A Prospective, Randomized A Prospective, Randomized Comparison of Paclitaxel-eluting Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Metal Stents TAXUS Stents vs. Bare Metal Stents During Primary Angioplasty in During Primary Angioplasty in Acute Myocardial Infarction Acute Myocardial Infarction – – One Year Results – One Year Results – Gregg W. Stone MD Gregg W. Stone MD For the HORIZONS-AMI Investigators For the HORIZONS-AMI Investigators
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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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A Prospective, Randomized Comparison of A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Paclitaxel-eluting TAXUS Stents vs. Bare
Metal Stents During Primary Angioplasty in Metal Stents During Primary Angioplasty in Acute Myocardial InfarctionAcute Myocardial Infarction
– – One Year Results –One Year Results –
Gregg W. Stone MDGregg W. Stone MDFor the HORIZONS-AMI InvestigatorsFor the HORIZONS-AMI Investigators
A Prospective, Randomized Comparison of A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Paclitaxel-eluting TAXUS Stents vs. Bare
Metal Stents During Primary Angioplasty in Metal Stents During Primary Angioplasty in Acute Myocardial InfarctionAcute Myocardial Infarction
– – One Year Results –One Year Results –
Gregg W. Stone MDGregg W. Stone MDFor the HORIZONS-AMI InvestigatorsFor the HORIZONS-AMI Investigators
Background No consensus exists regarding the safety and efficacy of drug-No consensus exists regarding the safety and efficacy of drug-
eluting stents in pts with STEMI undergoing primary PCIeluting stents in pts with STEMI undergoing primary PCI
– TLR and restenosis rates tend to be lower in STEMI vs. TLR and restenosis rates tend to be lower in STEMI vs. elective PCI patients because of less plaque burden and non elective PCI patients because of less plaque burden and non viable myocardiumviable myocardium
– The safety of implanting DES in ruptured plaques with The safety of implanting DES in ruptured plaques with thrombus has been questionedthrombus has been questioned
Outcomes from registry studies of DES vs. BMS in STEMI have Outcomes from registry studies of DES vs. BMS in STEMI have been conflicting, and no large-scale randomized trials have been conflicting, and no large-scale randomized trials have been performedbeen performed
HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in tents in AMIAMI
3602 pts with STEMI with symptom onset ≤12 hours3602 pts with STEMI with symptom onset ≤12 hours
Emergent angiography, followed by triage to…Emergent angiography, followed by triage to…
Primary PCIPrimary PCICABGCABG –– Medical RxMedical Rx––
UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)
Bivalirudin monotherapyBivalirudin monotherapy(± provisional GP IIb/IIIa)(± provisional GP IIb/IIIa)
Aspirin, thienopyridineAspirin, thienopyridine R 1:1
3000 pts eligible for stent randomization3000 pts eligible for stent randomization R 3:1
Bare metal EXPRESS stentBare metal EXPRESS stentPaclitaxel-eluting TAXUS stentPaclitaxel-eluting TAXUS stent
Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 months
Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 months
In patients with STEMI undergoing primary PCI, In patients with STEMI undergoing primary PCI, the use of paclitaxel-eluting TAXUS stents rather the use of paclitaxel-eluting TAXUS stents rather than bare metal EXPRESS stents will be:than bare metal EXPRESS stents will be:
– Efficacious, as evidenced by reduced rates of Efficacious, as evidenced by reduced rates of ischemia-driven target lesion revascularization ischemia-driven target lesion revascularization at 1-year and angiographic binary restenosis at 1-year and angiographic binary restenosis at 13 months; and at 13 months; and
– Safe, with non-inferior rates of the composite Safe, with non-inferior rates of the composite measure of death, reinfarction, stent thrombosis measure of death, reinfarction, stent thrombosis or stroke at 1-yearor stroke at 1-year
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
Principal Clinical Exclusion CriteriaPrincipal Clinical Exclusion Criteria Contraindication to any of the study medications
Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission inhibitors, LMWH or fondaparinux for the present admission (prior UFH (prior UFH allowed)allowed)
Current use of coumadin
History of bleeding diathesis or known coagulopathy (including HIT), or History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusionswill refuse blood transfusions
History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or 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 GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mmknown platelet count <100,000 cells/mm33 or hgb <10 g/dL or hgb <10 g/dL
Planned elective surgical procedure that would necessitate interruption of Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment thienopyridines during the first 6 months post enrollment
Angiographic Inclusion Criteria The presence of least 1 acute infarct artery target vessel* in The presence of least 1 acute infarct artery target vessel* in
which:which:
– a) ALL significant lesions are eligible for stenting a) ALL significant lesions are eligible for stenting with study with study stents, andstents, and
– b) ALL such lesions have a visually estimated b) ALL such lesions have a visually estimated reference reference diameter ≥2.25 mm and ≤4.0 mmdiameter ≥2.25 mm and ≤4.0 mm
Expected ability to deliver the stent(s) to all culprit lesions Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal tortuosity or severe (absence of excessive proximal tortuosity or severe calcification)calcification)
Expected ability to fully expand the stent(s) at all culprit Expected ability to fully expand the stent(s) at all culprit lesions lesions (absence of marked calcification)(absence of marked calcification)
*Arteries containing multiple lesions may be randomized if all lesions are study stent eligible; *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 eligiblemultiple vessels may be randomized if all lesions in each vessel are study stent eligible
Bifurcation lesion definitely requiring implantation of Bifurcation lesion definitely requiring implantation of stents stents in both the main vessel + side branchin both the main vessel + side branch
Infarct related artery is an Infarct related artery is an unprotected left mainunprotected left main
>100 mm >100 mm of study stent length anticipatedof study stent length anticipated
Infarction due to Infarction due to stent thrombosisstent thrombosis, or infarct lesion at the site , or infarct lesion at the site of a previously implanted stentof a previously implanted stent
High likelihood of High likelihood of CABG within 30 days CABG within 30 days anticipatedanticipated
2) Composite Safety MACE = 2) Composite Safety MACE = All cause death, reinfarction, stent thrombosis All cause death, reinfarction, stent thrombosis
(ARC definite or probable)**, or stroke (ARC definite or probable)**, or stroke
andand
* Related to randomized stent lesions (whether study or non * Related to randomized stent lesions (whether study or non study stents were implanted); study stents were implanted);
** In randomized stent lesions ** In randomized stent lesions with ≥1 stent implanted (whether study or non study stents)with ≥1 stent implanted (whether study or non study stents)
Statistical MethodologyStatistical Methodology Second randomization stratification Second randomization stratification
i.i. Results from the first randomization Results from the first randomization
ii.ii. Presence of medically treated diabetes mellitus Presence of medically treated diabetes mellitus
iii.iii. Presence of any lesion >26 mm in length Presence of any lesion >26 mm in length (requiring overlapping stents by protocol)(requiring overlapping stents by protocol)
iv.iv. U.S. vs. non-U.S. siteU.S. vs. non-U.S. site
Primary analysis conducted in the ITT cohort Primary analysis conducted in the ITT cohort using Kaplan-Meier methodology, with the using Kaplan-Meier methodology, with the groups compared by log-rankgroups compared by log-rank
1-sided 1-sided αα=0.025 for NI; 2-sided =0.025 for NI; 2-sided αα=0.05 for Sup=0.05 for Sup
Power AnalysisPower Analysis
Assumed event ratesAssumed event rates
One YearOne Year TestTest EXPRESS EXPRESS TAXUSTAXUS PowerPower
With angiographic FU in 1,125 randomized pts (analyzable)With angiographic FU in 1,125 randomized pts (analyzable)
* Assumed 5% withdrew or lost to FU at 1 year → 3000 randomized* Assumed 5% withdrew or lost to FU at 1 year → 3000 randomized
Study OrganizationStudy Organization Sponsor:Sponsor: The Cardiovascular Research FoundationThe Cardiovascular Research Foundation
Grant Support:Grant Support: Boston Scientific Corporation Boston Scientific Corporation (unrestricted) (unrestricted) The Medicines CompanyThe Medicines Company
Principal Investigator:Principal Investigator: Gregg W. Stone MDGregg W. Stone MD
Steering Committee:Steering Committee: Gregg W. Stone (Chair), Bruce R. Brodie, David Gregg W. Stone (Chair), Bruce R. Brodie, David A. Cox, Cindy L. Grines, Barry D. RutherfordA. Cox, Cindy L. Grines, Barry D. Rutherford
European SteeringEuropean Steering H Bonnier, A Colombo, Eulogio Garcia, H Bonnier, A Colombo, Eulogio Garcia, Committee: Committee: E Grube, G Guagliumi, A Kastrati, E Grube, G Guagliumi, A Kastrati, P Serruys, H SuryapranataP Serruys, H Suryapranata
Additional CountryAdditional Country Y Almagor, A Banning, J Belardi, D Dudek, Y Almagor, A Banning, J Belardi, D Dudek, Leaders:Leaders: L Grinfeld, K Huber, D Nilsen, G Olivecrona, L Grinfeld, K Huber, D Nilsen, G Olivecrona, L RasmussenL Rasmussen
PharmacologyPharmacology Deepak Bhatt, George Dangas, Fred Feit, Deepak Bhatt, George Dangas, Fred Feit, Committee:Committee: Magnus OhmanMagnus Ohman
Study OrganizationStudy Organization Data Management:Data Management: CRF, Roxana Mehran (Director), CRF, Roxana Mehran (Director),
Lynn Vandertie, Louise Gambone Lynn Vandertie, Louise Gambone (Ops), Allison Kellock (Ops), Allison Kellock
(Programming), (Programming), Helen Parise (Stats)Helen Parise (Stats)
Clinical Events Committee:Clinical Events Committee: CRF, S. Chiu Wong (Chair)CRF, S. Chiu Wong (Chair)
Site and Data Monitoring:Site and Data Monitoring: J. Tyson and Associates (USA), J. Tyson and Associates (USA), Premier (Europe), Tango (S.A.)Premier (Europe), Tango (S.A.)
Angiographic Core Lab:Angiographic Core Lab: CRF, Alexandra Lansky (Director), CRF, Alexandra Lansky (Director), Ecaterina Cristea (Ops)Ecaterina Cristea (Ops)
ECG Core Lab:ECG Core Lab: CRF, James Reiffel (Director)CRF, James Reiffel (Director)
DSMB:DSMB: Bernhard Gersh (Chair), David Bernhard Gersh (Chair), David Faxon, Faxon, Spencer King, Stuart Pocock, David Spencer King, Stuart Pocock, David
WilliamsWilliams
The Cardiovascular Research The Cardiovascular Research Foundation (CRF) HORIZONS-AMI TeamFoundation (CRF) HORIZONS-AMI Team
* Randomized in stent arm; stent procedure successful (DS <10%, TIMI-3 flow, * 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 ≤NHLBI type A peri-stent dissection); no stent thrombosis or CABG w/i 30 daysdays
4040 1111• • • • • • Died before angio FU • • • Died before angio FU • • •
N=942(72.0%)
N=307(69.6%)
CompletedCompletedAngio FUAngio FU
366366 134134 • • Angio FU not performed • Angio FU not performed •
* ITT: Includes all stent randomized lesions, whether or not a stent * ITT: Includes all stent randomized lesions, whether or not a stent was implanted, and whether or not non study stents were placedwas implanted, and whether or not non study stents were placed
** Any lesion with restenosis ** Any lesion with restenosis per pt restenosis per pt restenosis
– Potential bias was mitigated by high protocol Potential bias was mitigated by high protocol procedure compliance and use of blinded procedure compliance and use of blinded clinical event adjudication committees and clinical event adjudication committees and core laboratoriescore laboratories
Underpowered for stent thrombosis and deathUnderpowered for stent thrombosis and death
– The virtually identical rates of MACE in the The virtually identical rates of MACE in the TAXUS and EXPRESS groups makes it TAXUS and EXPRESS groups makes it unlikely that major safety differences exist unlikely that major safety differences exist favoring either stent type at 1-year favoring either stent type at 1-year
ConclusionsConclusions In this large-scale, prospective, randomized trial of pts In this large-scale, prospective, randomized trial of pts
with STEMI undergoing primary stenting, the with STEMI undergoing primary stenting, the
implantation of paclitaxel-eluting TAXUS stents implantation of paclitaxel-eluting TAXUS stents
compared to bare metal EXPRESS stents resulted in:compared to bare metal EXPRESS stents resulted in:
– A significant 41% reduction in the 1-year primary A significant 41% reduction in the 1-year primary
efficacy endpoint of ischemia-driven TLR, and a efficacy endpoint of ischemia-driven TLR, and a
significant 56% reduction in the 13 month major significant 56% reduction in the 13 month major
secondary efficacy endpoint of binary restenosissecondary efficacy endpoint of binary restenosis
– Non inferior rates of the primary composite safety Non inferior rates of the primary composite safety
endpoint of all cause death, reinfarction, stent endpoint of all cause death, reinfarction, stent
thrombosis or stroke at 1-year thrombosis or stroke at 1-year
ConclusionsConclusions
The long-term safety and efficacy profile The long-term safety and efficacy profile
of paclitaxel-eluting TAXUS stents of paclitaxel-eluting TAXUS stents
compared to bare metal EXPRESS stents compared to bare metal EXPRESS stents
in STEMI will be determined by the in STEMI will be determined by the
ongoing 5 year follow-up of patients ongoing 5 year follow-up of patients
randomized in the HORIZONS-AMI trialrandomized in the HORIZONS-AMI trial