European Ambulance Acute Coronary Syndrome (ACS) Angiography Trial

NCT ID: NCT01087723

Last Updated: 2016-02-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 2198 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-31
• Study Completion Date: 2014-08-31

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.

Conditions

Acute Coronary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bivalirudin

Given immediately upon enrollment as an intravenous (IV) bolus of 0.75 mg/kilogram (mg/kg), followed immediately by an infusion of 1.75 mg/kg/hour (mg/kg/h). This infusion was to be run continuously until completion of PCI, at which time the infusion was reduced to 0.25 mg/kg/h for at least 4 hours. An optional PCI-dose infusion of 1.75 mg/kg/h was also permitted for up to 4 hours at the discretion of the operator.

Group Type: EXPERIMENTAL

Bivalirudin

Intervention Type: DRUG

Standard of Care: Heparins with Optional GPI

Standard-of-care anti-thrombotic therapy as outlined in the European Society of Cardiology Dosing Guidelines for Management of STE-ACS, not including bivalirudin: UFH (100 international units/kg [IU/kg] without GPI and 60 IU/kg with GPI). Any of the following approved GPIs were used either as a routine strategy or as a bail out: eptifibatide (two 180-micrograms/kilogram [μg/kg] IV boluses with a 10-minute [min] interval followed by an infusion of 2.0 μg/kg/min for 72-96 hours); tirofiban (25 μg/kg followed by an infusion of 0.15 μg/kg/min for 18-24 hours); or abciximab (bolus of 0.25 mg/kg followed by an infusion of 0.125 μg/kg/min for 12-24 hours [maximum dose of 10 μg/min]).

For this study, the control consisted of treatment with UFH or low molecular weight heparin (LMWH) with or without GPI and is referred to as "heparins with optional GPI."

Group Type: ACTIVE_COMPARATOR

Heparin

Intervention Type: DRUG

Interventions

Bivalirudin

Intervention Type: DRUG

Heparin

Intervention Type: DRUG

Other Intervention Names

Angiox; Angiomax; UFH; LMWH

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Medicines Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gabriel Steg, Prof

Role: STUDY_CHAIR

Executive Committee

Christian Hamm, BSc, MD, PhD

Role: STUDY_CHAIR

International Steering Committee

Locations

Hanusch Krankenhaus

Vienna, , Austria

Magistratsabeilung 70, Wiener

Vienna, , Austria

Universitats-Klinik Fur

Vienna, , Austria

Wilhelminenspital MA 6 - BA 19

Vienna, , Austria

Zdravotnicka Zachranna Sluzba

České Budějovice, , Czechia

Aarhus Universitetshospital

Aarhus, , Denmark

Akutlaegebil Kobenhavn, Hc Andersens Boulevard 23

Copenhagen, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Gentofte Hospital

Hellerup, , Denmark

Akutlaegebil Nordsjaelland

Hillerød, , Denmark

Laegeambulancen Odense

Odense, , Denmark

Odense Universitets Hospital

Odense, , Denmark

Hopital Europeen Paris La Roseraie

Aubervilliers, , France

Hospital Avicenne, Pharmacie -Gestion Des Essais Cliniques

Bobigny, , France

Chu De Bordeaux - Hopital Pellegrin

Bordeaux, , France

Centre Hospitalier Bourg En Bresse

Bourg-en-Bresse, , France

Clinique Convert

Bourg-en-Bresse, , France

Ch Jacques Coeur

Bourges, , France

Centre Hospitalier Universitaire De Caen

Caen, , France

Hopital Prive Saint Martin

Caen, , France

Service De Cardiologie

Cedex, , France

Ch Chateauroux

Châteauroux, , France

Chu Clermont-Ferrand, Hopital

Clermont-Ferrand, , France

Samu-Smur Chu Clermont-Ferrand

Clermont-Ferrand, , France

Hopital Beaujon

Clichy, , France

Ch Sud Francilien - Site Corbeil

Corbeil Essonne, , France

Ch Sud Francilien - Site Corbeil, Pharmacie

Corbeil-Essonnes, , France

Capio - Clinique Des Cedres

Cornebarrieu, , France

Hospital Henri Mondor, Pharmacie

Créteil, , France

Samu 92 Hauts De Seine

Garches, , France

Clinique Les Eaux Claires Ghm

Grenoble, , France

Chu A Michallon Grenoble

La Tronche, , France

Samu Chu A Michallon Grenoble

La Tronche, , France

Hopital Andre Mignot - Centre Hospitalier De Versailles

Le Chesnay, , France

Chr Lille

Lille, , France

Samu 59/Samu Du Nord

Lille, , France

Centre Hospitalier De Longjumeau

Longjumeau, , France

Centre Hospitalier St Joseph St Luc

Lyon, , France

Institut Hospitalier Jacques Cartier

Massy, , France

Centre Hospitalier De Montelimar

Montélimar, , France

Chi Le Raincy - Montfermeil Site De Montfermeil

Montfermeil, , France

Clinique Ambroise Pare

Neuilly, , France

Centre Hospitalier

Paris, , France

Hopital Bichat Claude Bernard

Paris, , France

Hopital Europeen Georges Pompidou

Paris, , France

Ch De Pau Hopital Francois Mitterand

Pau, , France

Samu Ch De Pau

Pau, , France

Cardiologic Hospital - Coronary Care Unit, University of Bordeaux

Pessac, , France

Clinique Belledonne

Saint-Martin-d'Hères, , France

Pole Smur, Samu 77 - Medecine

Seine Et Marne, , France

Chu De Toulouse - Hopital Paule De Viguier

Toulouse, , France

Chu Toulouse - Hopital Rangueil

Toulouse, , France

Clinique Pasteur

Toulouse, , France

Polyclinique Du Parc

Toulouse, , France

Centre Hospitalier De Valence

Valence, , France

Centre Hospitalier De Vienne Centre Hospitalier Lucien Hussel

Vienne, , France

Kerckhoff Heart Center

Bad Nauheim, , Germany

Rettungsdienst Wetteraukreis

Bad Nauheim, , Germany

Charite Universitatsmedizin Berlin Campus Virchow-Klinikum

Berlin, , Germany

Lutzowstrabe

Berlin, , Germany

Sana Klinikum Lichtenberg Oskar Ziethen Krankenhaus, Fanningerstrasse 32

Berlin, , Germany

Universitatsklinikum Benjamin Franklin, Hindenburgdamm 30

Berlin, , Germany

Klinikum Links Der Weser

Bremen, , Germany

Evangelisches Bethesda Johanniter

Duisburg, , Germany

Feuerwehr Duisburg

Duisburg, , Germany

Herzzentrum Duisburg, Klinik Fur Kardiologie And Angiologie

Duisburg, , Germany

Klinikum Duisburg Ggmbh

Duisburg, , Germany

Klinikum Der Johann Wolfgang Goethe Universitat

Frankfurt, , Germany

Medizinische Hochschule Hannover, Carl Neuberg Str. 1

Hanover, , Germany

Klinikum Ludwigshafen

Ludwigshafen, , Germany

Stadtisches Klinikum Luneburg, Bogelstr. 1

Lüneburg, , Germany

Helios Klinik Der Universitat Witten Herdecke

Wuppertal, , Germany

Ospedale Maggiore

Bologna, , Italy

Ospedle Di Bentivoglio

Bologna, , Italy

Policlinico S.Orsola Malpighi

Bologna, , Italy

Ospedale Di Assisi

Perugia, , Italy

Ospedale Di Castiglione Del Lago

Perugia, , Italy

Ospedale Di Todi

Perugia, , Italy

Ospedale S.Maria Misericordia

Perugia, , Italy

Asur Marche- Zona 1 Pesaro

Pesaro, , Italy

Azienda Ospedaliera San Salvatore

Pesaro, , Italy

Emergency Rescue & Mobile Als Unit, Lanciarini Pub

Pesaro, , Italy

Betreft Research Regional

Amersfoort, , Netherlands

Meander Medisch Centrum

Amersfoort, , Netherlands

Rav Noord En Oost Gelderland

Amersfoort, , Netherlands

Pharmacy Department

Nieuwegein, , Netherlands

Regional Ambulance Service Gelderland Midden

Nieuwegein, , Netherlands

St Antonius Ziekenhuis

Nieuwegein, , Netherlands

Service Gelderland-Zuid Klinisch Geneesmiddelonderzoek Klinsche Farmacie Afd Klinsche Farmacie

Nijmegan, , Netherlands

Cwz Klinisch Geneesmiddelonderzoek Klinische

Nijmegen, , Netherlands

Kgo Team Regional Ambulance

Nijmegen, , Netherlands

Regional Ambulance Service Gelderland Zuid

Nijmegen, , Netherlands

Regional Ambulance Service Gelderland-Zuid Distributiecentrum

Nijmegen, , Netherlands

Regional Ambulance Service

Nijmegen, , Netherlands

Umc St.Radboud Nijmegen

Nijmegen, , Netherlands

Department Of Cardiology

Utrecht, , Netherlands

Umc Utrecht

Utrecht, , Netherlands

Isala Klinieken

Zwolle, , Netherlands

Tav Trial Team, Isala Klinieken Ioc Weezenlanden Afd

Zwolle, , Netherlands

Poradnia Kardiologiczna

Będzin, , Poland

Malopolskie Centrum Sercowo

Chrzanów, , Poland

Szpital Powiatowy W Chrzanowie

Chrzanów, , Poland

Oddzial Polskiej-Amerikanskiej Kliniki Serca

Dąbrowa Górnicza, , Poland

Szpital Powiatowy W Debicy

Dębica, , Poland

Specialist Hospital Gorlice

Gorlice, , Poland

Szpital Powiatowy Im. Jana Pawla Ii W Kolbuszowej

Kolbuszowa, , Poland

Jagiellonian University Medical College,

Krakow, , Poland

Krakowskie Centrum

Krakow, , Poland

Oddzial Kardiologii

Krakow, , Poland

Samodzielny Publiczny Zaklad Opieki

Krakow, , Poland

Szpital Specjalistyczny Im Szpitalny Oddzial Ratunkowy

Krakow, , Poland

Spzoz Szpital Im. J.Dietla W Krynicy Zdroj

Krynica-Zdrój, , Poland

Szpital Powiatowy W Limanowej

Limanowa, , Poland

Szpital Bieganskiego

Lodz, , Poland

Medical University Of Lublin

Lublin, , Poland

Polsko-Amerykanskie Kliniki Serca, Szpital Powiatowy

Mielec, , Poland

Samodzielny Pobliszny Zaklad W Mielcu

Mielec, , Poland

Myslowickie Centrum Zdrowia

Mysłowice, , Poland

Samodzielna Publiczna Stacja Pogotowia Ratunkowego, Samodzielna Publiczna Stacja Pogotowia Ratunkowego W Niepolomicach

Niepołomice, , Poland

Intercard Nowy Sacz

Nowy Sącz, , Poland

Nzoz Nowy Szpital W Olkuszu

Olkusz, , Poland

Szpital Powiatowy

Opatów, , Poland

Carint

Ostrowiec Świętokrzyski, , Poland

Spzoz Parczew

Parczew, , Poland

Samodzielny Szpital Wojewodski

Piotrkow Trybunalski, , Poland

Spzoz W Radzyniu Podlaskim

Radzyń Podlaski, , Poland

Szpital Powiatowy W Sedziszowie Malopolskim

Sędziszów Małopolski, , Poland

Oddzial Chorob Wewnetrznych

Staszów, , Poland

Oddzial Kardiologii Al.Lotnikow Polskich 18

Świdnik, , Poland

Szpital Zakonu Bonifratrow Sw.

Todz, , Poland

Spzoz Lask

Łask, , Poland

Zdravstveni Dom Celje

Celje, , Slovenia

Splosna Bolnisnica Izola, Polje 40

Izola, , Slovenia

Oe Zdravstveni Dom Jesenice

Jesenice, , Slovenia

Splosna Bolnisnica Jesenic

Jesenice, , Slovenia

Zdravstveni Dom Lenart, Maistrova 22

Lenart v Slov. Goricah, , Slovenia

Univerzitetni Klinicni Center Ljubljana

Ljubljana, , Slovenia

Zdravstveni Dom Ljubljana

Ljubljana, , Slovenia

Univerzitetni Klinicni Center Maribor

Maribor, , Slovenia

Zdravstveni Dom Dr. Adolfa Drolca Maribor

Maribor, , Slovenia

Splosna Bolnisnica Novo Mesto/ Community Hospital Novo Mesto, Smihelska Cesta 1

Novo Mesto, , Slovenia

Zdravstveni Dom Ormoz

Ormož, , Slovenia

Splosna Bolnisnica Ptuj, Interni Odelek, Potrceva Cesta 23

Ptuj, , Slovenia

Zdravstveni Dom Slovenska Bistrica

Slovenska Bistrica, , Slovenia

Zdravstveni Dom Slovenske Konjice

Slovenske Konjice, , Slovenia

Countries

Austria; Czechia; Denmark; France; Germany; Italy; Netherlands; Poland; Slovenia

References

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.

Reference Type: DERIVED

PMID: 29225903 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28273285 (View on PubMed)

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.

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PMID: 27287251 (View on PubMed)

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.

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PMID: 27165710 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26995053 (View on PubMed)

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Reference Type: DERIVED

PMID: 26056249 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25572507 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24268209 (View on PubMed)

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.

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PMID: 24171490 (View on PubMed)

Other Identifiers

TMC-BIV-08-03

Identifier Type: -

Identifier Source: org_study_id