Clinical trial NCT01087723: European Ambulance Acute Coronary Syndrome (ACS) Angiography Trial
Official title: Multi-centre, Multi-national, Prospective, Randomised, Open-label, Comparison of Bivalirudin to Other Guideline Based Current Therapies (Excluding Bivalirudin)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Coronary Syndrome
Keywords: EUROMAX
STEMI
STE-ACS
UFH
bivalirudin
PCI
ambulance study
STE-MI participants
Lead sponsor: The Medicines Company
Sponsor class: INDUSTRY
First posted: 2010-03-16
Enrollment: 2198
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To show that the early administration of bivalirudin improves 30 day outcomes when compared to the current standard of care in participants with ST segment elevation acute coronary syndrome (STE-ACS), intended for a primary percutaneous coronary intervention (PCI) management strategy, presenting either via ambulance or to centers where PCI is not performed.

Detailed description: The purpose of the trial is to show that the early administration of bivalirudin improves 30-day outcomes when compared to the current standard of care in participants with STE-ACS, with an onset of symptoms of \>20 minutes and \<12 hours, intended for a primary PCI management strategy, presenting either via ambulance or to centers where PCI is not performed.

All participants are to receive treatment with aspirin (150-325 milligrams \[mg\] administered orally or 250-500 mg intravenously \[IV\]), followed by 75-100 milligrams/day (mg/day) for at least 1 year and a loading dose of an approved P2Y12 receptor blocker, such as clopidogrel, prasugrel, or ticagrelor, that was to be continued as per European Society of Cardiology guidelines (preferably for 1 year) in all participants.

The primary objectives of the trial are to show that, when compared with standard anti-thrombotic therapies other than bivalirudin (which includes treatment with unfractionated heparin \[UFH\] and optional glycoprotein IIb/IIIa inhibitor \[GPI\]) that at 30 days:

• Bivalirudin is superior to control at reducing a composite of death and non-coronary artery bypass graft (CABG)-related protocol major bleeding.

Eligibility criteria: Inclusion Criteria:

The decision to randomize participants was made by a qualified physician or paramedic who was present at the time.

Participants were included in the study if they presented either via ambulance or to a center where PCI was not performed and met all of the following criteria:

1. Provided written informed consent before initiation of any study related procedures. Participants randomized in the ambulance may initially have signed an abridged version.
2. Aged ≥18 years at the time of randomization.
3. Had a presumed diagnosis of STE-ACS with onset of symptoms of \>20 minutes and \<12 hours with one or more of the following:

   * ST segment elevation of ≥1 millimeters (mm) in ≥2 contiguous leads
   * Presumably new left bundle branch block
   * An infero-lateral myocardial infarction with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave
4. All participants would proceed with emergent angiography and primary PCI if indicated \<2 hours after first medical contact

Exclusion Criteria:

Participants were excluded from the study if any of the following exclusion criteria applied prior to randomization:

1. Any bleeding diathesis or severe hematological disease or history of intra-cerebral mass, aneurysm, arterio-venous malformation, hemorrhagic stroke, intra-cranial hemorrhage, or gastrointestinal or genitourinary bleeding within the last 2 weeks.
2. Participants who had undergone recent surgery (including biopsy) within the last 2 weeks.
3. Participants who were on warfarin (not applicable if International Normalized Ratio known to be \<1.5).
4. Participants who had received UFH, LMWH, or bivalirudin immediately before randomization.
5. Thrombolytic therapy within the last 48 hours.
6. Absolute contra-indications or allergy that could not be pre-medicated to iodinated contrast or to any of the study medications including aspirin or clopidogrel.
7. Contraindications to angiography, including but not limited to severe peripheral vascular disease.
8. If it was known, pregnant or nursing mothers. Women of child-bearing age were asked if they were pregnant or thought that they may be pregnant.
9. If it is known, a creatinine clearance \<30 milliliter/minute or dialysis dependent.
10. Previous enrolment in this study.
11. Treatment with other investigational drugs or devices within the 30 days preceding randomization or planned use of other investigational drugs or devices in this trial.
12. Participants may not have been enrolled if the duration of randomized investigational medicinal product anti-thrombin infusion was likely to be \<30 minutes from the time of onset to the commencement of angiography.
13. Participants may not have been enrolled within a primary PCI-capable hospital (unless at the time of randomization, the catheter laboratory was not available, and the participant required transfer to another primary PCI capable hospital).
14. Estimated body weight of \>120 kg

Primary outcomes:
measure: The Composite Incidence of Death and Non-coronary Artery Bypass Graft (CABG) Major Bleeding
timeFrame: Within 30 days
Secondary outcomes:
measure: The Composite Incidence of Death, Re-infarction (MI), or Non-CABG Major Bleeding
timeFrame: Within 30 days
measure: The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR)
timeFrame: Within 30 days
measure: The Incidence of Death at 1 Year
timeFrame: Within 1 Year
measure: The Incidence of Major Bleeding: Thrombolysis in MI (TIMI) and Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO)
timeFrame: Within 30 days
measure: The Incidence of Minor Bleeding: TIMI and GUSTO
timeFrame: Within 30 days
measure: The Incidence of Stent Thrombosis (Academic Research Consortium [ARC Definition])
timeFrame: Within 30 days
measure: The Incidence of Thrombocytopenia
timeFrame: Within 30 days
measure: The Incidence of Stroke
timeFrame: Within 30 days
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Hanusch Krankenhaus
city: Wien
country: Austria
facility: Magistratsabeilung 70, Wiener
city: Wien
country: Austria
facility: Universitats-Klinik Fur
city: Wien
country: Austria
facility: Wilhelminenspital MA 6 - BA 19
city: Ceske Budejovice
country: Czech Republic
facility: Zdravotnicka Zachranna Sluzba
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital
city: Copenhagen
country: Denmark
facility: Akutlaegebil Kobenhavn, Hc Andersens Boulevard 23
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Hellerup
country: Denmark
facility: Gentofte Hospital
city: Hillerod
country: Denmark
facility: Akutlaegebil Nordsjaelland
city: Odense
country: Denmark
facility: Laegeambulancen Odense
city: Odense
country: Denmark
facility: Odense Universitets Hospital
city: Aubervilliers
country: France
facility: Hopital Europeen Paris La Roseraie
city: Bobigny
country: France
facility: Hospital Avicenne, Pharmacie -Gestion Des Essais Cliniques
city: Bordeaux Cedex
country: France
facility: Chu De Bordeaux - Hopital Pellegrin
city: Bourg En Bresse
country: France
facility: Centre Hospitalier Bourg En Bresse
city: Bourg En Bresse
country: France
facility: Clinique Convert
city: Bourges
country: France
facility: Ch Jacques Coeur
city: Caen
country: France
facility: Centre Hospitalier Universitaire De Caen
city: Caen
country: France
facility: Hopital Prive Saint Martin
city: Cedex
country: France
facility: Service De Cardiologie
city: Chateauroux
country: France
facility: Ch Chateauroux
city: Clermont Ferrand
country: France
facility: Chu Clermont-Ferrand, Hopital
city: Clermont Ferrand
country: France
facility: Samu-Smur Chu Clermont-Ferrand
city: Clichy
country: France
facility: Hopital Beaujon
city: Corbeil Essonne
country: France
facility: Ch Sud Francilien - Site Corbeil
city: Corbeil-Essonnes Cedex
country: France
facility: Ch Sud Francilien - Site Corbeil, Pharmacie
city: Cornebarrieu
country: France
facility: Capio - Clinique Des Cedres
city: Creteil
country: France
facility: Hospital Henri Mondor, Pharmacie
city: Garches
country: France
facility: Samu 92 Hauts De Seine
city: Grenoble
country: France
facility: Clinique Les Eaux Claires Ghm
city: La Tronche
country: France
facility: Chu A Michallon Grenoble
city: La Tronche
country: France
facility: Samu Chu A Michallon Grenoble
city: Le Chesnay Cedex
country: France
facility: Hopital Andre Mignot - Centre Hospitalier De Versailles
city: Lille
country: France
facility: Chr Lille
city: Lille
country: France
facility: Samu 59/Samu Du Nord
city: Longjumeau
country: France
facility: Centre Hospitalier De Longjumeau
city: Lyon
country: France
facility: Centre Hospitalier St Joseph St Luc
city: Massy
country: France
facility: Institut Hospitalier Jacques Cartier
city: Montelimar
country: France
facility: Centre Hospitalier De Montelimar
city: Montfermeil
country: France
facility: Chi Le Raincy - Montfermeil Site De Montfermeil
city: Neuilly
country: France
facility: Clinique Ambroise Pare
city: Paris
country: France
facility: Centre Hospitalier
city: Paris
country: France
facility: Hopital Bichat Claude Bernard
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Pau
country: France
facility: Ch De Pau Hopital Francois Mitterand
city: Pau
country: France
facility: Samu Ch De Pau
city: Pessac
country: France
facility: Cardiologic Hospital - Coronary Care Unit, University of Bordeaux
city: Seine et Marne
country: France
facility: Pole Smur, Samu 77 - Medecine
city: St Martin D Heres
country: France
facility: Clinique Belledonne
city: Toulouse
country: France
facility: Chu De Toulouse - Hopital Paule De Viguier
city: Toulouse
country: France
facility: Chu Toulouse - Hopital Rangueil
city: Toulouse
country: France
facility: Clinique Pasteur
city: Toulouse
country: France
facility: Polyclinique Du Parc
city: Valence
country: France
facility: Centre Hospitalier De Valence
city: Vienne
country: France
facility: Centre Hospitalier De Vienne Centre Hospitalier Lucien Hussel
city: Bad Nauheim
country: Germany
facility: Kerckhoff Heart Center
city: Bad Nauheim
country: Germany
facility: Rettungsdienst Wetteraukreis
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin Campus Virchow-Klinikum
city: Berlin
country: Germany
facility: Lutzowstrabe
city: Berlin
country: Germany
facility: Sana Klinikum Lichtenberg Oskar Ziethen Krankenhaus, Fanningerstrasse 32
city: Berlin
country: Germany
facility: Universitatsklinikum Benjamin Franklin, Hindenburgdamm 30
city: Bremen
country: Germany
facility: Klinikum Links Der Weser
city: Duisburg
country: Germany
facility: Evangelisches Bethesda Johanniter
city: Duisburg
country: Germany
facility: Feuerwehr Duisburg
city: Duisburg
country: Germany
facility: Herzzentrum Duisburg, Klinik Fur Kardiologie And Angiologie
city: Duisburg
country: Germany
facility: Klinikum Duisburg Ggmbh
city: Frankfurt
country: Germany
facility: Klinikum Der Johann Wolfgang Goethe Universitat
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Carl Neuberg Str. 1
city: Ludwigshafen
country: Germany
facility: Klinikum Ludwigshafen
city: Luneburg
country: Germany
facility: Stadtisches Klinikum Luneburg, Bogelstr. 1
city: Wuppertal
country: Germany
facility: Helios Klinik Der Universitat Witten Herdecke
city: Bologna
country: Italy
facility: Ospedale Maggiore
city: Bologna
country: Italy
facility: Ospedle Di Bentivoglio
city: Bologna
country: Italy
facility: Policlinico S.Orsola Malpighi
city: Perugia
country: Italy
facility: Ospedale Di Assisi
city: Perugia
country: Italy
facility: Ospedale Di Castiglione Del Lago
city: Perugia
country: Italy
facility: Ospedale Di Todi
city: Perugia
country: Italy
facility: Ospedale S.Maria Misericordia
city: Pesaro
country: Italy
facility: Asur Marche- Zona 1 Pesaro
city: Pesaro
country: Italy
facility: Azienda Ospedaliera San Salvatore
city: Pesaro
country: Italy
facility: Emergency Rescue & Mobile Als Unit, Lanciarini Pub
city: Amersfoort
country: Netherlands
facility: Betreft Research Regional
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amersfoort
country: Netherlands
facility: Rav Noord En Oost Gelderland
city: Nieuwegein
country: Netherlands
facility: Pharmacy Department
city: Nieuwegein
country: Netherlands
facility: Regional Ambulance Service Gelderland Midden
city: Nieuwegein
country: Netherlands
facility: St Antonius Ziekenhuis
city: Nijmegan
country: Netherlands
facility: Service Gelderland-Zuid Klinisch Geneesmiddelonderzoek Klinsche Farmacie Afd Klinsche Farmacie
city: Nijmegen
country: Netherlands
facility: Cwz Klinisch Geneesmiddelonderzoek Klinische
city: Nijmegen
country: Netherlands
facility: Kgo Team Regional Ambulance
city: Nijmegen
country: Netherlands
facility: Regional Ambulance Service Gelderland Zuid
city: Nijmegen
country: Netherlands
facility: Regional Ambulance Service Gelderland-Zuid Distributiecentrum
city: Nijmegen
country: Netherlands
facility: Regional Ambulance Service
city: Nijmegen
country: Netherlands
facility: Umc St.Radboud Nijmegen
city: Utrecht
country: Netherlands
facility: Department Of Cardiology
city: Utrecht
country: Netherlands
facility: Umc Utrecht
city: Zwolle
country: Netherlands
facility: Isala Klinieken
city: Zwolle
country: Netherlands
facility: Tav Trial Team, Isala Klinieken Ioc Weezenlanden Afd
city: Bedzin
country: Poland
facility: Poradnia Kardiologiczna
city: Chrzanow
country: Poland
facility: Malopolskie Centrum Sercowo
city: Chrzanow
country: Poland
facility: Szpital Powiatowy W Chrzanowie
city: Dabrowa Gornicza
country: Poland
facility: Oddzial Polskiej-Amerikanskiej Kliniki Serca
city: Debica
country: Poland
facility: Szpital Powiatowy W Debicy
city: Gorlice
country: Poland
facility: Specialist Hospital Gorlice
city: Kolbuszowa
country: Poland
facility: Szpital Powiatowy Im. Jana Pawla Ii W Kolbuszowej
city: Krakow
country: Poland
facility: Jagiellonian University Medical College,
city: Krakow
country: Poland
facility: Krakowskie Centrum
city: Krakow
country: Poland
facility: Oddzial Kardiologii
city: Krakow
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki
city: Krakow
country: Poland
facility: Szpital Specjalistyczny Im Szpitalny Oddzial Ratunkowy
city: Krynica Zdroj
country: Poland
facility: Spzoz Szpital Im. J.Dietla W Krynicy Zdroj
city: Lask
country: Poland
facility: Spzoz Lask
city: Limanowa
country: Poland
facility: Szpital Powiatowy W Limanowej
city: Lodz
country: Poland
facility: Szpital Bieganskiego
city: Lublin
country: Poland
facility: Medical University Of Lublin
city: Mielec
country: Poland
facility: Polsko-Amerykanskie Kliniki Serca, Szpital Powiatowy
city: Mielec
country: Poland
facility: Samodzielny Pobliszny Zaklad W Mielcu
city: Myslowice
country: Poland
facility: Myslowickie Centrum Zdrowia
city: Niepolomice
country: Poland
facility: Samodzielna Publiczna Stacja Pogotowia Ratunkowego, Samodzielna Publiczna Stacja Pogotowia Ratunkowego W Niepolomicach
city: Nowy Sacz
country: Poland
facility: Intercard Nowy Sacz
city: Olkusz
country: Poland
facility: Nzoz Nowy Szpital W Olkuszu
city: Opatow
country: Poland
facility: Szpital Powiatowy
city: Ostrowiec Swietokrzyski
country: Poland
facility: Carint
city: Parczew
country: Poland
facility: Spzoz Parczew
city: Piotrkow Trybunalski
country: Poland
facility: Samodzielny Szpital Wojewodski
city: Radzyn Podlaski
country: Poland
facility: Spzoz W Radzyniu Podlaskim
city: Sedziszow Malopolski
country: Poland
facility: Szpital Powiatowy W Sedziszowie Malopolskim
city: Staszow
country: Poland
facility: Oddzial Chorob Wewnetrznych
city: Swidnik
country: Poland
facility: Oddzial Kardiologii Al.Lotnikow Polskich 18
city: Todz
country: Poland
facility: Szpital Zakonu Bonifratrow Sw.
city: Celje
country: Slovenia
facility: Zdravstveni Dom Celje
city: Izola
country: Slovenia
facility: Splosna Bolnisnica Izola, Polje 40
city: Jesenice
country: Slovenia
facility: Oe Zdravstveni Dom Jesenice
city: Jesenice
country: Slovenia
facility: Splosna Bolnisnica Jesenic
city: Lenart
country: Slovenia
facility: Zdravstveni Dom Lenart, Maistrova 22
city: Ljubljana
country: Slovenia
facility: Univerzitetni Klinicni Center Ljubljana
city: Ljubljana
country: Slovenia
facility: Zdravstveni Dom Ljubljana
city: Maribor
country: Slovenia
facility: Univerzitetni Klinicni Center Maribor
city: Maribor
country: Slovenia
facility: Zdravstveni Dom Dr. Adolfa Drolca Maribor
city: Novo Mesto
country: Slovenia
facility: Splosna Bolnisnica Novo Mesto/ Community Hospital Novo Mesto, Smihelska Cesta 1
city: Ormoz
country: Slovenia
facility: Zdravstveni Dom Ormoz
city: Ptuj
country: Slovenia
facility: Splosna Bolnisnica Ptuj, Interni Odelek, Potrceva Cesta 23
city: Slovenska Bistrica
country: Slovenia
facility: Zdravstveni Dom Slovenska Bistrica
city: Slovenske Konjice
country: Slovenia
facility: Zdravstveni Dom Slovenske Konjice
Study officials:
affiliation: Executive Committee
name: Gabriel Steg, Prof
role: STUDY_CHAIR
affiliation: International Steering Committee
name: Christian Hamm, BSc, MD, PhD
role: STUDY_CHAIR
References:
citation: Huber K, Ducrocq G, Hamm CW, van 't Hof A, Lapostolle F, Coste P, Gordini G, Steinmetz J, Verheugt FWA, Adgey J, Nibbe L, Kanic V, Clemmensen P, Zeymer U, Bernstein D, Prats J, Deliargyris EN, Gabriel Steg P. Early clinical outcomes as a function of use of newer oral P2Y12 inhibitors versus clopidogrel in the EUROMAX trial. Open Heart. 2017 Nov 28;4(2):e000677. doi: 10.1136/openhrt-2017-000677. eCollection 2017.
citation: Fabris E, Kilic S, Van't Hof AWJ, Ten Berg J, Ayesta A, Zeymer U, Hamon M, Soulat L, Bernstein D, Anthopoulos P, Deliargyris EN, Steg PG. One-Year Mortality for Bivalirudin vs Heparins Plus Optional Glycoprotein IIb/IIIa Inhibitor Treatment Started in the Ambulance for ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of the EUROMAX Randomized Clinical Trial. JAMA Cardiol. 2017 Jul 1;2(7):791-796. doi: 10.1001/jamacardio.2016.5975.
citation: Ducrocq G, Steg PG, Van't Hof A, Zeymer U, Mehran R, Hamm CW, Bernstein D, Prats J, Deliargyris EN, Stone GW. Utility of post-procedural anticoagulation after primary PCI for STEMI: insights from a pooled analysis of the HORIZONS-AMI and EUROMAX trials. Eur Heart J Acute Cardiovasc Care. 2017 Oct;6(7):659-665. doi: 10.1177/2048872616650869. Epub 2016 Jun 10.
citation: Dangas GD, Schoos MM, Steg PG, Mehran R, Clemmensen P, van 't Hof A, Prats J, Bernstein D, Deliargyris EN, Stone GW. Early Stent Thrombosis and Mortality After Primary Percutaneous Coronary Intervention in ST-Segment-Elevation Myocardial Infarction: A Patient-Level Analysis of 2 Randomized Trials. Circ Cardiovasc Interv. 2016 May;9(5):e003272. doi: 10.1161/CIRCINTERVENTIONS.115.003272.
citation: Kilic S, Van't Hof AW, Ten Berg J, Lopez AA, Zeymer U, Hamon M, Soulat L, Bernstein D, Deliargyris EN, Steg PG. Frequency and prognostic significance of access site and non-access site bleeding and impact of choice of antithrombin therapy in patients undergoing primary percutaneous coronary intervention. The EUROMAX trial. Int J Cardiol. 2016 May 15;211:119-23. doi: 10.1016/j.ijcard.2016.02.131. Epub 2016 Mar 3.
citation: Hamon M, Coste P, Van't Hof A, Ten Berg J, Clemmensen P, Tabone X, Benamer H, Kristensen SD, Cavallini C, Marzocchi A, Hamm C, Kanic V, Bernstein D, Anthopoulos P, Deliargyris EN, Steg PG. Impact of arterial access site on outcomes after primary percutaneous coronary intervention: prespecified subgroup analysis from the EUROMAX trial. Circ Cardiovasc Interv. 2015 Jun;8(6):e002049. doi: 10.1161/CIRCINTERVENTIONS.114.002049.
citation: Stone GW, Mehran R, Goldstein P, Witzenbichler B, Van't Hof A, Guagliumi G, Hamm CW, Genereux P, Clemmensen P, Pocock SJ, Gersh BJ, Bernstein D, Deliargyris EN, Steg PG. Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary percutaneous coronary intervention: pooled patient-level analysis from the HORIZONS-AMI and EUROMAX trials. J Am Coll Cardiol. 2015 Jan 6;65(1):27-38. doi: 10.1016/j.jacc.2014.10.029.
citation: Steg PG, van 't Hof A, Clemmensen P, Lapostolle F, Dudek D, Hamon M, Cavallini C, Gordini G, Huber K, Coste P, Thicoipe M, Nibbe L, Steinmetz J, Ten Berg J, Eggink GJ, Zeymer U, Campo dell' Orto M, Kanic V, Deliargyris EN, Day J, Schuette D, Hamm CW, Goldstein P. Design and methods of European Ambulance Acute Coronary Syndrome Angiography Trial (EUROMAX): an international randomized open-label ambulance trial of bivalirudin versus standard-of-care anticoagulation in patients with acute ST-segment-elevation myocardial infarction transferred for primary percutaneous coronary intervention. Am Heart J. 2013 Dec;166(6):960-967.e6. doi: 10.1016/j.ahj.2013.08.025. Epub 2013 Nov 7.
citation: Steg PG, van 't Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, Ten Berg J, Van Grunsven P, Eggink GJ, Nibbe L, Zeymer U, Campo dell' Orto M, Nef H, Steinmetz J, Soulat L, Huber K, Deliargyris EN, Bernstein D, Schuette D, Prats J, Clayton T, Pocock S, Hamon M, Goldstein P; EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013 Dec 5;369(23):2207-17. doi: 10.1056/NEJMoa1311096. Epub 2013 Oct 30.