Safety MACE = death, reinfarction, stroke, or stent thrombosis

27 One-Year All-Cause Mortality Mortality (%) Time in Months Number at risk TAXUS DES EXPRESS BMS TAXUS DES (n=2257) EXPRESS BMS (n=749) 3.5% HR [95%CI] = 0.99 [0.64,1.55] P=0.98

28 One-Year Cardiac Mortality

29 One-Year Death or Reinfarction

30 Stent Thrombosis (ARC Definite or Probable)

31 Stent Thrombosis Rates* TAXUS(N=2238)EXPRESS(N=744) Hazard ratio [95%CI] P Value Stent thrombosis, 30 days 2.3%2.7% 0.87 [0.52,1.46] ARC definite - ARC definite1.9%2.3% 0.83 [0.47,1.45] ARC probable - ARC probable0.5%0.4% 1.11 [0.31,4.05] 0.87 Stent thrombosis, >30d – 1y 1.0%0.7% 1.39 [0.52,3.68] ARC definite - ARC definite0.9%0.7% 1.25 [0.47,3.35] ARC probable - ARC probable0.1%0%-0.42 Stent thrombosis, 1 year 3.1%3.4% 0.92 [0.58,1.45] ARC definite - ARC definite2.6%3.0% 0.86 [0.53,1.41] ARC probable - ARC probable0.5%0.4% 1.33 [0.38,4.73] 0.65 *Kaplan-Meier estimates

32 One Year Composite Safety Endpoints* TAXUS(N=2257)EXPRESS(N=749) HR [95%CI] P Value Safety MACE** 8.1%8.0% 1.02 [0.76,1.36] 0.92 Death, all-cause 3.5%3.5% 0.99 [0.64,1.55] Cardiac - Cardiac2.4%2.7% 0.90 [0.54,1.50] Non cardiac - Non cardiac1.1%0.8% 1.32 [0.54,3.22] 0.55 Reinfarction3.7%4.5% 0.81 [0.54,1.21] Q-wave - Q-wave2.0%1.9% 1.07 [0.59,1.94] Non Q-wave - Non Q-wave1.8%2.7% 0.68 [0.39,1.17] 0.16 Stent thrombosis Stent thrombosis 3.1%3.4% 0.92 [0.58,1.45] ARC definite - ARC definite2.6%3.0% 0.86 [0.53,1.41] ARC probable - ARC probable0.5%0.4% 1.33 [0.38,4.73] 0.65 Stroke1.0%0.7% 1.52 [0.58,4.00] 0.39 *Kaplan-Meier estimates; **Primary safety endpoint; ARC definite or probable

33 Angiographic Follow-up TAXUS DES N=1348 EXPRESS BMS N=452 Randomized Eligible N=1308N= consecutive eligible pts assigned to 13 month angiographic FU* * 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 4011 Died before angio FU Died before angio FU N=942 (72.0%) N=307 (69.6%) Completed Angio FU Angio FU not performed Angio FU not performed Not received/analyzable Not received/analyzable Out of window Out of window N=911N=293 Analyzed Lesions Lesions

34 Follow-up QCA TAXUS (L=1081, V=964) EXPRESS (L=332, V=302) P value TIMI flow - 0/1 - 0/12.8%3.6% %5.0% %91.4%0.55 FU RVD (mm) 2.91 ± ± FU MLD in-stent (mm) 2.36 ± ± 0.82 < FU MLD in-segment (mm) 2.08 ± ± 0.76 < FU %DS in-stent 18.8 ± ± 24.9 < FU %DS in-segment 28.8 ± ± 22.0 < Aneurysm0.5%0.9%0.40 Ulcerated0.5%0.6%0.67 Ectasia0.7%0.9%0.73

35 Binary Analysis Segment Restenosis at 13 Months Patient and Lesion Level Analysis* RR [95%CI] = 0.44 [0.33, 0.57] P< * 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 RR [95%CI] = 0.44 [0.33, 0.57] P< Major 2 endpoint

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

37 Binary Angiographic Restenosis at 13 Months Lesions with Stents Implanted RR [95%CI] = 0.42 [0.32, 0.54] P< RR [95%CI] = 0.39 [0.29, 0.52] P< P = 0.13 P = 0.42

38 Limitations Open label design 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 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

39 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: 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

40 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 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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