Bivaliru din or Unfractionated Heparin in Patients with Acute · Veronica Lodolini; Monia Monti,...

$: Bivaliru din or Unfractionated Heparin in Patients with Acute · Veronica Lodolini; Monia Monti, BSc; Maria Grazia Mazzone, Italy; Erika Delos, MD; Maria Teresa ... Giampaolo Pasquetto$
Confidential: For Review Only

Bivalirudin or Unfractionated Heparin in Patients with Acute

Coronary Syndromes Managed Invasively With and Without ST Elevation (MATRIX): a Randomised Controlled Trial

Journal: BMJ

Manuscript ID BMJ.2016.032733.R1

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 04-Jun-2016

Complete List of Authors: Leonardi, Sergio; Fondazione IRCCS Policlinico San Matteo, Cardiologia Frigoli, Enrico; EUSTRATEGY Association Rothenbühler, Martina; University of Bern, Clinical Trials Unit, Department of Clinical Research , and Institute of Social and Preventive Medicine (ISPM) Navarese, Eliano; Heinrich-Heine-University, Department of Internal Medicine, Division of Cardiology, Pneumology and Vascular Medicine Calabr=, Paolo; Second University of Naples, Division of Cardiology, Department of Cardiothoracic Sciences Bellotti, Sandro; Ospedale Villa Scassi, Department of Cardiology, ASL3 Briguori, Carlo; Clinica Mediterranea Ferlini, Marco; Fondazione IRCCS Policlinico San Matteo Cortese, Bernardo; Ospedale Fatebene Fratelli Lupi, Alessandro; Osped Maggiore della Carita, Ierna, Salvatore; Ospedale Sirai – Carbonia Zavalloni Parenti, Dennis; Humanitas Research Hospital, IRCCS Esposito, Giovanni; Federico II University, Tresoldi, Simone; A.O. Ospedale di Desio Zingarelli, Antonio; IRCCS San Martino - IST Rigattieri, Stefano; Sandro Pertini Hospital, Interventional Cardiology Palmieri, Cataldo; Ospedale Pasquinucci Liso, Armando; Citta Di Lecce Hospital Abate, Fabio; Ospedale Giovanni Paolo II Zimarino, Marco; Università degli Studi “G. d’Annunzio” Chieti e Pescara Comeglio, Marco; Ospedale San Jacopo Gabrielli, Gabriele; Azienda Ospedali Riuniti - Presidio "GM Lancisi" Chieffo, Alaide; Ospedale San Raffaele IRCCS Brugaletta, Salvatore; University Hospital Clinic, IDIBAPS, Cardiology Department, 08036 Barcelona, Mauro, Ciro; Azienda Ospedaliera Antonio Cardarelli Van Mieghem, Nicolas; Erasmus Medical Center, Thoraxcenter Heg, Dik; University of Bern, Clinical Trials Unit, Department of Clinical Research, and Institute of Social and Preventive Medicine (ISPM) Juni, Peter; University of Toronto, Knowledge Institute of St. Michael’s Hospital, and Department of Medicine

https://mc.manuscriptcentral.com/bmj

BMJ


Windecker, Stephan; Swiss Cardiovascular Center Valgimigli, Marco; Swiss Cardiovascular Center

Keywords: Acute Coronary Syndrome, Antithrombotic therapy, Bleeding Complications

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Bivalirudin or Unfractionated Heparin in Patients with Acute Coronary Syndromes Managed Invasively With and Without ST Elevation (MATRIX): a Randomised Controlled Trial

Leonardi et al.

MATRIX programme organisation: list of investigators ........................................................................... 2

Funding ................................................................................................................................................... 4

MATRIX programme inclusion and exclusion criteria ............................................................................. 5

Clinical event committee procedures ...................................................................................................... 6

MATRIX clinical outcome definitions ....................................................................................................... 6

Table S1. Medications administered before the catheterization laboratory in patients with STEACS and NSTEACS ...................................................................................................................................... 11

Table S2. Medications at discharge in patients with STEACS and NSTEACS .................................... 12

Table S3. Procedural characteristics in patients with STEACS and NSTEACS ................................... 13

Table S4. Effect on bleeding assessed with the TIMI scale, the GUSTO scale and the BARC scale in patients with STEACS and NSTEACS .................................................................................................. 16

Figure S1. Patient Flow Chart in patients with STEACS ...................................................................... 18

Figure S2. Patient Flow Chart in patients with NSTEACS .................................................................... 19

Figure S3. Stratified analysis of all cause mortality in patients with STEACS ...................................... 20

Figure S4. Stratified analysis of all cause mortality in patients with NSTEACS ................................... 21

Figure S5. Stratified analysis of major bleeding (BARC 3 or 5) in patients with STEACS ................... 22

Figure S6. Stratified analysis of major bleeding (BARC 3 or 5) in patients with NSTEACS ................. 23

References ............................................................................................................................................ 24

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MATRIX programme organisation: list of investigators Study Sponsors: Gruppo Italiano Studi Emodinamica (GISE) and EUSTRATEGY (co-sponsor). Study Director: Maria Salomone, MD, PhD, (Clinical Research Director), TFS, Italy. Data Monitoring: TFS, Italy and the Netherlands; FLS-Research Support, Spain; Gothia Forum,

Sweden. Data Management: EUSTRATEGY, Enrico Frigoli, MD (Project Leader), Italy; Pierpaolo Occhilupo; Veronica Lodolini; Monia Monti, BSc; Maria Grazia Mazzone, Italy; Erika Delos, MD; Maria Teresa Caruso; Maggie Testa; Nestor Ciociano; Maurizio Lazzero; Davide Gazzotti; Lorenzo Cagliari; Leila Shahmohammadi; Martina Caiazza; Vittorio Virga; Elena Guerra, MD; Eva Michalska; Sara Castellini; Vincenzo Serino; Gabriella Visconti, MD; Gianluca Pendenza, MD; Monica Portolan; Marco Anzini, MD; Elisa Silvetti; Tiziana Coco; Francesco Costa, MD; Sara Ariotti, MD; Linda Valli; Marianna Adamo, MD; Marcello Marino, MD. Clinical Event Committee: Pascal Vranckx, MD, PhD (Chair), Belgium; Sergio Leonardi, MD, MHS (Co-Chair), Italy; Pierluigi Tricoci, MD, PhD, USA. Statistical Committee: Peter Jüni, MD (Chair), Martina Rothenbühler, Dik Heg, Switzerland Participating countries: Italy, Netherlands, Spain, and Sweden. Executive Committee: Marco Valgimigli, MD, PhD, (Principal Investigator [PI] and Chair), Erasmus Medical Center, Rotterdam, Netherlands; Andrea Gagnor, MD, Ospedale degli Infermi, Rivoli (TO), Italy; Paolo Calabrò, MD, PhD, Ospedale dei Colli, Napoli, Italy; Paolo Rubartelli, MD, Ospedale Villa Scassi, Genova, Italy; Stefano Garducci, MD, A.O. Ospedale Civile di Vimercate (MB), Italy; Giuseppe Andò, MD, A.O. Universitaria G. Martino, Messina, Italy; Andrea Santarelli, MD, Ospedali degli Infermi, Rimini, Italy; Mario Galli, MD, Azienda Ospedaliera Sant'Anna, Como, Italy; Roberto Garbo, San Giovanni Bosco Hospital, Torino, Italy; Ezio Bramucci, MD, Policlinico San Matteo, Pavia, Italy; Salvatore Ierna, MD, Ospedale Sirai - Carbonia (CI), Italy; Carlo Briguori, MD, Clinica Mediterranea, Napoli, Italy; Bernardo Cortese, MD, Ospedale Fate bene Fratelli, Milano, Italy; Ugo Limbruno, MD, Ospedale della Misericordia, Grosseto, Italy; Roberto Violini, MD, A.O. San Camillo-Forlanini, Roma, Italy; Patrizia Presbitero, MD, IRCCS Humanitas, Rozzano (MI), Italy; Nicoletta de Cesare, MD, Policlinico San Marco, Zingonia (BG), Italy; Paolo Sganzerla, MD, A.O. Treviglio (BG),Italy; Arturo Ausiello, MD, Casa di Cura Villa Verde, Taranto, Italy; Paolo Tosi, MD, Ospedale Mater Salutis di Legnago (VR), Italy; Gennaro Sardella, MD, PhD, Policlinico Umberto I, Roma, Italy; Manel Sabate’, MD, PhD and Salvatore Brugaletta, MD, PhD, University Hospital Clinic, Barcelona, Spain. Steering Committee: Giovanni Saccone, MD, A.O. Giovanni Paolo II, Sciacca (AG), Italy; Pietro Vandoni, MD, A.O. Ospedale di Desio (MB), Italy; Antonio Zingarelli, MD, A.O. Universitaria San Martino, Genova, Italy; Armando Liso, MD, Città di Lecce Hospital (GVM), Lecce, Italy; Stefano Rigattieri, MD, A.O. Sandro Pertini, Roma, Italy; Emilio Di Lorenzo, MD, A.O. G. Moscati, Avellino, Italy; Carlo Vigna, MD, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; Cataldo Palmieri, MD, Ospedale Pasquinucci, Massa, Italy; Camillo Falcone, MD, Ospedale Sacra Famiglia, Erba (CO), Italy; Raffaele De Caterina, MD, PhD, Marcello Caputo, MD, Ospedale Clinicizzato SS. Annunziata Chieti, Italy; Giovanni Esposito, MD, PhD, Policlinico Federico II, Napoli, Italy; Alessandro Lupi, MD, A.O.U Maggiore della Carità, Novara, Italy; Pietro Mazzarotto, MD, Ospedale di Lodi, Italy; Fernando Varbella, MD, Ospedale degli Infermi, Rivoli (TO), Italy; Tiziana Zaro, MD, A.O. Ospedale Civile di Vimercate (MB), Italy; Marco Nazzaro, MD, A.O. San Camillo-Forlanini, Roma, Italy; Sunil V. Rao, MD, Duke Clinical Research Institute, Durham, NC, USA, Arnoud WJ van‘t Hof, MD, Isala Klinieken, Zwolle, Netherlands; Elmir Omerovic, MD, PhD, Sahlgrenska University Hospital, Sweden. National Coordinating Investigators Paolo Calabrò, MD, PhD, Ospedale dei Colli, Napoli, Italy Arnoud W J van‘t Hof, MD, Isala Klinieken, Zwolle, Netherlands

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Manel Sabate’, MD, PhD and Salvatore Brugaletta, MD, PhD, University Hospital Clinic, Barcelona, Spain Elmir Omerovic, MD, PhD, Sahlgrenska University Hospital, Sweden Investigators and Clinical Sites: Gianluca Campo (PI), Marco Valgimigli (PI until October 20, 2013),

Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy; Lucia Uguccioni (PI), A.O. Ospedali Riuniti, Marche Nord, Pesaro, Italy; Corrado Tamburino (PI), A.O. Universitaria Ferrarotto, Catania, Italy; Patrizia Presbitero (PI), Dennis Zavalloni-Parenti, IRCCS Humanitas, Rozzano (MI), Italy; Fabio Ferrari, (PI), A.O. Universitaria San Luigi Gonzaga di Orbassano (TO), Italy; Roberto Ceravolo (PI), Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy; Andrea Santarelli (PI), Ospedali degli Infermi, Rimini, Italy; Fabio Tarantino (PI), Ospedale G. B. Morgagni, Forlì, Italy; Paolo Calabrò (PI), Ospedale dei Colli, Napoli, Italy; Giampaolo Pasquetto (PI), P.O. di Este (PD), Italy; Giovanni Esposito (PI), Policlinico Federico II, Napoli, Italy; Salvatore Ierna (PI), Ospedale Sirai - Carbonia (CI), Italy; Gavino Casu (PI), Stefano Mameli, Maria Letizia Stochino, Ospedale San Francesco, Nuoro, Italy; Nicoletta de Cesare (PI), Policlinico San Marco, Zingonia (BG), Italy; Pietro Mazzarotto, (PI), Ospedale di Lodi, Italy; Alberto Cremonesi (PI), Villa Maria Cecilia Hospital, Cotignola (RA), Italy; Francesco Saia (PI), Policlinico S. Orsola, Bologna, Italy; Giovanni Saccone (PI), Fabio abate, A.O. Giovanni Paolo II, Sciacca (AG), Italy; Ugo Limbruno (PI), Andrea Picchi, Ospedale della Misericordia, Grosseto, Italy; Roberto Violini (PI), Marco Nazzaro, A.O. San Camillo-Forlanini, Roma, Italy; Roberto Garbo (PI), Salvatore Colangelo, Giacomo Boccuzzi, San Giovanni Bosco Hospital, Torino, Italy; Paolo Tosi (PI), Ospedale Mater Salutis di Legnago (VR), Italy; Vincenzo Guiducci (PI), A.O. Santa Maria Nuova, Reggio Emilia, Italy; Carlo Vigna (PI), IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; Antonio Zingarelli (PI), A.O. Universitaria San Martino, Genova, Italy; Andrea Gagnor (PI), Ferdinando Varbella, Ospedale degli Infermi, Rivoli (TO), Italy; Stefano Garducci (PI), Tiziana Zaro, A.O. Ospedale Civile di Vimercate (MB), Italy; Stefano Tresoldi (PI), Pietro Vandoni (PI until June 17, 2014), A.O. Ospedale di Desio (MB), Italy; Marco Contarini (PI), Ospedale Umberto I, Siracusa, Italy; Armando Liso (PI), Città di Lecce Hospital (GVM), Lecce, Italy; Antonio Dellavalle (PI), Ospedali Riuniti ASL 17, Savigliano (CN), Italy; Salvatore Curello (PI), A.O. Spedali Civili, Brescia, Italy; Fabio Mangiacapra (PI) Campus Biomedico, Roma, Italy; Paolo Rubartelli (PI), Ospedale Villa Scassi, Genova, Italy; Rosario Evola (PI), P.O. San Vincenzo, Taormina (ME), Italy; Giuseppe Andò (PI), A.O. Universitaria G. Martino, Messina, Italy; Cataldo Palmieri (PI), Ospedale Pasquinucci, Massa, Italy; Camillo Falcone (PI), Ospedale Sacra Famiglia, Erba (CO), Italy; Francesco Liistro (PI), Ospedale San Donato, Arezzo, Italy; Manuela Creaco (PI), Ospedale Gravina, Caltagirone (CT), Italy; Antonio Colombo (PI), Alaide Chieffo, Ospedale San Raffaele IRCCS, Milano, Italy; Andrea Perkan (PI), A.O.U. Ospedali Riuniti di Trieste, Italy; Stefano De Servi, Ospedale Civile di Legnano, Italy; Dionigi Fischetti (PI), Ospedale Vito Fazzi , Lecce, Italy; Stefano Rigattieri (PI), Alessandro Sciahbasi, A.O. Sandro Pertini, Roma, Italy; Edoardo Pucci (PI), Ospedale Santa Maria Goretti, Latina, Italy; Enrico Romagnoli (PI), Policlinico Casilino, Roma, Italy; Claudio Moretti (PI), A.O.U. San Giovanni Battista, Torino, Italy; Luciano Moretti (PI), A.O. C. G. Mazzoni, Ascoli Piceno, Italy; Raffaele De Caterina (PI), Marcello Caputo (PI), Marco Zimmarino, Ospedale Clinicizzato SS. Annunziata Chieti, Italy; Paolo Sganzerla (PI), A.O. Treviglio (BG), Italy; Maurizio Ferrario (PI), Ezio Bramucci (PI until June 17, 2014), Policlinico San Matteo, Pavia, Italy; Emilio Di Lorenzo (PI), A.O. G. Moscati, Avellino, Italy; Carlo Briguori, MD, Clinica Mediterranea, Napoli, Italy; Maurizio Turturo (PI), Ospedale Di Venere, Bari, Italy; Roberto Bonmassari (PI), Ospedale Santa Chiara, Trento, Italy; Carlo Penzo (PI), Ospedale Civile di Mirano (VE), Italy; Bruno Loi (PI), A.O. Brotzu, Cagliari, Italy; Ciro Mauro (PI), AORN Cardarelli, Napoli, Italy; Arturo Ausiello, MD, Casa di Cura Villa Verde, Taranto, Italy; Anna Sonia Petronio (PI), A.O. Universitaria Cisanello, Pisa, Italy; Gabriele Gabrielli (PI), Ospedali Riuniti Di Ancona, Italy; Gennaro Sardella, MD, PhD, Policlinico Umberto I, Roma, Italy; Antonio Micari (PI), Villa Maria Eleonora Hospital, Palermo, Italy; Flavia Belloni (PI), Ospedale Santo Spirito in Saxia, Roma, Italy; Alessandro Lupi (PI), A.O.U. Maggiore della Carità, Novara, Italy; Francesco Amico (PI), Ospedale Sant’Elia, Caltanissetta, Italy; Marco Comeglio (PI), Ospedale del Ceppo, Pistoia, Italy; Claudio Fresco (PI), A.O.U. S. Maria della Misericordia, Udine, Italy; Arnoud WJ van‘t Hof, (PI), Isala Klinieken, Zwolle, Netherlands; Nicolas Van Mieghem (PI), Roberto Diletti, Evelyn Regar, Thoraxcenter, Erasus Medical Center, Rotterdam, Netherlands; Elmir Omerovic (PI) Sahlgrenska University Hospital, Sweden; Salvatore Brugaletta (PI), Manel Sabaté, University Hospital Clinic, Barcelona, Spain; Joan Antoni Gómez Hospital (PI), Hospital de Bellvitge, Barcelona, Spain; José Francisco Díaz Fernández (PI) Hospital Juan Ramón Jiménez, Huelva, Spain; Vicente Mainar (PI) Hospital General Universitario de Alicante, Alicante, Spain; Jose Maria de la Torre Hernandez (PI), Hospital Marques de Valdecilla, Santander, Spain.

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Funding

The study sponsor, Gruppo Italiano Studi Emodinamica (GISE), a non-profit organisation, received grant support for the conduct of the MATRIX programme from The Medicines Company and TERUMO. Other than supplying financial support and bivalirudin, the funding companies were not involved with the study processes, including site selection and management, and data collection and analysis. No agreements exist regarding confidentiality of the data among the funding companies, the sponsor, and the investigators.

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MATRIX programme inclusion and exclusion criteria

Inclusion criteria

Inclusion criteria for non-ST-segment elevation acute coronary syndrome

ALL THREE MUST BE PRESENT FOR ELIGIBILITY

History consistent with new, or worsening ischaemia, occurring at rest or with minimal activity

Enrolment within 7 days of the most recent symptoms

Planned coronary angiography with indication to PCI

AT LEAST TWO OF THE FOLLOWING CRITERIA

Aged 60 years or older

Troponin T or I or creatine kinase MB above the upper limit of normal

Electrocardiographic changes compatible with ischaemia, i.e. ST depression of 1 mm or greater in two contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts

Inclusion criteria for ST-segment elevation myocardial infarction

BOTH CRITERIA MUST BE PRESENT FOR ELIGIBILITY

Chest pain for more than 20 min with an electrocardiographic ST-segment elevation 1 mm or greater in two or more contiguous leads, or with a new left bundle-branch block or with ST-segment depression of 1 mm or greater in two or more of leads V1–3 with a positive terminal T wave

Admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischaemia or previous fibrinolytic treatment.

Exclusion criteria

ANY OF THE FOLLOWING:

Patients who cannot give informed consent or have a life expectancy of less than 30 days

Allergy or intolerance to bivalirudin or unfractionated heparin

Treatment with low-molecular-weight heparin within the past 6 h

Treatment with any glycoprotein inhibitor in the previous 3 days

Absolute contraindications or allergy, that cannot be premedicated, to iodinated contrast or to any of the study medications, including both aspirin and clopidogrel

Contraindications to angiography, including but not limited to severe peripheral vascular disease

If it is known, a creatinine clearance less than 30 mL/min or dialysis dependent

Previous enrolment in this study

PCI in the previous 30 days

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Clinical event committee procedures

The following outcomes were adjudicated by the clinical events committee (CEC): death; myocardial infarction; stroke; transient ischaemic attack; bleeding; coronary stent thrombosis; and urgent target vessel coronary revascularisation. This list included all components of the composite primary outcome (i.e. death, reinfarction, or stroke, 30 days after randomisation) as well as other secondary outcomes.

Every effort was made to keep the members of the CEC blinded to treatment assignment throughout the adjudication process and the duration of the study. Owing to its open-label nature, keeping CEC members blinded to randomised treatment was essential for the scientific integrity of the study. Several steps were undertaken to assure this requirement was met. First, any reference to treatment assignment contained in the electronic case record form (eCRF) or source documents that could lead to unblinding was obliterated by the site, using a black marker, prior to submission to the CEC. Second, the CEC coordinator and operational personnel obliterated any reference to study drug assignment prior to distribution to the physicians if information was noted during the preparation of the event packet. Third, if a reviewer noted the treatment assignment during the review of a particular event, the CEC coordinator was notified, and the event was sent for review by the third expert reviewer.

All investigator-reported events were adjudicated as possible study outcomes. In addition, predefined ischaemic and bleeding CEC triggers were in place for the Identification of Suspected Events, which were not reported by investigators. Suspected events were identified systematically using a computer programme that queried key data fields in the eCRF, which were determined to be CEC-critical variables (CEC triggers). Once all eCRF CEC-critical data fields were query clean, the event was ready for adjudication. An initial trigger-specification programme was defined at the start of a trial, which was not subject to change during the course of the study. The CEC-adjudicated data were used in the final primary and secondary outcome analyses. MATRIX clinical outcome definitions

Death All deaths were adjudicated by the CEC. Deaths were considered cardiac unless an unequivocal non-cardiac cause could be established. Specifically, any unexpected death, even in patients with coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) was classified as cardiac. Cardiac death: Any death due to immediate cardiac cause (e.g. myocardial infarction, low output failure, fatal arrhythmia). Sudden death and death of unknown cause were also classified as cardiac death. This included all procedure-related deaths including those related to concomitant treatment. Vascular death: Death due to cerebrovascular disease, pulmonary embolism, ruptured aortic

aneurysm, dissecting aneurysm, or other vascular cause. Non-cardiovascular death: Any death not covered by the above definitions, including death due to infection, sepsis, pulmonary causes, accident, malignancy, suicide, or trauma. Myocardial infarction

All occurrences of myocardial infarction up to and including the 30-day time point were adjudicated by the CEC. Serial electrocardiograms (ECGs), the presence of symptoms consistent with myocardial ischaemia, and biomarkers of myocardial necrosis were obtained for each suspected recurrent myocardial infarction. A diagnosis of myocardial infarction was made when the following criteria were met: Myocardial infarction within 24 h of randomisation in patients with ST-segment elevation myocardial infarction (STEMI) or in patients with non-STEMI (NSTEMI) in whom cardiac markers before randomisation were not available or were higher than the upper reference level (URL) and were still in the ascending phase (i.e. markers were not stable or were decreasing in two or more assessments taken before the suspected event) • Presumed ischaemic symptoms (such as chest pain); and either • New ST-segment elevation of greater than 1 mm in two or more contiguous leads, or presumably

new left-bundle branch block. AND/OR • Angiographic complications including but not limited to reocclusion of a previously patent coronary

artery or bypass graft, no reflow (i.e. new onset of vessel closure or compromise defined as

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Thrombolysis In Myocardial Infarction [TIMI] 0/1 flow after baseline TIMI 2/3 flow) or slow reflow (i.e. TIMI 2 flow after baseline TIMI 3 flow), sustained distal embolisation, sustained side-branch closure of a vessel 2 mm or more in diameter.

Myocardial infarction 24 h to 7 days OR in patients in whom cardiac markers were stable or decreasing in two or more assessments taken before the suspected event Presumed ischaemic symptoms (such as chest pain) and either if cardiac markers were in the descending phase, a new re-elevation in biomarkers greater than 20% above the prior documented valley level (troponin I or T should be used first; if not available the second option was for creatine kinase-MB mass, and if creatine kinase-MB was not available total creatine kinase should be used). OR If cardiac markers were normal or returned to normal, the definition for subsequent ischaemic events >7 days was used. Myocardial infarction >7 days If the suspected myocardial infarction occurred more than 7 days after randomisation, the 2007 universal definition of myocardial infarction

1 was used. Under these conditions, any one of the

following criteria met the diagnosis for myocardial infarction: Type 1 myocardial infarction. Spontaneous myocardial infarction related to ischaemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection. Type 2 myocardial infarction. Myocardial infarction secondary to ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotension. Type 1 and type 2 myocardial infarction required the detection of a rise and/or a fall of cardiac biomarkers (preferably troponin) with at least one value above the 99

th percentile of the URL together

with evidence of myocardial ischaemia with at least one of the following:

• Symptoms of ischaemia. In the absence of pain, new ST-segment changes indicative of ischaemia, acute pulmonary oedema, ventricular arrhythmias, or hemodynamic instability presumed to be ischaemic in origin, constituted sufficient evidence of ischaemia.

• Electrocardiogram changes indicative of new ischaemia (new ST-T changes or new left bundle-branch block) or development of pathological Q waves in the ECG;

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Type 3 myocardial infarction. Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischaemia, and accompanied by presumably new ST elevation, or new left bundle-branch block, and/or evidence of fresh thrombus by coronary angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood. Type 4a myocardial infarction. For PCIs in patients with normal or abnormal and stable/falling baseline troponin values and increases of troponin biomarkers greater than three times the 99

th

percentile URL in at least one blood sample was designated as defining PCI related myocardial infarction. A subtype related to a documented stent thrombosis was recognized (type 4b myocardial infarction). Type 5 myocardial infarction. For coronary artery bypass grafting (CABG) in patients with normal or abnormal and stable/falling baseline troponin values, increases of troponin biomarkers greater than five times the 99

th percentile URL in at least one blood sample plus either new pathological Q waves

or new left bundle-branch block, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium is designated as defining CABG-related myocardial infarction. A myocardial infarction was also defined by the presence of pathological findings of an acute myocardial infarction on autopsy. Q wave definition: New Q waves were defined as Q waves with a duration of >0�04 seconds in at least two contiguous leads that were not present on previous ECGs. These electrocardiographic criteria were only valid in the absence of left bundle-branch block, Wolff-Parkinson-White syndrome, paced rhythm, or other artefacts that would preclude an electrocardiographic definition of myocardial infarction. (c) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in the presence of biomarker elevation, with or without other defining factors of myocardial infarction (clinical, electrocardiographic, biochemical) and in the absence of a non-ischaemic cause, could also be used to define a reinfarction. A wall motion abnormality alone did not define infarction.

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NOTE: There may have been patients who had a suspected reinfarction who had insufficient data to adjudicate the event according to the definitions outlined in this charter (e.g. symptom duration was missing). For these patients, a myocardial infarction might have been adjudicated by the CEC when there was a preponderance of clinical evidence based on signs, symptoms, electrocardiographic changes, and angiographic and biomarker data. Cerebrovascular accident (stroke or transient ischaemic attack) Cerebrovascular accidents comprised stroke and transient ischaemic attack (TIA). A stroke was defined as a sudden, focal neurologic deficit resulting from a cerebrovascular cause,

resulting in death or lasting longer than 24 h, that was not due to a readily identifiable cause such as a tumour, infection, or trauma. All suspected strokes were adjudicated using all available clinically relevant information including imaging studies to classify all strokes as:

• Haemorrhagic – a stroke with focal collections of intracranial blood.

• Ischaemic – a stroke without focal collections of intracranial blood.

• Unknown – no imaging or autopsy data were available. A TIA was defined as a new, transient episode of neurologic dysfunction (always resolving within 24 h) caused by focal brain, spinal cord, or retinal ischaemia, without acute infarction at neuroimaging. Stent thrombosis The incidence of stent thrombosis was assessed up to and including the 1-year time point. Stent thrombosis was reported as a cumulative value at the different time points and with the different separate time points. Time 0 was defined as the time point after the guiding catheter had been removed. The timing of stent thrombosis was reported as: acute (occurring 0–24 h post stent implantation); subacute (>24 h to 30 days post stent implantation); or late (>30 days to 1 year post stent implantation). Three categories of evidence were recognized in defining stent thrombosis: definite, probable, and possible. Definite (considered by either angiographic or pathologic confirmation): Angiographic confirmation of

stent thrombosis was considered to have occurred if: 1) TIMI flow was:

a) Grade 0 with occlusion originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus*. b) Grade 1, 2, or 3 originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus*.

AND at least one of the following criteria had been fulfilled within a 48-hour time window: 2) New onset of ischaemic symptoms at rest (typical chest pain with duration greater than 20 minutes or requiring medical treatment). 3) New ischaemic electrocardiographic changes suggestive of acute ischaemia. 4) Typical rise and fall in cardiac biomarkers. The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms was not considered a confirmed stent thrombosis (silent occlusion). *Intracoronary thrombus Non-occlusive thrombus: Intracoronary thrombus was defined as a (spheric, ovoid, or irregular) non-calcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolisation of intraluminal material downstream. Occlusive thrombus: TIMI 0 or TIMI 1 flow intra-stent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originating from the side branch). Pathological confirmation of stent thrombosis. Evidence of recent thrombus within the stent determined at autopsy. Probable: The clinical definition of probable stent thrombosis was considered to have occurred after

intracoronary stenting in the following cases: 1) Any unexplained death within the first 30 days.

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2) Any myocardial infarction, irrespective of the time after the index procedure, which was related to documented acute ischaemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause. Possible: Clinical definition of possible stent thrombosis was considered to have occurred with any

unexplained death following intracoronary stenting until the end of the follow-up period. Bleeding

The primary bleeding classification used was that proposed by the Bleeding Academic Research Consortium (BARC).

2 The TIMI and Global Utilization of Streptokinase and Tissue Plasminogen

Activator for Occluded Coronary Arteries (GUSTO) classifications were also assessed. BARC classification

2

Type 0: No evidence of bleeding. Type 1: Bleeding that is NOT ACTIONABLE and does not cause the patient to seek unscheduled performance of studies, hospitalisation, or treatment by a health care professional. Examples include, but are not limited to, bruising, hematoma, nosebleeds, or haemorrhoidal bleeding for which the patient does not seek medical attention. Type I bleeding may include episodes that lead to discontinuation of medications by the patient because of bleeding without visiting a health care provider. Type 2: Any clinically overt sign of haemorrhage (e.g. more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that is actionable, but does not meet criteria for Type 3 BARC bleeding, Type 4 BARC bleeding (CABG-related), or Type 5 BARC bleeding (fatal bleeding). The bleeding must require diagnostic studies, hospitalisation or treatment by a health care professional. In particular, the bleeding must meet at least one of the following criteria:

1) Requiring intervention: defined as a health care professional-guided medical treatment or percutaneous intervention to stop or treat bleeding, including temporarily or permanently discontinuing a medication or study drug. Examples include, but are not limited to, coiling, compression, use of reversal agents (e.g. vitamin K, protamine), local injections to reduce oozing, or a temporary/ permanent cessation of antiplatelet, antithrombin, or fibrinolytic therapy.

2) Leading to hospitalisation or an increased level of care: defined as leading to or prolonging hospitalisation or transfer to a hospital unit capable of providing a higher level of care.

3) Prompting evaluation: defined as leading to an unscheduled visit to a healthcare professional resulting in diagnostic testing (laboratory or imaging). Examples include, but are not limited to, haematocrit testing, haemoccult testing, endoscopy, colonoscopy, computed tomography scanning, or urinalysis. A visit or phone call to a healthcare professional where neither testing nor treatment is undertaken does not constitute Type 2 bleeding.

Type 3: Clinical, laboratory, and/or imaging evidence of bleeding with specific healthcare provider responses, as listed below: Type 3a • Any transfusion with overt bleeding. • Overt bleeding plus haemoglobin drop ≥3 to <5 g/dL† (provided haemoglobin drop is related to

bleeding). Type 3b

• Overt bleeding plus haemoglobin drop ≥5 g/dL† (provided haemoglobin drop is related to bleeding).

• Cardiac tamponade. • Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/haemorrhoid). • Bleeding requiring intravenous vasoactive drugs. Type 3c • Intracranial haemorrhage (does not include microbleeds or haemorrhagic transformation; does

include intraspinal). • Subcategories; Confirmed by autopsy or imaging or lumbar puncture. • Intra-ocular bleed compromising vision.

†Haemoglobin drop should be corrected for intracurrent transfusion, where one unit of packed red blood cells or one unit of whole blood would be expected to increase haemoglobin by 1 g/dL.

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Type 4: CABG-related bleeding

• Perioperative intracranial bleeding within 48 h.

• Reoperation following closure of sternotomy for the purpose of controlling bleeding.

• Transfusion of 5 or more units of whole blood or packed red blood cells within a 48-hour period (only allogeneic transfusions were considered as transfusions for CABG-related bleeds. Cell saver products were not counted.).

• Chest tube output ≥ 2 L within a 24-hour period. Note: A CABG-related bleed not adjudicated as at least a Type 3 severity event was classified as ‘not a bleeding event’. Type 5: Fatal bleeding. Fatal bleeding is bleeding that directly causes death with no other explainable

cause. BARC fatal bleeding is categorized as either definite or probable as follows: Type 5a – Probable fatal bleeding: Bleeding that is clinically suspicious as the cause of death, but

the bleeding is not directly observed and there is no autopsy or confirmatory imaging. Type 5b – Definite fatal bleeding: Bleeding that is directly observed (either by clinical specimen – blood, emesis, stool, etc., or by imaging) or confirmed on autopsy. The site of fatal bleeding is further categorized as intracranial, gastrointestinal, retroperitoneal, pulmonary, pericardial, gastro-urinary, or other. BARC fatal bleeding is meant to capture deaths that are directly due to bleeding with no other cause. The time interval from the bleeding event to the death should be considered with respect to likely causality, but there is no specific time limit proposed. Bleeding that is contributory but not directly causal to death is not classified as fatal bleeding, but may be categorized as other forms of bleeding. Bleeding that leads to cessation of antithrombotic or other therapies may be contributory, but again, would not be classified as fatal bleeding. Bleeding associated with trauma or with surgery may be fatal, depending on whether it was determined to be directly causal or not. TIMI classification Major bleeding was defined as:

• Intracranial haemorrhage.

• Bleeding associated with a decrease in haemoglobin > 5g/dL (3�1 mmol/L) (or 15% of haematocrit).

• Haemorrhagic death.

• Cardiac tamponade. Minor bleeding was defined as: • Blood loss that is spontaneous and observed as gross haematuria or hematemesis. • Observed (i.e. haeme-positive coffee ground emesis, haeme-positive melena, hematoma, or

retroperitoneal bleeding). • Spontaneous or non-spontaneous blood loss associated with a haemoglobin >3 g/dL (1�8 mmol/L)

and <5 g/dL (3�1 mmol/L) (or a haematocrit decrease of 9% and <15%). • Haemoglobin decrease >4 g/dL (2�5 mmol/L) and <5 g/dL (3�1 mmol/L) (or 12% of haematocrit

and <15%) with, despite attempts, no bleeding site identified. GUSTO classification Severe was defined as either intracranial haemorrhage or bleeding that causes hemodynamic compromise and requires intervention. Moderate was defined as bleeding that requires blood transfusion but does not result in hemodynamic compromise.

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Table S1. Medications administered before the catheterization laboratory in patients with STEACS and NSTEACS

STEACS NSTEACS

Bivalirudin (N=2012)

UFH (N=1998)

P value Bivalirudin (N=1598)

UFH (N=1605)

P value

Aspirin 1885 (93.7) 1861 (93.1) 0.49 1532 (95.9) 1515 (94.4) 0.052

Clopidogrel 766 (38.1) 706 (35.3) 0.072 932 (58.3) 908 (56.6) 0.32

Prasugrel 401 (19.9) 396 (19.8) 0.93 56 (3.5) 69 (4.3) 0.25

Ticagrelor 379 (18.8) 393 (19.7) 0.50 480 (30.0) 465 (29.0) 0.51

Enoxaparin 75 (3.7) 73 (3.7) 0.90 468 (29.3) 482 (30.0) 0.64

Fondaparinux 58 (2.9) 65 (3.3) 0.50 281 (17.6) 273 (17.0) 0.67

ACE inhibitors 283 (14.1) 268 (13.4) 0.55 717 (44.9) 758 (47.2) 0.18

ARB 141 (7.0) 135 (6.8) 0.75 227 (14.2) 219 (13.6) 0.65

Statins 403 (20.0) 410 (20.5) 0.70 1062 (66.5) 1043 (65.0) 0.38

Beta blockers 428 (21.3) 416 (20.8) 0.73 983 (61.5) 942 (58.7) 0.10

Warfarin 21 (1.0) 15 (0.8) 0.33 35 (2.2) 29 (1.8) 0.44

PPI 641 (31.9) 651 (32.6) 0.62 1126 (70.5) 1131 (70.5) 1.00

Previous UFH 944 (46.9) 957 (47.9) 0.53 222 (13.9) 227 (14.1) 0.84

Bivalirudin 1 (0.0) 2 (0.1) 0.62 1 (0.1) 1 (0.1) 1.00

GPI 1 (0.0) 2 (0.1) 0.62 4 (0.3) 4 (0.2) 1.00

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Table S2. Medications at discharge in patients with STEACS and NSTEACS STEACS NSTEACS


UFH (N=1949)

P value Bivalirudin (N=1589)

UFH (N=1590)

P value

Aspirin 1904 (96.3)

1881 (96.5) 0.73 1567 (98.6) 1560 (98.1) 0.26

Ticlopidine* 1 (0.1) 1 (0.1) 1.00 4 (0.3) 8 (0.5) 0.39

Clopidogrel 570 (28.8) 577 (29.6) 0.59 768 (48.3) 757 (47.6) 0.68

Prasugrel* 635 (32.1) 611 (31.3) 0.60 136 (8.6) 157 (9.9) 0.20

Ticagrelor 581 (29.4) 592 (30.4) 0.50 612 (38.5) 596 (37.5) 0.55

Any P2Y12 inhibition 1787 (90.4) 1780 (91.3) 0.31 1520 (95.7) 1518 (95.5) 0.80

ARB or ACE-I 1617 (81.8) 1549 (79.5) 0.067 1284 (80.8) 1285 (80.8) 0.99

Statins 1477 (74.7) 1399 (71.8) 0.038 1074 (67.6) 1061 (66.7) 0.61

Beta blockers 1649 (83.4) 1631 (83.7) 0.82 1315 (82.8) 1305 (82.1) 0.61

Warfarin 71 (3.6) 60 (3.1) 0.37 51 (3.2) 52 (3.3) 0.92

Diuretics 557 (28.2) 528 (27.1) 0.45 389 (24.5) 367 (23.1) 0.35

Insulin 216 (10.9) 190 (9.7) 0.23 219 (13.8) 184 (11.6) 0.061

Oral antidiabetics 163 (8.2) 141 (7.2) 0.24 178 (11.2) 202 (12.7) 0.19

PPI 1757 (88.9) 1734 (89.0) 0.92 1402 (88.2)

1410 (88.7) 0.69

H2 blockers 86 (4.4) 79 (4.1) 0.64 56 (3.5)

55 (3.5) 0.92

*one STEACS-patient randomised to radial access who was known with aspirin intolerance was treated with ticlopidine and prasugrel simultaneously

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Table S3. Procedural characteristics in patients with STEACS and NSTEACS

Procedural characteristics STEACS NSTEACS

Bivalirudin

(N=2012)

UFH

(N=1998) P value

Bivalirudin

(N=1598)

UFH

(N=1605) P value

No PCI attempted 186 (9.2) 163 (8.2) 0.22 25 (1.6) 30 (1.9) 0.51

CABG 22 (1.1) 14 (0.7) 0.19 2 (0.1) 3 (0.2) 0.66

Patient with significant lesion and medical treatment 130 (6.5) 107 (5.4) 0.14 16 (1.0) 12 (0.7) 0.44

Patient without significant lesion 31 (1.5) 40 (2.0) 0.27 7 (0.4) 15 (0.9) 0.089

No coronary angiography completed 3 (0.1) 2 (0.1) 0.66 0 (0.0) 0 (0.0) Not enough observations

PCI attempted 1826 (90.8) 1835 (91.8) 0.22 1573 (98.4) 1575 (98.1) 0.51

Died during PCI 1 (0.0) 1 (0.1) 1.00 0 (0.0) 0 (0.0) Not enough

observations

PCI completed 1825 (90.7) 1834 (91.8) 0.22 1573 (98.4) 1575 (98.1) 0.51

Medications administered in and after the catheterization laboratory

Aspirin 95 (4.7) 109 (5.5) 0.29 137 (8.6) 142 (8.8) 0.78

Clopidogrel 110 (5.5) 131 (6.6) 0.15 131 (8.2) 158 (9.8) 0.10

Prasugrel 256 (12.7) 246 (12.3) 0.69 56 (3.5) 68 (4.2) 0.28

Ticagrelor 261 (13.0) 252 (12.6) 0.73 139 (8.7) 126 (7.9) 0.38

Glycoprotein IIb/IIIa inhibitors 122 (6.1) 698 (34.9) <0.0001 43 (2.7) 235 (14.6) <0.0001

Planned GPI 0 (0.0) 613 (30.7) <0.0001 0 (0.0) 174 (10.8) <0.0001

Bailout GPI 122 (6.1) 85 (4.3) 0.0096 43 (2.7) 61 (3.8) 0.076

Unfractionated heparin 105 (5.2) 1874 (93.8) <0.0001 143 (8.9) 1599 (99.6) <0.0001

Unfractionated heparin (units per kilo) 36.5±23.6 71.5±27.4 <0.0001 43.0±29.9 85.7±27.2 <0.0001

Sub-therapeutic regimen (<50 units per kg) 78 (3.9) 319 (16.0) <0.0001 109 (6.8) 73 (4.5) 0.0055

Therapeutic regimen (>= 50 units per kg) 27 (1.3) 1555 (77.8) <0.0001 34 (2.1) 1526 (95.1) <0.0001

Bivalirudin 1877 (93.3) 11 (0.6) <0.0001 1565 (97.9) 3 (0.2) <0.0001

Prolonged infusion post-PCI 952 (47.3) 2 (0.1) <0.0001 785 (49.1) 1 (0.1) <0.0001

Average duration of post-PCI bivalirudin infusion 358.0±254.0 292.5±364.2 0.72 386.1±238.3 Not enough observations

Patients receiving full bivalirudin regimen post-PCI 412 (20.5) 1 (0.1) <0.0001 219 (13.7) 0 (0.0)

Average duration of full bivalirudin regimen 271.1±252.3 Not enough observations Not enough observations

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Patients receiving low bivalirudin regimen post-PCI 540 (26.8) 1 (0.1) <0.0001 566 (35.4) 1 (0.1)

Average duration of low bivalirudin regimen 424.4±234.7 Not enough observations 439.4±258.1 Not enough observations

Intra aortic balloon pump 63 (3.1) 75 (3.8)

0.28 19 (1.2) 24 (1.5)

0.45

PCI completed (N=1825) (N=1834)

(N=1573) (N=1575)

TIMI 3 flow in all treated lesions 1714 (93.9) 1734 (94.7) 0.34 1507 (95.8) 1511 (95.9) 0.85

Coronary stenosis<30% in all treated lesions 1750 (95.9) 1770 (96.5) 0.33 1500 (95.4) 1482 (94.1) 0.11

Procedural success in all treated lesions 1675 (91.8) 1703 (93.0) 0.18 1473 (93.6) 1462 (92.8) 0.36

Treated vessel(s) per patient

Left main coronary artery 71 (3.9) 55 (3.0) 0.14 88 (5.6) 94 (6.0) 0.65

Left anterior descending artery 929 (50.9) 857 (46.8) 0.013 795 (50.5) 823 (52.3) 0.34

Left circumflex artery 340 (18.6) 378 (20.6) 0.13 583 (37.1) 565 (35.9) 0.49

Right coronary artery 663 (36.3) 698 (38.1) 0.27 457 (29.1) 455 (28.9) 0.92

Bypass graft 9 (0.5) 7 (0.4) 0.61 23 (1.5) 18 (1.1) 0.43

At least two vessels treated 157 (8.6) 142 (7.8) 0.35 333 (21.2) 340 (21.6) 0.78

Lesions treated per patient (interquartile range) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 0.71 1.0 (1.0-2.0) 1.0 (1.0-2.0) 0.98

One lesion 1529 (83.8) 1552 (84.7)

1125 (71.5) 1129 (71.7)

Two lesions 246 (13.5) 237 (12.9)

361 (22.9) 355 (22.5)

Three or more lesions 50 (2.7) 43 (2.3)

87 (5.5) 91 (5.8)

At least one complex lesion 979 (53.6) 1003 (54.7) 0.50 789 (50.2) 789 (50.1) 0.97

Median number of stents per patient (interquartile range) 1.0 (1.0-2.0) 1.0 (1.0-2.0) 0.69 1.0 (1.0-2.0) 1.0 (1.0-2.0) 0.73

Overall stent length per patient — mm 30.6±17.9 30.5±17.7 0.87 33.0±22.2 34.0±21.6 0.22

Lesions

Number of lesions with PCI (N=2178) (N=2166)

(N=2129) (N=2132)

Lesions stented 2001 (91.9) 1976 (91.2) 0.52 1920 (90.2) 1926 (90.3) 0.93

At least one drug-eluting stent 1391 (63.9) 1329 (61.4) 0.072 1500 (70.5) 1524 (71.5) 0.66

At least one bare-metal stent 610 (28.0) 647 (29.9) 0.082 420 (19.7) 402 (18.9) 0.38

Lesions not stented 2001 (91.9) 1976 (91.2) 0.52 1920 (90.2) 1926 (90.3) 0.93

TIMI flow pre-procedure

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0 or 1 1291 (59.3) 1224 (56.5) 0.035 387 (18.2) 361 (16.9) 0.41

2 260 (11.9) 282 (13.0) 0.31 285 (13.4) 252 (11.8) 0.17

3 627 (28.8) 660 (30.5) 0.12 1457 (68.4) 1519 (71.2) 0.081

TIMI flow post-procedure

0 or 1 33 (1.5) 34 (1.6) 0.82 38 (1.8) 43 (2.0) 0.49

2 86 (3.9) 70 (3.2) 0.30 32 (1.5) 25 (1.2) 0.38

3 2059 (94.5) 2062 (95.2) 0.80 2059 (96.7) 2064 (96.8) 0.96

Coronary stenosis<30% 2100 (96.4) 2096 (96.8) 0.43 2049 (96.2) 2029 (95.2) 0.097

Procedural success 2018 (92.7) 2026 (93.5) 0.28 2020 (94.9) 2007 (94.1) 0.33

Number of lesions stented (N=2001) (N=1976)

(N=1920) (N=1926)

Total stent length per lesion — mm 26.3±14.0 26.6±14.4 0.52 25.6±14.7 25.8±14.5 0.51

Average stent diameter per lesion — mm 3.1±0.5 3.1±0.5 0.32 3.0±0.5 3.0±0.5 0.29

At least one direct stenting 551 (27.5) 488 (24.7) 0.065 333 (17.3) 347 (18.0) 0.89

Postdilatation 823 (41.1) 798 (40.4) 0.75 928 (48.3) 975 (50.6) 0.21

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Table S4. Effect on bleeding assessed with the TIMI scale, the GUSTO scale and the BARC scale in patients with STEACS and NSTEACS

STEACS NSTEACS

Bivalirudin UFH Rate Ratio

(95% CI) P value Bivalirudin UFH

Rate Ratio

(95% CI) P value PINT

TIMI

Major bleeding 13 (0.7) 28 (1.4) 0.46 (0.24-0.88) 0.017 3 (0.2) 5 (0.3) 0.60 (0.14-2.52) 0.48 0.73

Minor bleeding 10 (0.6) 18 (1.0) 0.55 (0.25-1.18) 0.12 7 (0.4) 15 (0.9) 0.47 (0.19-1.15) 0.089 0.80

Major or minor bleeding 23 (1.2) 46 (2.4) 0.49 (0.30-0.81) 0.0044 10 (0.6) 20 (1.3) 0.50 (0.23-1.07) 0.069 0.96

GUSTO

Severe bleeding 12 (0.6) 19 (1.0) 0.62 (0.30-1.28) 0.19 4 (0.3) 7 (0.4) 0.57 (0.17-1.96) 0.37 0.91

Moderate bleeding 8 (0.4) 14 (0.8) 0.56 (0.24-1.34) 0.19 8 (0.5) 12 (0.8) 0.67 (0.27-1.64) 0.38 0.78

Mild bleeding 206 (10.4) 240 (12.2) 0.84 (0.69-1.01) 0.065 152 (9.7) 186 (11.6) 0.81 (0.65-1.01) 0.059 0.83

Severe or moderate bleeding 20 (1.0) 33 (1.7) 0.60 (0.34-1.04) 0.064 12 (0.8) 19 (1.2) 0.63 (0.31-1.31) 0.21 0.89

Any BARC Bleeding 227 (11.4) 277 (14.1) 0.79 (0.66-0.95) 0.012 164 (10.4) 205 (12.8) 0.79 (0.64-0.98) 0.029 0.98

Type 1 109 (5.5) 133 (6.8) 0.80 (0.62-1.04) 0.092 81 (5.2) 104 (6.5) 0.77 (0.58-1.04) 0.085 0.85

Type 2 84 (4.2) 86 (4.4) 0.96 (0.71-1.30) 0.79 67 (4.3) 67 (4.2) 1.00 (0.71-1.41) 0.98 0.85

Type 3 (abc) 29 (1.5) 42 (2.2) 0.68 (0.42-1.09) 0.10 15 (0.9) 30 (1.9) 0.50 (0.27-0.93) 0.026 0.45

Type 3a 14 (0.8) 20 (1.1) 0.69 (0.35-1.36) 0.28 10 (0.6) 18 (1.1) 0.56 (0.26-1.21) 0.13 0.69

Type 3b 12 (0.6) 21 (1.1) 0.56 (0.28-1.14) 0.11 4 (0.3) 12 (0.8) 0.33 (0.11-1.04) 0.046 0.44

Type 3c 3 (0.2) 1 (0.1) 2.96 (0.31-28.42) 0.32 1 (0.1) 0 (0.0) 3.01 (0.12-73.83) 0.50 0.57

Type 4 1 (0�1) 4 (0�2) 0�25 (0�03-2�20) 0�17 0 (0�0) 0 (0�0) Not enough observations

Type 5 (ab) 4 (0.2) 12 (0.6) 0.33 (0.11-1.02) 0.042 1 (0.1) 4 (0.3) 0.25 (0.03-2.25) 0.18 0.83

Type 5a 3 (0.2) 8 (0.4) 0.37 (0.10-1.39) 0.13 1 (0.1) 3 (0.2) 0.33 (0.03-3.22) 0.32 0.94

Type 5b 1 (0.1) 4 (0.2) 0.25 (0.03-2.20) 0.17 0 (0.0) 1 (0.1) 0.33 (0.01-8.09) 1.00 0.63

Type 3 or 5 33 (1.7) 54 (2.8) 0.60 (0.39-0.92) 0.019 16 (1.0) 34 (2.1) 0.47 (0.26-0.85) 0.011 0.52

Type 3 or 5 related to access site 14 (0.8) 19 (1.0) 0.72 (0.36-1.45) 0.36 5 (0.3) 13 (0.8) 0.39 (0.14-1.08) 0.060 0.32

Type 3 or 5 NOT related to access site 19 (1.0) 35 (1.8) 0.53 (0.30-0.93) 0.025 11 (0.7) 21 (1.3) 0.52 (0.25-1.09) 0.078 0.97

Type 2, 3 or 5 117 (5.9) 140 (7.1) 0.82 (0.64-1.05) 0.11 83 (5.3) 101 (6.3) 0.82 (0.61-1.10) 0.19 0.97

Type 2, 3 or 5 related to access site 60 (3.1) 73 (3.7) 0.80 (0.57-1.13) 0.21 45 (2.8) 59 (3.7) 0.76 (0.52-1.13) 0.17 0.85

Type 2, 3 or 5 NOT related to access site 57 (2.9) 67 (3.5) 0.84 (0.59-1.20) 0.33 38 (2.5) 42 (2.6) 0.91 (0.58-1.41) 0.67 0.78

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Composite of surgical access site repair or blood products transfusion

22 (1.1) 43 (2.2) 0.50 (0.30-0.84) 0.0073 14 (0.9) 24 (1.5) 0.58 (0.30-1.13) 0.11 0.72

Surgical access site repair 3 (0.2) 8 (0.4) 0.37 (0.10-1.39) 0.13 2 (0.1) 4 (0.3) 0.50 (0.09-2.74) 0.42 0.78

Blood products transfusion 19 (1.0) 41 (2.1) 0.45 (0.26-0.78) 0.0036 12 (0.8) 22 (1.4) 0.55 (0.27-1.10) 0.087 0.68

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Figure S1. Patient Flow Chart in patients with STEACS

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Figure S2. Patient Flow Chart in patients with NSTEACS

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Figure S3. Stratified analysis of all cause mortality in patients with STEACS

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Figure S4. Stratified analysis of all cause mortality in patients with NSTEACS

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Figure S5. Stratified analysis of major bleeding (BARC 3 or 5) in patients with STEACS

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Figure S6. Stratified analysis of major bleeding (BARC 3 or 5) in patients with NSTEACS

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References

1. Thygesen K, Alpert JS, White HD, Joint ESC Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol 2007; 50: 2173-95.

2. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123: 2736-47.

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The MATRIX program enrolled 8404 ACS patients with (4010) or without (4394) ST elevation. Patients with STEACS were randomization simultaneously to all comparisons, ie the access-site comparison and the anti-thrombin comparison (including the treatment duration comparison in patients assigned to bivalirudin). In patients with NSTEACS randomization may occur in 1-step as in patients with STEACS (eg. patients with

known coronary anatomy in whom PCI was anticipated) or, more commonly, in 2-steps: first the access-site comparison and then, after coronary angiography indicated the need for PCI, the anti-thrombin comparison. The treatment duration comparison always occurred simultaneously with the anti-thrombin comparison.

Patients included in this analysis (in bold) included the entire STEACS cohort (4010 patients) and NSTEACS

patients with planned PCI (N=3203).

246x61mm (72 x 72 DPI)

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Interaction term: P= 0.680

3

6

9

12

15

18

Cum

ulat

ive

inci

denc

e (%

)

1598 1363 1353 1349 1346 1343 1335NSTEACS Bivalirudin1605 1368 1354 1349 1345 1341 1324NSTEACS UFH2012 1928 1905 1899 1894 1888 1869STEACS Bivalirudin1998 1911 1889 1875 1866 1859 1841STEACS UFH

Number at risk

0 5 10 15 20 25 30Days since randomisation

Coprimary composite endpoint of all-cause mortality,MI or stroke

A


3

6

9

12

15

18

Cum

ulat

ive

inci

denc

e (%

)


Number at risk


Coprimary composite endpoint of all-cause mortality,MI, stroke, BARC 3 or 5

B


3

6

9

12

15

18

Cum

ulat

ive

inci

denc

e (%

)


Number at risk



B


3

6

9

12

15

18

Cum

ulat

ive

inci

denc

e (%

)


Number at risk



B

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1

2

3

Cum

ulat

ive

inci

denc

e (%

)


Number at risk


All-Cause Mortality

A


3

6

9

12

15

Cum

ulat

ive

inci

denc

e (%

)


Number at risk


Myocardial Infarction

B

Interaction term: P=0.0052

0

0.5

1

Cum

ulat

ive

inci

denc

e (%

)


Number at risk


Stroke

C


1

2

3

Cum

ulat

ive

inci

denc

e (%

)


Number at risk


Bleeding BARC 3 or 5

D

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Bivalirudin UFH pValuepValuefortrendor

interactionCentre'sannualvolumeofPCI 0.031*Low(247-544) 50/682 39/680 1.28(0.84-1.96) 0.25Intermediate(548-991) 35/715 43/726 0.82(0.52-1.29) 0.39High(1000-1950) 33/615 47/592 0.67(0.43-1.05) 0.075

Age 0.57≥75yr 48/445 55/423 0.82(0.55-1.21) 0.32<75yr 70/1567 74/1575 0.95(0.68-1.32) 0.75

Gender 0.76Women 34/463 39/454 0.85(0.53-1.35) 0.50Men 84/1549 90/1544 0.93(0.69-1.25) 0.62

BMI 0.070≥25kg/m² 70/1344 89/1314 0.76(0.55-1.04) 0.089<25kg/m² 48/668 40/684 1.24(0.81-1.89) 0.32

Intendedstartorcontinuationofprasugrelorticagrelor 0.55Yes 72/1361 74/1350 0.96(0.70-1.34) 0.83No 46/651 55/648 0.82(0.55-1.22) 0.33

Diabetes 0.12Yes 29/366 42/357 0.65(0.40-1.06) 0.082No 89/1646 87/1641 1.02(0.76-1.37) 0.89

Estimatedglomerularfiltrationrate(eGFR) 0.0034≥60ml/min 87/1687 74/1675 1.17(0.86-1.60) 0.31<60ml/min 26/307 48/301 0.50(0.31-0.81) 0.0043

Historyofperipheralvasculardisease 0.93Yes 14/106 18/123 0.89(0.44-1.81) 0.74No 104/1906 111/1875 0.92(0.70-1.20) 0.54

PreviousUFH 0.0022Yes 32/944 60/957 0.53(0.35-0.82) 0.0035No 86/1068 69/1041 1.22(0.89-1.68) 0.22

Randomisationtoaccesssite 0.92Femoralaccess 60/1010 66/999 0.89(0.63-1.27) 0.53Radialaccess 58/1002 63/999 0.92(0.64-1.31) 0.63

RateRatio(95%CI)

0.25 0.5 1 2Risk ratio (95% CI)

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Age 0.37≥75yr 57/445 72/423 0.73(0.51-1.04) 0.079<75yr 82/1567 91/1575 0.90(0.67-1.22) 0.50

Gender 0.64Women 39/463 49/454 0.77(0.50-1.18) 0.22Men 100/1549 114/1544 0.87(0.66-1.14) 0.30

BMI 0.24≥25kg/m² 83/1344 106/1314 0.76(0.57-1.01) 0.057<25kg/m² 56/668 57/684 1.00(0.69-1.46) 0.99


Diabetes 0.27Yes 35/366 49/357 0.67(0.43-1.05) 0.079No 104/1646 114/1641 0.90(0.69-1.18) 0.46





RateRatio(95%CI)

0.25 0.5 1 2Risk ratio (95% CI)

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Age 0.17≥75yr 98/461 90/481 1.16(0.84-1.60) 0.36<75yr 155/1137 172/1124 0.88(0.69-1.12) 0.29

Gender 0.20Women 81/416 65/385 1.17(0.81-1.69) 0.39Men 172/1182 197/1220 0.89(0.71-1.11) 0.31

BMI 0.12≥25kg/m² 157/1095 177/1091 0.87(0.69-1.10) 0.24<25kg/m² 96/503 85/514 1.18(0.85-1.64) 0.31


Diabetes 0.38Yes 85/458 74/436 1.11(0.79-1.56) 0.55No 168/1140 188/1169 0.90(0.72-1.14) 0.40





RateRatio(95%CI)

0.5 1 2Risk ratio (95% CI)

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Age 0.15≥75yr 105/461 100/481 1.11(0.82-1.52) 0.49<75yr 157/1137 181/1124 0.84(0.66-1.06) 0.15

Gender 0.20Women 86/416 72/385 1.12(0.79-1.59) 0.53Men 176/1182 209/1220 0.85(0.68-1.06) 0.16

BMI 0.15≥25kg/m² 163/1095 189/1091 0.84(0.67-1.06) 0.14<25kg/m² 99/503 92/514 1.12(0.82-1.54) 0.48


Diabetes 0.26Yes 90/458 80/436 1.09(0.78-1.51) 0.63No 172/1140 201/1169 0.86(0.69-1.08) 0.19





RateRatio(95%CI)

0.5 1 2Risk ratio (95% CI)

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CTU Bern Statistical Analysis Plan MATRIX

Version: 0.1 Page 1 I 36

Statistical Analysis Plan

Study: MATRIX

CTU project number: 0337

Authored by: Eveline Nüesch

Date: 07.05.2014

Version: 1.0

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Statistical Analysis Plan Study: MATRIX

CTU Bern Statistical Analysis Plan MATRIX Date effective: 07.05.2014

Based on CS_STA_TEM-11_SAPtemplate_v01 Page 3 I 36

Change history:

Version Date Major changes

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Contents Approved by: ........................................................................................................................................... 2

1. Study synopsis .............................................................................................................................. 7

2. Study objectives ............................................................................................................................ 8

2.1. Primary objectives ................................................................................................................ 8

2.2. Secondary objectives ........................................................................................................... 8

2.3. Assessment of endpoints .................................................................................................... 9

2.4. Changes of the primary objective during the conduct of the study ............................. 10

3. Study design ................................................................................................................................ 11

3.1. General design and plan ................................................................................................... 11

3.2. Sample size ......................................................................................................................... 11

3.3. Randomization .................................................................................................................... 12

3.4. Blinding ................................................................................................................................. 12

3.5. Study assessments ............................................................................................................ 13

Table 1: Visit Schedule ...................................................................................................................... 13

4. Data management ...................................................................................................................... 15

4.1. Data export .......................................................................................................................... 15

4.2. Data validation..................................................................................................................... 15

5. Study populations ....................................................................................................................... 16

5.1. Patient flow .......................................................................................................................... 16

5.2. Definition of populations for analysis ............................................................................... 19

5.3. Full analysis set (FAS) ....................................................................................................... 19

5.4. Per-protocol (PP) ................................................................................................................ 19

5.5. PCI population ..................................................................................................................... 19

5.6. Safety population ................................................................................................................ 20

5.7. Definition of sub-group populations in different analyses ............................................. 20

6. Statistical analysis ...................................................................................................................... 21

6.1. General ................................................................................................................................. 21

6.2. Pooling of sites .................................................................................................................... 21

6.3. Interim analyses .................................................................................................................. 21

6.4. Time-points for analysis ..................................................................................................... 21

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6.5. Methods for handling missing data .................................................................................. 21

6.5.1. Handling of dropouts .................................................................................................. 21

6.6. Statistical analytical issues ................................................................................................ 21

6.6.1. Assessment of statistical assumptions .................................................................... 21

6.6.2. Adjustments for covariates ........................................................................................ 22

6.6.3. Multicentre studies ...................................................................................................... 22

6.6.4. Multiple comparisons ................................................................................................. 22

6.6.5. Use of efficacy subset ................................................................................................ 22

6.6.6. Active-control studies intended to show equivalence ........................................... 22

6.6.7. Examination of subgroups ......................................................................................... 22

7. Evaluation of demographic, baseline and procedural characteristics ................................ 23

7.1. Demographics and baseline characteristics ................................................................... 23

7.1.1. Shell table .................................................................................................................... 23

7.2. Procedural characteristics ................................................................................................. 25

7.3. Hospital discharge .............................................................................................................. 27

8. Evaluation of treatment compliance and exposure ............................................................... 29

8.1. Compliance to study treatment ......................................................................................... 29

8.1.1. Compliance to study treatment ................................................................................. 29

8.1.2. Measurement of study treatment compliance ........................................................ 29

8.2. Exposure to study treatment ............................................................................................. 29

8.2.1. Extent of exposure ...................................................................................................... 29

8.2.2. Duration of exposure .................................................................................................. 29

8.2.3. Dose of exposure ........................................................................................................ 29

8.2.4. Drug concentrations ................................................................................................... 29

9. Evaluation of pharmacokinetics ................................................................................................ 30

10. Evaluation of efficacy parameters ........................................................................................ 31

10.1. Analysis of primary, secondary, and other efficacy endpoints ................................. 31

10.1.1. Analysis of primary endpoint ................................................................................. 31

10.1.2. Analysis of secondary efficacy endpoints ........................................................... 31

10.1.3. Analysis of other efficacy endpoints .................................................................... 31

10.2. Method for analysis of efficacy endpoints ................................................................... 31

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10.2.1. Binary data ............................................................................................................... 31

10.2.2. Count data ............................................................................................................... 31

10.2.3. Continuous scale data ........................................................................................... 31

10.2.4. Time-to-event data ................................................................................................. 32

10.2.5. Ordinal scales and non-ordered scales data ...................................................... 32

10.3. Shell table ........................................................................................................................ 32

11. Evaluation of safety parameters ........................................................................................... 35

11.1. Adverse events ............................................................................................................... 35

11.1.1. Brief summary of adverse events ......................................................................... 35

11.1.2. Display of adverse events ..................................................................................... 35

11.1.3. Analysis of adverse events.................................................................................... 35

11.1.4. Listing of adverse events by patient .................................................................... 35

11.1.5. Deaths, serious adverse events, and significant other adverse events ......... 35

11.1.6. Analysis of deaths, serious adverse events, and significant other adverse events 35

11.2. Clinical laboratory evaluations ...................................................................................... 35

11.2.1. Analysis of abnormal laboratory values .............................................................. 35

11.2.2. Evaluation of each laboratory examination ......................................................... 35

11.3. Concomitant medications .............................................................................................. 36

11.3.1. Concomitant therapy .............................................................................................. 36

11.4. Vital signs and physical examination ........................................................................... 36

11.4.1. Findings in vital signs and physical examinations ............................................. 36

11.5. Other safety evaluations ................................................................................................ 36

11.5.1. Other observations related to safety .................................................................... 36

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1. Study synopsis

The Minimizing Adverse haemorrhagic events by TRansradial access site and systemic Implementation of AngioX (MATRIX) trial programme is a series of three multi-centre, prospective, randomised, open-label trials comparing trans-radial vs. trans-femoral intervention (MATRIX Access Site), bivalirudin vs. unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitor (MATRIX Anti-thrombin) and prolonged post-percutaneous coronary intervention (PCI) bivalirudin infusion versus no post-PCI infusion (MATRIX Treatment Duration) in all-comer patients with acute coronary syndrome undergoing early invasive management.

Objectives are to demonstrate that trans-radial intervention as compared to femoral access site is associated with lower rates of the two composite co-primary endpoints of (A) death, myocardial infarction (MI) or stroke and (B) death, MI, stroke or major bleeding, both endpoints within the first 30 days after randomization (MATRIX Access Site).

Objectives are to demonstrate that bivalirudin infusion as compared to standard of care therapy consisting of unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitors are associated with lower rates of the two composite co-primary endpoints of (A) death, MI or stroke and (B) death, MI, stroke or major bleeding, both endpoints within the first 30 days after randomization (MATRIX Anti-thrombin).

And the final objective is to test whether prolonged post-PCI bivalirudin infusion will be superior to no bivalirudin post-PCI infusion with respect to the net composite outcome consisting of any death, MI, stroke, urgent target vessel revascularisation (TVR), stent thrombosis and BARC-defined type 3 and 5 bleeding events within 30 days (MATRIX Treatment Duration). All patients will receive immediately upon enrolment a bolus of 0.75 mg/kg of bivalirudin, followed by an infusion of 1.75 mg/kg/h. This infusion should be run continuously until completion of PCI at which time the infusion should be stopped in the SDWLHQWV�UDQGRPL]HG�WR�³QR�ELYDOLUXGLQ�SRVW-3&,´��RU�UHGXFHG�WR�D�GRVH�RI��PJ�NJ�K�LQ�WKH�SDWLHQWV�UDQGRPL]HG�WR�³SURORQJHG�SRVW-3&,�ELYDOLUXGLQ´�IRU�DW�OHDVW��KRXUV��$Q�RSWLRQDO�higher-dose infusion of 1.75 mg/kg/h is also permitted for up to 4 hours in the prolonged post-PCI infusion arm (but again prohibited in the no bivalirudin post-PCI infusion group).

It is planned that 8200 patients will be enrolled into MATRIX.

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2. Study objectives

2.1. Primary objectives

x To evaluate whether the trans-radial access as compared with the trans-femoral access site is associated with lower rate of the composite of death, MI, or stroke and the composite of death, MI, stroke or major bleeding within the first 30 days after randomization (MATRIX Access Site)

x To evaluate whether bivalirudin infusion as compared to standard of care therapy consisting of unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitors is associated with lower rate of the composite endpoint of death, MI or stroke and the composite endpoint of death, MI, stroke or major bleeding within the first 30 days after randomization (MATRIX Anti-thrombin)

x To evaluate whether prolonged bivalirudin infusion after PCI (long bivalirudin arm) will be superior to bivalirudin administration discontinued at the end of PCI (short bivalirudin arm) with respect to the net composite outcome consisting of any death, MI, stroke, urgent TVR, stent thrombosis, BARC-defined type 3, or type 5 bleeding events within 30 days after randomization (MATRIX Treatment Duration).

2.2. Secondary objectives

The following secondary objectives will be evaluated for all three comparisons in the MATRIX trial programme.

x To compare the rate of each component of the composite endpoint of the first and co-primary endpoints at 30 days and 1 year between treatment groups.

x To compare the rate of stent thrombosis at any time during follow-up between treatment groups.

x To compare the rate of urgent TVR up to 30 days between treatment groups. x To compare the rate of procedural success defined as final TIMI 3 flow and a residual

coronary stenosis of less than 30% at visual estimation between treatment groups. x To compare the rate of bleeding based on BARC, TIMI and GUSTO classification

between treatment groups. x To compare net clinical outcomes (defined as the composite of death, MI, stroke and

TIMI minor or major bleedings according to TIMI) between treatment groups. x To compare the rate of thrombocytopenia between treatment groups. x To compare the length of hospitalisation between treatment groups. x To compare the need for surgical access site repair/intervention or blood products

transfusion between treatment groups.

The following additional objectives specified in the protocol will be addressed as major sub-projects of this trial programme, will be defined in more detail and analysed later, and will not be included in the main clinical study report:

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x To compare costs of hospitalisation between treatment groups. x To compare cost-effectiveness between transradial and transfemoral access and

between bivalirudin and UFH±GPI. x To determine the prognostic impact of bleeding complications on 30 days death, MI

or stroke rate as assessed based on various bleeding classifications including BARC, TIMI and GUSTO as well as the prognostic role of thrombocytopenia.

x To compare radial artery patency rates across the four tested pharmacological treatment strategies (i.e. UFH alone, UFH plus GPI, Bivalirudin short and Bivalirudin long) using an inverse-probability of treatment weights (IPTW) approach.

x To determine the differential prognostic impact of various MI definitions as well as how various MI definition may impact on treatment effect (See CEC Charter for more details)

x To determine the differential prognostic impact of various bleeding definitions as well how bleeding definition may impact on treatment effect (See CEC Charter for more details)

x To determine the differential prognostic impact of bleeding versus stent thrombosis and bleeding versus overall myocardial infarction (for overall and cardiovascular mortality) aiming to generate a weighed net clinical adverse including both ischemic and weighted bleeding endpoints and compare it across tested treatment strategies

x To determine the effect of treatment stratified based on bleeding or thrombosis risk using previously validated scoring systems, including CRUSADE, GRACE, ACUITY.

x To determine the prognostic value of on-treatment P2Y12 platelet residual activity measured via a point-of-care instruments at the time or immediately after PCI

2.3. Assessment of endpoints

The endpoints will be assessed at 30 days after randomization (primary and secondary objectives) and at 1 year (primary objectives only). Investigators will record events and the date of the events per patient. The Clinical Events Committee (CEC) will adjudicate the following events:

��'HDWK ��0\RFDUGLDO�,QIDUFWLRQ��0,� ��6WURNH ��7UDQVLHQW�LVFKHPLF�DWWDFN��7,$� ��%OHHGLQJ ��6WHQW�7KURPERVLV��67� ��8UJHQW�WDUJHW�YHVVHO�UHYDVFXODUL]DWLRQ��XUJHQW�795�

This list includes all of the components of the composite primary endpoint (a composite of death, re-infarction (MI), or stroke 30 day after randomization) as well as other secondary endpoints.

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2.4. Changes of the primary objective during the conduct of the study

No changes of the primary objective will be allowed during the conduct or after completion of the study.

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3. Study design

3.1. General design and plan

Multi-centre, prospective, randomised, open-label comparison of trans-radial vs. trans-femoral intervention (MATRIX Access Site), bivalirudin vs. unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitor (MATRIX Anti-thrombin), and early stopping vs. prolonged post-PCI bivalirudin infusions (MATRIX Treatment Duration) in all-comer patients with acute coronary syndrome undergoing early invasive management.

3.2. Sample size

MATRIX Access Site:

x It is expected that the incidence of the first co-primary end-point (death, MI, or stroke at 30 days) on an intention to treat basis will be 4.2% in the transradial group and 6% in the transfemoral group (relative risk, RR: 0.70) , respectively. A total of 8200 randomised patients or 4100 patients per group will provide 90% power with an alpha error set at 2.5% to correct for two co-primary endpoints.

x It is expected that the incidence of the second co-primary end-point (death, MI, stroke or major bleeding at 30 days) on an intention to treat basis will be 6.3% in the transradial group and 9.0% in transfemoral group (relative risk, RR: 0.70), respectively. A total of 8200 randomised patients or 4100 patients per group will provide 99% power with an alpha error set at 2.5% to correct for two co-primary endpoints.

MATRIX Anti-thrombin:

x It is expected that the incidence of the first co-primary end-point (death, MI or stroke at 30 days) on an intention to treat basis will be 4.2% in the bivalirudin group and 6% in the UFH group (relative risk, RR: 0.70) , respectively. A total of 6800 randomised patients or 3400 patients per group will provide 85% power with an alpha error set at 2.5% to correct for two co-primary endpoints.

x It is expected that the incidence of the second co-primary end-point (death, MI, stroke or major bleeding at 30 days) on an intention to treat basis will be 6.3% in the bivalirudin group and 9.0% in the UFH group (relative risk, RR: 0.70) , respectively. A total of 6800 randomised patients or 3400 patients per group will provide 95% power with an alpha error set at 2.5% to correct for two co-primary endpoints.

MATRIX Treatment Duration:

x A total of 3400 randomised patients, i.e. 1700 patients per group will provide 86% power to assess superiority of prolonged post-PCI bivalirudin infusion versus

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standard care post-PCI infusion assuming a background event rate of death, MI, stroke, urgent TVR, stent thrombosis and type 3 and 5 type BARC bleedings of 10% in the prolonged post-PCI bivalirudin infusion group versus 7.0% standard care post-PCI infusion group (relative risk, RR: 0.70) with a type I error set at 5.0%.

Note that the overall sample size is driven by the pharmacological comparison.

3.3. Randomization

Patients eligible for access site randomization will be randomized to transfemoral or transradial access on a 1:1 ratio. Patients with planned medical therapy or CABG will not be further randomized. Patients with planned PCI will be randomized using a 1:1 allocation ratio to bivalirudin or unfractionated heparin (UFH). Patients randomly assigned to receive bivalirudin will be randomized using a 1:1 allocation ratio to stop bivalirudin infusion at the end of PCI or to prolong bivalirudin at an infusion rate of 0.25 mg/kg/hour for at least 6 hours after completion of PCI or, at discretion of the treating physician at 1.75 mg/kg/h is also permitted for up to 4 hours.

Randomization will occur via a dedicated website. Randomization will be stratified based on the following variables:

x Type of ACS (3 groups: STEMI, NSTEACS troponin negative, NSTEACS troponin positive)

x Intended or ongoing use of prasugrel or ticagrelor (2 groups: prasugrel/ticagrelor vs clopidogrel).

x Site

Additionally, the NSTEACS patients will be randomized stratified on:

x Actual treatment strategy (i.e. Coronary angiography only not followed by PCI or coronary angiography followed by PCI/ planned PCI).

3.4. Blinding

The trial programme is open-label. Despite the obvious benefits of a double-blind design, the operator or the other patient medical and paramedical staff cannot be blinded as to access site. Similarly, blinding of the pharma-therapeutic strategy in this study would require a double dummy approach which may realistically delay the active treatment especially in the setting of STEMI patients or make the pre-hospital treatment phase impossible. Furthermore, all efforts must be taken not to retard time to reperfusion in patients with STE-ACS.

An independent Clinical Events Committee (CEC) will adjudicate all primary clinical endpoints plus bleedings and stent thrombosis. The committee members and the CEC management team will be completely blinded to the randomized therapy, as well as any

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patient identifying information. The CEC will adjudicate the events based on pre-determined definitions.

The study statistician will be blinded for the primary analyses.

3.5. Study assessments

Table 1: Visit Schedule

ACS Pre-Hospital In-Hospital

Follow-up Screening

Tx Pre-

Cathlab

Angio±PCI Post-Index PCI

��¶ 8±4 hs 16±4 hs

24±4 hs

Discharge

30±5 days

1 year

±30days

History and Examination

X1 X1 X1 X X X X X

Inclusion and Exclusion criteria

X1 X1 X

12-lead ECG ��X�� X X X X X

Informed consent

X1 X1 X

Randomisation

X1 X1 X

Concomitant medications

��X�� X X X X X X X

VerifyNow P2Y12 Assay

X X3

Cardiac markers

X2 X5 X X X

Instrumented radial artery patency and collateral circulation4

X X X

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Bivalirudin X1 X X X X X X

Standard Tx X X X X X X X X X

MACCE X1 X X X X X X X X X

Bleedings X1 X X X X X X X X X

AE/SAE X1 X X X X X X X X

1: Patients with STEMI can be randomized before arrival to the PCI facility centre. Patients with any type of ACS can be randomized upstream before arrival in the cath-lab. MAE denotes major adverse events. 2: in NSTEACS patients only 3: in selected sites only ��LQFOXGHV�$OOHQ¶V�WHVW�HYDOXDWLRQ�DQG�SXOVH�oximetry-based collateral circulation pattern evaluation (A-D pattern) 5: 3ULRU�WR�VWXG\�GUXJ�LQLWLDWLRQ�3&,¶

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4. Data management

Data management will be conducted by the Eustrategy Association, which will hire dedicated personnel. An electronic Case Report Form (eCRF) will be used to collect all patient data assessments that will be used for evaluation of specified analyses.

4.1. Data export

Data capture and export is provided through a web-based system (http://www.cardiostudy.it/matrix/web/). All visits and their corresponding eCRFs are exported into password-protected comma-delimited files using patient pseudonyms. An independent statistician will transform data files to Stata for analysis by the study statistician and will code treatment allocation to ensure that the study statistician will be blinded for the primary analyses.

4.2. Data validation

Data validation will be conducted by the data management team hired by the Eustrategy organization and will consist of both manual and automatic (i.e. computer based) validation scheme based on excel software tools (i.e. the format the initial database will be created by extraction from the e-CRF) as well as importing the excel spread-sheet into SPSS 20.0 and using available validation routines, including range tests, relational tests and trend tests.

The statistician will perform a plausibility-assessment of variables affecting the analyses of the primary and secondary outcomes, and affecting the flowchart (procedure date, discharge date, all follow-up dates, all event dates; valid clinical visit, lost-to-follow-up and withdrawal, baseline characteristics used to classify patients for stratified analyses).

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2) Flow Diagram: MATRIX Anti-thrombin

Assessed for eligibility (n= )

Excluded (n= ) i Medical trx/CABG planned (n= ) i Declined to participate (n= ) i Other reasons (n= )

Allocated to bivalirudin (n= ) i Received bivalirudin (n= )

i Did not receive bivalirudin (n= )

Received UFH± GPI (n=)

No PCI performed (n=) Refused PCI (n=) Died (n=) Other reasons (n=)

Allocated to UFH ± GPI (n= ) i Received UFH ± GPI (n= )

i Did not receive UFH ± GPI (n= )

Received bivalirudin (n=) No PCI performed (n=) Refused PCI (n=) Died (n=) Other reasons (n=)

Allocation

Randomized (n= )

Enrollment

Analysed at 30 days (n= ) i Censored at the time point, lost to follow-up

or withdrawn (n= )

Follow-up performed (n=)

No follow-up performed (n=) Lost to follow-up (n= ) Withdrew consent (n= ) Died (n= )


No follow-up performed (n=) Lost to follow-up (n= ) Withdrew consent (n= ) Died (n= )


or withdrawn (n= )

Analysis

Follow-Up 30 days

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3) Flow Diagram: MATRIX Treatment Duration


or withdrawn (n= )


No follow-up performed (n=) Lost to follow-up(n= ) Withdrew consent (n= ) Died (n= )

Allocated to prolonged bivalirudin (n= ) i Received prolonged bivalirudin (n= )

i Did not receive prolonged bivalirudin (n= )

No PCI performed (n=) Received UFH±GPI (n=) Discontinued bivalirudin post-PCI (n=) Died (n=) Other reasons (n=)


No follow-up performed (n=) Lost to follow-up(n= ) Withdrew consent (n= ) Died (n= )

Allocated to no post-PCI bivalirudin (n= ) i Discontinued bivalirudin post-PCI (n= )

i Did not discontinue bivalirudin (n= )

No PCI performed (n=) Received UFH±GPI (n=) Received bivalirudin post-PCI (n=) Died (n=) Other reasons (n=)


or withdrawn (n= )

Allocation

Analysis

Follow-Up 30 days

Randomized (n= )

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5.2. Definition of populations for analysis

The overall population randomly allocated to the access site or pharmacological treatment will be used for the analyses of the primary and secondary outcomes, the analyses will be by intention-to-treat. The observational period for the study will be 365 days. Any event occurring after the defined observational period, even if collected on the eCRF, will not be included in the planned statistical analysis.

5.3. Full analysis set (FAS)

The Full analysis set (FAS) will include all randomized subjects. Following the intent-to-treat (ITT) principle, subjects will be analysed according to the treatment they are assigned to at randomization irrespective of the final treatment (access site or pharmacological treatment), irrespective of whether a PCI has been performed.

Of note, some patients will not be scheduled for PCI, and hence will not be randomised for the MATRIX Anti-thrombin or the MATRIX Treatment Duration. These patients will be excluded from the ITT population for MATRIX Anti-thrombin or MATRIX Treatment Duration.

The ITT population will be the patient population in whom all primary and secondary endpoints will be assessed.

5.4. Per-protocol (PP)

The per-protocol population will be defined as all subjects who received treatment as allocated and had no major deviations from the allocated treatments up to 30 days. Major protocol deviations include:

x No angiography performed (MATRIX Access Site) x No PCI performed (MATRIX Anti-thrombin and Treatment Duration) x No bivalirudin received (MATRIX Treatment Duration) x Cross-overs

Sensitivity analyses of the primary and secondary endpoints will be performed in the per-protocol population.

5.5. PCI population

The PCI population consists of all subjects in the FAS who underwent PCI and were randomised to access site (MATRIX Access Site) or randomised to study medication (MATRIX Anti-thrombin and MATRIX Treatment Duration). Subjects will be analysed according to the treatment they are assigned to (ITT PCI population) as well as based on the treatment actually received (PP PCI population).

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Sensitivity analyses of the primary and secondary endpoints will be performed in the PCI population.

5.6. Safety population

The safety population consists of all subjects in the FAS who undergo angiography (MATRIX Access Site), who take at least one dose of study medication (MATRIX Anti-thrombin) or who receive at least one dose of bivalirudin (MATRIX Treatment Duration). Subjects will be classified according to the actual treatment received.

Sensitivity analyses of the primary and secondary endpoints which include bleeding events will be performed in the safety population.

5.7. Definition of sub-group populations in different analyses

See section 6.6.7.

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6. Statistical analysis

6.1. General

This is a superiority trial with an intention-to-treat analysis design for all primary and secondary outcomes. All randomized patients who provided written informed consent will be analysed as randomly allocated to their treatment arm (intention-to-treat).

6.2. Pooling of sites

All sites will be pooled in the analyses.

6.3. Interim analyses

No interim analyses are planned.

6.4. Time-points for analysis

The primary time point for the analyses of all outcomes is after 30 days follow-up of all patients. Primary endpoints and their components will also be analysed after a follow-up of all patients for 1 year.

6.5. Methods for handling missing data

This is a randomized clinical trial and as such, all analyses are based on the intention-to-treat. No multiple imputation techniques are needed for handling of missing data.

6.5.1. Handling of dropouts

The primary and secondary outcomes will be analysed on the last valid contact date with each patient and censored accordingly, using time-to-first-event.

6.6. Statistical analytical issues

6.6.1. Assessment of statistical assumptions

Continuous data will be visually inspected. In case of asymmetrical distributions, transformations (e.g. using natural logarithm) before testing will be considered. Testing will be performed on the transformed variable and p-values will be reported from tests on the transformed variable. Alternatively, robust descriptive statistics (i.e. medians and interquartile ranges) and non-parametric tests will be considered.

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6.6.2. Adjustments for covariates

No adjustments for covariates will be made.

6.6.3. Multicentre studies

All sites will be pooled in the main analyses. In a sensitivity analysis, we will adjust for the criteria used to stratify the randomization and the centres.

6.6.4. Multiple comparisons

MATRIX includes three independent trials (MATRIX Access Site, MATRIX Anti-thrombin and MATRIX Treatment Duration) and the overall significance level of each trial will be set at a two-VLGHG�.�RI��. Because the MATRIX Access Site and the MATRIX Anti-thrombin have two co-primary endpoints, the significance level for each of the co-primary endpoint will be set at a two-VLGHG�.�RI��25 in these two trials. The MATRIX Treatment Duration has only one primary endpoint, and the significance level will be set at a two-VLGHG�.�RI�� throughout this trial.

6.6.5. Use of efficacy subset

Not applicable.

6.6.6. Active-control studies intended to show equivalence

Not applicable.

6.6.7. Examination of subgroups

Stratified analysis of the primary endpoints will be performed according to the following patient characteristics at baseline in all three MATRIX trials:

- $JH��\HDUV�YV��\HDUV - Gender: Male vs Female - Body mass index (BMI): <25 kg/m2 YV��NJ�P2 - Overall annual PCI rate by centre: Low vs Intermediate vs High (grouped into tertiles) - Annual radial PCI rate by centre: Low vs Intermediate vs High (grouped into tertiles) - Type of ACS: STEMI vs NSTEACS troponin negative vs NSTEACS troponin positive - Intended or ongoing use of prasugrel or ticagrelor: Yes vs No - Diabetes: Yes vs No - Renal function at baseline: estimated glomerular filtration rate (eGFR)<60 mL/min vs

H*)5��P/�PLQ - History of peripheral vascular disease: Yes vs No

All stratified analyses will be accompanied by a test for interaction between treatment effect and stratification factor.

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7. Evaluation of demographic, baseline and procedural characteristics

7.1. Demographics and baseline characteristics

Continuous variables will be summarised by means, standard deviations (SD), medians, interquartile ranges and minimum and maximum values. Categorical variables will be summarised by frequencies and percentages.

P-values will not be shown in the baseline table since any significant difference can be explained by the play of chance if the randomization was performed properly.

7.1.1. Shell table

The following tables will be produced for all three comparisons: Comparison of patients randomised to transradial vs transfemoral access (MATRIX Access Site), to bivalirudin vs unfractionated heparin ± glycoprotein IIb/IIIa inhibitor (MATRIX Anti-thrombin) and to prolonged vs no post-PCI bivalirudin (MATRIX Treatment Duration) in the ITT populations as defined in 5.3.

Table 1. Baseline Characteristics

Experimental Treatment

Strategy

Reference Treatment

Strategy

Total number of patients N = xx N = xx

Age (years) n = xx xx.x ± xx.x n = xx xx.x ± xx.x

<75 years n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Hóñ�Ç�� n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Male gender n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Weight (kg) n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Body Mass Index (kg/m²) n = xx xx.x ± xx.x n = xx xx.x ± xx.x

<25 kg/m2 n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Hîñ�lPlu2 n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Medical history

Diabetes mellitus n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Insulin-dependent n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Non-insulin dependent n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Smoker n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Current smoker n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous smoker n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

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Strategy

Reference Treatment

Strategy


Hypercholesterolemia n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Hypertension n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Family history of coronary artery

disease n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous myocardial infarction n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous PCI n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous transradial catheterisation n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous transfemoral catheterisation n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous CABG n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous TIA or stroke n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Peripheral Vascular Disease n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Chronic Obstructive Pulmonary Disease n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Pulmonary hypertension n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Renal failureb n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Dialysis n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Clinical presentation

Cardiac arrest n = xx xx.x (xx.x%)

n = xx xx.x (xx.x%)

Killip II, III or IV n = xx xx.x (xx.x%)

n = xx xx.x (xx.x%)

Acute Coronary Syndrome n = xx xx.x (xx.x%)

n = xx xx.x (xx.x%)

STEMI n = xx xx.x (xx.x%)

n = xx xx.x (xx.x%)

NSTEACS, troponin negative n = xx xx.x (xx.x%)

n = xx xx.x (xx.x%)

NSTEACS, troponin positive n = xx xx.x (xx.x%)

n = xx xx.x (xx.x%)

Systolic arterial pressure (mmHg) n = xx xx.x ± x.xx n = xx xx.x ± x.xx

Heart rate (min-1) n = xx xx.x ± x.xx n = xx xx.x ± x.xx

Left ventricular ejection fraction (%) n = xx xx.x (xx.x-xx.x) n = xx xx.x (xx.x%)

Medications

Aspirin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Clopidogrel n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Prasugrel n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

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Strategy

Reference Treatment

Strategy


Ticagelor n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Enoxaparin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Fondaparinux n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

ACE inhibitors n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Angiotensin II receptor antagonist n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Statins n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Beta blockers n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Warfarin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

PPI n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous unfractionated heparin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Glycoprotein IIb/IIIa inhibitors n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous low weight molecular heparin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Previous fondaparinux n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Medications in the cath-lab

Clopidogrel n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Prasugrel n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Ticagrelor n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Glycoprotein IIb/IIIa inhibitors n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Depicted are sample sizes (n); and counts (%), means±standard deviations or medians (25%-75%

interquartile range).

a = Renal failure is defined as an estimated glomerular filtration rate (eGFR)<60ml/min.

7.2. Procedural characteristics

Procedural characteristics will be summarised by number (percentage) for categorical variables and means (standard deviations) or medians (interquartile ranges) for continuous variables. P-values will be computed using Chi-square or (in case of few events) )LVKHU¶V� WHVWV� IRU� categorical variables, 6WXGHQW¶V� t-tests for continuous variables (if needed on transformed variables to ensure QRUPDOLW\�� DQG�:LOFR[RQ¶V�Mann-Whitney U-tests for non- symmetrically distributed continuous variables; in each variable for the patient-level data.

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Table 2. Procedural Characteristics

Experimental

Treatment Strategy

Reference Treatment

Strategy p-value


PCI performed n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

First attempted vascular access site n = xx n = xx x.xxx

Femoral xx.x (xx.x%) xx.x (xx.x%)

Brachial xx.x (xx.x%) xx.x (xx.x%)

Radial xx.x (xx.x%) xx.x (xx.x%)

Successful vascular access site n = xx n = xx x.xxx

Femoral xx.x (xx.x%) xx.x (xx.x%)

Brachial xx.x (xx.x%) xx.x (xx.x%)

Radial xx.x (xx.x%) xx.x (xx.x%)

Number of lesions treated N = xx N = xx

Lesions treated per patient n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

One lesion xx.x (xx.x%) xx.x (xx.x%)

Two lesions xx.x (xx.x%) xx.x (xx.x%)

Three or more lesions xx.x (xx.x%) xx.x (xx.x%)

Treated vessel(s)

Left main coronary artery n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Left anterior descending artery n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Left circumflex artery n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Right coronary artery n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Bypass graft n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Hî�s��o�� n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

PCI Procedurea

No of stents per lesion n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Type of stent

x.xxx

Drug-eluting stent n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Bare metal stent n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

Total stent length per lesion (mm) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Average stent diameter per lesion (mm) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Direct stenting n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Postdilatation n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Intraaortic balloon counterpulsation n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

TIMI flow pre-procedure x.xxx

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Table 2. Procedural Characteristics

Experimental

Treatment Strategy

Reference Treatment

Strategy p-value


0 or 1 n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)

2 n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)


TIMI flow post-procedure x.xxx

0 or 1 n = xx xx.x (xx.x%) n = xx xx.x (xx.x%)



a= lesion-level data, P values will be derived from mixed-effects models.

7.3. Hospital discharge

Laboratory values and medications at discharge will be summarised by number (percentage) for categorical variables and means (standard deviations) or medians (interquartile ranges) for continuous variables. P-values will be computed using Chi-VTXDUH�RU��LQQ�FDVH�RI�IHZ�HYHQWV��)LVKHU¶V�WHVWV�IRU�FDWHJRULFDO�YDULDEOHV��6WXGHQW¶V�W-tests for continuous variables (if needed on transformed variables to ensure normality), DQG�:LOFR[RQ¶V�0DQQ-Whitney U-tests for non- symmetrically distributed continuous variables; in each variable for the patient-level data-

Table 3. Hospital discharge

Experimental

Treatment Strategy

Reference Treatment

Strategy p-value


Laboratory values n = xx n = xx

Creatinine (mg/dl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Creatinine peak* (mg/dl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Ck (U/l) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

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Table 3. Hospital discharge

Experimental

Treatment Strategy

Reference Treatment

Strategy p-value


Ck peak* (U/l) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

CktMB (ng/ml) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

CktMB peak* (ng/ml) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Troponin (ng/ml) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Troponin peak* (ng/ml) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Troponin Qualitative (above ULN) n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Platelets Volume () n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Platelets (x 1000/Pl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Platelets nadir** (x 1000/Pl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Haemoglobin (g/dl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Haemoglobin nadir** (g/dl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Glycemia (mg/dl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

WBC (x 1000/Pl) n = xx xx.x ± xx.x n = xx xx.x ± xx.x x.xxx

Medications

Aspirin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Ticlopidine n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Clopidogrel n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Prasugrel n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Ticagrelor n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

P2Y12 inhibition n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Angiotensin II receptor antagonist n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

ACE inhibitors n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Statins n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Beta blockers n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Warfarin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

H2 blockers n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Diuretics n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Insulin n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Oral hypoglicemic drugs n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

PPI n = xx xx.x (xx.x%) n = xx xx.x (xx.x%) x.xxx

Depicted are sample sizes (n); and counts (%), means±standard deviations or medians (25%-75%

interquartile range). *Peak post-PCI.

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8. Evaluation of treatment compliance and exposure

8.1. Compliance to study treatment

8.1.1. Compliance to study treatment

Access site used will be recorded during angiography and use of antithrombotic treatment will be recorded before, during and after PCI.

8.1.2. Measurement of study treatment compliance

Treatment compliance will be defined as

x The angiography was performed through the access site specified in the protocol and according to the random allocation (MATRIX Access Site).

x The patient received antithrombotic treatment during PCI as specified in the protocol and according to the random allocation (MATRIX Anti-thrombin).

x The patient received bivalirudin during PCI, and post-PCI bivalirudin infusion was performed as specified in the protocol (i.e. stopped at the time as per protocol) and according to the random allocation (MATRIX Treatment Duration).

8.2. Exposure to study treatment

8.2.1. Extent of exposure

Antithrombotic medication before, during and after PCI will be recorded including stop date/time and reasons for stopping.

8.2.2. Duration of exposure

Antithrombotic medication before, during and after PCI will be recorded including stop date/time and reasons for stopping.

8.2.3. Dose of exposure

Recommended dosages of exposures are specified in the protocol.

8.2.4. Drug concentrations

Drug concentrations are specified in the protocol.

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9. Evaluation of pharmacokinetics

Not applicable.

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10. Evaluation of efficacy parameters

10.1. Analysis of primary, secondary, and other efficacy endpoints

10.1.1. Analysis of primary endpoint

In MATRIX Access Site both co-primary endpoints (composite of all-cause mortality, stroke and MI; composite of all-cause mortality, stroke, MI and major bleeding) will be analysed at 30 days according to the intention-to-treat principle in the intent-to-treat population using the Mantel-Cox log-rank method.

In MATRIX Anti-thrombin both co-primary endpoints (composite of all-cause mortality, stroke and MI; composite of all-cause mortality, stroke, MI and major bleeding) will be analysed at 30 days according to the intention-to-treat principle in the intent-to-treat population using the Mantel-Cox log-rank method.

In MATRIX Treatment Duration the primary endpoint (composite of all-cause mortality, stroke and MI; composite of all-cause mortality, stroke, MI, urgent TVR, stent thrombosis and major bleeding) will be analysed at 30 days according to the intention-to-treat principle in the intent-to-treat population using the Mantel-Cox log-rank method.

Sensitivity analyses will be performed in the per-protocol population as defined in section 5.4. and in the PCI populations as defined in section 5.5.

10.1.2. Analysis of secondary efficacy endpoints

Secondary efficacy endpoints up to 30 days and up to 1 year will be analysed according to the intention-to-treat principle in the intent-to-treat population using the Mantel-Cox log-rank method as time-to-first event.

10.1.3. Analysis of other efficacy endpoints

Not applicable.

10.2. Method for analysis of efficacy endpoints

10.2.1. Binary data

Not available.

10.2.2. Count data

Not available.

10.2.3. Continuous scale data

Length and costs of hospital stay will be described using medians and interquartile ranges per group and compared between groups using :LOFR[RQ¶V�0DQQ-Whitney U-tests.

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10.2.4. Time-to-event data

All primary and secondary outcomes will be analysed on time-to-first event. The primary, all secondary and all other endpoints will be analysed using the Mantel-Cox method accompanied by the log-rank test to calculate corresponding p-values. Survival curves will be constructed using Kaplan-Meier estimates. Patients are start being at risk on the day of randomization for the access site comparisons and on the day of PCI (or on the day of randomization if no PCI was performed) for the pharmacological comparisons.

10.2.5. Ordinal scales and non-ordered scales data

Not available.

10.3. Shell table

The table below will be produced for all three trials in the MATRIX programme: MATRIX Access Site, MATRIX Anti-thrombin, and MATRIX Treatment Duration.

Table 4. Clinical Outcomes

Experimental

Treatment

Strategy

Control

Treatment

Strategy

Risk Ratio

(95% CI) p-value


At 30 Days

Composite of all-cause mortality, MI or

stroke xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Composite of all-cause mortality, MI,

stroke, and BARC 3-5 xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Composite of all-cause mortality, MI,

stroke, urgent TVR, stent thrombosis and

BARC 3-5

xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Mortality

All-cause xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Cardiac xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Myocardial infarction (MI) xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Q-wave MI xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Non Q-wave MI xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Stroke xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Ischemic stroke xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Haemorrhagic stroke xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Revascularisation xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

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Experimental

Treatment

Strategy

Control

Treatment

Strategy

Risk Ratio

(95% CI) p-value


Target vessel revascularisation (TVR) xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Stent thrombosis xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

BARC 3 or 5 Bleeding xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Composite of all-cause mortality,

stroke, MI and TIMI minor or major bleeding xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Procedural success* xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

TIMI-3 flow xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Coronary stenosis<30% xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

TIMI major or minor bleeding xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Thrombocytopenia xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Composite of surgical access site repair

or blood products transfusion xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Surgical access site repair xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Blood products transfusion xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

At 1 Year


stroke and MI xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx


stroke, MI and major bleeding (BARC) xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx


stroke, MI, urgent TVR, stent thrombosis

and major bleeding (BARC)

xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Mortality

All-cause xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Cardiac xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Myocardial infarction (MI) xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Q-wave MI xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Non Q-wave MI xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Stroke xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Ischemic stroke xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Haemorrhagic stroke xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Revascularisation xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Target vessel revascularisation (TVR) xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Stent thrombosis xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

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Experimental

Treatment

Strategy

Control

Treatment

Strategy

Risk Ratio

(95% CI) p-value


BARC 3 or 5 Bleeding xx (xx.x%) xx (xx.x%) xx.x (xx.x-xx.x) x.xxx

Data are number of first events (% incidence at follow-up from life-tables with censoring at last contact date). For each patient only the first event per outcome will be considered. Risk ratios (95% confidence interval, CI) and p-values from Mantel-Cox logrank tests. BARC denotes Bleeding Academic Research Consortium, MI denotes myocardial infarction, TIMI denotes Thrombolysis In Myocardial Infarction, TVR denotes target vessel revascularisation. *Procedural success will be defined as final TIMI 3 flow and a residual coronary stenosis of less than 30% at visual estimation.

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11. Evaluation of safety parameters

11.1. Adverse events

11.1.1. Brief summary of adverse events

All adverse events will be assessed and documented from informed consent of the patient until 1 year. Bleeding events will be specifically recorded for this trial and analysed as part of primary and secondary endpoints (see section 10.1.).

11.1.2. Display of adverse events

All adverse events will be sorted per patient and date of event, and lists provided to the PI, including first and recurrent events for each patient.

11.1.3. Analysis of adverse events

All analyses will be performed by the CTU on request and files will be provided to the PI on request.

11.1.4. Listing of adverse events by patient

All events will be provided to the PI on request.

11.1.5. Deaths, serious adverse events, and significant other adverse events

All events will be provided to the PI on request.

11.1.6. Analysis of deaths, serious adverse events, and significant other adverse events

Deaths will be specifically recorded for this trial and analysed as part of primary and secondary endpoints (see section 10.1.). Further analyses will be performed by the CTU on request and files will be provided to the PI on request.

11.2. Clinical laboratory evaluations

11.2.1. Analysis of abnormal laboratory values

Not applicable

11.2.2. Evaluation of each laboratory examination

Not applicable.

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11.3. Concomitant medications

11.3.1. Concomitant therapy

Not applicable.

11.4. Vital signs and physical examination

11.4.1. Findings in vital signs and physical examinations

Not applicable.

11.5. Other safety evaluations

11.5.1. Other observations related to safety

Not applicable.

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Study Initiation Protocol: Version n°2 Amendment of 7th

June 2011 (all sites

initiated with this version of Protocol) - CEC approval (Ethics Committee of Province

of Ferrara) 30 Jun 2011

1° Amendment: Protocol Version n°3 Amendment of April 14th

2013 - CEC approval

(Ethics Committee of Province of Ferrara) 30 May 2013

The drafting of the Amendment 3 to the Protocol was necessary in order to clarify and better

specify the objectives, the selection of patients and the study procedures.

In particular:

• The objectives of the study, that were generic for Acute Coronary Syndrome, were better

defined and specified for NSTEMI and STEMI patients.

• In the chapter of the Protocol relating to the design of the study it is stated that, in the

event that it is necessary to start anticoagulant therapy for obtaining tomographic (IVUS or

OCT) or functional (FFR) information that the physician deems necessary for evaluating

whether to proceed the PCI procedure, patients can be randomized before the decision to

proceed to PCI.

• In the exclusion criteria was further specified that only patients allergic or intolerant

simultaneously to clopidogrel and ASA will be excluded from the study.

• It has been specified the mode of administration of bivalirudin according to clinical

practice

• It has been better defined the statistical plan of the study: the statistical test that will be

used to evaluate both the primary and secondary endpoints of the study is the univariate

Cox regression with time-to-event as survival information and arm randomization

according to the concept of' intention to treat as a covariate (eg, transradial versus

Transfemoral, bivalirudin versus UFH +/- GPI and finally short bivalirudin versus bivalirudin

long). The threshold of significance for such analysis will be the conventional 5%, p <0.05.

• It was deleted the GENE-MATRIX substudy as the company that had proposed to provide

free Kits for performing genetic tests, decided not to supply them more free.

• The following substudies will be added:

1. Pru Matrix substudy

Personalized choice of the inhibitor of the platelet P2Y12 receptor according to an algorithm

integrated evaluation of the phenotype (platelet reactivity tested with the point-of care

VerifyNow)

In patients treated with oral inhibitor of the platelet P2Y12 receptor evaluation of phenotype

assessment based on PRU at follow-up has been identified as the most important predictor of

subsequent ischemic or bleeding events, whereas the presence of loss of function alles did not

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emerge as independent outcomes predictor if actual PRU while on-treatment was forced into the

model. This finding supports the concept that phenotype, bing downstream with respect to

genetic status, plays a much bigger role as risk-stratification tool in patients taking P2Y12

inhibitors. Therefore, phenotype alone may better guide the decision to modulate the intensity of

P2Y12 inhibition than genotype alone.

Based on these considerations, the objective of this sub-study is to demonstrate that in patients

Acute Coronary Syndrome (ACS) Patients undergoing early PCI, that an algorithm to select the

most proper oral P2Y12 blocker integrating phenotype information (and not of an integrated

assessment of phenotype and genotype as indicated in the previous version of the Protocol) will

result in a lower composite endpoint of cardiovascular death, myocardial infarction, stroke or

BARC defined bleeding type 2 or 3 at 1, in a year by PCI compared to standard of care.

Patients recruited in the MATRIX study who underwent successful PCI with stent implantation,

provided that the sub-study informed consent is signed, will be randomized at discharge in a 1:1

ratio in blocks of 6, stratified on type of ACS (STEMI vs. NSTEACS) and type of oral P2Y12 receptor

blocker during hospitalization (clopidogrel versus prasugrel/ticagrelor), into phenotype based

selection of P2Y12 blocker versus standard of care.

2. Optical Coherence Tomography (OCT) sub-study

The rationale of this sub-study is based on the hypothesis that The use of long-term bivalirudin

infusion, as compared to the intra-procedural only administration, reduces residual thrombosis of

stent struts evaluated by OCT at the end of procedure and at 3-5 days follow-up, in patients

affected by STEMI, treated by primary PCI and showing multivessel disease suitable for staged PCI.

As a primary endpoint, will be considered the percentage difference in Minimal Flow Area

(MinFA) measured:

1) at the end of primary PCI and

2) at the time of staged PCI

MinFA is defined as: [Stent area + incomplete stent apposition (ISA) area] – [intraluminal defect +

tissue prolapse area]

3. Radiation dose sub-study

The rationale of this sub-study is based on evidence of a possible higher radiation exposure

associated with transradial access (6-9) and the radiation risk might be increased both for the

physician and for the patient. The main reasons are probably due to the more complicate catheter

manipulation requiring prolonged fluoroscopy time and the more unfavorable operator position,

closer to X-ray source, associated with transradial approach. Despite these studies the magnitude

of radiation exposure during transradial compared to transfemoral access is still unclear

particularly for expert operators in transradial approach. The aim of this sub-study is Aim of our

study is to evaluate the radiation dose adsorbed by operators during percutaneous coronary

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procedures in the setting of acute coronary syndromes comparing the transradial and the

transfemoral approach. Moreover it will also evaluate the radiation dose adsorbed by operators

during right or left transradial approach. For this purpose it will be used three special set of three

dosimeters for the femoral approach, right radial and radial left.

The radiation absorbed dose will be evaluated at the end of the study at a central laboratory

(TECNORAD Srl -Verona).

Primary end-point of the study is the radiation dose adsorbed at wrist, thorax and eye by

operators comparing the femoral or radial approach and detected by the thermoluminescent

dosimeters.

A further primary end-point is the radiation dose adsorbed at wrist, thorax and eye by operators

comparing the right or left radial approach and detected by the thermoluminescent dosimeters.

4. Other prespecified substudies to be derived from the data collected for the main study who

have no additional impact on patients

• Impact of the access site and the drug regimen in patients who have recently undergone

PCI

• Impact of the access site and the drug regimen in patients with STEMI

• Impact of the access site and the drug regimen in patients with NSTEMI

• Impact of the experience of the operator on the results

• Impact of the access site in patients who were not undergoing PCI, including those treated

medically or underwent CABG

• Feasibility and safety of the intervention trans-radial in patients with abnormalities of the

patency of the radial artery as measured with the Allen test or the test Barbeu

• Patency of the radial artery in the short term (at discharge) and long term (30 days or

more) after intervention trans-radial in relation to variables pre, intra and post procedural

including previous surgery, cardiovascular risk factors, type and size introducer arterial

hemostasis technique, drug regimen, need to programmed procedures

• Role of Syntax score on comparative effectiveness and safety of the two access sites and

the three pharmacological options compared in the study

• Role of creatinine clearance on comparative effectiveness and safety of the two access

sites and the three pharmacological options compared in the study

• Impact of the risk of ischemic and bleeding, evaluated through computer systems default

risk including GRACE, CRUSADE, Mehran algorithm, on comparative effectiveness and

safety of the two access sites and the three pharmacological options compared in the

study

• Impact of the access site and / or the drug regimen on complications of bleeding related to

the access site versus those not related to the access site

• Impact of antithrombotic therapy pre-randomization on comparative effectiveness and

safety of the two access sites and the three pharmacological options compared in the

study

• Impact of delay in relation to the onset of symptoms on the results and on the

comparative effectiveness and safety of the two access sites and the three

pharmacological options compared in the study

• Impact of the access site and / or the drug regimen on myocardial perfusion assessed by

analysis associated with ECG

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• Impact of the access site and / or the drug regimen on the rate of myocardial infarction

according to the universal definition of MI in 2007 or 2012

• Comparison of the prognostic implications of the definition of MI according to the

protocol with respect to the universal definition of 2007 and 2012

• Role of the variables pre, intra and post procedural including the type of stent, the need

for overlapping stents, Syntax score, number of stents implanted, techniques for post-

dilation or stenting on the results

• Prediction of outcome of patients through the study of electrocardiographic evaluation of

the degree of reperfusion based on different access sites and drug regimen, based on the

resolution of the above-segment elevation of the ST segment or the presence of above-

segment elevation residue and the association of baseline characteristics and post-

procedural.

It was also added to the protocol to the chapter concerning the classification of Clinical Events

(CEC)

It has been then modified the address of the Coordinating Center that the name of the CRO

charge after return for his Company Name.

These changes have led to changes in the Informed Consent and the Synopsis of the Study.

2° Amendment: Protocol Version n° 4 Amendment of September 16th

2013 - CEC

approval (Ethics Committee of Colli Hospital of Naples ) 26 September 2013

The drafting of the Amendment 4 to the study protocol has become necessary for the following

reasons:

• Following the transfer abroad of the Principal Investigator of the Coordinating Center it

was necessary to change the Coordinating Center, and consequently the Principal

Investigator: Dr. Paolo Calabrò has been identified as Principal Investigator and the Ethics

Committee of the Colli Hospital of Naples as new Coordinating Center.

• The Principal Investigator of the old Coordinating Center has changed following the

transfer abroad of the old Principal Investigator.

These changes have resulted in a new version of the protocol, the Synopsis of the Study

and the List of centers.

3° Amendment: Protocol Version n°5 Amendment of February 10th 2014 - CEC

Notification (Ethics Committee of Colli Hospital of Naples ) 26 February 2014

The Amendment 5 to the study protocol is not a substantial Amendment but is only an

administrative change since also Sweden enter in the Countries participating in the study.

The Statistical part of the protocol has also been specified following the SAP.

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MATRIX protocoll11-I March, 2, 2011

1/63

Minimizing Adverse haemmhorragic events by TRansradial access site and systemic Implementation of angioX (MATRIX)

Synopsis RFBU 11-I

EUDRACT Number: 2011-000430-11

Prepared on 2nd March 2011

M. Valgimigli

University of Ferrara, Arcispedale S. Anna, Corso Giovecca 203, 44100 Ferrara (ITALY)

[email protected]

The information in this document is considered privileged and is a confidential communication of the Cardiovascular Department of the University of Ferrara. Acceptance of this document constitutes agreement that this protocol and related information may not be copied, published, or disclosed to others except to the extent necessary to obtain Ethics Committee approval, informed consent, or as required by Law

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mailto:[email protected]



2/63

1. SYNOPSIS EUDRACT Number: 2011-000430-11 Name of Sponsor: Gruppo Italiano Studi Emodinamica (GISE) Name of Investigational Strategy and/or Product: Trans-Radial access and Bivalirudin (Angiox®) Acronym of Study: Minimizing Adverse haemmhorragic events by TRansradial access site

and systemic Implementation of AngioX (MATRIX)

Study centre(s): Approximately 60 centres located in Italy Principal Investigator: Marco Valgimigli, MD, PhD Investigators: Network Italiano Studi Radiale (NIR) Study period (years): Estimated date first patient enrolled: May 2011. Estimated date last patient recruited: December 2013. Estimated last patient completed: December 2014

Phase of development: IV

Objectives:

1) To demonstrate that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management.

2) To demonstrate that bivalirudin infusion as compared to standard of care therapy consisting of unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitors are associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management.

Methodology: Multi-centre, prospective, randomised, open-label, 2 by 2 factorial comparison of trans-radial vs. trans-femoral intervention and bivalirudin vs. unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitor. Number of patients (planned): Approximately 6,800

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3/63

NSTEACS definition: Patients with all of the following criteria will be eligible: (1) history consistent with new, or worsening ischemia, occurring at rest or with minimal activity; (2) enrolment within 7 days of the most recent symptoms; (3) planned coronary angiography with possible indication to PCI; (4) at least 2 of the following criteria:

1. Aged 60 years or older, 2. Troponin T or I or creatine kinase MB above the upper limit of normal; 3. Electrocardiograph changes compatible with ischemia, ie, ST depression of 1 mm or

greater in 2 contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts;

STEMI definition: i) chest pain for >20 min with an electrocardiographic ST-segment elevation ≥1 mm in two or more contiguous electrocardiogram (ECG) leads, or with a new left bundle-branch block, or an infero-lateral myocardial infarction (MI) with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave and ii) admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia or previous lytic treatment. To be included in the study all patients should receive as soon as logistically feasible a European Society of Cardiology (ESC) guideline recommended dose of: • Aspirin at an initial dose of 150-325 mg orally (or 250-500 mg IV) followed by 75-100 mg/day for at least 1 year. • A P2Y12 receptor blocker such as clopidogrel at a loading dose of 600 mg followed by 75 mg daily or prasugrel at a lading dose of 60 mg followed by 10 or 5 mg daily or ticagrelor (if and when commercially available) at a loading dose of 180 mg followed by 90 mg b.i.d daily. This should be continued as per ESC guidelines (preferably for one year) in all patients. Enrolment of patients will be stratified based on type of ACS (STEMI vs NSTEMI-troponin positive vs. NSTEACS-troponin negative), Intended or ongoing use of prasugrel and final treatment (i.e. PCI vs. non PCI). Investigational treatment, dosage and mode of administration:

• Trans-radial intervention: will be performed according to institutional guidelines and established local practice.

• Bivalirudin: given immediately upon enrolment as bolus of 0.75 mg/kg followed immediately by an infusion of 1.75 mg/kg/h. This infusion should be run continuously until completion of PCI at which time the infusion should be either stopped or reduced

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to a dose of 0.25 mg/kg/h for at least 6 hours. An optional higher-dose infusion of 1.75 mg/kg/h is also permitted for up to 4 hours in the prolonged infusion arm but prohibited in the short bivalirudin group.

Patients who do not undergo PCI and are to be medically managed may continue the infusion of 0.25 mg/kg/h for up to 72 hours. Patients who are to undergo coronary artery bypass grafting (CABG) are to undergo anticoagulation as per local practice. Post-PCI anticoagulation for prophylaxis or otherwise may be continued as per local practice. Reference therapy, dosage and mode of administration:

• Trans-femoral intervention: will be performed according to institutional guidelines and established local practice. Access closure devices are allowed as per local practice.

• UFH±GPI: Unfractionated heparin (UFH) (100 IU/kg with no glycoprotein IIb/IIIa inhibitor (GPI) and 60 IU/kg with a GPI); +/- routine or bail out eptifibatide (two 180 μg /kg boluses with a 10 minute interval followed by an infusion of 2.0 μg /kg/min for 72-96 hours) or tirofiban (25 μg/kg followed by an infusion of 0.15 μg/kg/min for 18 to 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, 10 μg/min). Patients who are to undergo CABG are to undergo anticoagulation as per local practice. Post PCI anticoagulation for prophylaxis or otherwise may be continued as per local practice.

Primary Endpoint at 30 days: • A composite of death, re-infarction (MI) or stroke Key Secondary Endpoints: A composite of death, non-fatal MI, stroke or BARC-defined type 3 and 5 major bleeding complications at 30 days. Main Secondary Endpoints:

1) The rate of each component of the composite endpoint of the primary or the key secondary endpoint at 30 days and 1 year analyzed in various study populations including the ITT and PP access site group both in the whole recruited patient population (i.e. including patients who underwent angiography only) and in those who finally underwent PCI and in the ITT and PP pharmacology arm both in the whole recruited patient population (i.e. including patients who underwent angiography only) and in those who finally underwent PCI, stratified based on actual use of GPI in the reference group.

2) The rate of stent thrombosis at any time during follow-up and the rate of urgent target vessel revascularization up to 30 days.

3) The rate of procedural success defined as final TIMI 3 flow and a residual coronary stenosis of less than 20% at visual estimation.

4) TIMI major or minor bleeding events and net clinical outcomes (defined as the composite of death, MI, stroke and TIMI minor or major bleedings according to TIMI) and the rate of thrombocytopenia.

5) The length and costs of hospitalization as well as cost-effectiveness of transradial

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intervention versus transfemoral and bivalirudin versus UFH±GPI. 6) The need for surgical access site repair/intervention and/or blood products transfusion 7) The prognostic impact of major bleeding complications on 30 days death, MI or stroke

rate as assessed based on various bleeding classifications including BARC, TIMI and GUSTO as well as the prognostic role of thrombocytopenia.

8) The prognostic value of on-treatment P2Y12 platelet residual activity measured via a point-of-care instruments at the time or immediately after PCI

Sub-Randomization: Patients randomly assigned to receive bivalirudin will be randomized to stop bivalirudin infusion at the end of PCI or to prolong bivalirudin at an infusion rate of 0.25 mg/kg/hour for at least 6 hours after completion of PCI. The primary hypothesis in this sub-randomization is that prolonged post-intervention bivalirudin infusion will be superior to no bivalirudin post-PCI infusion with respect to the net composite outcome consisting of any death, MI, stroke, urgent TVR, stent thrombosis and BARC-defined type 3 and 5 bleeding events within 30 days. Secondary objectives for the sub-randomization of prolonged bivalirudin versus no post-PCI infusion in the bivalirudin group will consist of each component of the primary composite endpoint through the entire follow-up duration. Sample Size: Access site comparison: It is expected that the incidence of the primary end-point on an intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the transradial and transfemoral group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints). Pharmacology arm: It is expected that the incidence of the primary end-point on an intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the bivalirudin and UFH group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints). Statistical considerations for the key secondary endpoints: Six thousand eight hundred patients (3,400 in each arm) will provide greater than 98% power to detect a difference in the net clinical outcomes including death, MI, stroke and major bleeding complications (Type 3 and 5 in accordance to the BARC classification) from 9% in the transfemoral and UFH arms to 6% in the transradial and bivalirudin arm with a type I error set at 1%. Sample size considerations for the subrandomization Three thousand four hundred patients (1,700 in each arm) will provide 87% power to assess superiority of prolonged post-PCI bivalirudin infusion versus no post-PCI infusion assuming a background event rate of death, MI, stroke, urgent TVR, stent thrombosis and type 3 and 5 type BARC bleedings in the range of 10% in the prolonged arm versus 6.5% (RRR: 35%) witha type I error set at 1%.

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2. TABLE OF CONTENTS 1. SYNOPSIS ……………………………………………..…………………………

2. TABLE OF CONTENTS ……………………………………..…………………..

3. LIST OF ABBREVIATIONS ………………………………..……………………

4. INTRODUCTION .…………………………………………..…………………….

4.1. Background .………………………………………………..……………………..

4.2 Vascular access site ………………………………………..……………….……

4.3 Pooled analysis of the available evidence comparing TFA versus TRA ……

4.4 Incidence of vascular access complications after transradial approach with

a special focus on radial artery occlusion ...……………………………….…...

4.5 Incidence of vascular access complications after transfemoral approach

with focus on vascular closure devices ...………………………………….…...

4.6 Concluding remarks on comparative feasibility of the transradial with

respect to the transfemoral approach ...………………………………………..

4.7 Establishing the rational for the use of newer anti-thrombotic agents in

patients undergoing coronary interventions through TRA ...…………….……

4.8 Bivalirudin ..………………………………………………………………………..

5. TRIAL DESIGN .…………………………………………………………….…….

5.1 Stratification .……………………………………………………………….……...

5.2 Main study primary hypotheses .…………………………………………….…..

5.3 Main study primary objectives …………………………………………….…….

5.4 Main study key secondary objectives .…………………………………….……

5.5 Main study secondary objectives ………………………………………….……

5.6 Sub-randomization .………………………………………………………….……

5.6.1 Primary hypothesis for the Sub-randomization group .…………….………….

5.6.2 Secondary hypotheses for the Sub-randomization group ………..…………..

5.7 Schematic Diagram of Trial Design ……………………………….……………

5.8 Measures to Minimise/Avoid Bias .……………………………………….……..

6. RANDOMIZATION ………………………………………………………..………

6.1 Staged Procedures ……………………………………………………………….

7. SUBJECT POPULATION ……………………………………………..…………

7.1 Number of subjects ..………………………………………………….………….

7.2 NSTEACS definition ..………………………………………………….…………

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7.3 STEMI definition .…………………………………………………….……………

7.4 As exclusion criteria the following items will be considered ……….………...

7.5 Withdrawal Criteria ..……………………………………………………….……..

8. TREATMENT OF SUBJECTS ..………………………………………….……...

8.1 Control group ..……………………………………………………………….……

8.2 Study group ..………………………………………………………………….…..

8.3 Renal Impairment ...………………………………………………………………

8.4 Concomitant therapy ...…………………………………………………….……..

8.5 Upstream Therapy ...……………………………………………………………..

8.5.1 As per Randomisation scheme ...……………………………………………….

8.5.2 As per Investigator’s discretion ...……………………………………………….

8.6 Study Drug Packaging and Labelling …………………………………………..

8.7 Study Drug Storage ...……………………………………………………….……

8.8 Study Drug Preparation ………………………………………………………….

8.9 Administration ...…………………………………………………………………..

8.10 Study Drug Accountability ……………………………………………………….

8.11 Study Drug Handling and Disposal ...……………………………………….…..

9. ON-TREATMENT PLATELET REACTIVITY SUB-STUDY ………………….

10 SEQUENCE OF PROCEDURES ………………………………………….……

10.1 General Conduct of the Trial ………………………………………………….…

10.2 Pre-Hospital Management ………………………………………………….……

10.3 In-Hospital Management ...………………………………………………………

10.4 Follow-up Management ......………………………………………………….…..

11. STATISTICAL SECTION …………………………………………………….…..

11.1 Sample size justification for the two co-primary endpoints ……………….….

11.2 Sample size considerations for the key secondary endpoint …………….….

11.3 Sample size considerations for the duration of post-pci bivalirudin infusion

11.4 Definitions ………………………………………………………………………….

11.4.1 Subject Populations ………………………………………………………………

11.4.2 Observational period ……………………………………………………………..

11.5 Statistical Analysis ………………………………………………………………..

11.6 Endpoints ………………………………………………………………………….

12. OPERATOR CRITERIA FOR ELIGIBILITY…………………………………….

13. CLINICAL EFFICACY MEASUREMENTS …………………………………….

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13.1 A. Death …………………………………………………………………………...

13.2 B. Myocardial Infarction ………………………………………………………….

13.2.1 Q-wave MI ...………………………………………………………………………

13.2.2 Non-Q wave MI…………………………………………………………………….

13.2.3 Stroke ………………………………………………………………...……………

13.3 C. Revascularization ………………………………………….……..…………...

13.3.1 Target Lesion (TL) …………………………………………………….…….……

13.3.2 Target Lesion Revascularization (TLR) …………………………….……….….

13.3.3 Target Vessel (TV) ……………………………………………………….……….

13.3.4 Target Vessel Revascularization (TVR) ……………………………….……….

13.3.5 Clinically indicated …………………………………………………….………….

13.3.6 Not Clinically indicated ………………………………………….…….………….

13.3.7 Non Target Lesion Revascularization (nonTLR) …………….………………..

13.3.8 Non Target Vessel Revascularization (nonTVR) …………….….…………….

13.4 D. STENT THROMBOSIS …………………………………………………….…

13.4.1 Timing ………………………………………………………………………….…..

13.4.2 Pathologic confirmation of stent thrombosis …………………….……….…….

14. SAFETY MEASUREMENTS ………………………………………..…………..

15. SAFETY……………………………..………….

15.1 Adverse Events …………………………………………………………...………

15.2 Serious Adverse Events (SAEs) ………………………………………..….…...

15.3 Reporting of SAEs ………………………………………………….....…….……

15.4 Procedures in case of emergency, overdose or pregnancy …..….……

16. PROTOCOL DEVIATIONS ……………………………………………….……..

17. DATA COLLECTION ……………………………………………………….…….

17.1. Accountability ……………………………………………………………………..

18. RECORDS RETENTION ………………………………………………………..

19. QUALITY CONTROL AND QUALITY ASSURANCE ………………………...

19.1. Monitoring ………………………………………………………………….………

19.2. Auditing …………………………………………………………………….………

20. ETHICS AND RESPONSIBILITY ……………………………………….………

20.1. Informed Consent ...…………………………………………………….………...

20.2. Ethics Committee ...…………………………………………………….…………

21. CONFIDENTIALITY ...……………………………………………………………

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22. PUBLICATION POLICY………………………………………………………….

23. INVESTIGATOR AGREEMENT ………………………………………………..

24. REFERENCES .............................................................................................

APPENDIX 01 - SEVERITY AND CAUSALITY ASSESSMENTS FOR ADVERSE

EVENTS .......................................................................................................................

APPENDIX 02 - STUDY COMMITTEES ……………..………………….………………..

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3. LIST OF ABBREVIATIONS

Abbreviation Definition ACS Acute Coronary Syndrome

ACT Activated Clotting Time

ADP Adenosin Di-Phosphonate

ADPhs High Sensibility ADP

AE Adverse Event

AIFA Agenzia Italiana del Farmaco

AUC Area Under the Curve

BARC Bleeding Academic Research Consortium

CABG Coronary Artery Bypass Grafts

CEC Clinical Events Committee

CHF Congestive Heart Failure

CK-MB Creatine Kinase MB Isoenzyme

CMP Clinical Management Plan

CRO Clinical research Organisation

DCA Directional Coronary Atherectomy

dL Decilitre(s)

DSMB Data and Safety Monitoring Board

EC Ethics Committee

ECG Electrocardiogram

eCRF Electronic Case Report Form

GCP Good Clinical Practices

GPI Glycoprotein IIb/IIIa Inhibitor

ICH International Conference on Harmonisation Requirements for Registration of Pharmaceuticals

IDR Ischemia Driven Revascularisation

ITT Intent-to-treat

kg Kilogram(s)

LBBB Left Bundle Branch Block

LWMH Low Weight Molecular Heparin

MACE Major Adverse Cardiovascular Events

MACCE Major Adverse Cardio- and Cerebro-vascular Events

MI Myocardial Infarction

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mg Milligram(s)

min Minute(s)

mL Millilitre(s)

NNT Number Needed to Treat

NSTEACS Non-STSegment Elevation Acute Coronary Syndrome

PCI Percutaneous Coronary Intervention

PI Principal Investigator

PP Per protocol

PRU Platelet Reactivity Units

RCA Right Coronary Artery

SAE Serious Adverse Event

STEMI ST-Segment Elevation Myocardial Infarction

TFA Transfemoral Access

TIMI Thrombolysis in Myocardial Infarction TL Target Lesion

TRA Transradial Approach

TVR Target Vessel Revascularization

UFH Unfractionated Heparin

URL Upper Reference Limit

VCD Vascular Closure Devices

WPW Wolff Parkinson White syndrome

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4. INTRODUCTION This protocol describes a study to compare intended trans-radial versus trans-femoral intervention and bivalirudin monotherapy versus current Euorpean standard of care consisting of unfractionated heparin (UFH) plus provisional use of glycoprotein IIb/IIIa inhibition via the use of one of the three available agents on the market (e.g. abciximab, tirofiban or eptifibatide) in patients (≥18 years) with ACS, that are intended for an invasive management strategy. This study will be conducted in compliance with Good Clinical Practices (GCP) including the Declaration of Helsinki and all applicable regulatory requirements. 4.1 Background The use of combined antithrombotic therapies over the last two decades has decreased the risk of a heart attack after percutaneous coronary intervention substantially but has also been associated with a significant increase in bleeding risk1. Therapies or strategies that maintain the benefits seen with currently available antithrombotic therapies but which have lower bleeding risk are therefore of great clinical importance. Indeed, major bleeding is currently the most common non-cardiac complication of therapy for patients with coronary artery disease who have undergone PCI. Bleeding in patients with acute coronary syndrome (ACS) is associated with an increased risk of long term mortality and morbidity1-7, and this relationship is currently thought to be causal8, 9. Therefore' reducing the frequency of bleeding events while maintaining efficacy is an important goal in the management of patients with ACS. The most common site of bleeding in invasively managed patients with ACS is at the femoral artery puncture site used for heart catheterization10. 4.2 Vascular access site The transfemoral access (TFA), through the percutaneous Seldinger technique, is the preferred approach in most catheterization laboratories worldwide due to its long history of use, the large availability of several dedicated preformed Judkins-type catheters and the possibility to exploit relatively large diameter catheters and sheaths, should these be necessary for complex percutaneous coronary intervention (PCI). Being a relatively deep and terminal vessel however, the femoral artery as percutaneous access site may expose to rare ischemic but frequent bleeding complications which occurs between 3-7% of patients undergoing interventional procedures, especially with modern anti-thrombotic drugs, including glycoprotein IIb/IIIa receptor blockers and clopidogrel3. The difficulties in obtaining a stable and definitive local haemostasis, even when dedicated arterial vascular closure devices (VCD) are employed, make prolonged bed rest after TFA necessary in the majority of cases which result in patient discomfort and overall increase in medical expenditure. In the last fifteen years, after Campeau’s report of successful coronary angiography by transradial approach (TRA)11, the radial artery has been increasingly employed as an alternative access site both for diagnostic and interventional procedures.

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The main advantage offered by percutaneous TRA is represented by the very low incidence of relevant vascular access site complications and bleeding and allows for early mobilization of the patient and thus to early discharge. Advantages and disadvantages of transradial approach (TRA) and transfemoral approach (TFA) are more extensively detailed in Table 1 and 2, respectively. Table 1. Advantages and disadvantages of transradial approach.

Advantages Disadvantages not an end artery: no ischemic complications in case of occlusion if palmar arch is patent (i.e. good Allen test)

not possible in case of ischemic Allen test (about 10% of the population) and in Raynaud disease

superficial artery, hemostasis very easy, negligible risk for bleeding or pseudoaneurysm

long learning curve

negligible risk for arteriovenous fistula or nerve damage

risk of spasm (significant in very small radial arteries, typically in old women with a small wrist)

better patient comfort difficult manipulation in case of tortuous brachiocephalic trunk

bed rest not necessary (outpatient procedures possible)

max 7F (occasionally 8F!) catheters allowed (but only in large arteries); possible limitations to bifurcation treatment, DCA, Rotablator with larger burrs, other bulky devices

save time and personnel for dealing with sheaths or monitoring groin

movement of catheters induced by respiration, sometimes difficult stent positioning

save cost and complications of vascular closure devices

limited backup support needing more manipulation (but deep intubation possible with 5F guiding catheters)

better guiding catheter backup for RCA and LIMA intervention by left radial approach

increased procedure time and radiation exposure (but only in the first part of learning curve)

Ideal in selected subsets, such as obese patients, patients who can not lie flat (CHF, severe back pain, confused or non-compliant patients, urinary retention), with iliofemoral disease, with large abdominal aneurysm (especially if mural thrombosis is present), anticoagulated (INR>2)

Need to prepare a groin if IABP or venous access for temporary pacing or hemodynamic monitoring are needed

possible cost saving postprocedural risk of occlusion (about 5% for 6F and 1% for 5F), usually asymptomatic but possibly interfering with radial artery harvesting for CABG

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Table 2. Advantages and disadvantages of transfemoral approach.

Advantages Disadvantages easier, well-known, large experience risk of bleeding and vascular complications,

including pseudoaneurysm, arterovenous fistula, leg ischemia due to thrombosis or distal embolization

large catheters allowed risk of retroperitoneal hemorrage (with IIb/IIIa blockers and no front-wall puncture)

good for all coronary devices significant proportion of patients affected by iliofemoral and aortic disease

easy to obtain venous access if temporary pacing or hemodynamic monitoring are needed

difficulty in access and correct puncture (above the superficial-profunda bifurcation) in obese patients

hemostasis may be difficult in uncontrolled systemic hypertension, severe aortic regurgitation, fibrous groin

if manual compression is employed, wasting of time and personnel, especially after anticoagulation for PCI (ACT monitoring needed)

prolonged bed rest after sheath removal (at least 1h for each French, but often more than 12h)

closure devices shorten time to hemostasis and allow early ambulation but are expensive and not so effective in reducing vascular complications. Collagen devices, although less expensive, often limit access at the same site for weeks or even months.

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4.3 Pooled analysis of the available evidence comparing TFA versus TRA A meta-analysis comparing TRA and TFA both in diagnostic and interventional procedures, pooling together all the randomized trials published up to October 2005 has been previously reported12. It showed that TRA for coronary procedures appears as a very safe alternative to femoral access, as testified by similar major adverse cardiovascular events (MACE) rate12. Moreover, it was noted that TRA virtually eliminates local vascular complications, while it requires higher technical skills in comparison to femoral access, thus yielding to an overall lower success rate12. Nevertheless, an ongoing trend to equalization of the two procedures in terms of procedural success was evident through the years, suggesting that most of these differences could be eliminated with improved technical skills and developments in devices such as sheaths and catheters available nowadays12 To reach a more reliable and updated comparison between TFA vs. TRA, an updated systematic revision of the literature to include all comparative trials published up to 2008 has been subsequently published, involving 13 studies and 4,458 patients who had been randomized to radial versus femoral access site13. This pooled analysis demonstrated a significant 73% reduction of major bleeding complications in the radial arm. Interestingly, this dramatic reduction of major bleeding complications was associated to a trend towards lower death, myocardial infarction or stroke (OR: 0.71 95%CI: 0.40-1.01; p=0.06) compared to the femoral group13. Figure1 (ischemic composite endpoint in trans-radial versus trans-femoral access)

Corroborative data have also been generated by a post-hoc analysis of the OASIS 5 study where after adjustment for possible confounders patients undergoing intervention via radial artery trended to have lower mortality (3.4% versus 2.3%, adjusted HR 0.71 [0.45-1.13] p=0.15) compared to patients who received intervention via the femoral artery.

FFaavvoouurrss RRAADDIIAALL FFaavvoouurrss FFEEMMOORRAALL

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Figure 2 (adjusted mortality rate in the OASIS 5 study stratified based on access site)

HR 0.6895% CI [0.43-1.07]p=0.09

DaysDays

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NonNon--adjustedadjusted: HR 0.68 [0.43: HR 0.68 [0.43--1.07] p=0.091.07] p=0.09AdjustedAdjusted: HR 0.71 [0.45: HR 0.71 [0.45--1.13] p=0.151.13] p=0.15

3.4%

2.3%

Finally, between January 1, 2003, and June 30, 2009, there were 12, 407 adult patients who underwent PCI for ST-segment elevation myocardial infarction in Emilia Romagna. Of these patients, 8,000 (median follow-up 1,204 days) underwent trans-femoral and 3,068 (median follow-up 605 days) were primarily treated with tans-radial intervention. The rate of trans-radial intervention greatly increased over time, from less than 2% in 2003 up to greater than 60% in 2009, a trend which was consistent across all sites. The rate of cross-over from primarily indented trans-radial to trans-femoral access increased from 0% in 2003 up to 7.5% in 2006 and then stabilised to around 3.5% through 2008 and 2009. Figure 3

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The adjusted outcomes based on a propensity score analysis of the whole population showed a 30% mortality reduction (HR: 1.309; 95%CI, 1.070, 1.602; P=0.0089) at 2 years in favour of the trans-radial intervention (Figure 2A and Table 2), reflecting an early significant mortality benefit within 30 days after treatment (HR: 1.380, 95%CI: 1.016, 1.876; P=0.0395), whereas death rate in between 1 and 24 months did not differ in the trans-radial as compared to the trans-femoral group (HR: 1.289, 95%CI: 0.985, 1.687; P=0.0648). At subgroup analysis, the mortality benefit at 2 years favouring the trans-radial access site appeared largely consistent across several analysed covariates The composite endpoints of death or myocardial infarction (HR: 1.240, 95%CI, 1.050-1.465; P=0.0114) and death, myocardial infarction or stroke (HR: 1.259, 95%CI, 1.069-1.481; P=0.0057) were also significantly reduced at 2 years in the trans-radial group which was largely driven by the difference incidence of mortality in the two study groups. Similarly, the adjusted 30-day rate of major bleeding or vascular events remained lower in the trans-radial group (HR: 1.899, 95%CI, 1.116, 3.229;. P=0.018). After propensity-score matching was performed for the entire population, there were 1501 matched pairs of patients. Trans-radial intervention was associated to a significantly lower mortality at 2 years than trans-femoral group (8.8% vs. 11.4%, HR, 1.302; 95%CI, 1.030 to 1.647; P-value=0.0269). Figure 4 [Percentage of overall mortality reported on Y axis as a function of time (X axis)]

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At subgroup analysis, the mortality benefit favouring the trans-radial access site appeared again to be largely consistent across key pre-selected covariates. This difference was also significant in the matched cohort of patients without cardiogenic shock (6.8% vs.9.8%, HR, 1.474; 95%CI, 1.120 to 1.939; P-value=0.0056). The rates of myocardial infarction or stroke did not differ at 2 years in patients who underwent trans-radial as compared to trans-femoral group, yet both composite of death or MI and death, MI or stroke were lower in the trans-radial group at 2 years, entirely driven by the observed difference in mortality between groups. After propensity-score matching, the rate of major bleeding and vascular events were significantly reduced at 30 days by almost 60% in the trans-radial group (1.1% vs. 2.5%, HR, 2.287; 95%CI, 1.269 to 4.121; P-value=0.0046), a treatment effect which was consistent in the matched cohort of patients who did not suffer from cardiogenic shock (1.0% vs. 2.2, HR, 1.835; 95%CI, 1.103 to 3.278; P-value=0.015). The stratified rate of major bleeding and vascular events was also analysed in the matched-cohort of patients based on the timing of occurrence. There was a marked and significant difference of safety events which were observed during the index hospitalisation favouring the trans-radial group (0.9% vs. 2.5%, HR, 2.807; 95%CI, 1.489 to 5.292; P-value=0.0009) whereas bleeding and vascular events occurring after hospital discharge did not differ (0.3% vs. 0.2%, HR, 0.768; 95%CI, 0.172 to 3.432; P-value=0.729). Finally, In the overall patient population, the unadjusted length of hospitalisation was significantly lower in the trans-radial (median [IQR] 4 [6-8]) compared to the trans-femoral group (median [IQR] 7 [5-10]) (P<0.0001). Similarly, after propensity-score matching, duration of hospitalisation remained markedly shorter in the tans-radial (median [IQR] 4 [6-8]) compared to the trans-femoral group (median [IQR] 6 [5-9]) (P<0.0001). 4.4 Incidence of vascular access complications after transradial approach with a special focus on radial artery occlusion Given the anatomical features of the radial artery, clinically relevant vascular complications are almost absent. Indeed, provided that the Allen test is positive, even the occlusion of the radial artery is an asymptomatic event. Ultrasound studies after transradial catheterization reported an occlusion rate of around 5% 14, 15. However, the only drawbacks of this finding could be represented by the impossibility to use the artery as a conduit for coronary artery bypass surgery and to perform repeated ipsi-lateral TRA. Indeed, in those patients who require a second procedure through the same radial artery site it may be helpful to perform a reverse Allen test in order to detect proximal radial artery disease/occlusion. However, Yoo et al reported that the repeated use of the radial artery is feasible in most patients with a high procedural success rate and low vascular complications16. Of note, the rate of post-procedural radial occlusion seems much lower (about 1%) when 5F guiding catheters are used17 and increasing evidence from literature suggests the feasibility of PCI with 5F guiding catheters even in the most challenging coronary anatomy18. 4.5 Incidence of vascular access complications after transfemoral approach with focus on vascular closure devices. The most common vascular access site complications at femoral level are hematomas accompanied by significant blood loss, arterial pseudo-aneurysm and arteriovenous fistulas requiring surgery, with consequent increases in hospitalization length, hospital costs and periprocedural morbidity. The incidence of these complications ranges from 2% to 4% for noncomplex PCI to 10% to 14% for more complex PCI19, 20. Glycoprotein IIb/IIIa blockers and high loading doses of clopidogrel (up to 600 mg), now widely used in association with angioplasty, may also have a major impact on the occurrence of local complications. For example, in the pivotal

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EPIC trial minor and major complications were reported in 21.8% of patients who received abciximab vs. 9.1 of controls21. However, recent data have shown a progressively lower impact of glycoprotein IIb/IIIa blockers on the rate of local complications, as the associated dose of heparin was administered according to a more conservative weight-adjusted protocol22. Not surprisingly, there has been considerable interest in femoral artery vascular closure devices (VCD), which allow removal of sheaths directly after catheterization or intervention. These devices have been increasingly used in recent years to obtain hemostasis regardless of the level of anticoagulation and to allow early mobilization of patients. To date only 3 comparisons of TRA vs. TFA with VCD have been published. The only randomized trial was performed in a small number of patients undergoing only coronary angiography without intervention23. A second study, prospective but not-randomized, included more than 900 patients undergoing PCI by TRA (39.3%) or by TFA with the Perclose arterial suture device (60.7%), and showed 0 access complications in the TRA group versus 5 in the TFA group (0.8%). However, the very low incidence of TFA complications could be in part explained by smaller sheath size (mostly 6F) and only 5.1% of patients receiving abciximab24. In the third study, Mann et al. evaluated in a non-randomized registry, cost effectiveness of the Perclose device in patients undergoing coronary stenting from TFA as compared to TRA. Primary success, procedural complications, post-procedural length of stay and the percentage of patients discharged the same day were the same in both groups, but total procedure time was longer in TFA group. However, the suture device could not be used in 18% of patients for anatomic reasons and failed to obtain hemostasis in 10% of patients. Moreover, access site complications occurred only in the femoral group25. Nevertheless, it must be kept in mind that to date, both collagen-based and suture-based VCD, despite a significant reduction in time to hemostasis, are equally effective in reducing major local complications as manual compression, if not more harmful, as clearly shown by two recently published meta-analyses26, 27 (Figures 5-7). Furthermore, other pitfalls of VCD include the elevated cost, a not-insignificant learning curve, the occurrence of device-specific complications, such as groin infection and acute femoral occlusion, and, for collagen-based devices, the impossibility of reusing the same approach for 12 weeks. Figure 5 : Groin hematoma

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Figure 6 Groin bleeding

Figure 7

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4.6 Concluding remarks on comparative feasibility of the transradial with respect to the transfemoral approach The evidence coming from clinical studies extensively reviewed above shows that TRA can be performed as safely as TFA in most diagnostic and interventional procedures, unless bulky devices (>7F) are selected or hemodynamically unstable patients are considered. A great benefit in the reduction of access site complications and hospital stay is evident after TRA and patients discomfort may also be significantly reduced. The major drawbacks of TRA are related to a higher incidence of procedural failure and to a higher level of procedural complexity (as shown by the more elevated fluoroscopy time). However, with technological improvements and miniaturization of several percutaneous devices, with amelioration of concomitant anti-spasm therapy, and mainly with increased operators’ experience this gap appears progressively less significant. In fact, we believe that many operators are probably dissuaded to start a TRA program by the long learning curve and that they do not feel confident in dealing with complex anatomy because of risk of spasm, limited guiding catheter size and different catheter manipulation techniques. Despite the increasing evidence about feasibility, safety and effectiveness of TRA, this type of access will hardly replace transfemoral approach in the near future unless evidence that it significantly improves patient outcomes beyond reduction of local bleeding events is clearly provided. Yet, presumably it will have an ever-increasing role in diagnostic and interventional procedures, since these interventions will be more and more driven by cost containment, improvements in equipment, operator experience and, most importantly, patient preference. 4.7 Establishing the rational for the use of newer anti-thrombotic agents in patients undergoing coronary interventions through TRA A clear limit of available studies comparing TFA and TRA is that they have been conducted in the absence of a contemporary pharmacological environment, including the most recent achievement in terms of adjunctive treatment during PCI. By significantly reducing the rate of access site complications, mainly when TFA is employed, this emerging set of new antithrombotic therapies, while replacing unfractioned heparin, may drastically reduce the benefit of TRA in terms of site access complications as compared to TFA. Thus, the contemporary benefit of TRA versus TFA in the context of the emerging antithrombotic therapies, especially bivalirudin, needs to be established. 4.8. Bivalirudin Bivalirudin is currently indicated in Europe for “the treatment of adult patients with acute coronary syndromes (unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention and as an intravenous (IV) anticoagulant in patients undergoing percutaneous coronary intervention (PCI) including patients with ST segment elevation myocardial infarction (STEMI) undergoing primary PCI. Bivalirudin is intended for use with aspirin and clopidogrel.” [Summary of product characteristics, March 2010]. Being a direct thrombin inhibitor and unlike heparins (unfractionated or low molecular weight), bivalirudin is able to inhibits both soluble and fibrin bound thrombin with similar potency, providing a distinct pharmacological advantage particularly in ACS patients. Furthermore, heparins potentiate platelet activation, whereas bivalirudin inhibits platelet aggregation by blocking thrombin signalling to the protease activated receptor (PAR) family of platelet receptors28-32 Synthesised chemically, bivalirudin is a short peptide of 20 amino acids that binds to both the active site and substrate recognition exosite of thrombin, thus, directly and specifically inhibiting all known actions of thrombin33. The binding of bivalirudin to thrombin is reversible; thrombin is able to recognize the drug as a substrate and cleave it, restoring its haemostatic function. The plasma half-life of bivalirudin is 25 minutes.

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The bivalirudin European approval was based on three pivotal studies showing that bivalirudin has similar efficacy in reducing ischemic events with a better bleeding profile when compared to heparins plus glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing elective percutaneous coronary intervention (PCI) or with moderate or high risk ACS managed by PCI34-40. In the REPLACE-2 trial35 a total of 6010 patients undergoing urgent or elective PCI were were randomly assigned to receive intravenous bivalirudin, or heparin plus Gp IIb/IIIa inhibition. The key objective of this study was to evaluate the composite incidence of clinically-significant events reflecting ischaemic complications (death, MI, urgent revascularisation) and haemorrhage associated with PCI up to 30 days post-PCI as represented by the quadruple and triple composite endpoints. Bivalirudin was non inferior to the comparator group of heparin plus planned GP IIb/IIIa inhibition with regard to the composite incidence of clinically-significant events reflecting ischaemic complications and haemorrhage associated with PCI up to 30 days post-PCI, or the composite incidence of ischemic events (death, MI, urgent revascularisation). However, the bleeding incidence was significantly lower in the bivalirudin arm for all components (2.4% versus 4.1%; OR 0.59; p<0.001). In the ACUITY trial40 a total of 13,819 patients with moderate or high risk UA/NSTEMI were randomised to receive one of the following anti-thrombotic regimens: unfractionated heparin or enoxaparin plus a GP IIb/IIIa inhibitor; bivalirudin plus a GP IIb/IIIa inhibitor; or bivalirudin alone. All pre-specified tests of the primary and secondary objectives were met for all 30-day endpoints and support the efficacy of bivalirudin for use in all ACS patients undergoing an early invasive strategy. Use of bivalirudin alone was superior to heparins + GP IIb/IIIa inhibitor, for the net clinical outcome endpoint (incidence of death, myocardial infarction [MI], unplanned revascularisation for ischaemia, or major bleeding) (10.1% versus 11.7%, p=0.0147), and for major bleeding using the ACUITY scale (3.0% versus 5.7%, p<0.0001), bivalirudin alone was non-inferior for the composite ischaemic endpoint (7.8% versus 7.3%, p=0.0107). The HORIZONS AMI8 was a prospective, randomised, open label, double arm, single blinded trial in 3,602 STEMI patients undergoing primary PCI. Eligible patients were randomized to receive either bivalirudin monotherapy with a provisional GP IIb/IIIa inhibitor or UFH plus a routine GP IIb/IIIa inhibitor. At 30-days, bivalirudin monotherapy demonstrated statistical superiority versus UFH plus GP IIb/IIIa inhibitor for the two primary endpoints of net adverse clinical outcomes (9.2% versus 12.1% p=0.006) and major bleeding (4.9% versus 8.3% p=0.0001), and no significant differences for the secondary endpoint of major adverse cardiovascular events (5.4% versus 5.5% p=0.95). Treatment with bivalirudin rather than heparin plus a GP IIb/IIIa inhibitor also resulted in significantly lower 30-day rates of cardiac mortality (1.8% versus 2.9%, RR[95%CI] = 0.62 [0.40, 0.95], P=0.028) and all-cause mortality (2.1% versus 3.1%, RR[95%CI] = 0.66 [0.44, 1.00], P=0.047), with non significantly different rates of re-infarction, target vessel revascularization, and stroke. Therefore, based on previous data, a complementary strategy to access site selection in order to reduce bleeding complications is the use of bivalirudin. In a combined dataset from the REPLACE-2, ACUITY and HORIZONS-AMI trials in 17,393 PCI patients, the majority of patients (61.4%) with TIMI major/minor bleeding had a bleeding source other than the access site. While radial artery access (used in only 7.9% of patients) might eliminate the majority of access site bleeds, it does not reduce non-access site-related bleeding events, which not only constitute a significant proportion of TIMI bleeds but are also associated with an even greater risk of subsequent 1-year mortality. In this pooled analysis, randomization to bivalirudin resulted in a 38% relative reduction in TIMI major/minor bleeding and a 43% reduction in TIMI major bleeding. Bivalirudin decreased access and non-access site-related major/minor and

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major only TIMI bleeding events to a similar extent compared to treatment with a heparin plus a GPI. Considering non-CABG TIMI major/minor bleeding only, the NNT was 71 to prevent one non-access site-related and 74 to prevent one access site-related TIMI bleeding event by use of bivalirudin rather than heparin plus a GPI.

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5. TRIAL DESIGN Open-label factorial 2 by 2 prospective multicenter randomized phase IV clinical trial 5.1 Stratification To ensure appropriate distribution of variables that may affect primary endpoints, the randomisation for will be stratified based on:

Type of ACS (STEMI, NSTEACS troponin negative, NSTEACS troponin positive), Intended or ongoing use of prasugrel or ticagrelor PCI in NSTEACS population*

*: To account for the expected 30% patients with NSTEACS who will not undergo PCI after angiography and to minimize the risk that this may unbalance the distribution of patients with respect to the two tested pharmacological options, randomisation to either bivalirudin or standard of care will mainly occur after the decision to proceed to PCI has been taken after coronary angiography. To allow upstream randomisation (i.e. before coronary angiography) investigators can declare that the decision to proceed to PCI is not known and the full treatment scheme (access site and pharmacological treatment) will be provided before angiography. Per protocol, in these patients treatment has to start at least 1 hour before arrival of the patient in the cath-lab. To avoid any possible treatment delay in STEMI patients, and based on the consideration that PCI is here performed generally in greater than 90% of the cases, randomisation in this patient population will not be stratified based on revascularisation modality. This will additionally facilitate the initiation of study treatment as soon as possible. A schematic flow chart of the randomisation scheme is provided below: STEMI No Yes Troponin + Troponin - Prasugrel/Ticagrelor Prasugrel/Ticagrelor Prasugrel/Ticagrelor Yes No Yes No Yes No

If upstream planned

RANDOMIZE RANDOMIZE RANDOMIZE RANDOMIZE TRA vs TFA TRA vs TFA TRA vs TFA TRA vs TFA Bival vs UFH+/-GPI Bival vs

UFH+/-GPI

Angiography Angiography Angiography

RANDOMIZE RANDOMIZE Bival vs UFH+/-GPI

Bival vs UFH+/-GPI

PCI PCI PCI

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5.2 Main study primary hypotheses: Patients in whom the indented treatment strategy was coronary angiography±PCI who have been randomized to radial access site or to receive bivalirudin will experience a lower incidence at 30 days of death, myocardial infarction or stroke. 5.3 Main study primary objectives: This study has two co-primary objectives:

1) To demonstrate in ACS patients undergoing an early invasive management, i.e. diagnostic coronary angiogram±PCI or planned PCI that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization.

2) To demonstrate that in an ACS patients with an intended PCI treatment strategy or in whom upstream treatment was felt necessary by local investigators the use of bivalirudin as compared to unfractionated heparin (UFH) plus or minus Glycoprotein IIb/IIIa inhibitor (GPI) is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization.

5.4 Main study key secondary objectives: This study has two key secondary objectives:

1) To demonstrate in patients undergoing diagnostic coronary angiogram which may be followed by ad hoc PCI or planned PCI (Access site ITT population) that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI, stroke or BARC-defined type 3 and 5 major bleeding complications within the first 30 days after randomization.

2) To demonstrate in PCI patients or in patients who got randomized upstream (before arrival in the catheterization laboratory) (Pharmacology ITT population) that use of bivalirudin as compared to unfractionated heparin (UFH) plus or minus Glycoprotein IIb/IIIa inhibitor (GPI) is associated to lower rate of the composite endpoint of death, MI, stroke or BARC-defined type 3 and 5 major bleeding complications within the first 30 days after randomization.

5.5. Main study secondary objectives:





5) The length and costs of hospitalization as well as cost-effectiveness of transradial intervention versus transfemoral and bivalirudin versus UFH±GPI.

6) The need for surgical access site repair/intervention and/or blood products transfusion 7) The prognostic impact of major bleeding complications on 30 days death, MI or stroke rate

as assessed based on various bleeding classifications including BARC, TIMI and GUSTO as well as the prognostic role of thrombocytopenia.

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5.6 Sub-randomization Patients who have been assigned to receive bivalirudin will be randomized in an open-label fashion to stop bivalirudin infusion at the end of PCI or to prolong bivalirudin at an infusion rate of 0.25 mg/kg/hour for at least 6 hours after completion of PCI. In practice, patients randomized to no post-PCI bivalirudin infusion arm will stop bivalirudin immediately after angioplasty guide-wire removal whereas patients allocated to the prolonged infusion arm will down-titrate bivalirudin infusion from 1.75 mg/kg to 0.25 mg/kg after angioplasty guide-wire removal up to 6 hours thereafter. 5.6.1 Primary hypothesis for the Sub-randomization group The primary hypothesis of this sub-randomization is that prolonged post-intervention bivalirudin infusion (long bivalirudin arm) will be superior to peri-PCI bivalirudin infusion only (short bivalirudin arm) with respect to the net composite outcomes consisting of any death, MI, stroke, stent thrombosis or BARC-defined type 3 and 5 bleeding events within 30 days. 5.6.2 Secondary hypotheses for the Sub-randomization group Secondary objectives for the sub-randomization group will consist of each component of the primary composite endpoint through the entire follow-up duration as well as the incidence of acute and subacute stent thrombosis, cost-effectiveness and interaction between on-treatment residual platelet reactivity and duration of post-PCI bivalirudin infusion assessed as both dummy (yes or no) or continuous variables (duration of post-PCI bivalirudin infusion expressed in hours). Patency of the radial artery at clinical examination with respect to bivalirudin infusion duration will be also assessed.

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5.7 Schematic Diagram of Trial Design

ACS All Comer Patients ACS All Comer Patients scheduled for scheduled for AngioAngio±±PCIPCIAspirin + Clopidogrel 600 mg or Aspirin + Clopidogrel 600 mg or

Prasugrel 60mgPrasugrel 60mg

UFH±GPIUFHUFH±±GPIGPI BivalirudinBivalirudinBivalirudin UFH±GPIUFHUFH±±GPIGPI

1:1

1:11:1 N~6,800

DiscontinueDiscontinueDiscontinue ≥6 h Bivalirudin infusion≥≥6 h 6 h BivalirudinBivalirudin infusioninfusion

Radial AccessRadial Access Femoral AccessFemoral Access

Angiography

PCI

Post-PCI N~3,400

N>6,800

1:1

5.8 Measures to Minimise/Avoid Bias The trial is open-label. Randomisation will occur by the use of a dedicated website. Despite the obvious benefits of a double-blind design, the access site cannot be concealed to the operator nor to the other patient medical and paramedical staff. Similarly, the concealment of the pharma-therapeutic strategy in this study would require a double dummy approach which may realistically delay the active treatment especially in the setting of STEMI patients or make the pre-hospital treatment phase impossible. Furthermore, all efforts must be taken not to retard time to reperfusion in patients with STE-ACS. An independent Clinical Events Committee (CEC) will adjudicate all primary clinical endpoints plus bleedings and stent thrombosis. The committee members and the CEC management team will be completely blinded to the randomised therapy, as well as any patient identifying information. The CEC will adjudicate the events based on pre-determined definitions outlined below. Other measures to avoid or minimise bias introduced by the open-label design will include intent-to-treat principles of analysis and use of objective measures for repeat myocardial infarction and bleeding endpoints. 6. RANDOMIZATION Randomization will occur via a dedicated website. Randomization will be stratified based on three variables: 1) Type of ACS (STEMI, NSTEACS troponin negative, NSTEACS troponin positive; 2) Intended or ongoing use of prasugrel; 3) Actual treatment strategy (i.e. Coronary angiography only not followed by PCI or coronary angiography followed by PCI/ planned PCI) in the NSTEACS cohort only as detailed above in the section devoted to stratification. 6.1 Staged procedures Patients who have been previously randomized into the study and have to undergo a staged procedure do not have to be re-randomized but they have to be treated according to original randomization scheme for both access site and pharmacological treatment. This includes patients who underwent diagnostic angiogram and at a later stage undergo PCI (planned staged PCI).

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7. SUBJECT POPULATION Real world ACS patients undergoing coronary angiography±PCI will be recruited on a consecutive basis (Intention to treat patient population). Both Non-ST segment elevation and ST-segment elevation ACS will be eligible provided both trans-radial and trans-femoral access site are deemed feasible. Patients may be randomized BEFORE coronary angiography or just prior PCI provided coronary anatomy has been assessed at a remote site (i.e. an other hospital) or at remote timing leading to sheath removal and need to re-gain access site with the possibility to do so as per randomisation scheme. 7.1 Number of subjects The recruitment of this study will stop as soon as at least 6,800 randomized patients actually underwent PCI on an intention to treat basis. It is expected that at least 30% of included patients may not finally undergo PCI (i.e. medically managed or sent to coronary artery bypass grafting), therefore 8,850 patients are expected to be prospectively included in the study. 7.2. NSTEACS definition Patients with all of the following criteria will be eligible: (1) history consistent with new, or worsening ischemia, occurring at rest or with minimal activity; (2) enrolment within 7 days of the most recent symptoms; (3) planned coronary angiography with indication to PCI; (4) at least 2 of the following criteria: aged 60 years or older, troponin T or I or creatine kinase MB above the upper limit of normal; electrocardiograph changes compatible with ischemia, ie, ST depression of 1 mm or greater in 2 contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts; 7.3. STEMI definition STEMI will be defined as: i) chest pain for >20 min with an electrocardiographic ST-segment elevation ≥1 mm in two or more contiguous electrocardiogram (ECG) leads, or with a new left bundle-branch block or an infero-lateral myocardial infarction (MI) with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave and ii) admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia or previous lytic treatment. 7.4 As exclusion criteria the following items will be considered:

1. Patients who can not give informed consent or have a life expectancy of <30 days 2. Allergy/intolerance to Bivalirudin or unfractionated heparin. 3. Stable or silent CAD as indication to coronary angiography 4. Treatment with LWMH within the past 6 hours 5. Treatment with any GPI in the previous 3 days 6. Absolute contraindications or allergy that cannot 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 is known pregnant or nursing mothers. Women of child-bearing age will be asked if

they are pregnant or think that they may be pregnant. 9. If it is known a creatinine clearance <30 mL/min or dialysis dependent. 10. Previous enrolment in this study. 11. Treatment with other investigational drugs or devices within the 30 days preceding 12. Randomisation or planned use of other investigational drugs or devices in this trial. 13. Severe uncontrolled hypertension (defined as persistent systolic blood pressure higher

than 220 mmHg despite medical treatment). 14. Subacute bacterial endocarditis

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15. PCI in the previous 30 days 7.5 Withdrawal Criteria All patients have the right to withdraw at any point during treatment without prejudice. The investigator can discontinue any patient at any time if medically necessary. It will be documented whether or not each patient completed the clinical study. If for any patient study treatment or observations were discontinued, the reason will be recorded and the Sponsor should be notified promptly. Reasons that a patient may discontinue participation in a clinical study are considered to constitute one of the following:

• adverse event(s), including an event resulting in death • abnormal laboratory value(s) • abnormal test procedure result(s) • unsatisfactory therapeutic effect • protocol violation • patient withdrew consent • lost to follow-up • administrative reasons

It is imperative to obtain complete follow-up data for all patients whether or not they receive their assigned treatment or have discontinued study drug. Every attempt should be made to collect follow-up information except for those patients who specifically withdraw consent to release of such information. All procedures and laboratory specimens or tests requested for evaluation following administration of the Study Drug should be carried out when possible whether or not a patient continues to receive treatment according the protocol. Patients will not be replaced in this trial.

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8. TREATMENT OF SUBJECTS 8.1 Control group: Unfractionated heparin should be given according to guidelines in UFH group (70-100 U/kg in patients not receiving GPI and 50-70 U/kg in patients receiving GPI). UFH infusion post-PCI is highly discouraged. GPI can be added on top of UFH in the UFH arm at discretion of the treating physician. Based on current registry data in Europe, we expect a prevalence of GPI used on top of UFH in the range of 30% in the whole study population. Anticoagulation during angiography can only be implemented in STEMI cases, in which randomization to the pharmacological treatment group occurs before coronary angiography. UFH can be given as a bolus before or during coronary angiography. At the time of PCI, UFH may be re-bolused based on recommendations provided above. In NSTEACS cases, no anticoagulation is allowed during angiography, unless the patient has already been randomized upstream (i.e. before coronary angiography) as detailed in section 5.1. In patients randomly allocated in the control group in whom no upstream randomisation has occurred, UFH should be started immediately after coronary angiography as soon as the decision to proceed to PCI is taken. GPI: All three GPIs available on the market can be given at discretion of the treating physician based on the following recommended regimen: Eptifibatide: (two 180 μg /kg boluses with a 10 minute 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 to 24 hours) Abciximab: (bolus of 0.25 mg/kg followed by an infusion of 0.125 μg/kg/min for 12 hours (maximum dose, 10 μg/min). 8.2 Study group Bivalirudin should be given immediately upon enrolment as bolus of 0.75 mg/kg followed immediately by an infusion of 1.75 mg/kg/h. This infusion should be run continuously until completion of PCI at which time the infusion should be reduced to a dose of 0.25 mg/kg/h for at least 6 hours in the prolonged infusion arm or stopped upon removal of the angioplasty guide-wire in the short infusion arm. An optional higher-dose infusion of 1.75 mg/kg/h is also permitted for up to 4 hours in the prolonged infusion arm only. Patients who do not undergo PCI and are to be medically managed may continue the infusion of 0.25 mg/kg/h for up to 72 hours. Anticoagulation during angiography can only be implemented in STEMI cases, in which randomization to the pharmacological treatment group occurs before coronary angiography. Bivalirudin can be given with an intravenous bolus of 0.1 mg per kilogram and an infusion of 0.25 mg per kilogram per hour. Before PCI, an additional intravenous bolus of 0.5 mg per kilogram has to be administered, and the infusion increased to 1.75 mg per kilogram per hour. Alternatively, Bivalirudin can be started immediately as bolus of 0.75 mg/kg followed immediately by an infusion of 1.75 mg/kg/h during angiography and continued during PCI if performed. In NSTEACS cases, no anticoagulation is allowed during angiography, whereas bivalirudin should be started immediately after coronary angiography as soon as the decision to proceed to PCI is taken. Patients randomised to bivalirudin may only have a “bail out” GPI (abciximab bolus + 12 hour infusion or eptifibatide double bolus + 12-18 hour infusion or tirofiban 25 μg/kg bolus followed by an 18 to 24 hour infusion) administered during PCI for the following two reasons only:

The presence of a “giant” thrombus adjacent to the stent or in the coronary vessel (length >2x that of the diameter of the coronary vessel) after PCI in the absence of a mechanical obstruction

Sustained no reflow (TIMI 0-1 flow in the absence of a mechanical obstruction, refractory to intracoronary nitrates, adenosine or a calcium channel blocker delivered

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intracoronary to the distal coronary bed via an infusion catheter). The use of GPIs outside the pre-specified bailout criteria will be considered a protocol deviation.

8.3 Renal Impairment: As indicated, any of the above drug doses are to be adjusted for renal impairment according to their respective Summary of Product Characteristics. 8.4 Concomitant therapy Concomitant therapy is in accordance to guidelines.

Aspirin: Patients have to receive aspirin (either i.v. at 250 or 500 mg or oral 160-325 mg or

75-160 mg/day for at least 5 days) prior to coronary angiography. However, patients with allergy/intolerance to aspirin may still be included in the study. Aspirin should then be given at 80-160 mg/day indefinitely in patients who can tolerate this treatment.

Clopidogrel: Clopidogrel should be started in any case with a loading dose of 600 mg

followed by 75mg per day for at least 30 days in patients ultimately receiving coronary stenting. Recommended duration of clopidogrel is 1 year in accordance to current guidelines. The protocol encourages investigator to give clopidogrel at least 6 hours before PCI if elective or as soon as possible in emergent PCI cases.

Prasugrel: In clopidogrel naïve patients, prasugrel can be administered at a loading dose

of 60 mg followed by 10 mg/day or 5mg/day in patients with advanced age (>75) or low body weight (<60 kg). Switching from clopidogrel to prasugrel is allowed and left to the discretion of the treating physician.

Ticagrelor: Ticagrelor should be given as 180 mg LD followed by 90 mg BID in agreement with the tested regimen of the PLATO study. The use of ticagrelor in the study is restricted to sites in which the drug has become commercially available and the drug is in use according to local practice.

8.5 Upstream Therapy 8.5.1 As per Randomisation scheme At discretion of the treating physician, patients can be randomized before the start of any pharmacological therapy and will be treated early on according to the Randomization scheme to Bivalirudin mono-therapy or UFH±GPI. In the Bivalirudin arm, the drug should be given with an intravenous bolus of 0.1 mg per kilogram and an infusion of 0.25 mg per kilogram per hour. Before PCI, an additional intravenous bolus of 0.5 mg per kilogram has to be administered, and the infusion increased to 1.75 mg per kilogram per hour. In the control arm, UFH bolus plus or minus continuous infusion is allowed. Unfractionated heparin has to be administered as an intravenous bolus of 60 IU per kilogram of body weight plus an infusion of 12 IU per kilogram per hour to achieve an activated partial-thromboplastin time of 50 to 75 seconds before angiography and an activated clotting time of 200 to 250 seconds during PCI if concomitant GPI is implemented or >300 seconds if no GPI is administered. 8.5.2 As per Investigator’s discretion Patients who received UFH at any time before randomisation can be included in the study provided the patient is presenting with STEMI or last UFH bolus or UFH continuous infusion has been stopped at least 2 hours before arterial sheath insertion and ACT is not greater than 200 seconds.

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Patients who received Fondaparinux before randomisation can be included irrespective of the timing of last dose whereas patients who received enoxaparin or other LWMH can be randomised only provided last subcutaneous injection has been administered at least 8 hours before. Similarly, patients who received treatment with a GPI or with bivalirudin before randomisation in the previous 3 days are not eligible. 8.6 Study Drug Packaging and Labelling Bivalirudin will be provided by The Medicines Company as clinically labeled unblinded study drug. Vials will be labelled and packed by an authorized European company according to the Italian law.. Commercial hospital stock supplies of bivalirudin are not permitted to be used for this trial. Medication labels will comply with regulatory requirements. The storage conditions for each medication provided will be described on the medication label. Aspirin, unfractionated heparin and GPI will be obtained from hospital stock and prepared as per standard practice as outlined in Section 8.1. 8.7 Study Drug Storage Bivalirudin will be stored in a securely locked cabinet at the appropriate conditions as specified in the Pharmacy Manual. Access should be strictly limited to the investigators and their designees. Neither the investigators nor any designees may provide investigational bivalirudin to any subject not participating in this protocol. 8.8. Study Drug Preparation • Vial Reconstitution Reconstitute each 250 mg vial with 5 mL of preservative free sterile water for injection to yield a clear opalescent, colourless to slightly yellow solution, pH 5.0-6.0, with a concentration of 50 mg/mL. Gently swirl until all material is dissolved (1-2 minutes). Do not shake. The reconstituted vial (50 mg/mL) is stable at 2-8°C for up to 24 hours. • Syringe Driver/Bag Preparation The contents of one reconstituted vial, 5 mL (250 mg) should then be added to a 50 mL of 0.9% sodium chloride for injection or 5% dextrose in water. The prepared infusion will yield a final concentration of approximately 5 mg/mL. If it is known that the duration of therapy will be lengthy or that the patient will be receiving the high infusion rate, it is permissible to make larger volumes, however the concentration should remain at 5 mg/mL, regardless of the volume prepared. 8.9 Administration Refer to protocol Section (8.1) and/or the Pharmacy Manual for specifics on study drug administration. 8.10 Study Drug Accountability The investigator or his designee must maintain an inventory record of bivalirudin received and all administered to assure the regulatory authorities and the Sponsor that the investigational new drug will not be dispensed to any person who is not a subject under the terms and conditions set forth in this protocol. The bivalirudin supplied for use in this study is to be prescribed only by the Principal Investigator (PI) or named sub-investigators and may not be used for any purpose other than that outlined in this protocol.

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8.11 Study Drug Handling and Disposal At the termination of the study, all unused bivalirudin will be destroyed on site as permitted by local regulations. In the event that bivalirudin needs to be returned for any other reason, the site will receive a written request listing the drug lot number(s) to be returned and the reason for the return request. 9. ON-TREATMENT PLATELET REACTIVITY SUB-STUDY Immediately before PCI and in any case before GPI infusion in patients allocated to UFH arm in whom GPI is planned, VerifyNow P2Y12 Assay will be performed to collect PRU base, PRU post and percentage of P2Y12 inhibition. Results of P2Y12 assay will be collected by an independent study nurse who will not communicate the information to the treating physician, In particular, the decision to start GPI on top of UFH will NOT be affected by P2Y12 assay results. Main scopes of the current sub-study is to assess:

1) The value of residual on-treatment P2Y12-mediated platelet reactivity and its interaction with the 2 tested pharmacological strategies (i.e. Bivalirudin mnotherapy versus UFH±GPI

2) The value of residual on-treatment P2Y12-mediated platelet reactivity and its interaction with the duration of bivalirudin infusion in patients undergoing PCI

3) The prognostic value of residual on-treatment P2Y12-mediated platelet reactivity on both ischemia and bleeding endpoints.

10. SEQUENCE OF PROCEDURES The Schedule of Events summarises the study assessments by time point. This study consists of 3 periods: The Pre-Hospital Phase: STEMI Patients, upon discretion of the treating physician, can be randomized before arrival to the PCI facility centre. Therefore, in these patients the study will start in the pre-hospital phase and it consists of confirming eligibility, randomisation, and refers to collection of data regarding treatments administered in the ambulance or non-primary PCI capable referring hospital. The In-Hospital Phase: refers to the collection of data from arrival in the PCI capable hospital until discharge home or 7 days (whichever comes first), including any period of in-patient care occurring post-PCI back in a referring hospital. The Follow-Up Phase: consists of data collection at 30 days (± 5 days) post randomisation by an out-patient follow up visit and mortality at 1 year (± 30 days) post randomisation either by a follow-up telephone call or by viewing a centralised death register (if available).

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Table 3: Visit Schedule ACS Pre-Hospital In-Hospital Screening Tx Pre-

Cathlab Angio±PCI Post-Index PCI Follow-up

0±30’ 8±4 hs 16±4 hs

24±4 hs Discharge 30±5

days 1 year ±30days

History and Examination X1 X1 X1 X X X X X

Inclusion and Exclusion criteria

X1 X1 X

12-lead ECG X X X X X X Informed consent X1 X1 X

Randomisation X1 X1 X Concomitant medications X X X X X X X X

VerifyNow P2Y12 Assay X X3

Cardiac markers

X2 X5 X X X

Instrumented radial artery patency and collateral circulation4

X X X

Bivalirudin X1 X X X X Standard Tx X X X X X X X X X MACCE X1 X X X X X X X X X Bleedings X1 X X X X X X X X X AE/SAE X1 X X X X X X X X 1: Patients with STEMI can be randomized before arrival to the PCI facility center. Patients with any type of ACS can be randomized upstream before arrival in the cath-lab. MAE denotes major adverse events. 2: in NSTEACS patients only 3: in selected sites only 4: includes Allen’s test evaluation and pulse oxymetry-based collateral circulation pattern evaluation (A-D pattern) 5: Prior to study drug initiation/PCI’

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10.1 General Conduct of the Trial Written informed consent will be obtained for this study by the principal investigator or Subinvestigator from all patients before the performance of any protocol-specific procedures. Pre-Hospital Screening Pre-Hospital screening is mandatory only in STEMI cases in which investigators are willing to randomize the patient before arrival to the PCI facility centre. In this condition, the subject must meet the inclusion/exclusion criteria before the randomisation centre is contacted for treatment assignment. The following procedures will be performed:

• Review of inclusion and exclusion criteria • Explanation of the study to the subject with a date and signature documented on an

informed consent document • AE/SAE reporting commences • 12-lead ECG

10.2 Pre-Hospital Management Immediate management following randomisation comprises:

• Endpoint reporting (death, major & minor bleeding, stroke and thrombocytopenia) commences and AE/SAE reporting continues

• History and examination (blood pressure and heart rate and Killip class) • Aspirin at an initial dose of 150-325 mg orally (or 250-500 mg IV) • P2Y12 receptor blocker such as clopidogrel at a loading dose of 600mg • Collection of concomitant medication • Initiation of either bivalirudin or control as soon as logistically feasible postrandomisation

10.3 In-Hospital Management Immediate management in the pre-catheter and catheter laboratory comprises:

• Endpoint reporting (death, major & minor bleeding, stroke) and AE/SAE reporting continues

• Continue infusion of bivalirudin if randomised to treatment with bivalirudin and if the patients has been randomized before hospital arrival • 12-lead ECG prior to study drug initiation/PCI • Examination (blood pressure, heart rate and Killip class) • Collection of concomitant medication Biomarker obtained at baseline, i.e. before study drug initiation/PCI (Troponin I or T and/or CK-MB mass preferably)

In -hospital management post-index procedure: • Endpoint reporting of re-infaction (MI), urgent TVR and stent thrombosis commences and all other

endpoint reporting and AE/SAE reporting continues • If randomised to bivalirudin following PCI, the reduced infusion dose of 0.25 mg/kg/h is

resumed for at least 6 hours or stopped immediately after PCI based on randomisation scheme. An optional higher-dose infusion of 1.75 mg/kg/h is also permitted for up to 4 hours. • If randomised to heparin no IV heparin infusion should be started routinely either during or

after the procedure • In patients requiring ongoing anti-coagulation for reasons other than PCI (eg, haemofiltration, atrial fibrillation or intra-aortic balloon pump) then anti-coagulation should

be maintained as per local practice Biomarker obtained after PCI (Troponin I or T and/or CK-MB mass preferably) at 8, 16 and

24 hours thereafter. • 12-lead ECG (0 hour (+/- 30 minutes), 24 hours (+/- 1 hour), and at day

7 or discharge).

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Additional serial ECGs should be obtained for each suspected recurrent ischemic event.

• Examination (blood pressure and heart rate) • Collection of concomitant medication • Blood haematology (haemoglobin, haematocrit, platelets [total and corrected]) daily for at

least 2 days and on day 7 or discharge • Blood chemistry (creatinine) daily for at least 2 days and on day 7 or discharge • Biomarkers (6-8 hours (+/- 1 hour), (12 hours (+/- 1 hour), (24 hours (+/- 1 hour) and 48 hours (+/- 1 hour) (preferably CK-MB (mass) or Troponin I or Troponin T or alternatively CPK)).

Additional serial biomarkers should be obtained for each suspected recurrent ischemic event

• Aspirin continued at 75-100 mg/day for at least 1 year • P2Y12 receptor blocker (including clopidogrel 75 mg or prasugrel 5 or 10 mg or ticagrelor 180 mg daily if CE approved during the conduction of the study) should be continued as per ESC guidelines (preferably for 1 year) in all patients in whom PCI was performed

Management of Subsequent Ischemic Events: Serial ECGs and biomarkers should be obtained for each suspected recurrent ischemic event. Suspected Re-Occlusion: The patient who initially had chest pain relief with improvement in the ECG who later develops prolonged chest pain with new ischemic ECG changes (suspected re-occlusion) should undergo emergency repeat catheterisation. Further treatment is per operator discretion based on the angiographic findings. Anticoagulation regimens per local standard practice should be used. 10.4 Follow-up Management

Clinical follow-up (visit to a local hospital or general practitioner) will take place at 30 days (± 5 days) in all patients undergoing randomisation. Original source documents must be collected for any clinical events. Should the patient be re-admitted to a non-study hospital, all possible efforts should be made to obtain original source documents from that hospital. Information on medical resource use items of relevance for the health economic analysis will also be collected in this context.

On discharge, for all patients in whom a PCI was performed, aspirin (75-100 mg/day) and a

P2Y12 receptor blocker (including clopidogrel 75 mg daily) should be continued as per ESC guidelines, preferably for one year. 30-Day Follow-up Period

All subjects will require a follow-up visit (to a local hospital or general practitioner) at 30 days (±5 days) after randomisation. Subjects will undergo screening of SAEs, concomitant medication, ECG, blood haematology and chemistry. They will also be questioned regarding any hospitalisations for episodes of ischemia (re-infarction (MI), stroke and stent thrombosis) and bleeding events that may have occurred in the period between the index hospitalisation and the 30 day time point. If it is ascertained that the subject has died, the date and cause of death should be recorded on the eCRF. 1-Year Follow-up Period All subjects will require a follow-up visit (to a local hospital or general practitioner) at 1 year (±30 days) after randomisation. Subjects will undergo screening for concomitant medication and they will also be questioned regarding any hospitalisations for episodes of ischemia (re-infarction (MI), stroke and stent thrombosis) and bleeding events that may have occurred in the period between the 30 day time point and 1 year.

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11. STATISTICAL SECTION 11.1 Sample Size Justification For The Two Co-Primary Endpoints

• Access site comparison: It is expected that the incidence of the primary end-point on an intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the transradial and transfemoral group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints). To account for the expected at least 5% cross-over rate from radial to femoral access site, when 70% of the total sample size will be recruited, the actual cross over rate in this patient population will be estimated and the total sample size increased by the same rate accordingly.

• Pharmacology arm: It is expected that the incidence of the primary end-point on an

intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the bivalirudin and UFH group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints).

Comparing 2 Proportions: Sample Size CalculationTwo Proportions, Z-Test (H0: Pi1 = Pi2)

N vs. Power (Pi1 = 0,04, Pi2 = 0,06, Alpha = 0,01)

0,700,71

0,720,73

0,740,75

0,760,77

0,780,79

0,800,81

0,820,83

0,840,85

0,860,87

0,880,89

0,900,91

0,920,93

0,940,95

0,960,97

0,980,99

1,00

Power Goal (No Continuity Correction)

2500

3000

3400

3500

4000

Sam

ple

Siz

e fo

r Eac

h G

roup

(N1

= N

2)

Expected incidence of the primary endpoints in the four study arms Bivalirudin UFH Margin Trans-Radial 3% 5% 4% Trans-femoral 5% 7% 6% Margin 4% 6%

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11.2 Sample Size Considerations For The Key Secondary Endpoint Six thousand eight hundred patients (3,400 in each arm) will provide greater than 98% power to detect a difference in the net clinical outcomes including death, MI, stroke and major bleeding complications (Type 3 and 5 in accordance to the BARC classification) from 9% in the transfemoral and UFH arms to 6% in the transradial and bivalirudin arm with a type I error set at 1%.



0,700,71

0,720,73

0,740,75

0,760,77

0,780,79

0,800,81

0,820,83

0,840,85

0,860,87

0,880,89

0,900,91

0,920,93

0,940,95

0,960,97

0,980,99

1,001,01

1,02


1500

2000

2500

3000

3400

4000

Sam

ple

Siz

e fo

r Eac

h G

roup

(N1

= N

2)

Expected incidence of the key secondary endpoints in the four study arms Bivalirudin UFH Margin Trans-Radial 5% 7% 6% Trans-femoral 7% 11% 9% Margin 6% 9% 11.3 Sample Size Considerations For The Duration Of Post-PCI Bivalirudin Infusion Three thousand four hundred patients (1,700 in each arm) will provide 87% power to assess superiority of prolonged post-PCI bivalirudin infusion versus placebo post-PCI infusion assuming a background event rate of death, MI, stroke, urgent TVR, stent thrombosis and type 3 and 5 type BARC bleedings in the range of 10% in the prolonged arm versus 6.5% (RRR: 35%) with a type I error set at 1%.

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0,70 0,75 0,80 0,85 0,90 0,95 1,00


1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

Sam

ple

Size

for E

ach

Gro

up (N

1 =

N2)

11.4. Definitions 11.4.1. Subject populations For this trial, the following populations will be defined and used in the analysis and/or presentation of the data. Intent-to-treat (ITT) population: The ITT population will be defined as all subjects randomised into the trial. Treatment classification will be based on the randomised treatment. Per-protocol (PP) population: The PP population will be defined as all subjects randomised into the trial who received their randomised treatment and who underwent angiography. Safety population: The safety population will be defined as all randomised subjects who received study drug, and will be classified according to the actual treatment received. The primary and secondary efficacy analyses will be based on the ITT population. Analyses based on the PP populations will be considered secondary and confirmatory. All safety analyses will be performed on the safety population. 11.4.2. Observational period The observational period for the study will be 365 (±30) days. Any event occurring after the defined observational period, even if collected on the eCRF, will not be included in the planned statistical analysis. However, all data, including that reported after the defined observational period, will be included in the patient data listings. 11.5. Statistical Analysis Continuous variables will be summarised by means, standard deviations (SD), medians, interquartile ranges and minimum and maximum values. Categorical variables will be summarised by frequencies and percentages. 11.6. Endpoints

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The list of primary, key secondary and secondary endpoints is reported above at section 5.3-5.5 The above-defined secondary endpoints will be analysed in a manner similar to the primary endpoint. No multiple comparison adjustments will be applied to the secondary endpoint analyses.

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12. OPERATOR CRITERIA FOR ELIGIBILITY Trans-radial intervention requires specific skills and dedicated training. Therefore, scope of this study is not to investigate the learning curve of the technique, rather assessing the comparative efficacy and safety of trans-radial technique versus trans-femoral intervention in the context of fully trained interventional cardiologists having been properly exposed to both treatment options. Against this background, single operators qualify for the study provided i) they are familiar and have been exposed to trans-femoral intervention as senior cardiologist in the past for at least 2 years; ii) they have performed in the last 12 months at least 50% of intervention in ACS trans-radially and iii) the number of trans-radial coronary intervention within the previous 12 months is at least 75. In order to collect proper information on operator expertise a retrospective survey focusing on the period 1 January 2010 up to 31 October 2010 will be carried out at each investigational center investigating the following per operator variables: Number of total PCI performed transradially and transfemorally, number of total PCI performed in the context of ACS transradially versus transfemorally and if available percentage of GPI use. In addition, a prospective run-in phase (lasting a minimum of 3 months) will be also conducted forcing operators to perform a balanced number of interventions in ACS via both trans-femoral and trans-radial access site, while monitoring the proportion of GPI use per local practice.

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13. CLINICAL EFFICACY MEASUREMENTS 13.1 A. DEATH All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in patients with coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) should be classified as cardiac. Cardiac death Any death due to immediate cardiac cause (e.g. MI, low output failure, fatal arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death. This includes all procedure related deaths including those related to concomitant treatment. Vascular death Death due to cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. Non-cardiovascular death Any death not covered by the above definitions, including death due to infection, sepsis, pulmonary causes, accident, malignancy, suicide or trauma. 13.2 B. MYOCARDIAL INFARCTION The occurrence of re-infarction (MI) will be assessed up to and including the 30 day and 1 year time points. Serial ECGs, and biomarkers should be obtained for each suspected recurrent ischaemic event. A positive diagnosis of re-infarction is made when the following criteria are met: Subsequent Ischaemic Events <24 hours in patients with STEMI or in patients with ongoing NSTEMI in whom cardiac markers before randomization are not available or higher than URL and still in the ascending phase (i.e. markers are not stable or decreasing in two or more assessments taken before randomisation) Symptoms such as chest pain, lasting ≥20 minutes, presumed to be ischemic in origin. (a) And either

New ST segment elevation of ≥1 mm in ≥2 contiguous leads, or presumably new left bundle branch block

Or Angiographic evidence of re-occlusion of a previously patent coronary artery or bypass graft.

Subsequent Ischaemic Events 24 hours to 7 days Symptoms such as chest pain, lasting ≥20 minutes, presumed to be ischemic in origin. (a) And either

if biomarkers are presumed or known to be abnormal, a new elevation in biomarkers >20% above the prior documented valley level (Troponin I or T should be used first, if not available the second option is for CK-MB mass and if CK-MB not available total CK should be used)

Or If biomarkers are normal or back to normal, use the definition for subsequent ischemic events >7 days

Subsequent Ischemic Events >7 days Myocardial infarction should be determined based evidence of myocardial necrosis in a clinical setting consistent with myocardial ischaemia. Under these conditions any one of the following criteria meets the diagnosis for myocardial infarction: 1. Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischemia with at least one of the following:

• Symptoms of ischemia; • ECG changes indicative of new ischemia (new ST-T changes or new left bundle branch

block [LBBB]);

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• Development of pathological Q waves in the ECG; (b) • Imaging evidence of new loss of viable myocardium or new regional wall motion

abnormality. (c) 2. Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood. 3. For percutaneous coronary interventions (PCI) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By convention, increases of troponin biomarkers greater than 3 x 99th percentile URL in at least one blood sample have been designated as defining PCI related myocardial infarction. A subtype related to a documented stent thrombosis is recognised. 4. For coronary artery bypass grafting (CABG) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By convention, increases of troponin biomarkers greater than 5 > 99th percentile URL in at least one blood sample plus either new pathological Q waves or new LBBB, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium have been designated as defining CABG-related myocardial infarction. 5. Pathological findings of an acute myocardial infarction.

(a) In the absence of pain, new ST segment changes indicative of ischemia, acute pulmonary oedema, ventricular arrhythmias, or hemodynamic instability presumed to be ischemic in origin, will constitute sufficient evidence of ischemia.

(b) New Q waves are defined as Q waves with a duration of >0.04 seconds in at least 2 contiguous leads that were not present on previous ECGs. These ECG criteria are only valid in the absence of left bundle branch block (LBBB), Wolff Parkinson White syndrome (WPW), paced rhythm or other artefacts that would preclude an ECG definition of myocardial infarction.

(c) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in the presence of biomarker elevation with or without other defining factors of myocardial infarction (clinical, ECG, biochemical) and in the absence of a non-ischemic cause may also be used to define a re-infarction. A wall motion abnormality alone does not define infarction. 13.2.1 Q-wave MI Development of new pathological Q waves in 2 or more contiguous leads with or without post-procedure CK or CK-MB levels elevated above normal. 13.2.2 Non-Q wave MI: All MIs not classified as Q-wave 13.2.3 Stroke: is defined as a sudden, focal neurological defect resulting from a cerebrovascular cause, resulting in death or lasting greater than 24 hours, that is not due to a readily identifiable cause such as a tumour, infection or trauma. All suspected strokes will be adjudicated using all available clinically relevant information including imaging studies to classify all strokes as:

• Haemorrhagic stroke – a stroke with focal collections of intracranial blood • Ischemic stroke – a stroke without focal collections of intracranial blood • Unknown – no imaging or autopsy data are available

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13.3 C. REVASCULARIZATION 13.3.1 Target Lesion (TL) The target lesion is the treated lesion starting 5 mm proximal of the stented lesion and ends at 5 mm distal beyond the stented lesion. 13.3.2 Target Lesion Revascularization (TLR) TLR is defined as any repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel. All TLRs should be classified prospectively as either clinically or not clinically indicated by the investigator prior to the reintervention as well as retrospectively by the independent angiographic core laboratory (in the case of % diameter stenosis). 13.3.3 Target Vessel (TV) The target vessel is the entire major coronary vessel proximal and distal to the target lesion including upstream and downstream branches and the target lesion itself. (For example: if the original lesion is the first obtuse marginal branch, the target vessel includes the left main coronary artery, the circumflex coronary artery and its branches). Note: in three-vessel treatment every repeat revascularization becomes TVR. 13.3.4 Target Vessel Revascularization (TVR) TVR is defined as any repeat percutaneous intervention or bypass surgery of the target vessel (as defined above). 13.3.5 Clinically indicated: A revascularization (TLR/TVR) is clinically indicated if angiography at follow-up shows a percent diameter stenosis ≥50% (QCA) and if one of the following occurs:

1) A positive history of recurrent angina pectoris presumably related to the target vessel. 2) Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent)

presumably related to the target vessel. 3) Abnormal results of any invasive functional diagnostic test (e.g. fractional flow reserve). The results of the test must be documented in the

Case Report Form. A TLR/TVR with a diameter stenosis ≥70% (QCA) in the absence of the above mentioned ischemic signs or symptoms is also considered clinically indicated. 13.3.6 Not Clinically indicated TLRs/TVRs are reinterventions for:

1. all stenoses <50% (diameter stenosis by QCA) in the presence or absence of ischemic signs or symptoms;

2. all stenoses ≥50% but <70% (diameter stenosis by QCA) without ischemic signs or symptoms. Clinically indicated: documented provisional decision to re-intervene based on clinical symptoms and/or results of non invasive functional testing, before any coronary imaging. These criteria are intended to determine clinical indications for re-intervention in patients undergoing routine angiographic follow-up. In the patient cohorts assigned to clinical follow-up only, or in studies without routine angiographic follow-up, all revascularizations are considered clinically indicated. 13.3.7 Non Target Lesion Revascularization (nonTLR) Any revascularization in a lesion other than the target lesion is considered a non-TLR. 13.3.8 Non Target Vessel Revascularization (nonTVR) Any revascularization in a vessel other than the target vessel is considered a non-TVR.

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13.4 . STENT THROMBOSIS Stent Thrombosis should be reported as a cumulative value at the different time points and with the different separate time points. Time 0 is defined as the time point after the guiding catheter has been removed and the patient leaves the Cathlab. 13.4.1 Timing: Acute stent thrombosis(*): 0 . 24 hours post stent implantation Subacute stent thrombosis(*): >24 hours . 30 days post stent implantation Late stent thrombosis: >30 days . 1 year post stent implantation Very late stent thrombosis: >1 year post stent implantation (*) acute/subacute can also be replaced by early stent thrombosis. Early stent thrombosis (0.30 days) . this definition is currently used in the community. We recognize three categories of evidence in defining stent thrombosis:

1) Definite 2) Probable 3) Possible

1. Definite (is considered either by angiographic or pathologic confirmation). Angiographic confirmation of stent thrombosis is considered to have occurred if:

1) Thrombolysis In Myocardial Infarction (TIMI) flow is: a) TIMI flow grade 0 with occlusion originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus(*). b) TIMI flow grade 1, 2, or 3 originating in the stent or in the segment 5mm proximal or distal to the stent region in the presence of a thrombus(*).

AND at least one of the following criteria, has been fulfilled within a 48 hours time window: 2) new onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) 3) new ischemic ECG changes suggestive of acute ischemia 4) typical rise and fall in cardiac biomarkers

The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion). (*) Intracoronary thrombus [Ellis et al., Mabin et al., Capone et al.] Non-occlusive thrombus: Intracoronary thrombus is defined as a (spheric, ovoid or irregular) non-calcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolization of intraluminal material downstream. Occlusive thrombus: A TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originating from the side branch). 13.4.2 Pathologic confirmation of stent thrombosis: Evidence of recent thrombus within the stent determined at autopsy

2) Probable: Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases:

1) Any unexplained death within the first 30 days. 2) Irrespective of the time after the index procedure any myocardial infarction (MI), which is

related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause.

3) Possible:

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Clinical definition of possible stent thrombosis is considered to have occurred with any unexplained death following intracoronary stenting until the end of the follow-up period. 14. SAFETY MEASUREMENTS: The main bleeding classification which will be used in the study will be the Bleeding Academic Research Consortium (BARC) which is detailed below and summarized in the Table Type 0: No evidence of bleeding. Type 1: Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional. Examples include, but are not limited to, bruising, hematoma, nosebleeds, or hemorrhoidal bleeding for which the patient does not seek medical attention. Type I bleeding may include episodes that lead to discontinuation of medications by the patient because of bleeding without visiting a health care provider. Type 2: Any clinically overt sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that is actionable, but does not meet criteria for Type 3 BARC bleeding, Type 4 BARC bleeding (CABG-related), or Type 5 BARC bleeding (fatal bleeding). The bleeding must require diagnostic studies, hospitalization or treatment by a health care professional. In particular, the bleeding must meet at least one of the following criteria:

1) Requiring intervention: defined as a health care professional-guided medical treatment or percutaneous intervention to stop or treat bleeding, including temporarily or permanently discontinuing a medication or study drug. Examples include, but are not limited to, coiling, compression, use of reversal agents (e.g. vitamin K, protamine), local injections to reduce oozing, or a temporary/permanent cessation of antiplatelet, antithrombin, or fibrinolytic therapy;

2) Leading to hospitalization or an increased level of care: defined as leading to or prolonging hospitalization or transfer to a hospital unit capable of providing a higher level of care; or

3) Prompting evaluation: defined as leading to an unscheduled visit to a healthcare professional resulting in diagnostic testing (laboratory or imaging). Examples include, but are not limited to, hematocrit testing, hemoccult testing, endoscopy, colonoscopy, computed tomography scanning, or urinalysis. A visit or phone call to a healthcare professional where neither testing nor treatment is undertaken does not constitute Type 2 bleeding.

Type 3: Clinical, laboratory, and/or imaging evidence of bleeding with specific healthcare provider responses, as listed below: a. BARC Type 3a Bleeding

• Any transfusion with overt bleeding • Overt bleeding plus hemoglobin drop ≥3 to <5 g/dL* (provided hemoglobin drop is related to

bleeding) b. BARC Type 3b Bleeding

• Overt bleeding plus hemoglobin drop ≥ 5 g/dL* (provided hemoglobin drop is related to bleeding) • Cardiac tamponade • Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) • Bleeding requiring intravenous vasoactive drugs

c. BARC Type 3c Bleeding

• Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation; does include intraspinal).

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• Subcategories; Confirmed by autopsy or imaging or lumbar puncture (LP) • Intra-ocular bleed compromising vision

*Hb drop should be corrected for intracurrent transfusion, where 1 unit of packed red blood cells or 1 unit of whole blood would be expected to increase Hb by 1g/dl Type 4: CABG-Related Bleeding.

• Perioperative intracranial bleeding within 48 hours • Reoperation following closure of sternotomy for the purpose of controlling bleeding • Transfusion of ≥ 5 units of whole blood or packed red blood cells within a 48 hour period** • Chest tube output ≥ 2L within a 24 hour period.

Note: If a CABG-related bleed is not adjudicated as at least a Type 3 severity event, it will be classified as ‘not a bleeding event’. ** Only allogeneic transfusions are considered as transfusions for CABG-related bleeds. Cell saver products will not be counted. Type 5: Fatal Bleeding. Fatal bleeding is bleeding that directly causes death with no other explainable cause. BARC Fatal Bleeding is categorized as either definite or probable as follows:

a) Probable fatal bleeding (Type 5a) is bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed and there is no autopsy or confirmatory imaging.

b) Definite fatal bleeding (Type 5b) is bleeding that is directly observed (either by clinical specimen – blood, emesis, stool, etc.- or by imaging) or confirmed on autopsy.

The site of fatal bleeding is further categorized as intracranial, gastrointestinal, retroperitoneal, pulmonary, pericardial, gastrourinary, or other. BARC fatal bleeding is meant to capture deaths that are directly due to bleeding with no other cause. The time interval from the bleeding event to the death should be considered with respect to likely causality, but there is no specific time limit proposed. Bleeding that is contributory but not directly causal to death is not classified as fatal bleeding, but may be categorized as other forms of bleeding. Bleeding that leads to cessation of antithrombotic or other therapies may be contributory, but again, would not be classified as fatal bleeding. Bleeding associated with trauma or with surgery may be fatal, depending on whether it was determined to be directly causal or not. TIMI Major Bleeding is defined as [Bovil et al, 1991]:

• Intracranial haemorrhage • Associated with a decrease in Hgb >5g/dL (3.1 mmol/L) (or 15% of haematocrit) • Haemorrhagic Death • Cardiac Tamponade

TIMI Minor Bleeding is defined as [Bovil et al, 1991]:

• Blood loss that is spontaneous and observed as gross haematuria or haematemesis • Observed (ie, haeme-positive coffee ground emesis, haeme-positive melaena, haematoma or retroperitoneal bleeding) • Spontaneous or non-spontaneous blood loss associated with a haemoglobin >3 g/dL (1.8 mmol/L) and <5 g/dL (3.1 mmol/L) (or a haematocrit decrease of 9% and <15%) • Haemoglobin decrease >4 g/dL (2.5 mmol/L) and <5 g/dL (3.1 mmol/L) (or 12% of haematocrit and <15% ) with, despite attempts, no bleeding site identified

GUSTO Severe or life-threatening is defined as [GUSTO Investigators, 1993]:

• Either intracranial haemorrhage or bleeding that causes hemodynamic compromise and requires intervention

GUSTO Moderate is defined as [GUSTO Investigators, 1993]:

• Bleeding that requires blood transfusion but does not result in hemodynamic compromise

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GUSTO Mild is defined as [GUSTO Investigators, 1993]: Finally, in the outpatient setting the bleedscore (Am J Cardiol. 2007 Jan 15;99(2):288-90. Erratum in: Am J Cardiol. 2007 Aug 1;100(3):562 and Eur Heart J. 2010 Jan;31(2):227-35) will be also collected. Thrombocytopenia: will be defined as a post-procedural platelet count <100,000 cells/mm3 in a patient with a baseline or pre-procedural platelet count >100,000 cells/mm3. Further divided into mild (50,000 - <100,000 cells/mm3), moderate (20,000 - <50,000 cells/mm3), or severe (<20,000 cells/mm3, or requiring platelet transfusion).

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Table BARC bleeding classification BARC Definition for bleeding Type 0 No Bleeding Type 1 Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional. Type 2 Any overt, actionable sign of hemorrhage (e.g. more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that does not fit the criteria for Types 3, 4, or 5, but does meet at least one of the following criteria: 1) Requiring non-surgical, medical intervention by a health care professional 2) Leading to hospitalization or increased level of care 3) Prompting evaluation Type 3

Type 3a § Overt bleeding plus hemoglobin drop of 3 to <5*g/dL (provided hemoglobin drop is related to bleed) § Any transfusion with overt bleeding Type 3b § Overt bleeding plus hemoglobin drop ≥ 5*g/dL (provided hemoglobin drop is related to bleed) § Cardiac tamponade § Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) § Bleeding requiring intravenous vasoactive drugs

Type 3c § Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation; does include intraspinal).

• Subcategories; Confirmed by autopsy or imaging or LP § Intra-ocular bleed compromising vision

Type 4 - CABG–related bleeding § Perioperative intracranial bleeding within 48 hrs § Reoperation following closure of sternotomy for the purpose of controlling bleeding § Transfusion of ≥ 5 units of whole blood or packed red blood cells within a 48 period**. § Chest tube output ≥ 2L within a 24 hour period § If a CABG - related bleed is not adjudicated as at least a Type 3 severity event, it will be classified as ‘not a bleeding event’

Type 5 - Fatal Bleeding Type 5a § Probable fatal bleeding: no autopsy or imaging confirmation, but clinically suspicious Type 5b § Definite fatal bleeding: overt bleeding or autopsy or imaging confirmation

Obs: Platelet transfusions should be recorded and reported, but are not included in these definitions until further information is obtained about the relationship to outcomes. *Corrected for transfusion (1 unit PRBC or 1 unit whole blood = 1g/dL Hgb) * Only allogeneic transfusions are considered as transfusions for BARC Type 4 bleeding. Cell saver products will not be counted.

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15. SAFETY

All adverse events will be assessed and documented from informed consent of the patient until hospital discharge or day 7, whichever comes first following cessation of study drug infusion.

Those events that are serious in nature must be reported to the Sponsor in an expedited manner. SAEs will be followed for 30 days post randomization of the patient into the study.

Patients experiencing adverse events should be followed clinically until their health has returned to baseline status or until all parameters have returned to normal or have otherwise been explained. It is expected that the investigator will provide or arrange appropriate care for the patient if necessary.

The principal investigator is responsible for ensuring that all staff involved in the study are familiar with the content of this session. The methods for collecting safety data are described below. The reference safety information is the Investigator’s Brochure

15.1 Adverse events The definitions of adverse events (AEs) and serious adverse events (SAEs) are given below. Adverse event An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory findings, electrocardiogram). In clinical studies, an AE can include an undesirable medical condition occurring at any time, including run-in or washout periods, even if no study treatment has been administered. The terms AE is used to include both serious and non serious AEs. Serious adverse events require separate evaluation for reporting to regulatory authorities, competent authorities, central and local ethics committees and all Investigators involved in this clinical trial.

15.2 Serious adverse event A serious adverse event is an AE occurring after the signing of the informed consent during any study phase (ie, run-in, treatment, washout, follow-up), and at any dose of the investigational product, comparator or placebo, that fulfills one or more of the following criteria:

• results in death;

• is immediately life-threatening;

• requires in-patient hospitalization or prolongation of existing hospitalization;

• results in persistent or significant disability or incapacity;

• is a congenital abnormality or birth defect;

• is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above.

A distinction should be drawn between serious and severe AEs. Severity is an estimate or measure of the intensity of an AE, while the criteria for serious AEs are indications of adverse subject outcomes for regulatory reporting purposes. A severe AE need not necessarily be considered serious and a serious AE need not be considered severe. For example, nausea that

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persists for several hours may be considered severe nausea, but not an SAE. On the other hand, a myocardial infarction (MI) that may be considered minor could also be an SAE if it prolonged hospitalization. The Serious Adverse Event Report (SAER) is contained in the eCRF system and must be completed within 24 hours of when the SAE is recognized. Overdose, drug misuse, drug abuse, medication error and pregnancy also need to be reported within 24 hours using this form, regardless of whether they are associated with an adverse event or not. If a pregnant patient also experiences an SAE, the SAE must be reported using the SAE form. A medication error is defined as a preventable event that may cause or lead to inappropriate medication use or patient harm. A medication error is unintentional. Examples of medication error include, but are not limited to, administration of the wrong drug, the wrong drug dose, via the wrong route or over the wrong time interval. It is important to note that patients who experience an SAE may be discontinued from study treatment, but should not be discontinued from the clinical trial. Such patients should continue in the clinical trial to ensure that follow-up occurs at the clinically appropriate intervals and to ensure adequate ITT data collection for the study. Patients in this trial should be followed through the Day 365 follow-up visit. For any event involving death, the cause of death must be reported for the SAE. The result of an autopsy, if performed, should also be provided. Any serious adverse event that occurs outside of the designated study period, i.e. 30 days (+/- 5 days) and is deemed to be possibly related to study treatment by a study Investigator should also be reported immediately, but no later than 24 hours of when the SAE is recognized.

The investigator will assess casual relationship between Investigational Product and each Adverse Event will be categorized according to the semi-quantitative scale as follows:

1. Unrelated - this category applies to AEs that are clearly due to causes other than the study medication.

2. Unlikely related - this category applies to AEs for which there is no reasonable evidence

or argument to suggest a causal relationship between the study medication and the AE.

3. Possibly related - this category applies to AEs for which there is reasonable evidence or

argument to suggest a causal relationship between the AE and the study medication.

4. Definitely related - this category applies to AEs that are considered to be related to the study medication, with a high degree of certainty.

Recording of adverse events All AEs (non-serious and serious) spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedure must be recorded on the source documents and eCRF provided by the Sponsor.

AEs that occur from the time of informed consent until hospital discharge or day 7, whichever comes first following cessation of study drug infusion, must be assessed and recorded on the source documents and eCRF, regardless of causal relationship to the study drug.

The severity of an AE and the relationship to study drug will be assessed by the investigator. The investigator should ensure that any patient experiencing an AE receives appropriate medical support until the event resolves.

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Each adverse event recorded will include the following variables:

− onset of adverse event

− description of the adverse event

− resolution

− whether the patient was withdrawn

− outcome

− causality rating (yes/no) assessed by the Investigator

− whether or not it is serious

− intensity

The patient or clinician who identifies the adverse event will be asked to provide a description of the event, the dates of onset and resolution, treatment administered, and assessment of the intensity of the reported adverse event according to the following scale:

1. Mild: awareness of sign or symptom, but easily tolerated.

2. Moderate: discomfort sufficient to cause interference with normal activities.

3. Severe: incapacitating, with inability to perform normal activities.

During the course of the study every effort should be made to obtain an outcome for all adverse events. At study completion / withdrawal, all ongoing SAEs should be followed until the event has resolved, or stabilized and no further change is expected. Laboratory results that constitute SAEs must be recorded and reported as serious adverse events. Patients that discontinue due to abnormal laboratory results should have the abnormal laboratory results recorded and reported as adverse events. Abnormal creatine kinase and liver enzymes laboratory values will be followed up until they have returned to baseline values or until the Investigator considers them resolved. Should an overdose (accidental or deliberate) occur, it must be reported in accordance with the procedures described in section Procedures in case of overdose, regardless of whether the overdose was associated with an adverse event not. All symptoms associated with the overdose should be reported as AEs. Non-serious adverse events, unless they meet one or more of the criteria for seriousness. All events of overdose should be reported to the Sponsor ithin 24 hours of awareness of the event by the Investigator whether or not the overdose was associated with any adverse event(s). If the overdose is associated with a serious adverse event, it should be reported in the same manner as all other serious adverse events. Should a medication error occur (for example: administration of the wrong drug dose, wrong route of administration, wrong rate, wrong reconstitution) it must be reported to the Sponsor. All events of medication error should be reported to MDCO within 24 hours of awareness of the event by the Investigator whether or not the overdose was associated with any adverse event(s). If the medication error is associated with a serious adverse event, it should be reported in the same manner as al other serious adverse events. Should a pregnancy occur, it must be reported in accordance with the procedures described in Section Procedure in case of Pregnancy. Pregnancy in itself is not regarded as an AE unless

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there is a suspicion that an investigational product may have interfered with the effectiveness of a contraceptive medication. All events of pregnancy should be reported to the Sponsor within 24 hours of awareness of the event by the Investigator whether or not the pregnancy was associated with any adverse event(s). If the pregnancy is associated with a serious adverse event, it should be reported in the same manner as al other serious adverse events. 15.3 Reporting of serious adverse events The Sponsor/Investigator is responsible for meeting all regulatory safety reporting requirements and obligations. This includes expedited reporting off all serious, unexpected and possibly study-drug-related SAEs (SUSAR) from the study to the Regulatory Authority and IEC/IRB, as required. The Investigator must inform the Sponsor through the Dimensione Ricerca (CRO) of any SUSAR that occurs in the course of the study within 24 hours or at latest the following working day. Patient Safety contacts are: Dr. Maria Salomone Tel.: 06 - 8076072 Fax: 06 – 80693521

15.4 Procedures in case of emergency, overdose or pregnancy

Procedures in case of medical emergency

The principal Investigator(s) is responsible for ensuring that procedures and expertise are available to cope with medical emergencies during the study. Procedures in case of overdose

− Use of study medication in doses in excess of that specified in the protocol should not be recorded in the CRF as an AE of ‘Overdose’ unless there are associated symptoms or signs.

− An Overdose with associated SAEs should be recorded as the SAE diagnosis/symptoms recorded on the relevant SAE forms in the CRF.

− An Overdose with associated non-serious AEs should be recorded as the AE diagnosis/symptoms recorded on the relevant AE forms in the CRF.

− An Overdose without associated symptoms should not be recorded as an AE in the CRF.

All events of Overdose should be reported to the Sponsor.

Procedures in case of pregnancy Although it is unlikely that pregnancy will occur in this study, patients should be instructed to stop study drug immediately if pregnancy is suspected or confirmed, and to notify the Sponsor/Investigators.

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Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the investigational product under study may have interfered with the effectiveness of a contraceptive medication. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital abnormality) must be followed up and documented even if the patient was discontinued from the study. All pregnancies should be reported within 1 day of the time the Sponsor/investigators personnel becomes aware of the pregnancy. All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be reported and handled as SAEs. Elective abortions without complications should not be handled as AEs. All reports of pregnancy, congenital abnormalities/birth defects, spontaneous miscarriages and elective abortions should be reported to the Sponsor.

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16. PROTOCOL DEVIATIONS This study will be conducted as described in this protocol, except for an emergency situation in which the protection, safety, and well being of the subject requires immediate intervention, based on the judgment of the investigator (or a responsible, appropriately trained professional designated by the investigator). In the event of a significant deviation from the protocol due to an emergency, accident, or mistake, the investigator or designee should contact the Sponsor, or their agent, at the earliest possible time by telephone. This will allow an early joint decision regarding the subject’s continuation in the study. The EC will be informed of all protocol changes by the investigator in accordance with the EC established procedure. 17. DATA COLLECTION An electronic Case Report Form (eCRF) will be used to collect all patient data assessments that will be used for evaluation of specified analyses. 17.1. Accountability The investigator or his designee must maintain an inventory record of bivalirudin received and all administered to assure the regulatory authorities and the Sponsor that the investigational drug will not be dispensed to any person who is not a subject under the terms and conditions set forth in this protocol. The bivalirudin supplied for use in this study is to be prescribed only by the Principal Investigator or named sub-investigators and may not be used for any purpose other than that outlined in this protocol. At the end of the study, all unused bivalirudin will be destroyed locally once the bivalirudin has been accounted for and the monitor has reviewed the accountability records. In the event that bivalirudin needs to be returned for any other reason, the site will receive a written request listing the drug lot number(s) to be returned and the reason for the return request. 18. RECORDS RETENTION Current EU Directive and ICH guidelines collectively require that essential clinical trial documents (including case report forms) other than the subject’s medical files must be retained for the following time period:

• For at least 15 years after completion or discontinuation of the trial, • Or 2 years after the last approval of a marketing application in an ICH region and until

there are no pending or contemplated marketing applications in an ICH region, • Or at least 2 years have elapsed since the formal discontinuation of clinical development

of the investigational product. Investigators shall retain the essential documents relating to a clinical trial for at least five years after its completion. They shall retain the documents for a longer period, where so required by applicable local requirements. To comply with these requirements, the investigator will not dispose of any records relevant to this study without either (1) written permission from the Sponsor or (2) providing an opportunity for the Sponsor to collect such records.

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19. QUALITY CONTROL AND QUALITY ASSURANCE 19.1. Monitoring The Sponsor has ethical, legal and scientific obligations to carefully follow this study in a detailed and orderly manner in accordance with established research principles and applicable regulations. The investigator, as part of his responsibilities, is expected to cooperate with the Sponsor in ensuring that the study adheres to the protocol and GCP requirements. As part of a concerted effort to fulfil these obligations, the Sponsor will authorise a Clinical research Organisation (CRO) to perform monitoring tasks and visit the centre(s) during the study in accordance with the Clinical Management Plan (CMP) set forth for this trial as well as maintain frequent telephone and written communication. The investigator will permit the Sponsor’ authorised CRO personnel to monitor the study as frequently as is deemed necessary and provide access to medical records to ensure that data are being recorded adequately, that data are verifiable and that protocol is adhered to. 19.2. Auditing As part of implementing quality assurance, the Sponsor may conduct audits at the study centre(s) in order to evaluate trial conduct and compliance with the protocol, SOPs, GCP and applicable regulatory requirements. The investigator agrees to cooperate with the Sponsor and/or its designee in the conduct of these audits and provide access to medical records and other relevant documentation, as required. Regulatory authorities worldwide may inspect the investigator during or after the study. The investigator should contact the Sponsor immediately if this occurs, and must fully cooperate with regulatory authority inspections as required. 20. ETHICS AND RESPONSIBILITY This study will be conducted in compliance with the protocol, with the Sponsor’s standard operating procedures and/or guidelines, European Union regulations, the International Conference on Harmonisation (ICH) GCP guidelines and the Declaration of Helsinki. The investigator is responsible for ensuring the investigation is conducted according to all signed agreements, the study protocol and GCP requirements. Also, each investigator must complete and sign the Investigator's Agreement. In signing, the investigator agrees to:

• Adhere to the Investigator Agreement

• Participate in Investigator meetings as scheduled by the Sponsor

• Maintain up-to-date angiographic and PCI equipment

• Have access to cardiac surgery

• Be willing to perform and be capable of performing treatment procedures as outlined

in this protocol

• Comply with all required elements of this protocol (eg, perform testing and follow-up

as specified, especially during personnel transitions) and supply angiographic material

suitable for quantitative analysis

• Obtain written Informed Consent from each study participant before any study specific

procedures are performed in accordance with GCP

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• Complete all electronic CRFs for completed patients visits and or applicable events (ie,

death, re-infarction (MI), IDR, non-CABG-related protocol major bleeding) prior to

scheduled monitoring visits

• Adhere to the study protocol at all times, except to eliminate an immediate hazard to

trial subject(s). Comply with all European Union requirements for investigators, and

with all other applicable regulations and codes of approvals from ECs and other

Regulatory Authorities.

20.1. Informed Consent The investigator(s) has both ethical and legal responsibility to ensure that each prospective subject is given a full explanation of the protocol. This shall be documented on a written informed consent form, which shall be approved by the same EC responsible for approval of this protocol. Each patient shall be given a copy of the signed informed consent form, and the original shall be kept in the site’s regulatory file. A second copy may be filed in the patient's medical record, if allowed by the institution. 20.2. Ethics Committee This protocol and the written informed consent form shall be submitted to the appropriate EC at each site in Italy. The study may not commence until written approval from the EC is available, either as a letter or as a copy of the appropriate section of the EC meeting minutes where this protocol and associated informed consent form were discussed. The investigator will not participate in the decision. If the investigator is an EC member, the written approval must indicate such non-participation. The Sponsor or authorised designee will submit status reports to the EC at least annually (when applicable and according to local regulations). The EC must be notified by the Sponsor or designee in writing of the interruption and/or completion of the study; the Sponsor or designee must promptly report to the EC all changes in research (protocol amendments) and will not make such changes without EC approval except where necessary to eliminate apparent immediate hazards to human patients. In these cases, the EC must be notified within five days of the change. The Sponsor or designee will promptly report to the EC all unanticipated problems involving risk to patients or others. The investigator is required to maintain an accurate and complete record of all written correspondence to and received from the EC and must agree to share all such documents and reports with the Sponsor or designee. 21. CONFIDENTIALITY All information generated in this study must be considered highly confidential and must not be disclosed to any persons not directly concerned with the study without written prior permission from the Sponsor. However, authorised regulatory officials and Sponsor personnel will be allowed full access to the records. All medications provided and patient bodily fluids and/or other materials collected shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the Sponsor. Only initials and unique patient numbers in CRFs will identify patients. Patients full names may, however, be made known to a regulatory agency or other authorised official if necessary.

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22. PUBLICATION POLICY The sponsor and as well as the PI of this study, recognising the seminal importance of this investigation, are committed to the unrestricted and widespread dissemination of all primary and secondary endpoint results and tertiary analyses. At the conclusion of the Trial, a multi-centre abstract reporting the primary results will be prepared by the Principal Investigator (in collaboration with the Executive Committee, International Steering Committee, Publication Committee and local principal investigators from high enrolling sites) and presented at an annual high calibre scientific meeting. A multicenter publication will similarly be prepared for publication in a reputable scientific journal. The publication of the principal results from any single centre experience within the trial is not allowed until both the preparation and publication of the multicenter results. Following analysis and presentation of the primary endpoint results, active participation of all committee members and investigators from high enrolling sites, will be enthusiastically solicited for data analysis and abstract and manuscript preparation. Submission of all abstracts and publications regarding the primary endpoint and secondary endpoints from the study requires approval by the study Principal Investigator after review by the Sponsor and Executive Committee. All original manuscripts and abstracts of data and information relating to the clinical trial described in this protocol (collectively, “Publications”) will be submitted in advance to the Publication Committee for review according to the procedure described in this section. The Publication Committee will act as an independent body of scientific and medical experts with the following charter:

• The Publication Committee must review and approve all proposed analyses and topics suggested by the investigators and participating institutions in the clinical trial; • All Publications discussing the trial data and conclusions must be submitted to the Publication Committee for review and approval prior to submission for presentation or publication; and • All other Publications relating to the clinical trial will be submitted to the Publication

All draft Publications must be submitted to the Publication Committee at least 30 days prior to submission to a journal or public presentation. The Publication Committee will consider each manuscript proposal with due regard for the scientific merit of the proposed publication. Decisions of the Publication Committee will be by majority vote. All manuscripts approved by the Publication Committee will conform to the Uniform Requirements for Manuscripts

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23. INVESTIGATOR AGREEMENT I have read and understand the protocol (including the Investigator’s Brochure) and agree that it

contains all the ethical, legal and scientific information necessary to conduct this study. I will

personally conduct the study as described.

I will provide copies of the protocol to all physicians, nurses and other professional personnel

responsible to me who will participate in the study. I will discuss the protocol with them to assure

myself that they are sufficiently informed regarding the investigational drug [bivalirudin], the

concurrent medications, the efficacy and safety parameters and the conduct of the study in general.

I am aware that this protocol must be approved by the Ethics Committee (EC) responsible for such

matters in the Clinical Study Facility where bivalirudin will be tested prior to commencement of this

study. I agree to adhere strictly to the attached protocol. I agree that clinical data entered on case

report forms by me and my staff will be utilised by the Sponsor for non-for-profit purposes including

presentations and publications in the medical literature. I agree to allow Sponsor monitors and

auditors full access to all medical records at the research facility for patients screened or

randomised in the study.

I agree to provide all patients with informed consent forms, as required by government and ICH

regulations. I further agree to report to the Sponsor any adverse experiences in accordance with

the terms of this protocol.

____________________________________________ _______________ Principal Investigator Date

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24. REFERENCES 1. Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation 2009;119(14):1873-82. 2. Eikelboom JW, Quinlan DJ, O'Donnell M. Major bleeding, mortality, and efficacy of fondaparinux in venous thromboembolism prevention trials. Circulation 2009;120(20):2006-11. 3. Elbarouni B, Elmanfud O, Yan RT, et al. Temporal trend of in-hospital major bleeding among patients with non ST-elevation acute coronary syndromes. American heart journal;160(3):420-7. 4. Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. European heart journal 2009;30(12):1457-66. 5. Ndrepepa G, Schulz S, Keta D, et al. Bleeding after percutaneous coronary intervention with Bivalirudin or unfractionated Heparin and one-year mortality. The American journal of cardiology;105(2):163-7. 6. Prandoni P, Trujillo-Santos J, Sanchez-Cantalejo E, et al. Major bleeding as a predictor of mortality in patients with venous thromboembolism. J Thromb Haemost. 7. Rao SV. Bleeding as a predictor of mortality risk. Reviews in cardiovascular medicine 2006;7 Suppl 3:S12-8. 8. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. The New England journal of medicine 2008;358(21):2218-30. 9. Majure DT, Aberegg SK. Fondaparinux versus enoxaparin in acute coronary syndromes. The New England journal of medicine 2006;354(26):2829; author reply 30. 10. Lindsey JB, Cohen DJ, Stolker JM, et al. The impact of bivalirudin on percutaneous coronary intervention-related bleeding. EuroIntervention;6(2):206-13. 11. Campeau L. Percutaneous radial artery approach for coronary angiography. Catheterization and cardiovascular diagnosis 1989;16(1):3-7. 12. Agostoni P, Biondi-Zoccai GG, de Benedictis ML, et al. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; Systematic overview and meta-analysis of randomized trials. Journal of the American College of Cardiology 2004;44(2):349-56. 13. Jolly SS, Amlani S, Hamon M, Yusuf S, Mehta SR. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: a systematic review and meta-analysis of randomized trials. American heart journal 2009;157(1):132-40. 14. Nagai S, Abe S, Sato T, et al. Ultrasonic assessment of vascular complications in coronary angiography and angioplasty after transradial approach. Am J Cardiol 1999;83(2):180-6. 15. Hall JJ, Arnold AM, Valentine RP, McCready RA, Mick MJ. Ultrasound imaging of the radial artery following its use for cardiac catheterization. Am J Cardiol 1996;77(1):108-9. 16. Yoo BS, Lee SH, Ko JY, et al. Procedural outcomes of repeated transradial coronary procedure. Catheter Cardiovasc Interv 2003;58(3):301-4. 17. Dahm JB, Vogelgesang D, Hummel A, Staudt A, Volzke H, Felix SB. A randomized trial of 5 vs. 6 French transradial percutaneous coronary interventions. Catheter Cardiovasc Interv 2002;57(2):172-6. 18. Hamon M, Sabatier R, Zhao Q, Niculescu R, Valette B, Grollier G. Mini-invasive strategy in acute coronary syndromes: direct coronary stenting using 5 Fr guiding catheters and transradial approach. Catheter Cardiovasc Interv 2002;55(3):340-3.

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19. Omoigui NA, Califf RM, Pieper K, et al. Peripheral vascular complications in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I). J Am Coll Cardiol 1995;26(4):922-30. 20. Waksman R, King SB, 3rd, Douglas JS, et al. Predictors of groin complications after balloon and new-device coronary intervention. Am J Cardiol 1995;75(14):886-9. 21. Blankenship JC, Hellkamp AS, Aguirre FV, Demko SL, Topol EJ, Califf RM. Vascular access site complications after percutaneous coronary intervention with abciximab in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. Am J Cardiol 1998;81(1):36-40. 22. Blankenship JC, Balog C, Sapp SK, et al. Reduction in vascular access site bleeding in sequential abciximab coronary intervention trials. Catheter Cardiovasc Interv 2002;57(4):476-83. 23. Reddy BK, Brewster PS, Walsh T, Burket MW, Thomas WJ, Cooper CJ. Randomized comparison of rapid ambulation using radial, 4 French femoral access, or femoral access with AngioSeal closure. Catheter Cardiovasc Interv 2004;62(2):143-9. 24. Morice MC, Dumas P, Lefevre T, Loubeyre C, Louvard Y, Piechaud JF. Systematic use of transradial approach or suture of the femoral artery after angioplasty: attempt at achieving zero access site complications. Catheter Cardiovasc Interv 2000;51(4):417-21. 25. Mann T, Cowper PA, Peterson ED, et al. Transradial coronary stenting: comparison with femoral access closed with an arterial suture device. Catheter Cardiovasc Interv 2000;49(2):150-6. 26. Koreny M, Riedmuller E, Nikfardjam M, Siostrzonek P, Mullner M. Arterial puncture closing devices compared with standard manual compression after cardiac catheterization: systematic review and meta-analysis. Jama 2004;291(3):350-7. 27. Nikolsky E, Mehran R, Halkin A, et al. Vascular complications associated with arteriotomy closure devices in patients undergoing percutaneous coronary procedures: a meta-analysis. J Am Coll Cardiol 2004;44(6):1200-9. 28. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998;97(3):251-6. 29. Aggarwal A, Sobel BE, Schneider DJ. Decreased platelet reactivity in blood anticoagulated with bivalirudin or enoxaparin compared with unfractionated heparin: implications for coronary intervention. Journal of thrombosis and thrombolysis 2002;13(3):161-5. 30. Keating FK, Dauerman HL, Whitaker DA, Sobel BE, Schneider DJ. The effects of bivalirudin compared with those of unfractionated heparin plus eptifibatide on inflammation and thrombin generation and activity during coronary intervention. Coronary artery disease 2005;16(6):401-5. 31. Keating FK, Dauerman HL, Whitaker DA, Sobel BE, Schneider DJ. Increased expression of platelet P-selectin and formation of platelet-leukocyte aggregates in blood from patients treated with unfractionated heparin plus eptifibatide compared with bivalirudin. Thrombosis research 2006;118(3):361-9. 32. Schneider DJ, Keating F, Sobel BE. Greater inhibitory effects of bivalirudin compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation. Coronary artery disease 2006;17(5):471-6. 33. Leger AJ, Jacques SL, Badar J, et al. Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation 2006;113(9):1244-54. 34. Lincoff AM. Direct thrombin inhibitors for non-ST-segment elevation acute coronary syndromes: what, when, and where? American heart journal 2003;146(4 Suppl):S23-30. 35. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. Jama 2003;289(7):853-63. 36. Lincoff AM, Bittl JA, Kleiman NS, et al. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to

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Reduced Clinical Events [REPLACE]-1 trial). The American journal of cardiology 2004;93(9):1092-6. 37. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. Jama 2004;292(6):696-703. 38. Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). American heart journal 2002;143(5):847-53. 39. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. American heart journal 2004;148(5):764-75. 40. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. The New England journal of medicine 2006;355(21):2203-16. APPENDIX 01 - SEVERITY AND CAUSALITY ASSESSMENTS FOR ADVERSE EVENTS SEVERITY Adverse events (AEs) will be graded on a 3-point scale and reported as indicated on the electronic case report form. The intensity of an AE is defined as follows:

1 = Mild: Discomfort noticed, but no disruption to daily activity. 2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 3 = Severe: Inability to work or perform normal daily activity.

STUDY DRUG CAUSALITY The relationship of an AE to study treatment will be assessed with consideration to the following criteria:

• temporal relationship to the initiation of study medication • response of the event to withdrawal of study medication • AE profile of concomitant therapies • clinical circumstances during which the AE occurred • patient’s clinical condition and medical history

Categorisation* of causality will be designated by the investigator as stated below:


2. Unlikely related - this category applies to AEs for which there is no reasonable evidence or argument to suggest a causal relationship between the study medication and the

AE.

3. Possibly related - this category applies to AEs for which there is reasonable evidence or argument to suggest a causal relationship between the AE and the study medication.

4. Definitely related - this category applies to AEs that are considered to be related to the

study medication, with a high degree of certainty. * for the purposes of regulatory reporting, categories ‘3’ and ‘4’ will be considered “related”.

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APPENDIX 02 - STUDY COMMITTEES The Sponsor will appoint chairmen and members to the Executive Committee, the International Steering Committee and to an independent DSMB. Executive Committee This committee will be composed of physicians considered expert in the field of Emergency Medicine, ACS and PCI, including a physician from the Sponsor. The members will provide the scientific direction for the trial. In consultation with the DSMB, this group will be responsible for evaluating the progress of the trial and will make recommendations to the Sponsor regarding termination or continuation thereof. Further, this committee, in collaboration with the Sponsor, may decide to increase or decrease the sample size. Clinical Events Committee (CEC) A CEC will be formed to review clinical data and to adjudicated all primary endpoints plus stroke and stent thrombosis while blinded to the assigned study drug. The CEC will be composed of physicians. The CEC processes will be described in the CEC charter. International Steering Committee This committee will be composed of physicians considered experts in the field of Emergency Medicine, ACS and PCI. As a rule, each participating country will have at least one representative of emergency physicians and one representative of hospital cardiologists. The members will provide the scientific direction for the trial, with particular focus on national and regional variations in practice that may differ across Europe. Data and Safety Monitoring Board (DSMB) An independent DSMB will monitor the progress of the trial and ensure that the safety of subjects enrolled in the trial is not compromised. The DSMB will consist of a clinical chairman, several physicians experienced in clinical trials, but not participating in this study and at least 1 statistician. The DSMB processes is described in the DSMB charter. Publications Committee The Publication Committee will be comprised of a minimum of 5 physician representatives of institutions participating in the study and 1 physician from the Sponsor. The members will be appointed by the Executive Committee. The Publication Committee will be co-chaired by the physician from the Sponsor and 1 physician representative.

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MATRIX protocoll11-I Version II, Amendment, June, 7, 2011

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Minimizing Adverse haemmhorragic events by TRansradial access site and systemic Implementation of angioX (MATRIX)

Synopsis RFBU 11-I

EUDRACT Number: 2011-000430-11

Version II, Amendment Prepared on 7th June 2011

M. Valgimigli

University of Ferrara, Arcispedale S. Anna, Corso Giovecca 203, 44100 Ferrara (ITALY)

[email protected]

The information in this document is considered privileged and is a confidential

communication of the Cardiovascular Department of the University of Ferrara.

Acceptance of this document constitutes agreement that this protocol and related

information may not be copied, published, or disclosed to others except to the

extent necessary to obtain Ethics Committee approval, informed consent, or as

required by Law

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1. SYNOPSIS EUDRACT Number: 2011-000430-11

Name of Sponsor: Gruppo Italiano Studi Emodinamica (GISE) Name of Investigational Strategy and/or Product: Trans-Radial access and Bivalirudin (Angiox®) Acronym of Study: Minimizing Adverse haemmhorragic events by TRansradial access site

and systemic Implementation of AngioX (MATRIX)

Study centre(s): Approximately 60 centres located in Italy Principal Investigator: Marco Valgimigli, MD, PhD Investigators: Network Italiano Studi Radiale (NIR) Study period (years): Estimated date first patient enrolled: May 2011. Estimated date last patient recruited: December 2013. Estimated last patient completed: December 2014

Phase of development: IV

Objectives:

1) To demonstrate that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management.

2) To demonstrate that bivalirudin infusion as compared to standard of care therapy consisting of unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitors are associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management.

Methodology: Multi-centre, prospective, randomised, open-label, 2 by 2 factorial comparison of trans-radial vs. trans-femoral intervention and bivalirudin vs. unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitor. Number of patients (planned): Approximately 6,800

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NSTEACS definition: Patients with all of the following criteria will be eligible: (1) history consistent with new, or worsening ischemia, occurring at rest or with minimal activity; (2) enrolment within 7 days of the most recent symptoms; (3) planned coronary angiography with possible indication to PCI; (4) at least 2 of the following criteria:

1. Aged 60 years or older, 2. Troponin T or I or creatine kinase MB above the upper limit of normal; 3. Electrocardiograph changes compatible with ischemia, ie, ST depression of 1 mm or

greater in 2 contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts;

STEMI definition: i) chest pain for >20 min with an electrocardiographic ST-segment elevation ≥1 mm in two or more contiguous electrocardiogram (ECG) leads, or with a new left bundle-branch block, or an infero-lateral myocardial infarction (MI) with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave and ii) admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia or previous lytic treatment. To be included in the study all patients should receive as soon as logistically feasible a European Society of Cardiology (ESC) guideline recommended dose of: • Aspirin at an initial dose of 150-325 mg orally (or 250-500 mg IV) followed by 75-100 mg/day for at least 1 year. • A P2Y12 receptor blocker such as clopidogrel at a loading dose of 600 mg followed by 75 mg daily or prasugrel at a lading dose of 60 mg followed by 10 or 5 mg daily or ticagrelor (if and when commercially available) at a loading dose of 180 mg followed by 90 mg b.i.d daily. This should be continued as per ESC guidelines (preferably for one year) in all patients. Enrolment of patients will be stratified based on type of ACS (STEMI vs NSTEMI-troponin positive vs. NSTEACS-troponin negative), Intended or ongoing use of prasugrel and final treatment (i.e. PCI vs. non PCI). Investigational treatment, dosage and mode of administration:

• Trans-radial intervention: will be performed according to institutional guidelines and established local practice.

• Bivalirudin: given immediately upon enrolment as bolus of 0.75 mg/kg followed immediately by an infusion of 1.75 mg/kg/h. This infusion should be run continuously until completion of PCI at which time the infusion should be either stopped or reduced

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to a dose of 0.25 mg/kg/h for at least 6 hours. An optional higher-dose infusion of 1.75 mg/kg/h is also permitted for up to 4 hours in the prolonged infusion arm but prohibited in the short bivalirudin group.

Patients who do not undergo PCI and are to be medically managed may continue the infusion of 0.25 mg/kg/h for up to 72 hours. Patients who are to undergo coronary artery bypass grafting (CABG) are to undergo anticoagulation as per local practice. Post-PCI anticoagulation for prophylaxis or otherwise may be continued as per local practice. Reference therapy, dosage and mode of administration:

• Trans-femoral intervention: will be performed according to institutional guidelines and established local practice. Access closure devices are allowed as per local practice.

• UFH±GPI: Unfractionated heparin (UFH) (100 IU/kg with no glycoprotein IIb/IIIa inhibitor (GPI) and 60 IU/kg with a GPI); +/- routine or bail out eptifibatide (two 180 µg /kg boluses with a 10 minute interval followed by an infusion of 2.0 µg /kg/min for 72-96 hours) or tirofiban (25 µg/kg followed by an infusion of 0.15 µg/kg/min for 18 to 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, 10 µg/min). Patients who are to undergo CABG are to undergo anticoagulation as per local practice. Post PCI anticoagulation for prophylaxis or otherwise may be continued as per local practice.

Primary Endpoint at 30 days: • A composite of death, re-infarction (MI) or stroke Key Secondary Endpoints: A composite of death, non-fatal MI, stroke or BARC-defined type 3 and 5 major bleeding complications at 30 days. Main Secondary Endpoints:





5) The length and costs of hospitalization as well as cost-effectiveness of transradial

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intervention versus transfemoral and bivalirudin versus UFH±GPI. 6) The need for surgical access site repair/intervention and/or blood products transfusion 7) The prognostic impact of major bleeding complications on 30 days death, MI or stroke

rate as assessed based on various bleeding classifications including BARC, TIMI and GUSTO as well as the prognostic role of thrombocytopenia.


Sub-Randomization: Patients randomly assigned to receive bivalirudin will be randomized to stop bivalirudin infusion at the end of PCI or to prolong bivalirudin at an infusion rate of 0.25 mg/kg/hour for at least 6 hours after completion of PCI. The primary hypothesis in this sub-randomization is that prolonged post-intervention bivalirudin infusion will be superior to no bivalirudin post-PCI infusion with respect to the net composite outcome consisting of any death, MI, stroke, urgent TVR, stent thrombosis and BARC-defined type 3 and 5 bleeding events within 30 days. Secondary objectives for the sub-randomization of prolonged bivalirudin versus no post-PCI infusion in the bivalirudin group will consist of each component of the primary composite endpoint through the entire follow-up duration. Sample Size: Access site comparison: It is expected that the incidence of the primary end-point on an intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the transradial and transfemoral group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints). Pharmacology arm: It is expected that the incidence of the primary end-point on an intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the bivalirudin and UFH group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints). Statistical considerations for the key secondary endpoints: Six thousand eight hundred patients (3,400 in each arm) will provide greater than 98% power to detect a difference in the net clinical outcomes including death, MI, stroke and major bleeding complications (Type 3 and 5 in accordance to the BARC classification) from 9% in the transfemoral and UFH arms to 6% in the transradial and bivalirudin arm with a type I error set at 1%. Sample size considerations for the subrandomization Three thousand four hundred patients (1,700 in each arm) will provide 87% power to assess superiority of prolonged post-PCI bivalirudin infusion versus no post-PCI infusion assuming a background event rate of death, MI, stroke, urgent TVR, stent thrombosis and type 3 and 5 type BARC bleedings in the range of 10% in the prolonged arm versus 6.5% (RRR: 35%) with a type I error set at 1%.

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2. TABLE OF CONTENTS 1. SYNOPSIS ……………………………………………..…………………………

2. TABLE OF CONTENTS ……………………………………..…………………..

3. LIST OF ABBREVIATIONS ………………………………..……………………

4. INTRODUCTION .…………………………………………..…………………….

4.1. Background .………………………………………………..……………………..

4.2 Vascular access site ………………………………………..……………….……

4.3 Pooled analysis of the available evidence comparing TFA versus TRA ……

4.4 Incidence of vascular access complications after transradial approach with

a special focus on radial artery occlusion ...……………………………….…...

4.5 Incidence of vascular access complications after transfemoral approach

with focus on vascular closure devices ...………………………………….…...

4.6 Concluding remarks on comparative feasibility of the transradial with

respect to the transfemoral approach ...………………………………………..

4.7 Establishing the rational for the use of newer anti-thrombotic agents in

patients undergoing coronary interventions through TRA ...…………….……

4.8 Bivalirudin ..………………………………………………………………………..

5. TRIAL DESIGN .…………………………………………………………….…….

5.1 Stratification .……………………………………………………………….……...

5.2 Main study primary hypotheses .…………………………………………….…..

5.3 Main study primary objectives …………………………………………….…….

5.4 Main study key secondary objectives .…………………………………….……

5.5 Main study secondary objectives ………………………………………….……

5.6 Sub-randomization .………………………………………………………….……

5.6.1 Primary hypothesis for the Sub-randomization group .…………….………….

5.6.2 Secondary hypotheses for the Sub-randomization group ………..…………..

5.7 Schematic Diagram of Trial Design ……………………………….……………

5.8 Measures to Minimise/Avoid Bias .……………………………………….……..

6. RANDOMIZATION ………………………………………………………..………

6.1 Staged Procedures ……………………………………………………………….

7. SUBJECT POPULATION ……………………………………………..…………

7.1 Number of subjects ..………………………………………………….………….

7.2 NSTEACS definition ..………………………………………………….…………

2

6

10

12

12

12

16

19

19

22

22

22

25

25

26

26

26

26

27

27

27

28

28

28

28

29

29

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7.3 STEMI definition .…………………………………………………….……………

7.4 As exclusion criteria the following items will be considered ……….………...

7.5 Withdrawal Criteria ..……………………………………………………….……..

8. TREATMENT OF SUBJECTS ..………………………………………….……...

8.1 Control group ..……………………………………………………………….……

8.2 Study group ..………………………………………………………………….…..

8.3 Renal Impairment ...………………………………………………………………

8.4 Concomitant therapy ...…………………………………………………….……..

8.5 Upstream Therapy ...……………………………………………………………..

8.5.1 As per Randomisation scheme ...……………………………………………….

8.5.2 As per Investigator’s discretion ...……………………………………………….

8.6 Study Drug Packaging and Labelling …………………………………………..

8.7 Study Drug Storage ...……………………………………………………….……

8.8 Study Drug Preparation ………………………………………………………….

8.9 Administration ...…………………………………………………………………..

8.10 Study Drug Accountability ……………………………………………………….

8.11 Study Drug Handling and Disposal ...……………………………………….…..

9. ON-TREATMENT PLATELET REACTIVITY SUB-STUDY ………………….

10 SEQUENCE OF PROCEDURES ………………………………………….……

10.1 General Conduct of the Trial ………………………………………………….…

10.2 Pre-Hospital Management ………………………………………………….……

10.3 In-Hospital Management ...………………………………………………………

10.4 Follow-up Management ......………………………………………………….…..

11. STATISTICAL SECTION …………………………………………………….…..

11.1 Sample size justification for the two co-primary endpoints ……………….….

11.2 Sample size considerations for the key secondary endpoint …………….….

11.3 Sample size considerations for the duration of post-pci bivalirudin infusion

11.4 Definitions ………………………………………………………………………….

11.4.1 Subject Populations ………………………………………………………………

11.4.2 Observational period ……………………………………………………………..

11.5 Statistical Analysis ………………………………………………………………..

11.6 Endpoints ………………………………………………………………………….

12. OPERATOR CRITERIA FOR ELIGIBILITY…………………………………….

13. MATRIX SUBSTUDY: Customized Choice of P2Y12 oral receptor blocker

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based on an integration of clopidogrel loss of function allele and phenotype

assessment via Point of care testing ..………………………………………….

13.1 Objective of the sub-study ……………………………………………………….

13.2 Primary endpoint ………………………………………………………………….

13.2.1 Major secondary endpoint ……………………………………..........................

13.3 Patient population ………………………………………………………………...

13.4 Randomization …………………………………………………..........................

13.5 Sub-study description and study procedures ………………….......................

13.6 Definitions of events ……………………………………………………………...

13.7 Statistical considerations ………………………………………………………...

14. CLINICAL EFFICACY MEASUREMENTS …………………………………….

14.1 A. Death …………………………………………………………………………...

14.2 B. Myocardial Infarction ………………………………………………………….

14.2.1 Q-wave MI ...………………………………………………………………………

14.2.2 Non-Q wave MI…………………………………………………………………….

14.2.3 Stroke ………………………………………………………………...……………

14.3 C. Revascularization ………………………………………….……..…………...

14.3.1 Target Lesion (TL) …………………………………………………….…….……

14.3.2 Target Lesion Revascularization (TLR) …………………………….……….….

14.3.3 Target Vessel (TV) ……………………………………………………….……….

14.3.4 Target Vessel Revascularization (TVR) ……………………………….……….

14.3.5 Clinically indicated …………………………………………………….………….

14.3.6 Not Clinically indicated ………………………………………….…….………….

14.3.7 Non Target Lesion Revascularization (nonTLR) …………….………………..

14.3.8 Non Target Vessel Revascularization (nonTVR) …………….….…………….

14.4 D. STENT THROMBOSIS …………………………………………………….…

14.4.1 Timing ………………………………………………………………………….…..

14.4.2 Pathologic confirmation of stent thrombosis …………………….……….…….

15. SAFETY MEASUREMENTS ………………………………………..…………..

16. SAFETY……………………………..……………………………………………..

16.1 Adverse Events …………………………………………………………...………

16.2 Serious Adverse Events (SAEs) ………………………………………..….…...

16.3 Reporting of SAEs ………………………………………………….....…….……

16.4 Procedures in case of emergency, overdose or pregnancy …..….……

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17. PROTOCOL DEVIATIONS ……………………………………………….……..

18. DATA COLLECTION ……………………………………………………….…….

18.1. Accountability ……………………………………………………………………..

19. RECORDS RETENTION ………………………………………………………..

20. QUALITY CONTROL AND QUALITY ASSURANCE ………………………...

20.1. Monitoring ………………………………………………………………….………

20.2. Auditing …………………………………………………………………….………

21. ETHICS AND RESPONSIBILITY ……………………………………….………

21.1. Informed Consent ...…………………………………………………….………...

21.2. Ethics Committee ...…………………………………………………….…………

22. CONFIDENTIALITY ...……………………………………………………………

23. PUBLICATION POLICY………………………………………………………….

24. INVESTIGATOR AGREEMENT ………………………………………………..

25. REFERENCES .............................................................................................

APPENDIX 01 - SEVERITY AND CAUSALITY ASSESSMENTS FOR ADVERSE

EVENTS .......................................................................................................................

APPENDIX 02 - STUDY COMMITTEES ……………..………………….………………..

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3. LIST OF ABBREVIATIONS

Abbreviation Definition ACS Acute Coronary Syndrome

ACT Activated Clotting Time

ADP Adenosin Di-Phosphonate

ADPhs High Sensibility ADP

AE Adverse Event

AIFA Agenzia Italiana del Farmaco

AUC Area Under the Curve

BARC Bleeding Academic Research Consortium

CABG Coronary Artery Bypass Grafts

CEC Clinical Events Committee

CHF Congestive Heart Failure

CK-MB Creatine Kinase MB Isoenzyme

CMP Clinical Management Plan

CRO Clinical research Organisation

DCA Directional Coronary Atherectomy

dL Decilitre(s)

DSMB Data and Safety Monitoring Board

EC Ethics Committee

ECG Electrocardiogram

eCRF Electronic Case Report Form

GCP Good Clinical Practices

GPI Glycoprotein IIb/IIIa Inhibitor

ICH International Conference on Harmonisation Requirements for Registration of Pharmaceuticals

IDR Ischemia Driven Revascularisation

ITT Intent-to-treat

kg Kilogram(s)

LBBB Left Bundle Branch Block

LWMH Low Weight Molecular Heparin

MACE Major Adverse Cardiovascular Events

MACCE Major Adverse Cardio- and Cerebro-vascular Events

MI Myocardial Infarction

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mg Milligram(s)

min Minute(s)

mL Millilitre(s)

NNT Number Needed to Treat

NSTEACS Non-STSegment Elevation Acute Coronary Syndrome

PCI Percutaneous Coronary Intervention

PI Principal Investigator

PP Per protocol

PRU Platelet Reactivity Units

RCA Right Coronary Artery

SAE Serious Adverse Event

STEMI ST-Segment Elevation Myocardial Infarction

TFA Transfemoral Access

TIMI Thrombolysis in Myocardial Infarction

TL Target Lesion

TRA Transradial Approach

TVR Target Vessel Revascularization

UFH Unfractionated Heparin

URL Upper Reference Limit

VCD Vascular Closure Devices

WPW Wolff Parkinson White syndrome

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4. INTRODUCTION This protocol describes a study to compare intended trans-radial versus trans-femoral intervention and bivalirudin monotherapy versus current Euorpean standard of care consisting of unfractionated heparin (UFH) plus provisional use of glycoprotein IIb/IIIa inhibition via the use of one of the three available agents on the market (e.g. abciximab, tirofiban or eptifibatide) in patients (≥18 years) with ACS, that are intended for an invasive management strategy. This study will be conducted in compliance with Good Clinical Practices (GCP) including the Declaration of Helsinki and all applicable regulatory requirements. 4.1 Background The use of combined antithrombotic therapies over the last two decades has decreased the risk of a heart attack after percutaneous coronary intervention substantially but has also been associated with a significant increase in bleeding risk1. Therapies or strategies that maintain the benefits seen with currently available antithrombotic therapies but which have lower bleeding risk are therefore of great clinical importance. Indeed, major bleeding is currently the most common non-cardiac complication of therapy for patients with coronary artery disease who have undergone PCI. Bleeding in patients with acute coronary syndrome (ACS) is associated with an increased risk of long term mortality and morbidity1-7, and this relationship is currently thought to be causal8, 9. Therefore' reducing the frequency of bleeding events while maintaining efficacy is an important goal in the management of patients with ACS. The most common site of bleeding in invasively managed patients with ACS is at the femoral artery puncture site used for heart catheterization10. 4.2 Vascular access site The transfemoral access (TFA), through the percutaneous Seldinger technique, is the preferred approach in most catheterization laboratories worldwide due to its long history of use, the large availability of several dedicated preformed Judkins-type catheters and the possibility to exploit relatively large diameter catheters and sheaths, should these be necessary for complex percutaneous coronary intervention (PCI). Being a relatively deep and terminal vessel however, the femoral artery as percutaneous access site may expose to rare ischemic but frequent bleeding complications which occurs between 3-7% of patients undergoing interventional procedures, especially with modern anti-thrombotic drugs, including glycoprotein IIb/IIIa receptor blockers and clopidogrel3. The difficulties in obtaining a stable and definitive local haemostasis, even when dedicated arterial vascular closure devices (VCD) are employed, make prolonged bed rest after TFA necessary in the majority of cases which result in patient discomfort and overall increase in medical expenditure. In the last fifteen years, after Campeau’s report of successful coronary angiography by transradial approach (TRA)11, the radial artery has been increasingly employed as an alternative access site both for diagnostic and interventional procedures.

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The main advantage offered by percutaneous TRA is represented by the very low incidence of relevant vascular access site complications and bleeding and allows for early mobilization of the patient and thus to early discharge. Advantages and disadvantages of transradial approach (TRA) and transfemoral approach (TFA) are more extensively detailed in Table 1 and 2, respectively. Table 1. Advantages and disadvantages of transradial approach.

Advantages Disadvantages

not an end artery: no ischemic complications in case of occlusion if palmar arch is patent (i.e. good Allen test)

not possible in case of ischemic Allen test (about 10% of the population) and in Raynaud disease

superficial artery, hemostasis very easy, negligible risk for bleeding or pseudoaneurysm

long learning curve

negligible risk for arteriovenous fistula or nerve damage

risk of spasm (significant in very small radial arteries, typically in old women with a small wrist)

better patient comfort difficult manipulation in case of tortuous

brachiocephalic trunk bed rest not necessary (outpatient procedures possible)

max 7F (occasionally 8F!) catheters allowed (but only in large arteries); possible limitations to bifurcation treatment, DCA, Rotablator with larger burrs, other bulky devices

save time and personnel for dealing with sheaths or monitoring groin

movement of catheters induced by respiration, sometimes difficult stent positioning

save cost and complications of vascular closure devices

limited backup support needing more manipulation (but deep intubation possible with 5F guiding catheters)

better guiding catheter backup for RCA and LIMA intervention by left radial approach

increased procedure time and radiation exposure (but only in the first part of learning curve)

Ideal in selected subsets, such as obese patients, patients who can not lie flat (CHF, severe back pain, confused or non-compliant patients, urinary retention), with iliofemoral disease, with large abdominal aneurysm (especially if mural thrombosis is present), anticoagulated (INR>2)

Need to prepare a groin if IABP or venous access for temporary pacing or hemodynamic monitoring are needed

possible cost saving postprocedural risk of occlusion (about 5%

for 6F and 1% for 5F), usually asymptomatic but possibly interfering with radial artery harvesting for CABG

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Table 2. Advantages and disadvantages of transfemoral approach.

Advantages Disadvantages

easier, well-known, large experience risk of bleeding and vascular complications,

including pseudoaneurysm, arterovenous fistula, leg ischemia due to thrombosis or distal embolization

large catheters allowed risk of retroperitoneal hemorrage (with IIb/IIIa

blockers and no front-wall puncture) good for all coronary devices significant proportion of patients affected by

iliofemoral and aortic disease easy to obtain venous access if temporary pacing or hemodynamic monitoring are needed

difficulty in access and correct puncture (above the superficial-profunda bifurcation) in obese patients

hemostasis may be difficult in uncontrolled

systemic hypertension, severe aortic regurgitation, fibrous groin

if manual compression is employed, wasting of

time and personnel, especially after anticoagulation for PCI (ACT monitoring needed)

prolonged bed rest after sheath removal (at

least 1h for each French, but often more than 12h)

closure devices shorten time to hemostasis

and allow early ambulation but are expensive and not so effective in reducing vascular complications. Collagen devices, although less expensive, often limit access at the same site for weeks or even months.

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4.3 Pooled analysis of the available evidence comparing TFA versus TRA A meta-analysis comparing TRA and TFA both in diagnostic and interventional procedures, pooling together all the randomized trials published up to October 2005 has been previously reported12. It showed that TRA for coronary procedures appears as a very safe alternative to femoral access, as testified by similar major adverse cardiovascular events (MACE) rate12. Moreover, it was noted that TRA virtually eliminates local vascular complications, while it requires higher technical skills in comparison to femoral access, thus yielding to an overall lower success rate12. Nevertheless, an ongoing trend to equalization of the two procedures in terms of procedural success was evident through the years, suggesting that most of these differences could be eliminated with improved technical skills and developments in devices such as sheaths and catheters available nowadays12 To reach a more reliable and updated comparison between TFA vs. TRA, an updated systematic revision of the literature to include all comparative trials published up to 2008 has been subsequently published, involving 13 studies and 4,458 patients who had been randomized to radial versus femoral access site13. This pooled analysis demonstrated a significant 73% reduction of major bleeding complications in the radial arm. Interestingly, this dramatic reduction of major bleeding complications was associated to a trend towards lower death, myocardial infarction or stroke (OR: 0.71 95%CI: 0.40-1.01; p=0.06) compared to the femoral group13. Figure1 (ischemic composite endpoint in trans-radial versus trans-femoral access)

Corroborative data have also been generated by a post-hoc analysis of the OASIS 5 study where after adjustment for possible confounders patients undergoing intervention via radial artery trended to have lower mortality (3.4% versus 2.3%, adjusted HR 0.71 [0.45-1.13] p=0.15) compared to patients who received intervention via the femoral artery.

FFaavvoouurrss RRAADDIIAALL FFaavvoouurrss FFEEMMOORRAALL

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Figure 2 (adjusted mortality rate in the OASIS 5 study stratified based on access site)

HR 0.6895% CI [0.43-1.07]

p=0.09

DaysDays

Cu

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azard

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FemoralFemoralRadialRadial

NonNon--adjustedadjusted: HR 0.68 [0.43: HR 0.68 [0.43--1.07] p=0.091.07] p=0.09

AdjustedAdjusted: HR 0.71 [0.45: HR 0.71 [0.45--1.13] p=0.151.13] p=0.15

3.4%

2.3%

Finally, between January 1, 2003, and June 30, 2009, there were 12, 407 adult patients who underwent PCI for ST-segment elevation myocardial infarction in Emilia Romagna. Of these patients, 8,000 (median follow-up 1,204 days) underwent trans-femoral and 3,068 (median follow-up 605 days) were primarily treated with tans-radial intervention. The rate of trans-radial intervention greatly increased over time, from less than 2% in 2003 up to greater than 60% in 2009, a trend which was consistent across all sites. The rate of cross-over from primarily indented trans-radial to trans-femoral access increased from 0% in 2003 up to 7.5% in 2006 and then stabilised to around 3.5% through 2008 and 2009. Figure 3

0 1.9 3.57.5 4.8 3.3 3.4

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Cross-Over Radial to Femoral Trans-Femoral Trans-Radial

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The adjusted outcomes based on a propensity score analysis of the whole population showed a 30% mortality reduction (HR: 1.309; 95%CI, 1.070, 1.602; P=0.0089) at 2 years in favour of the trans-radial intervention (Figure 2A and Table 2), reflecting an early significant mortality benefit within 30 days after treatment (HR: 1.380, 95%CI: 1.016, 1.876; P=0.0395), whereas death rate in between 1 and 24 months did not differ in the trans-radial as compared to the trans-femoral group (HR: 1.289, 95%CI: 0.985, 1.687; P=0.0648). At subgroup analysis, the mortality benefit at 2 years favouring the trans-radial access site appeared largely consistent across several analysed covariates The composite endpoints of death or myocardial infarction (HR: 1.240, 95%CI, 1.050-1.465; P=0.0114) and death, myocardial infarction or stroke (HR: 1.259, 95%CI, 1.069-1.481; P=0.0057) were also significantly reduced at 2 years in the trans-radial group which was largely driven by the difference incidence of mortality in the two study groups. Similarly, the adjusted 30-day rate of major bleeding or vascular events remained lower in the trans-radial group (HR: 1.899, 95%CI, 1.116, 3.229;. P=0.018). After propensity-score matching was performed for the entire population, there were 1501 matched pairs of patients. Trans-radial intervention was associated to a significantly lower mortality at 2 years than trans-femoral group (8.8% vs. 11.4%, HR, 1.302; 95%CI, 1.030 to 1.647; P-value=0.0269). Figure 4 [Percentage of overall mortality reported on Y axis as a function of time (X axis)]

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At subgroup analysis, the mortality benefit favouring the trans-radial access site appeared again to be largely consistent across key pre-selected covariates. This difference was also significant in the matched cohort of patients without cardiogenic shock (6.8% vs.9.8%, HR, 1.474; 95%CI, 1.120 to 1.939; P-value=0.0056). The rates of myocardial infarction or stroke did not differ at 2 years in patients who underwent trans-radial as compared to trans-femoral group, yet both composite of death or MI and death, MI or stroke were lower in the trans-radial group at 2 years, entirely driven by the observed difference in mortality between groups. After propensity-score matching, the rate of major bleeding and vascular events were significantly reduced at 30 days by almost 60% in the trans-radial group (1.1% vs. 2.5%, HR, 2.287; 95%CI, 1.269 to 4.121; P-value=0.0046), a treatment effect which was consistent in the matched cohort of patients who did not suffer from cardiogenic shock (1.0% vs. 2.2, HR, 1.835; 95%CI, 1.103 to 3.278; P-value=0.015). The stratified rate of major bleeding and vascular events was also analysed in the matched-cohort of patients based on the timing of occurrence. There was a marked and significant difference of safety events which were observed during the index hospitalisation favouring the trans-radial group (0.9% vs. 2.5%, HR, 2.807; 95%CI, 1.489 to 5.292; P-value=0.0009) whereas bleeding and vascular events occurring after hospital discharge did not differ (0.3% vs. 0.2%, HR, 0.768; 95%CI, 0.172 to 3.432; P-value=0.729). Finally, In the overall patient population, the unadjusted length of hospitalisation was significantly lower in the trans-radial (median [IQR] 4 [6-8]) compared to the trans-femoral group (median [IQR] 7 [5-10]) (P<0.0001). Similarly, after propensity-score matching, duration of hospitalisation remained markedly shorter in the tans-radial (median [IQR] 4 [6-8]) compared to the trans-femoral group (median [IQR] 6 [5-9]) (P<0.0001). 4.4 Incidence of vascular access complications after transradial approach with a special focus on radial artery occlusion Given the anatomical features of the radial artery, clinically relevant vascular complications are almost absent. Indeed, provided that the Allen test is positive, even the occlusion of the radial artery is an asymptomatic event. Ultrasound studies after transradial catheterization reported an occlusion rate of around 5% 14, 15. However, the only drawbacks of this finding could be represented by the impossibility to use the artery as a conduit for coronary artery bypass surgery and to perform repeated ipsi-lateral TRA. Indeed, in those patients who require a second procedure through the same radial artery site it may be helpful to perform a reverse Allen test in order to detect proximal radial artery disease/occlusion. However, Yoo et al reported that the repeated use of the radial artery is feasible in most patients with a high procedural success rate and low vascular complications16. Of note, the rate of post-procedural radial occlusion seems much lower (about 1%) when 5F guiding catheters are used17 and increasing evidence from literature suggests the feasibility of PCI with 5F guiding catheters even in the most challenging coronary anatomy18. 4.5 Incidence of vascular access complications after transfemoral approach with focus on vascular closure devices. The most common vascular access site complications at femoral level are hematomas accompanied by significant blood loss, arterial pseudo-aneurysm and arteriovenous fistulas requiring surgery, with consequent increases in hospitalization length, hospital costs and periprocedural morbidity. The incidence of these complications ranges from 2% to 4% for noncomplex PCI to 10% to 14% for more complex PCI19, 20. Glycoprotein IIb/IIIa blockers and high loading doses of clopidogrel (up to 600 mg), now widely used in association with angioplasty, may also have a major impact on the occurrence of local complications. For example, in the pivotal

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EPIC trial minor and major complications were reported in 21.8% of patients who received abciximab vs. 9.1 of controls21. However, recent data have shown a progressively lower impact of glycoprotein IIb/IIIa blockers on the rate of local complications, as the associated dose of heparin was administered according to a more conservative weight-adjusted protocol22. Not surprisingly, there has been considerable interest in femoral artery vascular closure devices (VCD), which allow removal of sheaths directly after catheterization or intervention. These devices have been increasingly used in recent years to obtain hemostasis regardless of the level of anticoagulation and to allow early mobilization of patients. To date only 3 comparisons of TRA vs. TFA with VCD have been published. The only randomized trial was performed in a small number of patients undergoing only coronary angiography without intervention23. A second study, prospective but not-randomized, included more than 900 patients undergoing PCI by TRA (39.3%) or by TFA with the Perclose arterial suture device (60.7%), and showed 0 access complications in the TRA group versus 5 in the TFA group (0.8%). However, the very low incidence of TFA complications could be in part explained by smaller sheath size (mostly 6F) and only 5.1% of patients receiving abciximab24. In the third study, Mann et al. evaluated in a non-randomized registry, cost effectiveness of the Perclose device in patients undergoing coronary stenting from TFA as compared to TRA. Primary success, procedural complications, post-procedural length of stay and the percentage of patients discharged the same day were the same in both groups, but total procedure time was longer in TFA group. However, the suture device could not be used in 18% of patients for anatomic reasons and failed to obtain hemostasis in 10% of patients. Moreover, access site complications occurred only in the femoral group25. Nevertheless, it must be kept in mind that to date, both collagen-based and suture-based VCD, despite a significant reduction in time to hemostasis, are equally effective in reducing major local complications as manual compression, if not more harmful, as clearly shown by two recently published meta-analyses26, 27 (Figures 5-7). Furthermore, other pitfalls of VCD include the elevated cost, a not-insignificant learning curve, the occurrence of device-specific complications, such as groin infection and acute femoral occlusion, and, for collagen-based devices, the impossibility of reusing the same approach for 12 weeks. Figure 5 : Groin hematoma

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Figure 6 Groin bleeding

Figure 7

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4.6 Concluding remarks on comparative feasibility of the transradial with respect to the transfemoral approach The evidence coming from clinical studies extensively reviewed above shows that TRA can be performed as safely as TFA in most diagnostic and interventional procedures, unless bulky devices (>7F) are selected or hemodynamically unstable patients are considered. A great benefit in the reduction of access site complications and hospital stay is evident after TRA and patients discomfort may also be significantly reduced. The major drawbacks of TRA are related to a higher incidence of procedural failure and to a higher level of procedural complexity (as shown by the more elevated fluoroscopy time). However, with technological improvements and miniaturization of several percutaneous devices, with amelioration of concomitant anti-spasm therapy, and mainly with increased operators’ experience this gap appears progressively less significant. In fact, we believe that many operators are probably dissuaded to start a TRA program by the long learning curve and that they do not feel confident in dealing with complex anatomy because of risk of spasm, limited guiding catheter size and different catheter manipulation techniques. Despite the increasing evidence about feasibility, safety and effectiveness of TRA, this type of access will hardly replace transfemoral approach in the near future unless evidence that it significantly improves patient outcomes beyond reduction of local bleeding events is clearly provided. Yet, presumably it will have an ever-increasing role in diagnostic and interventional procedures, since these interventions will be more and more driven by cost containment, improvements in equipment, operator experience and, most importantly, patient preference. 4.7 Establishing the rational for the use of newer anti-thrombotic agents in patients undergoing coronary interventions through TRA A clear limit of available studies comparing TFA and TRA is that they have been conducted in the absence of a contemporary pharmacological environment, including the most recent achievement in terms of adjunctive treatment during PCI. By significantly reducing the rate of access site complications, mainly when TFA is employed, this emerging set of new antithrombotic therapies, while replacing unfractioned heparin, may drastically reduce the benefit of TRA in terms of site access complications as compared to TFA. Thus, the contemporary benefit of TRA versus TFA in the context of the emerging antithrombotic therapies, especially bivalirudin, needs to be established. 4.8. Bivalirudin Bivalirudin is currently indicated in Europe for “the treatment of adult patients with acute coronary syndromes (unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention and as an intravenous (IV) anticoagulant in patients undergoing percutaneous coronary intervention (PCI) including patients with ST segment elevation myocardial infarction (STEMI) undergoing primary PCI. Bivalirudin is intended for use with aspirin and clopidogrel.” [Summary of product characteristics, March 2010]. Being a direct thrombin inhibitor and unlike heparins (unfractionated or low molecular weight), bivalirudin is able to inhibits both soluble and fibrin bound thrombin with similar potency, providing a distinct pharmacological advantage particularly in ACS patients. Furthermore, heparins potentiate platelet activation, whereas bivalirudin inhibits platelet aggregation by blocking thrombin signalling to the protease activated receptor (PAR) family of platelet receptors28-32 Synthesised chemically, bivalirudin is a short peptide of 20 amino acids that binds to both the active site and substrate recognition exosite of thrombin, thus, directly and specifically inhibiting all known actions of thrombin33. The binding of bivalirudin to thrombin is reversible; thrombin is able to recognize the drug as a substrate and cleave it, restoring its haemostatic function. The plasma half-life of bivalirudin is 25 minutes.

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The bivalirudin European approval was based on three pivotal studies showing that bivalirudin has similar efficacy in reducing ischemic events with a better bleeding profile when compared to heparins plus glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing elective percutaneous coronary intervention (PCI) or with moderate or high risk ACS managed by PCI34-40. In the REPLACE-2 trial35 a total of 6010 patients undergoing urgent or elective PCI were were randomly assigned to receive intravenous bivalirudin, or heparin plus Gp IIb/IIIa inhibition. The key objective of this study was to evaluate the composite incidence of clinically-significant events reflecting ischaemic complications (death, MI, urgent revascularisation) and haemorrhage associated with PCI up to 30 days post-PCI as represented by the quadruple and triple composite endpoints. Bivalirudin was non inferior to the comparator group of heparin plus planned GP IIb/IIIa inhibition with regard to the composite incidence of clinically-significant events reflecting ischaemic complications and haemorrhage associated with PCI up to 30 days post-PCI, or the composite incidence of ischemic events (death, MI, urgent revascularisation). However, the bleeding incidence was significantly lower in the bivalirudin arm for all components (2.4% versus 4.1%; OR 0.59; p<0.001). In the ACUITY trial40 a total of 13,819 patients with moderate or high risk UA/NSTEMI were randomised to receive one of the following anti-thrombotic regimens: unfractionated heparin or enoxaparin plus a GP IIb/IIIa inhibitor; bivalirudin plus a GP IIb/IIIa inhibitor; or bivalirudin alone. All pre-specified tests of the primary and secondary objectives were met for all 30-day endpoints and support the efficacy of bivalirudin for use in all ACS patients undergoing an early invasive strategy. Use of bivalirudin alone was superior to heparins + GP IIb/IIIa inhibitor, for the net clinical outcome endpoint (incidence of death, myocardial infarction [MI], unplanned revascularisation for ischaemia, or major bleeding) (10.1% versus 11.7%, p=0.0147), and for major bleeding using the ACUITY scale (3.0% versus 5.7%, p<0.0001), bivalirudin alone was non-inferior for the composite ischaemic endpoint (7.8% versus 7.3%, p=0.0107). The HORIZONS AMI8 was a prospective, randomised, open label, double arm, single blinded trial in 3,602 STEMI patients undergoing primary PCI. Eligible patients were randomized to receive either bivalirudin monotherapy with a provisional GP IIb/IIIa inhibitor or UFH plus a routine GP IIb/IIIa inhibitor. At 30-days, bivalirudin monotherapy demonstrated statistical superiority versus UFH plus GP IIb/IIIa inhibitor for the two primary endpoints of net adverse clinical outcomes (9.2% versus 12.1% p=0.006) and major bleeding (4.9% versus 8.3% p=0.0001), and no significant differences for the secondary endpoint of major adverse cardiovascular events (5.4% versus 5.5% p=0.95). Treatment with bivalirudin rather than heparin plus a GP IIb/IIIa inhibitor also resulted in significantly lower 30-day rates of cardiac mortality (1.8% versus 2.9%, RR[95%CI] = 0.62 [0.40, 0.95], P=0.028) and all-cause mortality (2.1% versus 3.1%, RR[95%CI] = 0.66 [0.44, 1.00], P=0.047), with non significantly different rates of re-infarction, target vessel revascularization, and stroke. Therefore, based on previous data, a complementary strategy to access site selection in order to reduce bleeding complications is the use of bivalirudin. In a combined dataset from the REPLACE-2, ACUITY and HORIZONS-AMI trials in 17,393 PCI patients, the majority of patients (61.4%) with TIMI major/minor bleeding had a bleeding source other than the access site. While radial artery access (used in only 7.9% of patients) might eliminate the majority of access site bleeds, it does not reduce non-access site-related bleeding events, which not only constitute a significant proportion of TIMI bleeds but are also associated with an even greater risk of subsequent 1-year mortality. In this pooled analysis, randomization to bivalirudin resulted in a 38% relative reduction in TIMI major/minor bleeding and a 43% reduction in TIMI major bleeding. Bivalirudin decreased access and non-access site-related major/minor and

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major only TIMI bleeding events to a similar extent compared to treatment with a heparin plus a GPI. Considering non-CABG TIMI major/minor bleeding only, the NNT was 71 to prevent one non-access site-related and 74 to prevent one access site-related TIMI bleeding event by use of bivalirudin rather than heparin plus a GPI.

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5. TRIAL DESIGN Open-label factorial 2 by 2 prospective multicenter randomized phase IV clinical trial 5.1 Stratification To ensure appropriate distribution of variables that may affect primary endpoints, the randomisation for will be stratified based on:

Type of ACS (STEMI, NSTEACS troponin negative, NSTEACS troponin positive),

Intended or ongoing use of prasugrel or ticagrelor

PCI in NSTEACS population*

*: To account for the expected 30% patients with NSTEACS who will not undergo PCI after angiography and to minimize the risk that this may unbalance the distribution of patients with respect to the two tested pharmacological options, randomisation to either bivalirudin or standard of care will mainly occur after the decision to proceed to PCI has been taken after coronary angiography. To allow upstream randomisation (i.e. before coronary angiography) investigators can declare that the decision to proceed to PCI is not known and the full treatment scheme (access site and pharmacological treatment) will be provided before angiography. Per protocol, in these patients treatment has to start at least 1 hour before arrival of the patient in the cath-lab. To avoid any possible treatment delay in STEMI patients, and based on the consideration that PCI is here performed generally in greater than 90% of the cases, randomisation in this patient population will not be stratified based on revascularisation modality. This will additionally facilitate the initiation of study treatment as soon as possible. A schematic flow chart of the randomisation scheme is provided below:

STEMI No

Yes Troponin + Troponin -

Prasugrel/Ticagrelor Prasugrel/Ticagrelor Prasugrel/Ticagrelor

Yes No Yes No Yes No

If upstream

planned

RANDOMIZE RANDOMIZE RANDOMIZE RANDOMIZE TRA vs TFA TRA vs TFA TRA vs TFA TRA vs TFA

Bival vs UFH+/-GPI Bival vs

UFH+/-GPI

Angiography Angiography Angiography

RANDOMIZE RANDOMIZE Bival vs UFH+/-GPI

Bival vs UFH+/-GPI

PCI PCI PCI

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5.2 Main study primary hypotheses: Patients in whom the indented treatment strategy was coronary angiography±PCI who have been randomized to radial access site or to receive bivalirudin will experience a lower incidence at 30 days of death, myocardial infarction or stroke. 5.3 Main study primary objectives: This study has two co-primary objectives:

1) To demonstrate in ACS patients undergoing an early invasive management, i.e. diagnostic coronary angiogram+PCI or ad hoc planned PCI that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization.

2) To demonstrate that in an ACS patients with an intended PCI treatment strategy or in whom upstream treatment was felt necessary by local investigators the use of bivalirudin as compared to unfractionated heparin (UFH) plus or minus Glycoprotein IIb/IIIa inhibitor (GPI) is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization.

5.4 Main study key secondary objectives: This study has two key secondary objectives:

1) To demonstrate in patients undergoing diagnostic coronary angiogram which may be followed by ad hoc PCI or planned PCI (Access site ITT population) that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI, stroke or BARC-defined type 3 and 5 major bleeding complications within the first 30 days after randomization.

2) To demonstrate in PCI patients or in patients who got randomized upstream (before arrival in the catheterization laboratory) (Pharmacology ITT population) that use of bivalirudin as compared to unfractionated heparin (UFH) plus or minus Glycoprotein IIb/IIIa inhibitor (GPI) is associated to lower rate of the composite endpoint of death, MI, stroke or BARC-defined type 3 and 5 major bleeding complications within the first 30 days after randomization.

5.5. Main study secondary objectives:





5) The length and costs of hospitalization as well as cost-effectiveness of transradial intervention versus transfemoral and bivalirudin versus UFH±GPI.

6) The need for surgical access site repair/intervention and/or blood products transfusion 7) The prognostic impact of major bleeding complications on 30 days death, MI or stroke rate

as assessed based on various bleeding classifications including BARC, TIMI and GUSTO as well as the prognostic role of thrombocytopenia.

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5.6 Sub-randomization Patients who have been assigned to receive bivalirudin will be randomized in an open-label fashion to stop bivalirudin infusion at the end of PCI or to prolong bivalirudin at an infusion rate of 0.25 mg/kg/hour for at least 6 hours after completion of PCI. In practice, patients randomized to no post-PCI bivalirudin infusion arm will stop bivalirudin immediately after angioplasty guide-wire removal whereas patients allocated to the prolonged infusion arm will down-titrate bivalirudin infusion from 1.75 mg/kg to 0.25 mg/kg after angioplasty guide-wire removal up to 6 hours thereafter. 5.6.1 Primary hypothesis for the Sub-randomization group The primary hypothesis of this sub-randomization is that prolonged post-intervention bivalirudin infusion (long bivalirudin arm) will be superior to peri-PCI bivalirudin infusion only (short bivalirudin arm) with respect to the net composite outcomes consisting of any death, MI, stroke, stent thrombosis or BARC-defined type 3 and 5 bleeding events within 30 days. 5.6.2 Secondary hypotheses for the Sub-randomization group Secondary objectives for the sub-randomization group will consist of each component of the primary composite endpoint through the entire follow-up duration as well as the incidence of acute and subacute stent thrombosis, cost-effectiveness and interaction between on-treatment residual platelet reactivity and duration of post-PCI bivalirudin infusion assessed as both dummy (yes or no) or continuous variables (duration of post-PCI bivalirudin infusion expressed in hours). Patency of the radial artery at clinical examination with respect to bivalirudin infusion duration will be also assessed.

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5.7 Schematic Diagram of Trial Design

ACS All Comer Patients ACS All Comer Patients

scheduled for scheduled for AngioAngio±±PCIPCI

Aspirin + Clopidogrel 600 mg or Aspirin + Clopidogrel 600 mg or

Prasugrel 60mgPrasugrel 60mg

UFH±GPIUFHUFH±±GPIGPI BivalirudinBivalirudinBivalirudin UFH±GPIUFHUFH±±GPIGPI

1:1

1:11:1 N~6,800

DiscontinueDiscontinueDiscontinue ≥6 h Bivalirudin infusion≥≥6 h 6 h BivalirudinBivalirudin infusioninfusion

Radial AccessRadial Access Femoral AccessFemoral Access

Angiography

PCI

Post-PCI N~3,400

N>6,800

1:1

5.8 Measures to Minimise/Avoid Bias The trial is open-label. Randomisation will occur by the use of a dedicated website. Despite the obvious benefits of a double-blind design, the access site cannot be concealed to the operator nor to the other patient medical and paramedical staff. Similarly, the concealment of the pharma-therapeutic strategy in this study would require a double dummy approach which may realistically delay the active treatment especially in the setting of STEMI patients or make the pre-hospital treatment phase impossible. Furthermore, all efforts must be taken not to retard time to reperfusion in patients with STE-ACS. An independent Clinical Events Committee (CEC) will adjudicate all primary clinical endpoints plus bleedings and stent thrombosis. The committee members and the CEC management team will be completely blinded to the randomised therapy, as well as any patient identifying information. The CEC will adjudicate the events based on pre-determined definitions outlined below. Other measures to avoid or minimise bias introduced by the open-label design will include intent-to-treat principles of analysis and use of objective measures for repeat myocardial infarction and bleeding endpoints. 6. RANDOMIZATION Randomization will occur via a dedicated website. Randomization will be stratified based on three variables: 1) Type of ACS (STEMI, NSTEACS troponin negative, NSTEACS troponin positive; 2) Intended or ongoing use of prasugrel; 3) Actual treatment strategy (i.e. Coronary angiography only not followed by PCI or coronary angiography followed by PCI/ planned PCI) in the NSTEACS cohort only as detailed above in the section devoted to stratification. 6.1 Staged procedures Patients who have been previously randomized into the study and have to undergo a staged procedure do not have to be re-randomized but they have to be treated according to original randomization scheme for both access site and pharmacological treatment. This includes patients who underwent diagnostic angiogram and at a later stage undergo PCI (planned staged PCI).

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7. SUBJECT POPULATION Real world ACS patients undergoing coronary angiography±PCI will be recruited on a consecutive basis (Intention to treat patient population). Both Non-ST segment elevation and ST-segment elevation ACS will be eligible provided both trans-radial and trans-femoral access site are deemed feasible. Patients may be randomized BEFORE coronary angiography or just prior PCI provided coronary anatomy has been assessed at a remote site (i.e. an other hospital) or at remote timing leading to sheath removal and need to re-gain access site with the possibility to do so as per randomisation scheme. 7.1 Number of subjects The recruitment of this study will stop as soon as at least 6,800 randomized patients actually underwent PCI on an intention to treat basis. It is expected that at least 30% of included patients may not finally undergo PCI (i.e. medically managed or sent to coronary artery bypass grafting), therefore 8,850 patients are expected to be prospectively included in the study. 7.2. NSTEACS definition Patients with all of the following criteria will be eligible: (1) history consistent with new, or worsening ischemia, occurring at rest or with minimal activity; (2) enrolment within 7 days of the most recent symptoms; (3) planned coronary angiography with indication to PCI; (4) at least 2 of the following criteria: aged 60 years or older, troponin T or I or creatine kinase MB above the upper limit of normal; electrocardiograph changes compatible with ischemia, ie, ST depression of 1 mm or greater in 2 contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts; 7.3. STEMI definition STEMI will be defined as: i) chest pain for >20 min with an electrocardiographic ST-segment elevation ≥1 mm in two or more contiguous electrocardiogram (ECG) leads, or with a new left bundle-branch block or an infero-lateral myocardial infarction (MI) with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave and ii) admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia or previous lytic treatment. 7.4 As exclusion criteria the following items will be considered:

1. Patients who can not give informed consent or have a life expectancy of <30 days 2. Allergy/intolerance to Bivalirudin or unfractionated heparin. 3. Stable or silent CAD as indication to coronary angiography 4. Treatment with LWMH within the past 6 hours 5. Treatment with any GPI in the previous 3 days 6. Absolute contraindications or allergy that cannot 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 is known pregnant or nursing mothers. Women of child-bearing age will be asked if

they are pregnant or think that they may be pregnant. 9. If it is known a creatinine clearance <30 mL/min or dialysis dependent. 10. Previous enrolment in this study. 11. Treatment with other investigational drugs or devices within the 30 days preceding 12. Randomisation or planned use of other investigational drugs or devices in this trial. 13. Severe uncontrolled hypertension (defined as persistent systolic blood pressure higher

than 220 mmHg despite medical treatment). 14. Subacute bacterial endocarditis

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15. PCI in the previous 30 days 7.5 Withdrawal Criteria All patients have the right to withdraw at any point during treatment without prejudice. The investigator can discontinue any patient at any time if medically necessary. It will be documented whether or not each patient completed the clinical study. If for any patient study treatment or observations were discontinued, the reason will be recorded and the Sponsor should be notified promptly. Reasons that a patient may discontinue participation in a clinical study are considered to constitute one of the following:

• adverse event(s), including an event resulting in death • abnormal laboratory value(s) • abnormal test procedure result(s) • unsatisfactory therapeutic effect • protocol violation • patient withdrew consent • lost to follow-up • administrative reasons

It is imperative to obtain complete follow-up data for all patients whether or not they receive their assigned treatment or have discontinued study drug. Every attempt should be made to collect follow-up information except for those patients who specifically withdraw consent to release of such information. All procedures and laboratory specimens or tests requested for evaluation following administration of the Study Drug should be carried out when possible whether or not a patient continues to receive treatment according the protocol. Patients will not be replaced in this trial.

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8. TREATMENT OF SUBJECTS 8.1 Control group: Unfractionated heparin should be given according to guidelines in UFH group (70-100 U/kg in patients not receiving GPI and 50-70 U/kg in patients receiving GPI). UFH infusion post-PCI is highly discouraged. GPI can be added on top of UFH in the UFH arm at discretion of the treating physician. Based on current registry data in Europe, we expect a prevalence of GPI used on top of UFH in the range of 30% in the whole study population. Anticoagulation during angiography can only be implemented in STEMI cases, in which randomization to the pharmacological treatment group occurs before coronary angiography. UFH can be given as a bolus before or during coronary angiography. At the time of PCI, UFH may be re-bolused based on recommendations provided above. In NSTEACS cases, no anticoagulation is allowed during angiography, unless the patient has already been randomized upstream (i.e. before coronary angiography) as detailed in section 5.1. In patients randomly allocated in the control group in whom no upstream randomisation has occurred, UFH should be started immediately after coronary angiography as soon as the decision to proceed to PCI is taken. GPI: All three GPIs available on the market can be given at discretion of the treating physician based on the following recommended regimen: Eptifibatide: (two 180 µg /kg boluses with a 10 minute 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 to 24 hours) Abciximab: (bolus of 0.25 mg/kg followed by an infusion of 0.125 µg/kg/min for 12 hours (maximum dose, 10 µg/min). 8.2 Study group Bivalirudin should be given immediately upon enrolment as bolus of 0.75 mg/kg followed immediately by an infusion of 1.75 mg/kg/h. This infusion should be run continuously until completion of PCI at which time the infusion should be reduced to a dose of 0.25 mg/kg/h for at least 6 hours in the prolonged infusion arm or stopped upon removal of the angioplasty guide-wire in the short infusion arm. An optional higher-dose infusion of 1.75 mg/kg/h is also permitted for up to 4 hours in the prolonged infusion arm only. Patients who do not undergo PCI and are to be medically managed may continue the infusion of 0.25 mg/kg/h for up to 72 hours. Anticoagulation during angiography can only be implemented in STEMI cases, in which randomization to the pharmacological treatment group occurs before coronary angiography. Bivalirudin can be given with an intravenous bolus of 0.1 mg per kilogram and an infusion of 0.25 mg per kilogram per hour. Before PCI, an additional intravenous bolus of 0.5 mg per kilogram has to be administered, and the infusion increased to 1.75 mg per kilogram per hour. Alternatively, Bivalirudin can be started immediately as bolus of 0.75 mg/kg followed immediately by an infusion of 1.75 mg/kg/h during angiography and continued during PCI if performed. In NSTEACS cases, no anticoagulation is allowed during angiography, whereas bivalirudin should be started immediately after coronary angiography as soon as the decision to proceed to PCI is taken. Patients randomised to bivalirudin may only have a “bail out” GPI (abciximab bolus + 12 hour infusion or eptifibatide double bolus + 12-18 hour infusion or tirofiban 25 µg/kg bolus followed by an 18 to 24 hour infusion) administered during PCI for the following two reasons only:

The presence of a “giant” thrombus adjacent to the stent or in the coronary vessel (length >2x that of the diameter of the coronary vessel) after PCI in the absence of a mechanical obstruction

Sustained no reflow (TIMI 0-1 flow in the absence of a mechanical obstruction, refractory to intracoronary nitrates, adenosine or a calcium channel blocker delivered

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intracoronary to the distal coronary bed via an infusion catheter). The use of GPIs outside the pre-specified bailout criteria will be considered a protocol deviation.

8.3 Renal Impairment: As indicated, any of the above drug doses are to be adjusted for renal impairment according to their respective Summary of Product Characteristics. 8.4 Concomitant therapy Concomitant therapy is in accordance to guidelines.

Aspirin: Patients have to receive aspirin (either i.v. at 250 or 500 mg or oral 160-325 mg or

75-160 mg/day for at least 5 days) prior to coronary angiography. However, patients with allergy/intolerance to aspirin may still be included in the study. Aspirin should then be given at 80-160 mg/day indefinitely in patients who can tolerate this treatment.

Clopidogrel: Clopidogrel should be started in any case with a loading dose of 600 mg

followed by 75mg per day for at least 30 days in patients ultimately receiving coronary stenting. Recommended duration of clopidogrel is 1 year in accordance to current guidelines. The protocol encourages investigator to give clopidogrel at least 6 hours before PCI if elective or as soon as possible in emergent PCI cases.

Prasugrel: In clopidogrel naïve patients, prasugrel can be administered at a loading dose

of 60 mg followed by 10 mg/day or 5mg/day in patients with advanced age (>75) or low body weight (<60 kg). Switching from clopidogrel to prasugrel is allowed and left to the discretion of the treating physician.

Ticagrelor: Ticagrelor should be given as 180 mg LD followed by 90 mg BID in agreement with the tested regimen of the PLATO study. The use of ticagrelor in the study is restricted to sites in which the drug has become commercially available and the drug is in use according to local practice.

8.5 Upstream Therapy 8.5.1 As per Randomisation scheme

At discretion of the treating physician, patients can be randomized before the start of any pharmacological therapy and will be treated early on according to the Randomization scheme to Bivalirudin mono-therapy or UFH±GPI. In the Bivalirudin arm, the drug should be given with an intravenous bolus of 0.1 mg per kilogram and an infusion of 0.25 mg per kilogram per hour. Before PCI, an additional intravenous bolus of 0.5 mg per kilogram has to be administered, and the infusion increased to 1.75 mg per kilogram per hour. In the control arm, UFH bolus plus or minus continuous infusion is allowed. Unfractionated heparin has to be administered as an intravenous bolus of 60 IU per kilogram of body weight plus an infusion of 12 IU per kilogram per hour to achieve an activated partial-thromboplastin time of 50 to 75 seconds before angiography and an activated clotting time of 200 to 250 seconds during PCI if concomitant GPI is implemented or >300 seconds if no GPI is administered. 8.5.2 As per Investigator’s discretion Patients who received UFH at any time before randomisation can be included in the study provided the patient is presenting with STEMI or last UFH bolus or UFH continuous infusion has been stopped at least 2 hours before arterial sheath insertion and ACT is not greater than 200 seconds.

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Patients who received Fondaparinux before randomisation can be included irrespective of the timing of last dose whereas patients who received enoxaparin or other LWMH can be randomised only provided last subcutaneous injection has been administered at least 8 hours before. Similarly, patients who received treatment with a GPI or with bivalirudin before randomisation in the previous 3 days are not eligible. 8.6 Study Drug Packaging and Labelling Bivalirudin will be provided by The Medicines Company as clinically labeled unblinded study drug. Vials will be labelled and packed by an authorized European company according to the Italian law.. Commercial hospital stock supplies of bivalirudin are not permitted to be used for this trial. Medication labels will comply with regulatory requirements. The storage conditions for each medication provided will be described on the medication label. Aspirin, unfractionated heparin and GPI will be obtained from hospital stock and prepared as per standard practice as outlined in Section 8.1. 8.7 Study Drug Storage Bivalirudin will be stored in a securely locked cabinet at the appropriate conditions as specified in the Pharmacy Manual. Access should be strictly limited to the investigators and their designees. Neither the investigators nor any designees may provide investigational bivalirudin to any subject not participating in this protocol. 8.8. Study Drug Preparation • Vial Reconstitution Reconstitute each 250 mg vial with 5 mL of preservative free sterile water for injection to yield a clear opalescent, colourless to slightly yellow solution, pH 5.0-6.0, with a concentration of 50 mg/mL. Gently swirl until all material is dissolved (1-2 minutes). Do not shake. The reconstituted vial (50 mg/mL) is stable at 2-8°C for up to 24 hours. • Syringe Driver/Bag Preparation The contents of one reconstituted vial, 5 mL (250 mg) should then be added to a 50 mL of 0.9% sodium chloride for injection or 5% dextrose in water. The prepared infusion will yield a final concentration of approximately 5 mg/mL. If it is known that the duration of therapy will be lengthy or that the patient will be receiving the high infusion rate, it is permissible to make larger volumes, however the concentration should remain at 5 mg/mL, regardless of the volume prepared. 8.9 Administration Refer to protocol Section (8.1) and/or the Pharmacy Manual for specifics on study drug administration. 8.10 Study Drug Accountability The investigator or his designee must maintain an inventory record of bivalirudin received and all administered to assure the regulatory authorities and the Sponsor that the investigational new drug will not be dispensed to any person who is not a subject under the terms and conditions set forth in this protocol. The bivalirudin supplied for use in this study is to be prescribed only by the Principal Investigator (PI) or named sub-investigators and may not be used for any purpose other than that outlined in this protocol.

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8.11 Study Drug Handling and Disposal At the termination of the study, all unused bivalirudin will be destroyed on site as permitted by local regulations. In the event that bivalirudin needs to be returned for any other reason, the site will receive a written request listing the drug lot number(s) to be returned and the reason for the return request. 9. ON-TREATMENT PLATELET REACTIVITY SUB-STUDY Immediately before PCI and in any case before GPI infusion in patients allocated to UFH arm in whom GPI is planned, VerifyNow P2Y12 Assay will be performed to collect PRU base, PRU post and percentage of P2Y12 inhibition. Results of P2Y12 assay will be collected by an independent study nurse who will not communicate the information to the treating physician, In particular, the decision to start GPI on top of UFH will NOT be affected by P2Y12 assay results. Main scopes of the current sub-study is to assess:

1) The value of residual on-treatment P2Y12-mediated platelet reactivity and its interaction with the 2 tested pharmacological strategies (i.e. Bivalirudin mnotherapy versus UFH±GPI

2) The value of residual on-treatment P2Y12-mediated platelet reactivity and its interaction with the duration of bivalirudin infusion in patients undergoing PCI

3) The prognostic value of residual on-treatment P2Y12-mediated platelet reactivity on both ischemia and bleeding endpoints.

10. SEQUENCE OF PROCEDURES The Schedule of Events summarises the study assessments by time point. This study consists of 3 periods: The Pre-Hospital Phase: STEMI Patients, upon discretion of the treating physician, can be randomized before arrival to the PCI facility centre. Therefore, in these patients the study will start in the pre-hospital phase and it consists of confirming eligibility, randomisation, and refers to collection of data regarding treatments administered in the ambulance or non-primary PCI capable referring hospital. The In-Hospital Phase: refers to the collection of data from arrival in the PCI capable hospital until discharge home or 7 days (whichever comes first), including any period of in-patient care occurring post-PCI back in a referring hospital. The Follow-Up Phase: consists of data collection at 30 days (± 5 days) post randomisation by an out-patient follow up visit and mortality at 1 year (± 30 days) post randomisation either by a follow-up telephone call or by viewing a centralised death register (if available).

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Table 3: Visit Schedule

ACS Pre-Hospital In-Hospital

Screening Tx

Pre-

Cathlab Angio±PCI Post-Index PCI

Follow-up

0±30’ 8±4 hs

16±

4 hs

24±

4 hs Discharge

30±5

days

1 year

±30days

History and

Examination X

1 X

1 X

1 X X X X X

Inclusion and

Exclusion

criteria

X1 X

1 X

12-lead ECG X X X X X X

Informed

consent X

1 X

1 X

Randomisation X1 X

1 X

Concomitant

medications X X X X X X X X

VerifyNow

P2Y12 Assay X X

3

Cardiac

markers X

2 X

5 X X X

Instrumented

radial artery

patency and

collateral

circulation4

X X X

Bivalirudin X1 X X X X

Standard Tx X X X X X X X X X

MACCE X1 X X X X X X X X X

Bleedings X1 X X X X X X X X X

AE/SAE X1 X X X X X X X X

1: Patients with STEMI can be randomized before arrival to the PCI facility center. Patients with any type of ACS can

be randomized upstream before arrival in the cath-lab. MAE denotes major adverse events.

2: in NSTEACS patients only

3: in selected sites only

4: includes Allen’s test evaluation and pulse oxymetry-based collateral circulation pattern evaluation (A-D pattern)

5: Prior to study drug initiation/PCI’

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10.1 General Conduct of the Trial Written informed consent will be obtained for this study by the principal investigator or Subinvestigator from all patients before the performance of any protocol-specific procedures. Pre-Hospital Screening Pre-Hospital screening is mandatory only in STEMI cases in which investigators are willing to randomize the patient before arrival to the PCI facility centre. In this condition, the subject must meet the inclusion/exclusion criteria before the randomisation centre is contacted for treatment assignment. The following procedures will be performed:

• Review of inclusion and exclusion criteria • Explanation of the study to the subject with a date and signature documented on an

informed consent document • AE/SAE reporting commences • 12-lead ECG

10.2 Pre-Hospital Management Immediate management following randomisation comprises:

• Endpoint reporting (death, major & minor bleeding, stroke and thrombocytopenia) commences and AE/SAE reporting continues

• History and examination (blood pressure and heart rate and Killip class) • Aspirin at an initial dose of 150-325 mg orally (or 250-500 mg IV) • P2Y12 receptor blocker such as clopidogrel at a loading dose of 600mg • Collection of concomitant medication • Initiation of either bivalirudin or control as soon as logistically feasible postrandomisation

10.3 In-Hospital Management Immediate management in the pre-catheter and catheter laboratory comprises:

• Endpoint reporting (death, major & minor bleeding, stroke) and AE/SAE reporting continues

• Continue infusion of bivalirudin if randomised to treatment with bivalirudin and if the patients has been randomized before hospital arrival • 12-lead ECG prior to study drug initiation/PCI • Examination (blood pressure, heart rate and Killip class) • Collection of concomitant medication Biomarker obtained at baseline, i.e. before study drug initiation/PCI (Troponin I or T and/or CK-MB mass preferably)

In -hospital management post-index procedure: • Endpoint reporting of re-infaction (MI), urgent TVR and stent thrombosis commences and all other

endpoint reporting and AE/SAE reporting continues • If randomised to bivalirudin following PCI, the reduced infusion dose of 0.25 mg/kg/h is

resumed for at least 6 hours or stopped immediately after PCI based on randomisation scheme. An optional higher-dose infusion of 1.75 mg/kg/h is also permitted for up to 4 hours. • If randomised to heparin no IV heparin infusion should be started routinely either during or

after the procedure • In patients requiring ongoing anti-coagulation for reasons other than PCI (eg, haemofiltration, atrial fibrillation or intra-aortic balloon pump) then anti-coagulation should

be maintained as per local practice Biomarker obtained after PCI (Troponin I or T and/or CK-MB mass preferably) at 8, 16 and

24 hours thereafter. • 12-lead ECG (0 hour (+/- 30 minutes), 24 hours (+/- 1 hour), and at day

7 or discharge).

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Additional serial ECGs should be obtained for each suspected recurrent ischemic event.

• Examination (blood pressure and heart rate) • Collection of concomitant medication • Blood haematology (haemoglobin, haematocrit, platelets [total and corrected]) daily for at

least 2 days and on day 7 or discharge • Blood chemistry (creatinine) daily for at least 2 days and on day 7 or discharge • Biomarkers (6-8 hours (+/- 1 hour), (12 hours (+/- 1 hour), (24 hours (+/- 1 hour) and 48 hours (+/- 1 hour) (preferably CK-MB (mass) or Troponin I or Troponin T or alternatively CPK)).

Additional serial biomarkers should be obtained for each suspected recurrent ischemic event

• Aspirin continued at 75-100 mg/day for at least 1 year • P2Y12 receptor blocker (including clopidogrel 75 mg or prasugrel 5 or 10 mg or ticagrelor 180 mg daily if CE approved during the conduction of the study) should be continued as per ESC guidelines (preferably for 1 year) in all patients in whom PCI was performed

Management of Subsequent Ischemic Events: Serial ECGs and biomarkers should be obtained for each suspected recurrent ischemic event. Suspected Re-Occlusion: The patient who initially had chest pain relief with improvement in the ECG who later develops prolonged chest pain with new ischemic ECG changes (suspected re-occlusion) should undergo emergency repeat catheterisation. Further treatment is per operator discretion based on the angiographic findings. Anticoagulation regimens per local standard practice should be used. 10.4 Follow-up Management

Clinical follow-up (visit to a local hospital or general practitioner) will take place at 30 days (± 5 days) in all patients undergoing randomisation. Original source documents must be collected for any clinical events. Should the patient be re-admitted to a non-study hospital, all possible efforts should be made to obtain original source documents from that hospital. Information on medical resource use items of relevance for the health economic analysis will also be collected in this context.

On discharge, for all patients in whom a PCI was performed, aspirin (75-100 mg/day) and a

P2Y12 receptor blocker (including clopidogrel 75 mg daily) should be continued as per ESC guidelines, preferably for one year. 30-Day Follow-up Period

All subjects will require a follow-up visit (to a local hospital or general practitioner) at 30 days (±5 days) after randomisation. Subjects will undergo screening of SAEs, concomitant medication, ECG, blood haematology and chemistry. They will also be questioned regarding any hospitalisations for episodes of ischemia (re-infarction (MI), stroke and stent thrombosis) and bleeding events that may have occurred in the period between the index hospitalisation and the 30 day time point. If it is ascertained that the subject has died, the date and cause of death should be recorded on the eCRF. 1-Year Follow-up Period All subjects will require a follow-up visit (to a local hospital or general practitioner) at 1 year (±30 days) after randomisation. Subjects will undergo screening for concomitant medication and they will also be questioned regarding any hospitalisations for episodes of ischemia (re-infarction (MI), stroke and stent thrombosis) and bleeding events that may have occurred in the period between the 30 day time point and 1 year.

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11. STATISTICAL SECTION 11.1 Sample Size Justification For The Two Co-Primary Endpoints

• Access site comparison: It is expected that the incidence of the primary end-point on an intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the transradial and transfemoral group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints). To account for the expected at least 5% cross-over rate from radial to femoral access site, when 70% of the total sample size will be recruited, the actual cross over rate in this patient population will be estimated and the total sample size increased by the same rate accordingly.

• Pharmacology arm: It is expected that the incidence of the primary end-point on an

intention to treat basis will be in the range of 4% and 6% (~30% relative risk reduction) in the bivalirudin and UFH group, respectively. 3400 patients per group will provide >88% power with an alpha error set at 1% to correct for multiple endpoints (three primary and two key secondary endpoints).

Comparing 2 Proportions: Sample Size Calculation

Two Proportions, Z-Test (H0: Pi1 = Pi2)


0,700,71

0,720,73

0,740,75

0,760,77

0,780,79

0,800,81

0,820,83

0,840,85

0,860,87

0,880,89

0,900,91

0,920,93

0,940,95

0,960,97

0,980,99

1,00


2500

3000

3400

3500

4000

Sam

ple

Siz

e f

or

Ea

ch

Gro

up (

N1 =

N2)

Expected incidence of the primary endpoints in the four study arms Bivalirudin UFH Margin

Trans-Radial 3% 5% 4% Trans-femoral 5% 7% 6% Margin 4% 6%

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11.2 Sample Size Considerations For The Key Secondary Endpoint Six thousand eight hundred patients (3,400 in each arm) will provide greater than 98% power to detect a difference in the net clinical outcomes including death, MI, stroke and major bleeding complications (Type 3 and 5 in accordance to the BARC classification) from 9% in the transfemoral and UFH arms to 6% in the transradial and bivalirudin arm with a type I error set at 1%.




0,700,71

0,720,73

0,740,75

0,760,77

0,780,79

0,800,81

0,820,83

0,840,85

0,860,87

0,880,89

0,900,91

0,920,93

0,940,95

0,960,97

0,980,99

1,001,01

1,02


1500

2000

2500

3000

3400

4000

Sam

ple

Siz

e f

or

Ea

ch

Gro

up (

N1 =

N2)

Expected incidence of the key secondary endpoints in the four study arms Bivalirudin UFH Margin

Trans-Radial 5% 7% 6% Trans-femoral 7% 11% 9% Margin 6% 9% 11.3 Sample Size Considerations For The Duration of Post-PCI Bivalirudin Infusion Three thousand four hundred patients (1,700 in each arm) will provide 87% power to assess superiority of prolonged post-PCI bivalirudin infusion versus placebo post-PCI infusion assuming a background event rate of death, MI, stroke, urgent TVR, stent thrombosis and type 3 and 5 type BARC bleedings in the range of 10% in the prolonged arm versus 6.5% (RRR: 35%) with a type I error set at 1%.

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0,70 0,75 0,80 0,85 0,90 0,95 1,00


1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

Sa

mp

le S

ize

fo

r E

ach

Gro

up

(N

1 =

N2

)

11.4. Definitions 11.4.1. Subject populations For this trial, the following populations will be defined and used in the analysis and/or presentation of the data. Intent-to-treat (ITT) population: The ITT population will be defined as all subjects randomised into the trial. Treatment classification will be based on the randomised treatment. Per-protocol (PP) population: The PP population will be defined as all subjects randomised into the trial who received their randomised treatment and who underwent angiography. Safety population: The safety population will be defined as all randomised subjects who received study drug, and will be classified according to the actual treatment received. The primary and secondary efficacy analyses will be based on the ITT population. Analyses based on the PP populations will be considered secondary and confirmatory. All safety analyses will be performed on the safety population. 11.4.2. Observational period The observational period for the study will be 365 (±30) days. Any event occurring after the defined observational period, even if collected on the eCRF, will not be included in the planned statistical analysis. However, all data, including that reported after the defined observational period, will be included in the patient data listings. 11.5. Statistical Analysis Continuous variables will be summarised by means, standard deviations (SD), medians, interquartile ranges and minimum and maximum values. Categorical variables will be summarised by frequencies and percentages.

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11.6. Endpoints The list of primary, key secondary and secondary endpoints is reported above at section 5.3-5.5 The above-defined secondary endpoints will be analysed in a manner similar to the primary endpoint. No multiple comparison adjustments will be applied to the secondary endpoint analyses.

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12. OPERATOR CRITERIA FOR ELIGIBILITY Trans-radial intervention requires specific skills and dedicated training. Therefore, scope of this study is not to investigate the learning curve of the technique, rather assessing the comparative efficacy and safety of trans-radial technique versus trans-femoral intervention in the context of fully trained interventional cardiologists having been properly exposed to both treatment options. Against this background, single operators qualify for the study provided i) they are familiar and have been exposed to trans-femoral intervention as senior cardiologist in the past for at least 2 years; ii) they have performed in the last 12 months at least 50% of intervention in ACS trans-radially and iii) the number of trans-radial coronary intervention within the previous 12 months is at least 75. In order to collect proper information on operator expertise a retrospective survey focusing on the period 1 January 2010 up to 31 October 2010 will be carried out at each investigational center investigating the following per operator variables: Number of total PCI performed transradially and transfemorally, number of total PCI performed in the context of ACS transradially versus transfemorally and if available percentage of GPI use. In addition, a prospective run-in phase (lasting a minimum of 3 months) will be also conducted forcing operators to perform a balanced number of interventions in ACS via both trans-femoral and trans-radial access site, while monitoring the proportion of GPI use per local practice.

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13. MATRIX SUBSTUDY: Customized Choice of P2Y12 oral receptor blocker based on an integration of clopidogrel loss of function allele and phenotype assessment via Point of care testing Up to 20-30% of clopidogrel treated patients do not adequately respond to the drug and are at higher risk for ischemic events including death, myocardial infarction, stroke and stent thrombosis. Residual high on-treatment platelet reactivity while the patient is on clopidogrel depends on a complex interplay of phenotypic (spontaneous platelet reactivity, inflammatory status, acuity of the clinical presentation, age, renal function) and genetic variables. Two main Loss of function alleles have been identified: 1) CYP450 2C19*2 is present in around 25% of the Caucasian population and result in a lower amount of clopidogrel active metabolite. Carriers of 2C19*2 are at higher risk for death or MI and 2.7 fold increase in the risk of stent thrombosis if treated with conventional clopidogrel; 2) ABCB-1 C carriers have reduced clopidogrel absorption and they have similarly been shown to be at higher risk for ischemic adverse events if treated with clopidogrel. We have recently shown however, that the positive predictive value of genetic testing alone at the time of PCI is limited and the knowledge of genetic status alone with respect to the two previously described loss of function alleles is only poorly able to identify to long-term clopidogrel poor responders. An Algorithm has therefore been developed, combining both genotype and phenotype which has been shown to risk stratify both ischemic and bleeding events up to one year follow-up in PCI patients.

ABCB1 and CYP2C19*2 gene polymorphisms

ABCB1 CC homozygote and CYP2C19 wild type

0 resistent

0 event

ABCB1 T carriers and/or CYP2C19*2 A carriers

Platelet Reactivity e Creatinine Clearance

PRU <258and

CrCl >52

4% resistents

2% events

PRU >258or

CrCl <52

PRU >258and

CrCl <52

21% resistents

15% events

71% resistents

35% events

RiskRisk score 0score 0 RiskRisk score 1score 1 RiskRisk score 2score 2 RiskRisk score 3score 3

The scope of this genetic sub-study is to prospectively validate this algorithm under the hypothesis that its routine application may result in a lower incidence of composite ischemic and bleeding endpoints.

A flow chart of the study is provided below:

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Pts receiving DAPT with aspirin and an approved P2Y12 blocker

VerifyNow P2Y12 PRU before PCI as per MATRIX protocol

RANDOMIZATION into customized DAPT substudy before discharge

Genotype-Phenotype driven Therapy at discharge

No *2 carriers and

ABCB1 CC homozygous

Standard Therapy

CYP2C19*2 and ABCB1 genotype evaluation

Cardiologists blinded

to PRU value

*2 carriers or

ABCB1 T carriers and

PRU < 230 and

CrCl>52 ml/min

At least 2:

• 2C19*2

• ABCB1 T

• PRU > 230

• CrCl<52 ml/min

ASA + 10 mg Prasugrel to be continued or started

immediately

30 day VerifyNow Assesment

Genotype and phenotype driven DAPT substudy

All patients are encouraged to receive prasugrel or ticagrelor up to discharge irrespective of randomization scheme

ASA + 75 mg Clopidogrel to bestarted not later than day 20

ASA + any P2Y12 per clinical choice

Continue the P2Y12 inhibitor as per clinical choice

irrespective of PRU

ASA + 75 mg Clopidogrel ASA + 10 mg Prasugrel

30 day VerifyNow Assesment

Standard Care

If PRU >230 switch to prasugrel*

If PRU < 85 Clopidogrel75 mg every other day

If PRU <85Reduce to 5 mg

* 5mg if Age >75 or BW<60 or previous CVA

if PRU >230Switch to ticagrelor

(if available)

Genotype and phenotype driven DAPT substudy

13.1 Objective of the sub-study To demonstrate in ACS patients undergoing early percutaneous intervention that an algorithm to select the most proper oral P2Y12 blocker integrating both gentotype and phenotype information will result in a lower composite endpoint of cardiovascular death, myocardial infarction, stroke or BARC defined bleeding type 2 or 3 at 1 year follow-up compared to standard of care. 13.2 Primary endpoint The occurrence of cardiovascular death, myocardial infarction, stroke or BARC defined bleeding type 2 or 3 at one year

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13.2.1 Major secondary endpoint Each component of the primary endpoint, the incidence of definite, definite, probable, definite, probable or possible ST and the relationship between PRU or Loss of gain of function alleles and 1-year outcomes. 13.3 Patient population Patients recruited in the MATRIX trial will be eligible for randomization. 13.4 Randomization Patients recruited in the MATRIX study who underwent successful PCI with stent implantation, provided that the sub-study informed consent is signed, will be randomized at discharge in a 1:1 ratio in blocks of 6, stratified on type of ACS (STEMI vs. NSTEACS) and type of oral P2Y12 receptor blocker during hospitalization (clopidogrel versus prasugrel/ticagrelor), into genotype/phenotype based selection of P2Y12 blocker versus standard of care. 13.5 Sub-study description and study procedures During hospitalization, patients are encouraged to receive potent P2Y12 blockers (prasugrel or ticagrelor if available) according to clinical preference. At discharge, patients who are randomized into the standard of care group will continue with the P2Y12 blocker which, according to the treating cardiologist’s clinical judgment, is believed to be the most appropriate. Whereas the patients randomized into the customized group will receive the P2Y12 inhibitor which is believed to maximize efficacy over safety based on the presence of clopidogrel loss of function alleles and they interplay with the following phenotypic variables: P2Y12 reaction units measured at discharge with the VerifyNow point of care and the estimated creatinine clearance based on the Cockcroft-Gault formula. Clopidogrel loss of function alleles will be assessed via the use of Spartan Rx, a commercially available genetic point of care which is based on swab check and has a turn around time of roughly 30 minutes. Patients who are wild type for the presence of both CYP2C19*2 and for ABCB-1 T alleles will receive clopidogrel to be started at the treating physician’s discretion at any moment from, or immediately before discharge, and up to no later than 20 days after index PCI. Patients in whom one of the two loss of function alleles is detected, who show a P2Y12 PRU value of less than 230 AND creatinine clearance is above 52 ml/min will be similarly randomized to receive clopidogrel with the same modalities as previously described for the wild type patients. On the other hand, patients in whom the presence of both loss of function alleles is detected or those with one loss of function allele plus at least one additional phenotypic risk factor among PRU >230 or Creatinine clearance < 52 ml/min will be randomized to prasugrel (or ticagrelor if available at the treating physician’s discretion) to be started immediately. 30 Day Assessment At 30 days patients will undergo a Verifynow P2Y12 assessment by an unblended study nurse. This information will not be shared with treating cardiologist(s) or patients for those who have been randomized in the standard of care arm. Whereas depending on PRU values, patients may be switched to clopidogrel or prasugrel/ticagrelor based on the notion that the level of PRU in-between 86 and 230, is the one which minimized ischemic event at no expense of higher bleeding complication. Therefore, clopidogrel treated patients showing a PRU value greater than 230 will be switched to Prasugrel. Those showing a PRU value of less than 85 will take clopidogrel every other day. Patients receiving prasugrel who show a PRU value greater than 230 will receive ticagrelor if available or will continue with prasugrel 10 mg if ticagrelor is not available (the estimated proportion of poor responders to prasugrel is 1% based on available evidence). Whereas hyper-responders to prasugrel defined as PRU less than 85 will receive prasugrel at 5 mg/daily. 13.6 Definitions of events The definitions for primary and secondary endpoint of this substudy will be in keeping with the ones employed for the main study

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13.7 Statistical considerations It is expected that the incidence of the primary end-point on an intention to treat basis will be in the range of 10% and 7.5% (~25% relative risk reduction) in the standard of care and study group, respectively. 2,000 patients per group will provide 80% power with an alpha error set at 5%.

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14. CLINICAL EFFICACY MEASUREMENTS 14.1 A. DEATH All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in patients with coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) should be classified as cardiac. Cardiac death Any death due to immediate cardiac cause (e.g. MI, low output failure, fatal arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death. This includes all procedure related deaths including those related to concomitant treatment. Vascular death Death due to cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. Non-cardiovascular death Any death not covered by the above definitions, including death due to infection, sepsis, pulmonary causes, accident, malignancy, suicide or trauma. 14.2 B. MYOCARDIAL INFARCTION The occurrence of re-infarction (MI) will be assessed up to and including the 30 day and 1 year time points. Serial ECGs, and biomarkers should be obtained for each suspected recurrent ischaemic event. A positive diagnosis of re-infarction is made when the following criteria are met: Subsequent Ischaemic Events <24 hours in patients with STEMI or in patients with ongoing NSTEMI in whom cardiac markers before randomization are not available or higher than URL and still in the ascending phase (i.e. markers are not stable or decreasing in two or more assessments taken before randomisation) Symptoms such as chest pain, lasting ≥20 minutes, presumed to be ischemic in origin. (a) And either

New ST segment elevation of ≥1 mm in ≥2 contiguous leads, or presumably new left bundle branch block

Or Angiographic evidence of re-occlusion of a previously patent coronary artery or bypass graft.

Subsequent Ischaemic Events 24 hours to 7 days Symptoms such as chest pain, lasting ≥20 minutes, presumed to be ischemic in origin. (a) And either

if biomarkers are presumed or known to be abnormal, a new elevation in biomarkers >20% above the prior documented valley level (Troponin I or T should be used first, if not available the second option is for CK-MB mass and if CK-MB not available total CK should be used)

Or If biomarkers are normal or back to normal, use the definition for subsequent ischemic events >7 days

Subsequent Ischemic Events >7 days Myocardial infarction should be determined based evidence of myocardial necrosis in a clinical setting consistent with myocardial ischaemia. Under these conditions any one of the following criteria meets the diagnosis for myocardial infarction: 1. Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischemia with at least one of the following:

• Symptoms of ischemia; • ECG changes indicative of new ischemia (new ST-T changes or new left bundle branch

block [LBBB]);

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• Development of pathological Q waves in the ECG; (b) • Imaging evidence of new loss of viable myocardium or new regional wall motion

abnormality. (c) 2. Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood. 3. For percutaneous coronary interventions (PCI) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By convention, increases of troponin biomarkers greater than 3 x 99th percentile URL in at least one blood sample have been designated as defining PCI related myocardial infarction. A subtype related to a documented stent thrombosis is recognised. 4. For coronary artery bypass grafting (CABG) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By convention, increases of troponin biomarkers greater than 5 > 99th percentile URL in at least one blood sample plus either new pathological Q waves or new LBBB, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium have been designated as defining CABG-related myocardial infarction. 5. Pathological findings of an acute myocardial infarction.

(a) In the absence of pain, new ST segment changes indicative of ischemia, acute pulmonary oedema, ventricular arrhythmias, or hemodynamic instability presumed to be ischemic in origin, will constitute sufficient evidence of ischemia.

(b) New Q waves are defined as Q waves with a duration of >0.04 seconds in at least 2 contiguous leads that were not present on previous ECGs. These ECG criteria are only valid in the absence of left bundle branch block (LBBB), Wolff Parkinson White syndrome (WPW), paced rhythm or other artefacts that would preclude an ECG definition of myocardial infarction.

(c) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in the presence of biomarker elevation with or without other defining factors of myocardial infarction (clinical, ECG, biochemical) and in the absence of a non-ischemic cause may also be used to define a re-infarction. A wall motion abnormality alone does not define infarction. 14.2.1 Q-wave MI Development of new pathological Q waves in 2 or more contiguous leads with or without post-procedure CK or CK-MB levels elevated above normal. 14.2.2 Non-Q wave MI: All MIs not classified as Q-wave 14.2.3 Stroke: is defined as a sudden, focal neurological defect resulting from a cerebrovascular cause, resulting in death or lasting greater than 24 hours, that is not due to a readily identifiable cause such as a tumour, infection or trauma. All suspected strokes will be adjudicated using all available clinically relevant information including imaging studies to classify all strokes as:

• Haemorrhagic stroke – a stroke with focal collections of intracranial blood • Ischemic stroke – a stroke without focal collections of intracranial blood • Unknown – no imaging or autopsy data are available

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14.3 C. REVASCULARIZATION 14.3.1 Target Lesion (TL) The target lesion is the treated lesion starting 5 mm proximal of the stented lesion and ends at 5 mm distal beyond the stented lesion. 14.3.2 Target Lesion Revascularization (TLR) TLR is defined as any repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel. All TLRs should be classified prospectively as either clinically or not clinically indicated by the investigator prior to the reintervention as well as retrospectively by the independent angiographic core laboratory (in the case of % diameter stenosis). 14.3.3 Target Vessel (TV) The target vessel is the entire major coronary vessel proximal and distal to the target lesion including upstream and downstream branches and the target lesion itself. (For example: if the original lesion is the first obtuse marginal branch, the target vessel includes the left main coronary artery, the circumflex coronary artery and its branches). Note: in three-vessel treatment every repeat revascularization becomes TVR. 14.3.4 Target Vessel Revascularization (TVR) TVR is defined as any repeat percutaneous intervention or bypass surgery of the target vessel (as defined above). 14.3.5 Clinically indicated: A revascularization (TLR/TVR) is clinically indicated if angiography at follow-up shows a percent diameter stenosis ≥50% (QCA) and if one of the following occurs:

1) A positive history of recurrent angina pectoris presumably related to the target vessel. 2) Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent)

presumably related to the target vessel. 3) Abnormal results of any invasive functional diagnostic test (e.g. fractional flow reserve). The results of the test must be documented in the

Case Report Form. A TLR/TVR with a diameter stenosis ≥70% (QCA) in the absence of the above mentioned ischemic signs or symptoms is also considered clinically indicated. 14.3.6 Not Clinically indicated TLRs/TVRs are reinterventions for:

1. all stenoses <50% (diameter stenosis by QCA) in the presence or absence of ischemic signs or symptoms;

2. all stenoses ≥50% but <70% (diameter stenosis by QCA) without ischemic signs or symptoms. Clinically indicated: documented provisional decision to re-intervene based on clinical symptoms and/or results of non invasive functional testing, before any coronary imaging. These criteria are intended to determine clinical indications for re-intervention in patients undergoing routine angiographic follow-up. In the patient cohorts assigned to clinical follow-up only, or in studies without routine angiographic follow-up, all revascularizations are considered clinically indicated. 14.3.7 Non Target Lesion Revascularization (nonTLR) Any revascularization in a lesion other than the target lesion is considered a non-TLR. 14.3.8 Non Target Vessel Revascularization (nonTVR) Any revascularization in a vessel other than the target vessel is considered a non-TVR.

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14.4 STENT THROMBOSIS Stent Thrombosis should be reported as a cumulative value at the different time points and with the different separate time points. Time 0 is defined as the time point after the guiding catheter has been removed and the patient leaves the Cathlab. 14.4.1 Timing: Acute stent thrombosis(*): 0 . 24 hours post stent implantation Subacute stent thrombosis(*): >24 hours . 30 days post stent implantation Late stent thrombosis: >30 days . 1 year post stent implantation Very late stent thrombosis: >1 year post stent implantation (*) acute/subacute can also be replaced by early stent thrombosis. Early stent thrombosis (0.30 days) . this definition is currently used in the community. We recognize three categories of evidence in defining stent thrombosis:

1) Definite 2) Probable 3) Possible

1. Definite (is considered either by angiographic or pathologic confirmation). Angiographic confirmation of stent thrombosis is considered to have occurred if:

1) Thrombolysis In Myocardial Infarction (TIMI) flow is: a) TIMI flow grade 0 with occlusion originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus(*). b) TIMI flow grade 1, 2, or 3 originating in the stent or in the segment 5mm proximal or distal to the stent region in the presence of a thrombus(*).

AND at least one of the following criteria, has been fulfilled within a 48 hours time window: 2) new onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) 3) new ischemic ECG changes suggestive of acute ischemia 4) typical rise and fall in cardiac biomarkers

The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion). (*) Intracoronary thrombus [Ellis et al., Mabin et al., Capone et al.] Non-occlusive thrombus: Intracoronary thrombus is defined as a (spheric, ovoid or irregular) non-calcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolization of intraluminal material downstream. Occlusive thrombus: A TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originating from the side branch). 14.4.2 Pathologic confirmation of stent thrombosis: Evidence of recent thrombus within the stent determined at autopsy

2) Probable: Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases:

1) Any unexplained death within the first 30 days. 2) Irrespective of the time after the index procedure any myocardial infarction (MI), which is

related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause.

3) Possible:

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Clinical definition of possible stent thrombosis is considered to have occurred with any unexplained death following intracoronary stenting until the end of the follow-up period. 15. SAFETY MEASUREMENTS: The main bleeding classification which will be used in the study will be the Bleeding Academic Research Consortium (BARC) which is detailed below and summarized in the Table Type 0: No evidence of bleeding. Type 1: Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional. Examples include, but are not limited to, bruising, hematoma, nosebleeds, or hemorrhoidal bleeding for which the patient does not seek medical attention. Type I bleeding may include episodes that lead to discontinuation of medications by the patient because of bleeding without visiting a health care provider. Type 2: Any clinically overt sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that is actionable, but does not meet criteria for Type 3 BARC bleeding, Type 4 BARC bleeding (CABG-related), or Type 5 BARC bleeding (fatal bleeding). The bleeding must require diagnostic studies, hospitalization or treatment by a health care professional. In particular, the bleeding must meet at least one of the following criteria:

1) Requiring intervention: defined as a health care professional-guided medical treatment or percutaneous intervention to stop or treat bleeding, including temporarily or permanently discontinuing a medication or study drug. Examples include, but are not limited to, coiling, compression, use of reversal agents (e.g. vitamin K, protamine), local injections to reduce oozing, or a temporary/permanent cessation of antiplatelet, antithrombin, or fibrinolytic therapy;

2) Leading to hospitalization or an increased level of care: defined as leading to or prolonging hospitalization or transfer to a hospital unit capable of providing a higher level of care; or

3) Prompting evaluation: defined as leading to an unscheduled visit to a healthcare professional resulting in diagnostic testing (laboratory or imaging). Examples include, but are not limited to, hematocrit testing, hemoccult testing, endoscopy, colonoscopy, computed tomography scanning, or urinalysis. A visit or phone call to a healthcare professional where neither testing nor treatment is undertaken does not constitute Type 2 bleeding.

Type 3: Clinical, laboratory, and/or imaging evidence of bleeding with specific healthcare provider responses, as listed below: a. BARC Type 3a Bleeding

• Any transfusion with overt bleeding

• Overt bleeding plus hemoglobin drop ≥3 to <5 g/dL* (provided hemoglobin drop is related to bleeding)

b. BARC Type 3b Bleeding

• Overt bleeding plus hemoglobin drop ≥ 5 g/dL* (provided hemoglobin drop is related to bleeding)

• Cardiac tamponade

• Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid)

• Bleeding requiring intravenous vasoactive drugs c. BARC Type 3c Bleeding

• Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation; does include intraspinal).

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• Subcategories; Confirmed by autopsy or imaging or lumbar puncture (LP)

• Intra-ocular bleed compromising vision *Hb drop should be corrected for intracurrent transfusion, where 1 unit of packed red blood cells or 1 unit of whole blood would be expected to increase Hb by 1g/dl Type 4: CABG-Related Bleeding.

• Perioperative intracranial bleeding within 48 hours • Reoperation following closure of sternotomy for the purpose of controlling bleeding • Transfusion of ≥ 5 units of whole blood or packed red blood cells within a 48 hour period** • Chest tube output ≥ 2L within a 24 hour period.

Note: If a CABG-related bleed is not adjudicated as at least a Type 3 severity event, it will be classified as ‘not a bleeding event’. ** Only allogeneic transfusions are considered as transfusions for CABG-related bleeds. Cell saver products will not be counted. Type 5: Fatal Bleeding. Fatal bleeding is bleeding that directly causes death with no other explainable cause. BARC Fatal Bleeding is categorized as either definite or probable as follows:

a) Probable fatal bleeding (Type 5a) is bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed and there is no autopsy or confirmatory imaging.

b) Definite fatal bleeding (Type 5b) is bleeding that is directly observed (either by clinical specimen – blood, emesis, stool, etc.- or by imaging) or confirmed on autopsy.

The site of fatal bleeding is further categorized as intracranial, gastrointestinal, retroperitoneal, pulmonary, pericardial, gastrourinary, or other. BARC fatal bleeding is meant to capture deaths that are directly due to bleeding with no other cause. The time interval from the bleeding event to the death should be considered with respect to likely causality, but there is no specific time limit proposed. Bleeding that is contributory but not directly causal to death is not classified as fatal bleeding, but may be categorized as other forms of bleeding. Bleeding that leads to cessation of antithrombotic or other therapies may be contributory, but again, would not be classified as fatal bleeding. Bleeding associated with trauma or with surgery may be fatal, depending on whether it was determined to be directly causal or not. TIMI Major Bleeding is defined as [Bovil et al, 1991]:

• Intracranial haemorrhage • Associated with a decrease in Hgb >5g/dL (3.1 mmol/L) (or 15% of haematocrit) • Haemorrhagic Death • Cardiac Tamponade

TIMI Minor Bleeding is defined as [Bovil et al, 1991]:

• Blood loss that is spontaneous and observed as gross haematuria or haematemesis • Observed (ie, haeme-positive coffee ground emesis, haeme-positive melaena, haematoma or retroperitoneal bleeding) • Spontaneous or non-spontaneous blood loss associated with a haemoglobin >3 g/dL (1.8 mmol/L) and <5 g/dL (3.1 mmol/L) (or a haematocrit decrease of 9% and <15%) • Haemoglobin decrease >4 g/dL (2.5 mmol/L) and <5 g/dL (3.1 mmol/L) (or 12% of haematocrit and <15% ) with, despite attempts, no bleeding site identified

GUSTO Severe or life-threatening is defined as [GUSTO Investigators, 1993]:

• Either intracranial haemorrhage or bleeding that causes hemodynamic compromise and requires intervention

GUSTO Moderate is defined as [GUSTO Investigators, 1993]:

• Bleeding that requires blood transfusion but does not result in hemodynamic compromise

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GUSTO Mild is defined as [GUSTO Investigators, 1993]: Finally, in the outpatient setting the bleedscore (Am J Cardiol. 2007 Jan 15;99(2):288-90. Erratum in: Am J Cardiol. 2007 Aug 1;100(3):562 and Eur Heart J. 2010 Jan;31(2):227-35) will be also collected. Thrombocytopenia: will be defined as a post-procedural platelet count <100,000 cells/mm3 in a patient with a baseline or pre-procedural platelet count >100,000 cells/mm3. Further divided into mild (50,000 - <100,000 cells/mm3), moderate (20,000 - <50,000 cells/mm3), or severe (<20,000 cells/mm3, or requiring platelet transfusion).

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Table BARC bleeding classification BARC Definition for bleeding

Type 0 No Bleeding

Type 1 Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional.

Type 2 Any overt, actionable sign of hemorrhage (e.g. more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that does not fit the criteria for Types 3, 4, or 5, but does meet at least one of the following criteria: 1) Requiring non-surgical, medical intervention by a health care professional 2) Leading to hospitalization or increased level of care 3) Prompting evaluation

Type 3 Type 3a � Overt bleeding plus hemoglobin drop of 3 to <5*g/dL (provided hemoglobin drop is related to bleed) � Any transfusion with overt bleeding Type 3b � Overt bleeding plus hemoglobin drop ≥ 5*g/dL (provided hemoglobin drop is related to bleed) � Cardiac tamponade � Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) � Bleeding requiring intravenous vasoactive drugs

Type 3c

� Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation; does include intraspinal).

• Subcategories; Confirmed by autopsy or imaging or LP � Intra-ocular bleed compromising vision

Type 4 - CABG–related bleeding

� Perioperative intracranial bleeding within 48 hrs � Reoperation following closure of sternotomy for the purpose of controlling bleeding � Transfusion of ≥ 5 units of whole blood or packed red blood cells within a 48 period**. � Chest tube output ≥ 2L within a 24 hour period � If a CABG - related bleed is not adjudicated as at least a Type 3 severity event, it will be classified as ‘not a bleeding event’

Type 5 - Fatal Bleeding

Type 5a � Probable fatal bleeding: no autopsy or imaging confirmation, but clinically suspicious Type 5b � Definite fatal bleeding: overt bleeding or autopsy or imaging confirmation

Obs: Platelet transfusions should be recorded and reported, but are not included in these definitions until further information is obtained about the relationship to outcomes. *Corrected for transfusion (1 unit PRBC or 1 unit whole blood = 1g/dL Hgb) * Only allogeneic transfusions are considered as transfusions for BARC Type 4 bleeding. Cell saver products will not be counted.

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16. SAFETY

All adverse events will be assessed and documented from informed consent of the patient until hospital discharge or day 7, whichever comes first following cessation of study drug infusion.

Those events that are serious in nature must be reported to the Sponsor in an expedited manner. SAEs will be followed for 30 days post randomization of the patient into the study.

Patients experiencing adverse events should be followed clinically until their health has returned to baseline status or until all parameters have returned to normal or have otherwise been explained. It is expected that the investigator will provide or arrange appropriate care for the patient if necessary.

The principal investigator is responsible for ensuring that all staff involved in the study are familiar with the content of this session. The methods for collecting safety data are described below. The reference safety information is the Investigator’s Brochure

16.1 Adverse events

The definitions of adverse events (AEs) and serious adverse events (SAEs) are given below. Adverse event An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory findings, electrocardiogram). In clinical studies, an AE can include an undesirable medical condition occurring at any time, including run-in or washout periods, even if no study treatment has been administered. The terms AE is used to include both serious and non serious AEs. Serious adverse events require separate evaluation for reporting to regulatory authorities, competent authorities, central and local ethics committees and all Investigators involved in this clinical trial.

16.2 Serious adverse event

A serious adverse event is an AE occurring after the signing of the informed consent during any study phase (ie, run-in, treatment, washout, follow-up), and at any dose of the investigational product, comparator or placebo, that fulfills one or more of the following criteria:

• results in death;

• is immediately life-threatening;

• requires in-patient hospitalization or prolongation of existing hospitalization;

• results in persistent or significant disability or incapacity;

• is a congenital abnormality or birth defect;

• is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above.

A distinction should be drawn between serious and severe AEs. Severity is an estimate or measure of the intensity of an AE, while the criteria for serious AEs are indications of adverse subject outcomes for regulatory reporting purposes. A severe AE need not necessarily be considered serious and a serious AE need not be considered severe. For example, nausea that

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persists for several hours may be considered severe nausea, but not an SAE. On the other hand, a myocardial infarction (MI) that may be considered minor could also be an SAE if it prolonged hospitalization. The Serious Adverse Event Report (SAER) is contained in the eCRF system and must be completed within 24 hours of when the SAE is recognized. Overdose, drug misuse, drug abuse, medication error and pregnancy also need to be reported within 24 hours using this form, regardless of whether they are associated with an adverse event or not. If a pregnant patient also experiences an SAE, the SAE must be reported using the SAE form. A medication error is defined as a preventable event that may cause or lead to inappropriate medication use or patient harm. A medication error is unintentional. Examples of medication error include, but are not limited to, administration of the wrong drug, the wrong drug dose, via the wrong route or over the wrong time interval. It is important to note that patients who experience an SAE may be discontinued from study treatment, but should not be discontinued from the clinical trial. Such patients should continue in the clinical trial to ensure that follow-up occurs at the clinically appropriate intervals and to ensure adequate ITT data collection for the study. Patients in this trial should be followed through the Day 365 follow-up visit. For any event involving death, the cause of death must be reported for the SAE. The result of an autopsy, if performed, should also be provided. Any serious adverse event that occurs outside of the designated study period, i.e. 30 days (+/- 5 days) and is deemed to be possibly related to study treatment by a study Investigator should also be reported immediately, but no later than 24 hours of when the SAE is recognized.

The investigator will assess casual relationship between Investigational Product and each Adverse Event will be categorized according to the semi-quantitative scale as follows:


2. Unlikely related - this category applies to AEs for which there is no reasonable evidence

or argument to suggest a causal relationship between the study medication and the AE.

3. Possibly related - this category applies to AEs for which there is reasonable evidence or

argument to suggest a causal relationship between the AE and the study medication.

4. Definitely related - this category applies to AEs that are considered to be related to the study medication, with a high degree of certainty.

Recording of adverse events

All AEs (non-serious and serious) spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedure must be recorded on the source documents and eCRF provided by the Sponsor.

AEs that occur from the time of informed consent until hospital discharge or day 7, whichever comes first following cessation of study drug infusion, must be assessed and recorded on the source documents and eCRF, regardless of causal relationship to the study drug.

The severity of an AE and the relationship to study drug will be assessed by the investigator. The investigator should ensure that any patient experiencing an AE receives appropriate medical support until the event resolves.

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Each adverse event recorded will include the following variables:

− onset of adverse event

− description of the adverse event

− resolution

− whether the patient was withdrawn

− outcome

− causality rating (yes/no) assessed by the Investigator

− whether or not it is serious

− intensity

The patient or clinician who identifies the adverse event will be asked to provide a description of the event, the dates of onset and resolution, treatment administered, and assessment of the intensity of the reported adverse event according to the following scale:

1. Mild: awareness of sign or symptom, but easily tolerated.

2. Moderate: discomfort sufficient to cause interference with normal activities.

3. Severe: incapacitating, with inability to perform normal activities.

During the course of the study every effort should be made to obtain an outcome for all adverse events. At study completion / withdrawal, all ongoing SAEs should be followed until the event has resolved, or stabilized and no further change is expected. Laboratory results that constitute SAEs must be recorded and reported as serious adverse events. Patients that discontinue due to abnormal laboratory results should have the abnormal laboratory results recorded and reported as adverse events. Abnormal creatine kinase and liver enzymes laboratory values will be followed up until they have returned to baseline values or until the Investigator considers them resolved. Should an overdose (accidental or deliberate) occur, it must be reported in accordance with the procedures described in section Procedures in case of overdose, regardless of whether the overdose was associated with an adverse event not. All symptoms associated with the overdose should be reported as AEs. Non-serious adverse events, unless they meet one or more of the criteria for seriousness. All events of overdose should be reported to the Sponsor ithin 24 hours of awareness of the event by the Investigator whether or not the overdose was associated with any adverse event(s). If the overdose is associated with a serious adverse event, it should be reported in the same manner as all other serious adverse events. Should a medication error occur (for example: administration of the wrong drug dose, wrong route of administration, wrong rate, wrong reconstitution) it must be reported to the Sponsor. All events of medication error should be reported to MDCO within 24 hours of awareness of the event by the Investigator whether or not the overdose was associated with any adverse event(s). If the medication error is associated with a serious adverse event, it should be reported in the same manner as al other serious adverse events. Should a pregnancy occur, it must be reported in accordance with the procedures described in Section Procedure in case of Pregnancy. Pregnancy in itself is not regarded as an AE unless

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there is a suspicion that an investigational product may have interfered with the effectiveness of a contraceptive medication. All events of pregnancy should be reported to the Sponsor within 24 hours of awareness of the event by the Investigator whether or not the pregnancy was associated with any adverse event(s). If the pregnancy is associated with a serious adverse event, it should be reported in the same manner as al other serious adverse events. 16.3 Reporting of serious adverse events

The Sponsor/Investigator is responsible for meeting all regulatory safety reporting requirements and obligations. This includes expedited reporting off all serious, unexpected and possibly study-drug-related SAEs (SUSAR) from the study to the Regulatory Authority and IEC/IRB, as required. The Investigator must inform the Sponsor through the Dimensione Ricerca (CRO) of any SUSAR that occurs in the course of the study within 24 hours or at latest the following working day. Patient Safety contacts are: Dr. Maria Salomone Tel.: 06 - 8076072 Fax: 06 – 80693521

16.4 Procedures in case of emergency, overdose or pregnancy

Procedures in case of medical emergency

The principal Investigator(s) is responsible for ensuring that procedures and expertise are available to cope with medical emergencies during the study. Procedures in case of overdose

− Use of study medication in doses in excess of that specified in the protocol should not be recorded in the CRF as an AE of ‘Overdose’ unless there are associated symptoms or signs.

− An Overdose with associated SAEs should be recorded as the SAE diagnosis/symptoms recorded on the relevant SAE forms in the CRF.

− An Overdose with associated non-serious AEs should be recorded as the AE diagnosis/symptoms recorded on the relevant AE forms in the CRF.

− An Overdose without associated symptoms should not be recorded as an AE in the CRF.

All events of Overdose should be reported to the Sponsor.

Procedures in case of pregnancy

Although it is unlikely that pregnancy will occur in this study, patients should be instructed to stop study drug immediately if pregnancy is suspected or confirmed, and to notify the Sponsor/Investigators.

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Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the investigational product under study may have interfered with the effectiveness of a contraceptive medication. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital abnormality) must be followed up and documented even if the patient was discontinued from the study. All pregnancies should be reported within 1 day of the time the Sponsor/investigators personnel becomes aware of the pregnancy. All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be reported and handled as SAEs. Elective abortions without complications should not be handled as AEs. All reports of pregnancy, congenital abnormalities/birth defects, spontaneous miscarriages and elective abortions should be reported to the Sponsor.

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17. PROTOCOL DEVIATIONS This study will be conducted as described in this protocol, except for an emergency situation in which the protection, safety, and well being of the subject requires immediate intervention, based on the judgment of the investigator (or a responsible, appropriately trained professional designated by the investigator). In the event of a significant deviation from the protocol due to an emergency, accident, or mistake, the investigator or designee should contact the Sponsor, or their agent, at the earliest possible time by telephone. This will allow an early joint decision regarding the subject’s continuation in the study. The EC will be informed of all protocol changes by the investigator in accordance with the EC established procedure. 18. DATA COLLECTION An electronic Case Report Form (eCRF) will be used to collect all patient data assessments that will be used for evaluation of specified analyses. 18.1. Accountability The investigator or his designee must maintain an inventory record of bivalirudin received and all administered to assure the regulatory authorities and the Sponsor that the investigational drug will not be dispensed to any person who is not a subject under the terms and conditions set forth in this protocol. The bivalirudin supplied for use in this study is to be prescribed only by the Principal Investigator or named sub-investigators and may not be used for any purpose other than that outlined in this protocol. At the end of the study, all unused bivalirudin will be destroyed locally once the bivalirudin has been accounted for and the monitor has reviewed the accountability records. In the event that bivalirudin needs to be returned for any other reason, the site will receive a written request listing the drug lot number(s) to be returned and the reason for the return request. 19. RECORDS RETENTION Current EU Directive and ICH guidelines collectively require that essential clinical trial documents (including case report forms) other than the subject’s medical files must be retained for the following time period:

• For at least 15 years after completion or discontinuation of the trial, • Or 2 years after the last approval of a marketing application in an ICH region and until

there are no pending or contemplated marketing applications in an ICH region, • Or at least 2 years have elapsed since the formal discontinuation of clinical development

of the investigational product. Investigators shall retain the essential documents relating to a clinical trial for at least five years after its completion. They shall retain the documents for a longer period, where so required by applicable local requirements. To comply with these requirements, the investigator will not dispose of any records relevant to this study without either (1) written permission from the Sponsor or (2) providing an opportunity for the Sponsor to collect such records.

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20. QUALITY CONTROL AND QUALITY ASSURANCE 20.1. Monitoring The Sponsor has ethical, legal and scientific obligations to carefully follow this study in a detailed and orderly manner in accordance with established research principles and applicable regulations. The investigator, as part of his responsibilities, is expected to cooperate with the Sponsor in ensuring that the study adheres to the protocol and GCP requirements. As part of a concerted effort to fulfil these obligations, the Sponsor will authorise a Clinical research Organisation (CRO) to perform monitoring tasks and visit the centre(s) during the study in accordance with the Clinical Management Plan (CMP) set forth for this trial as well as maintain frequent telephone and written communication. The investigator will permit the Sponsor’ authorised CRO personnel to monitor the study as frequently as is deemed necessary and provide access to medical records to ensure that data are being recorded adequately, that data are verifiable and that protocol is adhered to. 20.2. Auditing As part of implementing quality assurance, the Sponsor may conduct audits at the study centre(s) in order to evaluate trial conduct and compliance with the protocol, SOPs, GCP and applicable regulatory requirements. The investigator agrees to cooperate with the Sponsor and/or its designee in the conduct of these audits and provide access to medical records and other relevant documentation, as required. Regulatory authorities worldwide may inspect the investigator during or after the study. The investigator should contact the Sponsor immediately if this occurs, and must fully cooperate with regulatory authority inspections as required. 21. ETHICS AND RESPONSIBILITY This study will be conducted in compliance with the protocol, with the Sponsor’s standard operating procedures and/or guidelines, European Union regulations, the International Conference on Harmonisation (ICH) GCP guidelines and the Declaration of Helsinki. The investigator is responsible for ensuring the investigation is conducted according to all signed agreements, the study protocol and GCP requirements. Also, each investigator must complete and sign the Investigator's Agreement. In signing, the investigator agrees to:

• Adhere to the Investigator Agreement

• Participate in Investigator meetings as scheduled by the Sponsor

• Maintain up-to-date angiographic and PCI equipment

• Have access to cardiac surgery

• Be willing to perform and be capable of performing treatment procedures as outlined

in this protocol

• Comply with all required elements of this protocol (eg, perform testing and follow-up

as specified, especially during personnel transitions) and supply angiographic material

suitable for quantitative analysis

• Obtain written Informed Consent from each study participant before any study specific

procedures are performed in accordance with GCP

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• Complete all electronic CRFs for completed patients visits and or applicable events (ie,

death, re-infarction (MI), IDR, non-CABG-related protocol major bleeding) prior to

scheduled monitoring visits

• Adhere to the study protocol at all times, except to eliminate an immediate hazard to

trial subject(s). Comply with all European Union requirements for investigators, and

with all other applicable regulations and codes of approvals from ECs and other

Regulatory Authorities.

21.1. Informed Consent The investigator(s) has both ethical and legal responsibility to ensure that each prospective subject is given a full explanation of the protocol. This shall be documented on a written informed consent form, which shall be approved by the same EC responsible for approval of this protocol. Each patient shall be given a copy of the signed informed consent form, and the original shall be kept in the site’s regulatory file. A second copy may be filed in the patient's medical record, if allowed by the institution. 21.2. Ethics Committee This protocol and the written informed consent form shall be submitted to the appropriate EC at each site in Italy. The study may not commence until written approval from the EC is available, either as a letter or as a copy of the appropriate section of the EC meeting minutes where this protocol and associated informed consent form were discussed. The investigator will not participate in the decision. If the investigator is an EC member, the written approval must indicate such non-participation. The Sponsor or authorised designee will submit status reports to the EC at least annually (when applicable and according to local regulations). The EC must be notified by the Sponsor or designee in writing of the interruption and/or completion of the study; the Sponsor or designee must promptly report to the EC all changes in research (protocol amendments) and will not make such changes without EC approval except where necessary to eliminate apparent immediate hazards to human patients. In these cases, the EC must be notified within five days of the change. The Sponsor or designee will promptly report to the EC all unanticipated problems involving risk to patients or others. The investigator is required to maintain an accurate and complete record of all written correspondence to and received from the EC and must agree to share all such documents and reports with the Sponsor or designee. 22. CONFIDENTIALITY All information generated in this study must be considered highly confidential and must not be disclosed to any persons not directly concerned with the study without written prior permission from the Sponsor. However, authorised regulatory officials and Sponsor personnel will be allowed full access to the records. All medications provided and patient bodily fluids and/or other materials collected shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the Sponsor. Only initials and unique patient numbers in CRFs will identify patients. Patients full names may, however, be made known to a regulatory agency or other authorised official if necessary.

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23. PUBLICATION POLICY The sponsor and as well as the PI of this study, recognising the seminal importance of this investigation, are committed to the unrestricted and widespread dissemination of all primary and secondary endpoint results and tertiary analyses. At the conclusion of the Trial, a multi-centre abstract reporting the primary results will be prepared by the Principal Investigator (in collaboration with the Executive Committee, International Steering Committee, Publication Committee and local principal investigators from high enrolling sites) and presented at an annual high calibre scientific meeting. A multicenter publication will similarly be prepared for publication in a reputable scientific journal. The publication of the principal results from any single centre experience within the trial is not allowed until both the preparation and publication of the multicenter results. Following analysis and presentation of the primary endpoint results, active participation of all committee members and investigators from high enrolling sites, will be enthusiastically solicited for data analysis and abstract and manuscript preparation. Submission of all abstracts and publications regarding the primary endpoint and secondary endpoints from the study requires approval by the study Principal Investigator after review by the Sponsor and Executive Committee. All original manuscripts and abstracts of data and information relating to the clinical trial described in this protocol (collectively, “Publications”) will be submitted in advance to the Publication Committee for review according to the procedure described in this section. The Publication Committee will act as an independent body of scientific and medical experts with the following charter:

• The Publication Committee must review and approve all proposed analyses and topics suggested by the investigators and participating institutions in the clinical trial; • All Publications discussing the trial data and conclusions must be submitted to the Publication Committee for review and approval prior to submission for presentation or publication; and • All other Publications relating to the clinical trial will be submitted to the Publication

All draft Publications must be submitted to the Publication Committee at least 30 days prior to submission to a journal or public presentation. The Publication Committee will consider each manuscript proposal with due regard for the scientific merit of the proposed publication. Decisions of the Publication Committee will be by majority vote. All manuscripts approved by the Publication Committee will conform to the Uniform Requirements for Manuscripts

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24. INVESTIGATOR AGREEMENT I have read and understand the protocol (including the Investigator’s Brochure) and agree that it

contains all the ethical, legal and scientific information necessary to conduct this study. I will

personally conduct the study as described.

I will provide copies of the protocol to all physicians, nurses and other professional personnel

responsible to me who will participate in the study. I will discuss the protocol with them to assure

myself that they are sufficiently informed regarding the investigational drug [bivalirudin], the

concurrent medications, the efficacy and safety parameters and the conduct of the study in general.

I am aware that this protocol must be approved by the Ethics Committee (EC) responsible for such

matters in the Clinical Study Facility where bivalirudin will be tested prior to commencement of this

study. I agree to adhere strictly to the attached protocol. I agree that clinical data entered on case

report forms by me and my staff will be utilised by the Sponsor for non-for-profit purposes including

presentations and publications in the medical literature. I agree to allow Sponsor monitors and

auditors full access to all medical records at the research facility for patients screened or

randomised in the study.

I agree to provide all patients with informed consent forms, as required by government and ICH

regulations. I further agree to report to the Sponsor any adverse experiences in accordance with

the terms of this protocol.

____________________________________________ _______________ Principal Investigator Date

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25. REFERENCES

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2. Eikelboom JW, Quinlan DJ, O'Donnell M. Major bleeding, mortality, and efficacy of

fondaparinux in venous thromboembolism prevention trials. Circulation 2009;120(20):2006-11.

3. Elbarouni B, Elmanfud O, Yan RT, et al. Temporal trend of in-hospital major bleeding

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4. Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial

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5. Ndrepepa G, Schulz S, Keta D, et al. Bleeding after percutaneous coronary intervention with

Bivalirudin or unfractionated Heparin and one-year mortality. The American journal of

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6. Prandoni P, Trujillo-Santos J, Sanchez-Cantalejo E, et al. Major bleeding as a predictor of

mortality in patients with venous thromboembolism. J Thromb Haemost.

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8. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute

myocardial infarction. The New England journal of medicine 2008;358(21):2218-30.

9. Majure DT, Aberegg SK. Fondaparinux versus enoxaparin in acute coronary syndromes.

The New England journal of medicine 2006;354(26):2829; author reply 30.

10. Lindsey JB, Cohen DJ, Stolker JM, et al. The impact of bivalirudin on percutaneous

coronary intervention-related bleeding. EuroIntervention;6(2):206-13.

11. Campeau L. Percutaneous radial artery approach for coronary angiography. Catheterization

and cardiovascular diagnosis 1989;16(1):3-7.

12. Agostoni P, Biondi-Zoccai GG, de Benedictis ML, et al. Radial versus femoral approach for

percutaneous coronary diagnostic and interventional procedures; Systematic overview and meta-

analysis of randomized trials. Journal of the American College of Cardiology 2004;44(2):349-56.

13. Jolly SS, Amlani S, Hamon M, Yusuf S, Mehta SR. Radial versus femoral access for

coronary angiography or intervention and the impact on major bleeding and ischemic events: a

systematic review and meta-analysis of randomized trials. American heart journal 2009;157(1):132-

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14. Nagai S, Abe S, Sato T, et al. Ultrasonic assessment of vascular complications in coronary

angiography and angioplasty after transradial approach. Am J Cardiol 1999;83(2):180-6.

15. Hall JJ, Arnold AM, Valentine RP, McCready RA, Mick MJ. Ultrasound imaging of the

radial artery following its use for cardiac catheterization. Am J Cardiol 1996;77(1):108-9.

16. Yoo BS, Lee SH, Ko JY, et al. Procedural outcomes of repeated transradial coronary

procedure. Catheter Cardiovasc Interv 2003;58(3):301-4.

17. Dahm JB, Vogelgesang D, Hummel A, Staudt A, Volzke H, Felix SB. A randomized trial of

5 vs. 6 French transradial percutaneous coronary interventions. Catheter Cardiovasc Interv

2002;57(2):172-6.

18. Hamon M, Sabatier R, Zhao Q, Niculescu R, Valette B, Grollier G. Mini-invasive strategy

in acute coronary syndromes: direct coronary stenting using 5 Fr guiding catheters and transradial

approach. Catheter Cardiovasc Interv 2002;55(3):340-3.

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19. Omoigui NA, Califf RM, Pieper K, et al. Peripheral vascular complications in the Coronary

Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I). J Am Coll Cardiol

1995;26(4):922-30.

20. Waksman R, King SB, 3rd, Douglas JS, et al. Predictors of groin complications after balloon

and new-device coronary intervention. Am J Cardiol 1995;75(14):886-9.

21. Blankenship JC, Hellkamp AS, Aguirre FV, Demko SL, Topol EJ, Califf RM. Vascular

access site complications after percutaneous coronary intervention with abciximab in the Evaluation

of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. Am J Cardiol 1998;81(1):36-40.

22. Blankenship JC, Balog C, Sapp SK, et al. Reduction in vascular access site bleeding in

sequential abciximab coronary intervention trials. Catheter Cardiovasc Interv 2002;57(4):476-83.

23. Reddy BK, Brewster PS, Walsh T, Burket MW, Thomas WJ, Cooper CJ. Randomized

comparison of rapid ambulation using radial, 4 French femoral access, or femoral access with

AngioSeal closure. Catheter Cardiovasc Interv 2004;62(2):143-9.

24. Morice MC, Dumas P, Lefevre T, Loubeyre C, Louvard Y, Piechaud JF. Systematic use of

transradial approach or suture of the femoral artery after angioplasty: attempt at achieving zero

access site complications. Catheter Cardiovasc Interv 2000;51(4):417-21.

25. Mann T, Cowper PA, Peterson ED, et al. Transradial coronary stenting: comparison with

femoral access closed with an arterial suture device. Catheter Cardiovasc Interv 2000;49(2):150-6.

26. Koreny M, Riedmuller E, Nikfardjam M, Siostrzonek P, Mullner M. Arterial puncture

closing devices compared with standard manual compression after cardiac catheterization:

systematic review and meta-analysis. Jama 2004;291(3):350-7.

27. Nikolsky E, Mehran R, Halkin A, et al. Vascular complications associated with arteriotomy

closure devices in patients undergoing percutaneous coronary procedures: a meta-analysis. J Am

Coll Cardiol 2004;44(6):1200-9.

28. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic

concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin

inhibitor. Circulation 1998;97(3):251-6.

29. Aggarwal A, Sobel BE, Schneider DJ. Decreased platelet reactivity in blood anticoagulated

with bivalirudin or enoxaparin compared with unfractionated heparin: implications for coronary

intervention. Journal of thrombosis and thrombolysis 2002;13(3):161-5.

30. Keating FK, Dauerman HL, Whitaker DA, Sobel BE, Schneider DJ. The effects of

bivalirudin compared with those of unfractionated heparin plus eptifibatide on inflammation and

thrombin generation and activity during coronary intervention. Coronary artery disease

2005;16(6):401-5.

31. Keating FK, Dauerman HL, Whitaker DA, Sobel BE, Schneider DJ. Increased expression of

platelet P-selectin and formation of platelet-leukocyte aggregates in blood from patients treated with

unfractionated heparin plus eptifibatide compared with bivalirudin. Thrombosis research

2006;118(3):361-9.

32. Schneider DJ, Keating F, Sobel BE. Greater inhibitory effects of bivalirudin compared with

unfractionated heparin plus eptifibitide on thrombin-induced platelet activation. Coronary artery

disease 2006;17(5):471-6.

33. Leger AJ, Jacques SL, Badar J, et al. Blocking the protease-activated receptor 1-4

heterodimer in platelet-mediated thrombosis. Circulation 2006;113(9):1244-54.

34. Lincoff AM. Direct thrombin inhibitors for non-ST-segment elevation acute coronary

syndromes: what, when, and where? American heart journal 2003;146(4 Suppl):S23-30.

35. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa

blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous

coronary intervention: REPLACE-2 randomized trial. Jama 2003;289(7):853-63.

36. Lincoff AM, Bittl JA, Kleiman NS, et al. Comparison of bivalirudin versus heparin during

percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to

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Reduced Clinical Events [REPLACE]-1 trial). The American journal of cardiology

2004;93(9):1092-6.

37. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and

provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade

during percutaneous coronary revascularization: REPLACE-2 randomized trial. Jama

2004;292(6):696-703.

38. Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned or

provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary

revascularization: results of the Comparison of Abciximab Complications with Hirulog for

Ischemic Events Trial (CACHET). American heart journal 2002;143(5):847-53.

39. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention

Triage strategY (ACUITY) trial: study design and rationale. American heart journal

2004;148(5):764-75.

40. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary

syndromes. The New England journal of medicine 2006;355(21):2203-16.

APPENDIX 01 - SEVERITY AND CAUSALITY ASSESSMENTS FOR ADVERSE EVENTS SEVERITY Adverse events (AEs) will be graded on a 3-point scale and reported as indicated on the electronic case report form. The intensity of an AE is defined as follows:

1 = Mild: Discomfort noticed, but no disruption to daily activity. 2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 3 = Severe: Inability to work or perform normal daily activity.

STUDY DRUG CAUSALITY The relationship of an AE to study treatment will be assessed with consideration to the following criteria:

• temporal relationship to the initiation of study medication • response of the event to withdrawal of study medication • AE profile of concomitant therapies • clinical circumstances during which the AE occurred • patient’s clinical condition and medical history

Categorisation* of causality will be designated by the investigator as stated below:


2. Unlikely related - this category applies to AEs for which there is no reasonable evidence or argument to suggest a causal relationship between the study medication and the

AE.

3. Possibly related - this category applies to AEs for which there is reasonable evidence or argument to suggest a causal relationship between the AE and the study medication.

4. Definitely related - this category applies to AEs that are considered to be related to the

study medication, with a high degree of certainty. * for the purposes of regulatory reporting, categories ‘3’ and ‘4’ will be considered “related”.

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APPENDIX 02 - STUDY COMMITTEES The Sponsor will appoint chairmen and members to the Executive Committee, the International Steering Committee and to an independent DSMB. Executive Committee This committee will be composed of physicians considered expert in the field of Emergency Medicine, ACS and PCI, including a physician from the Sponsor. The members will provide the scientific direction for the trial. In consultation with the DSMB, this group will be responsible for evaluating the progress of the trial and will make recommendations to the Sponsor regarding termination or continuation thereof. Further, this committee, in collaboration with the Sponsor, may decide to increase or decrease the sample size. Clinical Events Committee (CEC) A CEC will be formed to review clinical data and to adjudicated all primary endpoints plus stroke and stent thrombosis while blinded to the assigned study drug. The CEC will be composed of physicians. The CEC processes will be described in the CEC charter. International Steering Committee This committee will be composed of physicians considered experts in the field of Emergency Medicine, ACS and PCI. As a rule, each participating country will have at least one representative of emergency physicians and one representative of hospital cardiologists. The members will provide the scientific direction for the trial, with particular focus on national and regional variations in practice that may differ across Europe. Data and Safety Monitoring Board (DSMB) An independent DSMB will monitor the progress of the trial and ensure that the safety of subjects enrolled in the trial is not compromised. The DSMB will consist of a clinical chairman, several physicians experienced in clinical trials, but not participating in this study and at least 1 statistician. The DSMB processes is described in the DSMB charter. Publications Committee The Publication Committee will be comprised of a minimum of 5 physician representatives of institutions participating in the study and 1 physician from the Sponsor. The members will be appointed by the Executive Committee. The Publication Committee will be co-chaired by the physician from the Sponsor and 1 physician representative.

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Bivalirudin or Unfractionated Heparin in Patients with Acute Coronary Syndromes

Managed Invasively With and Without ST Elevation (MATRIX): a Randomised

Controlled Trial

Sergio Leonardi, Enrico Frigoli, Martina Rothenbühler, Eliano Navarese, Paolo Calabró, Paolo

Bellotti, Carlo Briguori, Marco Ferlini, Bernardo Cortese, Alessandro Lupi, Salvatore Ierna,

Dennis ZavallonitoParenti, Giovanni Esposito, Simone Tresoldi, Antonio Zingarelli, Stefano

Rigattieri, Cataldo Palmieri, Armando Liso, Fabio Abate, Marco Zimarino, Marco Comeglio,

Gabriele Gabrielli, Alaide Chieffo, Salvatore Brugaletta, Ciro Mauro, Nicolas M Van Mieghem,

Dik Heg, Peter Jüni, Stephan Windecker, and Marco Valgimigli, for the MATRIX Investigators

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (Dr S Leonardi MD and Dr Marco

Ferlini MD); EUSTRATEGY Association, Forli’ (FC), Italy (Dr E Frigoli MD); Clinical Trials

Unit, Department of Clinical Research, and Institute of Social and Preventive Medicine

(ISPM), University of Bern, Switzerland (Ms M Rothenbühler, MSc, Dr D Heg PhD);

Department of Internal Medicine, Division of Cardiology, Pneumology and Vascular

Medicine, HeinrichtoHeine-University, Dusseldorf, Germany and Systematic

Investigation and Research on Intervention and Outcomes (SIRIO) MEDICINE research

network (Dr E Navarese MD); Division of Cardiology, Department of Cardiothoracic

Sciences, Second University of Naples, Naples, Italy (Dr P Calabró MD); Department of

Cardiology, ASL3 Ospedale Villa Scassi, Genoa, Italy (Dr P Bellotti MD); Clinica

Mediterranea, Napoli, Italy (Dr C Briguori MD); Ospedale Fatebene Fratelli, Milano, Italy

(Dr B Cortese MD); University Hospital "Maggiore della Carità", Novara, Italy (Dr A Lupi

MD); Ospedale Sirai – Carbonia, Carbonia, Italy (Dr S Ierna MD); Humanitas Research

Hospital, IRCCS, Rozzano (MI), Italy (Dr D Zavalloni-Parenti MD); Division of Cardiology -

Department of Advanced Biomedical Sciences, Federico II University of Naples (Dr G

Esposito MD); A.O. Ospedale di Desio (MB), Lombardia, Italy (Dr S Tresoldi MD); IRCCS

San Martino - IST, Genoa, Italy (Dr A Zingarelli MD); Interventional Cardiology Sandro

Pertini Hospital Rome, Italy (Dr S Rigattieri MD); Ospedale Pasquinucci, Massa, Italy (Dr

C Palmieri MD); Citta’ di Lecce Hospital, Lecce, Italy (Dr A Liso MD); Ospedale Giovanni

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Paolo II, Sciacca, Italy (Dr F Abate MD); Università degli Studi “G. d’Annunzio” Chieti e

Pescara, Chieti, Italy (Dr M Zimarino MD); Ospedale San Jacopo, Pistoia, Italy (Dr M

Comeglio MD); Azienda Ospedali Riuniti - Presidio "GM Lancisi", Ancona, Italy (Dr G

Gabrielli MD); Ospedale San Raffaele IRCCS, Milano, Italy (Dr A Chieffo MD); Hospital

Clinic, Cardiovascular Institute, IDIBAPS, Barcelona, Spain (Dr S Brugaletta MD); AORN

Cardarelli, Napoli, Italy (Dr C Mauro MD); Erasmus MC, Rotterdam, The Netherlands (Dr

N Van Mieghem, MD, PhD); Applied Health Research Centre (AHRC), Li Ka Shing

Knowledge Institute of St. Michael’s Hospital, and Department of Medicine, University

of Toronto, Canada (Prof. P Jüni MD) and Swiss Cardiovascular Center Bern, Bern

University Hospital (Prof. Stephan Windecker MD and Prof. M Valgimigli MD).

Funding The Medicines Company and Terumo

Brief Title: MATRIX Antithrombin in STEACS and NSTEACS

Word count abstract: 300

Correspondence to:

Dr. Marco Valgimigli, Swiss Cardiovascular Center Bern, Bern University Hospital, CH-

3010 Bern, Switzerland or at [email protected]

Phone: +41 31 632 96 53

Fax: +41 31 632 47 71

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Abstract

Objective

To test the optimal antithrombotic regimen in patients with acute coronary syndrome (ACS)

Design

Randomised controlled trial

Setting

Patients with ACS with and without ST segment elevation

Participants

We randomized 4010 ACS patients with ST elevation (STEACS) and 3203 ACS patients

without ST elevation (NSTEACS) and planned percutaneous coronary intervention. The

primary study results in the overall population have been previously reported.

Interventions

Patients were randomly assigned, in an open label fashion, to one of two regimens:

bivalirudin with glycoprotein IIb/IIIa inhibitors (GPIs) restricted to procedural complications or

heparin, with or without GPIs.

Main outcome measure

Primary endpoints were the occurrence of major adverse cardiovascular events (MACE),

defined as death, myocardial infarction or stroke; and net adverse clinical events (NACE),

defined as major bleeding or MACE, both assessed at 30 days. Analyses were performed by

the principle of intention to treat.

Results Use of a GPI in patients assigned to heparin was planned at baseline in 30.7 % of

STEACS patients, in 10.9% of NSTEACS patients and in no patient assigned to bivalirudin. In

patients with STEACS, MACE occurred in 118 (5.9%) patients with bivalirudin and 129 (6.5%)

patients with heparin [rate ratio (RR) 0.90, 95% CI, 0.70 to 1.16; P=0.43] while NACE

occurred in 139 (7.0%) patients with bivalirudin and 163 (8.2%) patients with heparin (RR

0.84, 95% CI 0.67 to 1.05; P=0.13). In patients with NSTEACS, MACE occurred in 253

(15.9%) patients with bivalirudin and 262 (16.4%) patients with heparin (RR 0.97, 95% CI

0.80 to 1.17; P=0.74) while NACE occurred in 262 (16.5%) patients with bivalirudin and 281

(17.6%) patients with heparin (RR 0.93, 95% CI 0.77 to 1.12; P=0.43).

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Conclusions A bivalirudin monotherapy strategy, as compared with heparin with or without

GPI, does not significantly reduce MACE or NACE in patients with STEACS nor with

NSTEACS.

Trial Registration: ClinicalTrials.gov ID: NCT01433627.

Key words: Acute Coronary Syndrome – Antithrombotic therapy – Bleeding Complications

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Print Abstract (300 words)

Study question

To test the optimal antithrombotic regimen in patients with acute coronary syndrome (ACS).

Methods

We randomized 4010 ACS patients with ST elevation (STEACS) and 3203 ACS patients

without ST elevation (NSTEACS) and planned percutaneous coronary intervention.

Patients were randomly assigned, in an open label fashion, to one of two regimens:

bivalirudin with glycoprotein IIb/IIIa inhibitors (GPIs) restricted to procedural complications or

heparin, with or without GPIs. Primary endpoints were the occurrence of major adverse

cardiovascular events (MACE), defined as death, myocardial infarction or stroke; and net

adverse clinical events (NACE), defined as major bleeding or MACE, both at 30 days.

Study answer and limitations

In patients with STEACS, MACE occurred in 118 (5.9%) patients with bivalirudin and 129

(6.5%) patients with heparin [rate ratio (RR) 0.90, 95% CI, 0.70 to 1.16; P=0.43] and NACE in

139 (7.0%) patients with bivalirudin and 163 (8.2%) patients with heparin (RR 0.84, 95% CI

0.67 to 1.05; P=0.13). In patients with NSTEACS, MACE occurred in 253 (15.9%) patients

with bivalirudin and 262 (16.4%) patients with heparin (RR 0.97, 95% CI 0.80 to 1.17; P=0.74)

while NACE occurred in 262 (16.5%) patients with bivalirudin and 281 (17.6%) patients with

heparin (RR 0.93, 95% CI 0.77 to 1.12; P=0.43). Although the ACS subgroups were pre-

specified, we did not adjust for multiple comparisons.

What this study adds Our main finding is that bivalirudin monotherapy, as compared with

unfractionated heparin with or without GPI, is not associated with a reduction of major

adverse cardiovascular events or net adverse clinical events.

Funding, competing interests, data sharing The MATRIX program received support from

The Medicines Company and TERUMO. All authors have completed the ICMJE uniform

disclosure form at www.icmje.org/coi_disclosure.pdf and declare no support from any

organisation for the submitted work. No additional data will be available.

Study registration: ClinicalTrials.gov ID: NCT01433627.

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Simple Table (Adapted Table 2) for Print Abstract. Pre-specified clinical outcomes at 30 days in patients with STEACS and NSTEACS.

STEACS NSTEACS

Rate Ratio

(95% CI) B v H

P value Rate Ratio

(95% CI)

P value PINT

Coprimary composite–MACE 0.90 (0.70to1.16) 0.43 0.97 (0.80to1.17) 0.72 0.68

Coprimary composite–NACE 0.84 (0.67to1.05) 0.13 0.93 (0.77to1.12) 0.43 0.50

Alltocause mortality 0.68 (0.46to1.01) 0.053 0.77 (0.41to1.46) 0.43 0.73

Myocardial infarction 1.24 (0.88to1.76) 0.21 0.95 (0.78to1.16) 0.64 0.19

Stroke 0.35 (0.13to0.97) 0.035 4.04 (0.86to19.04) 0.057 0.0052

BARC Type 3 or 5 Bleeding 0.60 (0.39to0.92) 0.019 0.47 (0.26to0.85) 0.012 0.52

Definite stent thrombosis 1.84 (0.96to3.52) 0.063 1.44 (0.55to3.77) 0.46 0.68

Acute ST 1.87 (0.83to4.20) 0.13 0.75 (0.17to3.38) 0.71 0.29

Subacute ST 1.78 (0.59to5.31) 0.30 2.35 (0.61to9.12) 0.20 0.75

Definite or probable stent thrombosis

1.58 (0.90to2.77) 0.11 0.87 (0.41to1.83) 0.71 0.21

Acute ST 1.88 (0.87to4.06) 0.10 0.50 (0.13to2.01) 0.32 0.092

Subacute ST 1.28 (0.56to2.93) 0.55 1.12 (0.45to2.75) 0.81 0.82

Percentages are cumulative incidence estimates. †Continuity corrected rate ratio (95% CI) with p value from Fisher’s test.

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Introduction

In patients with acute coronary syndromes (ACS) managed invasively with coronary

angiography and revascularization the optimal strategy for preventing coronary thrombosis

and ischemia, while limiting bleeding, is uncertain. Two commonly adopted regimens consist

of unfractionated heparin, an indirect thrombin inhibitor, with or without concomitant use of a

glycoprotein IIb/IIIa inhibitor (GPIs) in case of percutaneous coronary intervention (PCI), and

bivalirudin, a direct thrombin inhibitor, with the use of GPIs restricted to periprocedural

thrombotic complications. This latter strategy has been associated with reduced bleeding, an

outcome extensively associated with mortality. Previous moderately sized studies in patients

with ACS provided conflicting results on the comparative efficacy and safety of these two

strategies. 1-4

We therefore designed the Minimizing Adverse Haemorrhagic Events by

Transradial Access Site and Systemic Implementation of Angiox (MATRIX) phase 3

programme in ACS patients managed invasively via the radial or femoral route as a large,

randomised controlled trial, to assess whether bivalirudin is superior to unfractionated heparin

with or without concomitant GPIs.5 Bivalirudin did not significantly reduce the two coprimary

endpoints of major adverse cardiovascular events and net adverse clinical events in the

overall ACS population of 7213 patients.6

The use of these two strategies in clinical practice however,7 as well as the profile of efficacy

on ischemic and thrombotic complications (e.g. stent thrombosis), and safety in terms of

bleeding 8 may differ depending on the type of ACS at presentation – that is with or without

persistent ST elevation.

Here, we present the results of pre-specified, randomised comparisons of bivalirudin

with heparin in two MATRIX subpopulations: a) MATRIX STEACS, consisting of 4010 ACS

patients presenting with persistent ST elevation and b) MATRIX NSTEACS, consisting of

3203 ACS patients presenting without persistent ST elevation for whom PCI was planned at

the time of coronary angiography.

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Methods

Study Design

MATRIX was a program of three independent randomised controlled trials (RCTs) in an all

comers ACS population, with or without persistent ST elevation. The first trial, MATRIX

Access Site, compared trans-radial versus trans-femoral access in 8404 ACS patients, 4010

(47.7%) with ST elevation and 4394 (52.3%) without ST elevation.9 The second trial, MATRIX

Anti-Thrombin, was a randomised comparison of two antithrombotic strategies: bivalirudin

with GPI use restricted to angiographic complications (eg. giant thrombus) versus

unfractionated heparin with GPI use left at the discretion of the investigator.6 These strategies

were compared in the overall STEACS population (4010 patients) and in NSTEACS patients

for whom PCI was planned (3203 patients, 72.9% of the overall NSTEACS population). The

third trial, MATRIX Treatment Duration, was a randomised comparison within patients

assigned to bivalirudin, comparing extended bivalirudin administration after PCI with short-

term administration during PCI only.6 (Figure 1)

Participants

Patients with STEACS were eligible if they experienced >20 min of ischemic symptoms with

ST-segment elevation of ≥1 mm in ≥2 contiguous electrocardiogram (ECG) leads, or with a

new left bundle-branch block or an infero-lateral myocardial infarction (MI) with ST segment

depression of ≥1 mm in ≥2 of leads V1-V3 with a positive terminal T wave if presented within

12 hours of symptom onset, or between 12 and 24 hours after symptom onset if there was

evidence of continuing ischemia or previous fibrinolytic treatment.

Patients with NSTEACS were eligible if they had a history consistent with new or worsening

cardiac ischemia, occurring at rest or with minimal activity within 7 days before randomisation

and fulfilled at least two high-risk criteria among the following: age 60 years or older, elevation

of cardiac biomarkers, or electrocardiographic changes consistent with cardiac ischemia;

consideration as possible candidate for PCI after completion of coronary angiography.

Key exclusion criteria (for both STEACS and NSTEACS patients) were i) treatment with low

molecular weight heparins within the past 6 hours ii) treatment with any glycoprotein IIb/IIIa

inhibitors in the previous 3 days iii) contraindications to angiography, including but not limited

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to severe peripheral vascular disease iv) presumed life expectancy of < 30 days. Detailed

inclusion and exclusion criteria have been published elsewhere and are listed in the

appendix.1,2

All patients gave written informed consent and the study was approved by ethics

committee from each participating site. No patients were involved in setting the research

question or the outcome measures, nor were they involved in developing plans for

recruitment, design, or implementation of the study. No patients were asked to advise on

interpretation or writing up of results. We plan to disseminate the results of the research to all

the scientific community, including study participants.

Randomisation

Using a computer-generated random sequence, patients were randomised on a 1:1 ratio to

receive the bivalirudin strategy or unfractionated heparin strategy, with a random block size

stratified by type of acute coronary syndrome – ie STEACS versus NSTEACS troponin

negative and NSTEACS troponin positive – intended or ongoing use of P2Y12 inhibitor

(clopidogrel versus ticagrelor or prasugrel), and study site.

Due to the high likelihood of patients with STEACS to receive PCI, all STEACS patients in

MATRIX were simultaneously randomized to the access site comparison, the anti-thrombin

comparison, and the treatment duration comparison (1-step randomization process). To

account for the patients with NSTEACS who will not undergo PCI after angiography and to

minimize the risk that this may unbalance the distribution of patients with respect to the tested

pharmacologic options, randomization to the anti-thrombin comparison (either bivalirudin or

heparin strategy) was also allowed after coronary angiography and the decision to proceed to

PCI had been taken. Hence, a 2-step randomization process (access site randomization

before angiography followed by anti-thrombin randomization, including treatment duration

randomization, only in those undergoing PCI) was selected in the majority of NSTEACS

patients. Additionally, randomisation of NSTEACS for which a 2-step randomization was

selected by the investigator was stratified by the actual treatment strategy (i.e. coronary

angiography only not followed by PCI or coronary angiography followed by planned PCI).

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Procedures

All interventions were administered in an open-label fashion. Bivalirudin was given according

to the product labelling, with a bolus of 0.75 mg per kilogram followed immediately by an

infusion of 1.75 mg per kilogram per hour until completion of PCI. Bivalirudin was then

stopped at the end of PCI, or prolonged in accordance with the subsequent random

assignment. In patients allocated to prolonged treatment, bivalirudin could be administered

either for up to 4 hours at the full dose or at a reduced dose of 0.25 mg per kilogram per hour

for at least 6 hours, at the discretion of the treating physicians. Heparin was dosed at 70 to

100 units per kilogram in patients not receiving GPIs and at 50 to 70 units per kilogram in

patients receiving GPIs. Subsequent heparin dosing based on activated clotting time, was

again left to the discretion of the investigator. A GPI could be administered before PCI in

patients in the heparin group based on the investigator judgment, but, in the bivalirudin group,

it was restricted only to patients with periprocedural thrombotic complications at the time of

PCI, including no reflow or giant thrombus. Use of other medications was allowed as per

guidelines. Clinical follow-up was performed at 30 days.

Outcomes

MATRIX Antithrombin had two coprimary outcomes, identical for patients with STEACS and

with NSTEACS: major adverse cardiovascular events (MACE) and net adverse clinical events

(NACE), both assessed at 30 days. Considering the extensive association of bleeding with

mortality and that both experimental treatments tested in MATRIX (radial access and

bivalirudin monotherapy) were expected to reduce bleeding, we included NACE as co-primary

endpoint.

Major adverse cardiovascular events were defined as the composite of all-cause mortality,

myocardial infarction, or stroke; and NACE were defined as the composite of major bleeding

unrelated to coronary-artery bypass graft (Bleeding Academic Research Consortium [BARC]

type 3 or 5) 10

, or MACE. Secondary outcomes included each component of the composite

outcomes, cardiovascular mortality, and stent thrombosis. Bleeding was also assessed and

adjudicated on the basis of the Thrombolysis In Myocardial Infarction (TIMI) and Global

Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries

(GUSTO) scales.11

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An independent clinical events committee (CEC), blinded to randomised treatment allocation,

adjudicated all suspected events according to pre-specified definitions. Complete endpoint

definitions and CEC procedures are provided in the appendix.

Statistical Analysis

The overall MATRIX Anti-Thrombin programme was designed as a superiority study on two

coprimary outcomes, MACE and NACE. We expected that the incidence of MACE (death, MI

or stroke at 30 days) on an intention to treat basis to be 4.2% in the bivalirudin group and 6%

in the UFH group (relative risk 0.70), respectively. A sample size of 6800 randomised patients

or 3400 patients per group was deemed to provide 85% power with an alpha error set at 2.5%

to correct for two coprimary endpoints. For NACE (death, MI, stroke or major bleeding at 30

days), we expected an incidence on an intention to treat basis of 6.3% in the bivalirudin group

and 9.0% in the UFH group (relative risk 0.70), respectively. A total of 6800 randomised

patients or 3400 patients per group were calculated to provide 95% power with an alpha error

set at 2.5% to correct for two coprimary endpoints. Otherwise, no adjustments for multiple

comparisons were made when analysing secondary endpoints. We analysed the data

according the intention to treat principle. Outcomes were assessed separately for STEACS

and NSTEACS as time-to-first event using the Mantel-Cox method to estimate rate ratios and

corresponding 95% confidence intervals. 12

The proportional hazard assumption was verified

on the basis of Schoenfeld residuals. We used a two-sided log-rank test and survival curves

were constructed using Kaplan-Meier estimates. We performed stratified analyses according

to pre-specified subgroups (centre’s annual volume of PCI, age, gender, BMI, intended start

or continuation of prasugrel or ticagrelor, diabetes, estimated glomerular filtration rate, history

of peripheral vascular disease, previous heparin and randomisation to access site) and

estimated possible effect modifications using interaction terms or tests for trend across

ordered groups. All analyses were performed using the statistical packages Stata 14.1 and R

3.3.0.

Role of the funding source

The MATRIX program was sponsored by the Italian Society of Invasive Cardiology (GISE), a

non-profit organisation, and received grant support from The Medicines Company and

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TERUMO. The Medicines Company provided bivalirudin for the study; the sponsor had no

role in study design, data collection, data monitoring, analysis, interpretation, or writing of the

report. The Corresponding Author has the right to grant on behalf of all authors and does

grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in

perpetuity, in all forms, formats and media (whether known now or created in the future), to i)

publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution

into other languages, create adaptations, reprints, include within collections and create

summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative

work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the

inclusion of electronic links from the Contribution to third party material where-ever it may be

located; and, vi) licence any third party to do any or all of the above.

Results

Patients

Between October 11, 2011 and November 7, 2014 a total of 7213 patients were randomised

in the MATRIX anti-thrombin trial in 78 centres in Italy, the Netherlands, Spain, and Sweden.

Of these, 4010 (56%) qualified for STEACS at presentation (randomised after a median of 3.1

hours from symptom onset) and 3203 (44%) for NSTEACS (randomised after a median of

36.4 hours from symptom onset). Of the 4010 patients with STEACS, investigator reported

primary PCI as indication in 3647 – ie 91%. Of the remaining 363 STEACS patients (9%), 190

did not receive PCI and 173 had PCI for an indication different than primary PCI. Three

thousand four hundred forty two patients (95.3%) in the bivalirudin group and 3474 (96.4%)

patients in the heparin group actually received the allocated treatment. At 30 days, complete

follow-up information was available for 7198 (99.8%) patients (Figure S1 and S2). Baseline

characteristics were similar within qualifying ACS groups, with burden of risk factors for

atherothrombosis and co-morbidities (including hypertension, diabetes, hypercholesterolemia,

prior MI) higher in patients who qualified for NSTEACS as compared with STEACS (Table 1).

Use of a GPI in patients assigned to heparin was planned at the time of randomisation in

30.7 % of STEACS patients and 10.9% of NSTEACS patients. In accordance with the

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protocol, there was no patient assigned to bivalirudin for whom a GPI was planned at the time

of randomisation (appendix). Bailout use of GPI was not significantly different between

randomised groups in patients with NSTEACS and higher in the bivalirudin group (6.0%) as

compared to heparin (4.3%) in the STEACS population (P=0.014). Administration of an oral

P2Y12 inhibitor (clopidogrel, ticagrelor or prasugrel) upstream (ie before coronary

angiography) was similar in patients in the bivalirudin group and heparin group, both in the

STEACS and in the NSTEACS population (Table S1). Other procedural characteristics are

listed in the appendix.

Clinical Outcomes

In patients with STEACS, MACE occurred in 118 (5.9%) patients with bivalirudin and 129

(6.5%) patients with heparin [rate ratio (RR) 0.90, 95% CI, 0.70 to 1.16, p=0.43] while NACE

occurred in 139 (7.0%) patients with bivalirudin and 163 (8.2%) patients with heparin (RR

0.84, 95% CI 0.67 to 1.05, p=0.13) (Figure 2 and Table 2).

In patients with NSTEACS, MACE occurred in 253 (15.9%) patients with bivalirudin and 262

(16.4%) patients with heparin (RR 0.97, 95% CI 0.80 to 1.17, p=0.72) while NACE occurred in

262 (16.5%) patients with bivalirudin and 281 (17.6%) patients with heparin (RR 0.93, 95% CI

0.77 to 1.12, p=0.43) (Figure 2 and Table 2).

There was no heterogeneity of treatment effect on mortality according to qualifying ACS at

baseline (P=0.73) with bivalirudin associated with less cases of all-cause death (RR 0.68,

95% CI 0.46 to 1.01, P=0.053) and cardiovascular death (RR 0.67, 95% CI 0.45 to 1.00,

P=0.048) as compared to heparin in patients with STEACS and directionally similar effect in

patients with NSTEACS (RR 0.77, 95% CI 0.41 to 1.46, P=0.43 and RR 0.76, 95% CI 0.40 to

1.47, P=0.42 respectively (Table 2 and Figure 3A).

Bivalirudin was associated with lower rates of BARC 3 or 5 bleeding, both in patients with

STEACS (RR 0.60, 95% CI 0.39-0.92; P=0.019) and with NSTEACS (RR 0.47, 95% CI 0.26

to 0.85; P=0.011) with similar treatment effect using the GUSTO (moderate or severe) and

the TIMI (major or minor) classifications of bleeding (Table 2, Figure 3D and appendix).

Acute stent thrombosis (definite and definite or probable) were not statistically different

between randomised groups in STEACS (RR 1.87, 95% CI 0.83 to 4.20, P=0.13 and RR 1.88,

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95% CI 0.87 to 4.06, P=0.10 respectively) and NSTEACS (RR 0.75, 95% CI 0.17 to 3.37,

P=0.71 and RR 0.50, 95% CI 0.13 to 2.01, P=0.32 respectively) with p value for interaction

with qualifying ACS of 0.29 for acute definite ST and 0.09 for acute definite or probable ST.

Rates of myocardial infarction were similar between bivalirudin and heparin in ACS patients

with and without ST elevation (RR 1.24, 95% CI 0.88 to 1.76 and RR 0.95, 95% CI 0.78 to

1.16 respectively, P for interaction=0.19). Notably, event rates at 30 day differed markedly

between the two population: 3.3% in patients with STEACS and 15% in those with NSTEACS.

Randomised treatment effect on stroke were directionally opposite in patients with and

without ST elevation (P for interaction=0.0052) with bivalirudin associated with lower risk of

stroke as compared to heparin in STEACS patients (RR 0.35, 95% CI 0.13 to 0.97, P=0.036)

and higher risk of stroke in NSTEACS patients (RR 4.02, 95% CI 0.85 to 18.95, P=0.057).

Additional analyses

Randomised treatment effect on MACE and NACE as well as all cause mortality and bleeding

in STEACS and NSTEACS patients according to pre-specified subgroups are listed in Figure

4 and in the appendix. In patients with STEACS, randomised treatment effect appeared

consistent across most subgroups with the exception of patients with estimated glomerular

filtration rate <60 ml/min, with previous use of UFH, and treated in centres at high PCI volume,

where the bivalirudin strategy appeared more effective and safe than the heparin strategy. In

patients with estimated glomerular filtration rate <60 ml/min bivalirudin appeared associated

with reduced death and major bleeding. Treatment effects appeared consistent also in

patients who qualified for NSTEACS, with a weak nominally significant interaction for intended

or ongoing use of prasugrel or ticagrelor as compared with clopidogrel.

Discussion

The main finding of this analysis – the largest randomised comparison of bivalirudin

with heparin in patients with STEACS and one of the largest in patients with NSTEACS

treated with modern antiplatelet agents – is that a regimen of bivalirudin monotherapy, as

compared with unfractionated heparin with provisional GPI, is not associated with a reduction

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of major adverse cardiovascular events or net adverse clinical events. These results are

consistent with the findings from the overall ACS population.6

Efficacy and Safety of Bivalirudin Monotherapy vs Heparin with or Without GPIs

according to type of ACS

As previously reported, a strategy of bivalirudin monotherapy was associated with reduced

bleeding as compared with heparin with provisional use of GPI.2,3,4,8

This reduction of bleeding

was consistent across bleeding classifications (including fatal events), not clearly related to

access site randomised (which was randomly allocated in MATRIX), and of similar magnitude

in ACS patients with and without ST elevation. These observations suggest that bivalirudin, if

intended as a strategy to minimize bleeding, may be complimentary to other strategies (e.g.

radial access) and could be applied with few restrictions to the general ACS population, as

also suggested by the association of bivalirudin with reduced death and bleeding in patients

with low GFR. In secondary analyses we observed that bivalirudin was associated with a

reduction in all-cause mortality due to lower CV mortality, a difference that in this analysis was

similar in patients with STEACS and with NSTEACS (p for interaction=0.72).

The excess risk of acute stent thrombosis associated with bivalirudin is well documented.2,3,8

We did not observe significant differences in the rate of acute stent thrombosis between

randomised strategies in ACS patients with and without ST elevation. While the risk of acute

ST with bivalirudin in patients with STEACS has been well documented (and is directionally

similar in MATRIX) we observe no increased risk in patients with NSTEACS, especially if

treated with potent P2Y12 inhibitors.

There was no clear effect of randomised treatment on MI according to qualifying ACS. The MI

component was far more common (>4 times) in NSTEACS patients as compared to STEACS,

reflecting the contribution of procedural-related MI events in NSTEACS patients with a

planned PCI. So, even when procedural MIs are not accounted for (i.e. STEACS), a strategy

of bivalirudin monotherapy did not have a measurable effect on either coprimary endpoints,

indicating a complex, competitive balance between thrombosis and bleeding, which may

explain the overall neutral results. Unexpectedly, a nominally significant interaction effect

between randomised antithrombotic strategies vs. qualifying ACS on stroke was detected. No

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such effect has previously been reported, and since it currently defies – to our knowledge –

any plausible biological explanation, we concur it may represent a spurious finding.

Finally, subgroup analysis indicates that a strategy of bivalirudin monotherapy with GPI

restricted to angiographic complications might be useful in STEACS patients pre-treated with

heparin and with renal dysfunction. A benefit of bivalirudin in patients who have received

heparin has been consistently reported.13-15

This effect, perhaps related to insufficient level of

anticoagulation provided by bivalirudin alone, suggests that the common practice of an

immediate heparin bolus in STEACS followed by bivalirudin appear safe. The effect of

bivalirudin in patients with renal dysfunction is less consistent 16,17

but suggests that in the

acute setting (where data on renal function are often not available) bivalirudin has a

favourable safety profile. Finally, a benefit of bivalirudin as compared to a heparin strategy in

NSTEACS patients (but not STEACS) treated with novel P2Y12 inhibitors may reflect a longer

time required for these agents to reach their desired effect, a possible consideration for the

selection of antithrombotic regimen in this population.18

Limitations

We acknowledge some limitations in the current analysis. Although the reported subgroups

were pre-specified in the protocol and separate statistical analyses on these subgroups were

planned, we did not adjust for multiple comparisons increasing the risk of type I error. Also,

the coprimary endpoints were all negative. Therefore, differential effects across subgroups of

the randomised treatments, if any, must be considered hypothesis-generating. Also, the

study was not powered for qualifying type of ACS at baseline. Accordingly, our ability to

detect smaller treatment differences is limited. Finally, MATRIX compared two antithrombotic

strategies (with the heparin arm intended to reflect GPI use in clinical practice) rather than two

drugs. The different use of GPIs in the two study arms has thus challenged our ability to

understand the efficacy and safety of the anticoagulants drugs alone.

Conclusions

In conclusion, a strategy of bivalirudin monotherapy as compared with heparin with or

without GPIs was not associated with reduction of MACE or NACE in patients with ACS, with

or without ST elevation. The choice of the anticoagulant regimen thus requires balancing

carefully the expected risk of bleeding and thrombotic complications vs the expected benefits

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in terms of efficacy for each patient. Further research is needed to better understand optimal

patients, settings, and combinations of antithrombotic therapies, particularly in patients with

high risk of early thrombotic complications and/or high risk of bleeding.

Acknowledgements

We thank all the MATRIX patients and investigators who volunteered to help others.

"What this paper adds" box

1. What is already known on this subject

The optimal antithrombotic combining anticoagulants and/or antiplatelets in patients with

acute coronary syndrome (ACS) with and without ST elevation are not yet defined. Previous

small and medium sized studies provided conflicting results on the comparative efficacy and

safety of these two strategies.

2. What this study adds

The main finding of this analysis – the largest randomised comparison of bivalirudin with

heparin in patients with STEACS and one of the largest in patients with NSTEACS treated

with modern antiplatelet agents – is that a regimen of bivalirudin monotherapy, as compared

with unfractionated heparin with provisional GPI, is not associated with a reduction of major

adverse cardiovascular events or net adverse clinical events.

Author contributions, transparency statement, and data sharing statement: SL wrote

the first draft of the manuscript and subsequent revision and interpreted it in collaboration with

all remaining authors. SL, EF, PC, PB, CB, MF, BC, AL, SI, D Z-P, GE, ST, AZ, SR CP, AL,

FA, MZ, MC, GG, AC, SB, CM, NvM, SW, and MV were responsible for the acquisition of data.

MR, EN, DH, PJ performed the analysis and interpreted it in collaboration with all remaining

authors. MV was responsible for conception and design and obtained funding for the study.

SL and MV had full access to the final data, had final responsibility for the content of the

report and the decision to submit for publication. All authors critically revised the paper for

important intellectual content and approved the final version.

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The manuscript's guarantors – Dr. Leonardi and Dr. Valgimigli – affirm that the manuscript is

an honest, accurate, and transparent account of the study being reported; that no important

aspects of the study have been omitted; and that any discrepancies from the study as

planned have been explained. The data presented are all in this manuscript and

supplementary material and no additional data will be available. The default license, a CC BY

NC license, is needed for publication.

Figures titles

Figure 1: MATRIX ACS Study Diagram

Figure 2: Co-primary composite outcomes at 30 days in patients with STEACS and

NSTEACS: (A) all-cause mortality, myocardial infarction, or stroke; and (B) all-cause

mortality, myocardial infarction, stroke, or BARC 3 or 5 bleeding

Figure 3: Components of co-primary composite at 30 days in patients with STEACS

and NSTEACS: (A) all-cause mortality; (B) myocardial infarction; (C) stroke; and (D)

BARC 3 or 5 bleeding

Figure 4: Stratified analysis of co-primary outcomes in patients with STEACS and

NSTEACS: (A) all-cause mortality, myocardial infarction, or stroke in patients with

STEACS and (B) all-cause mortality, myocardial infarction, or stroke, or BARC 3 or 5

bleeding in patients with STEACS (C) all-cause mortality, myocardial infarction, or

stroke in patients with NSTEACS and (D) all-cause mortality, myocardial infarction, or

stroke, or BARC 3 or 5 bleeding in patients with NSTEACS

Competing interests

All authors have completed the ICMJE uniform disclosure form at

www.icmje.org/coi_disclosure.pdf and declare no support from any organisation for the

submitted work. They declare the following financial relationships: Dr Leonardi reports

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honoraria for advisory boards from The Medicines Company during the conduct of the study

outside the submitted work; Dr Ferlini received honoraria for advisory boards or as speaker at

scientific congresses or as consultant from Astra Zeneca, Eli Lilly and the Medicines

Company, outside the submitted work; Dr. Cortese reports lectures fee from Abbott, AB

Medica, Hexacath, Astra, Movi, Concept Medicals and research grants from AB Medica,

Aachen Resonance, Movi, all outside the submitted work; Dr Zimarino received honoraria as

speaker at scientific congresses from Astra Zeneca and Pfizer, outside the submitted work; Dr.

Rigattieri reports personal fees for advisory board participation from AstraZeneca; Dr. Jüni

has received research grants to the institution from Astra Zeneca, Biotronik, Biosensors

International, Eli Lilly and The Medicines Company, and serves as unpaid member of the

steering group of trials funded by Astra Zeneca, Biotronik, Biosensors, St. Jude Medical and

The Medicines Company; Dr. Valgimigli reports grants from The Medicines Company, grants

from Terumo, during the conduct of the study; the other authors report nothing to disclose. No

other relationships or activities that could appear to have influenced the submitted work is

reported. All authors have read and understood BMJ policy on declaration of interests and

have no other relevant interests to declare in addition to these.

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Tables

Table 1. Baseline characteristics STEACS NSTEACS


UFH (N=1998) Bivalirudin (N=1598)

UFH (N=1605)

Age – yr 63.9±12.2 63.9±12.0 67.4±11.2 67.3±11.4

≥ 75 yr 445 (22.1) 423 (21.2) 461 (28.8) 481 (30.0)

Male sex 1549 (77.0) 1544 (77.3) 1182 (74.0) 1220 (76.0)

Weight (kg) 77.8±13.5 77.4±14.0 77.7±14.0 77.4±13.7

Body Mass Index (kg/m2) 27.1±4.1 26.9±4.1 27.3±4.3 27.2±4.1

Diabetes mellitus 363 (18.0) 355 (17.8) 452 (28.3) 431 (26.9)

Insulin-dependent 73 (3.6) 79 (4.0) 123 (7.7) 108 (6.7)

Current smoker 820 (40.8) 815 (40.8) 487 (30.5) 487 (30.3)

Hypercholesterolemia 783 (38.9) 785 (39.3) 813 (50.9) 773 (48.2)

Hypertension 1150 (57.2) 1084 (54.3) 1114 (69.7) 1138 (70.9)

Family history of CAD 561 (27.9) 563 (28.2) 430 (26.9) 429 (26.7)

Previous MI 188 (9.3) 196 (9.8) 342 (21.4) 305 (19.0)

Previous PCI 200 (9.9) 186 (9.3) 336 (21.0) 318 (19.8)

Previous CABG 29 (1.4) 23 (1.2) 98 (6.1) 72 (4.5)

Previous TIA or stroke 88 (4.4) 84 (4.2) 93 (5.8) 101 (6.3)

Peripheral Vascular Disease

106 (5.3) 123 (6.2) 190 (11.9) 161 (10.0)

COPD 100 (5.0) 85 (4.3) 116 (7.3) 135 (8.4)

History of renal failure 21 (1.0) 24 (1.2) 27 (1.7) 23 (1.4)

Dialysis 3 (0.1) 0 (0.0) 2 (0.1) 2 (0.1)

Clinical presentation

Cardiac arrest 67 (3.3) 72 (3.6) 13 (0.8) 11 (0.7)

Killip class

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I 1814 (90.2) 1778 (89.0) 1461 (91.4) 1462 (91.1)

II 129 (6.4) 157 (7.9) 95 (5.9) 107 (6.7)

III 38 (1.9) 29 (1.5) 38 (2.4) 35 (2.2)

IV 31 (1.5) 34 (1.7) 4 (0.3) 1 (0.1)

Previous lytic therapy 96 (4.8) 101 (5.1) 1 (0.1) 0 (0.0)

Systolic BP (mmHg) 136.2±26.8 136.0±27.1 141.5±24.6 140.9±24.0

Heart rate (min-1) 77.0±17.3 77.1±17.2 75.2±16.3 74.1±15.3

LVEF (%) 48.7±9.5 49.1±9.5 52.8±9.1 53.2±9.1

eGFR (ml/min-1

) 84.4±25.5 85.2±25.8 82.6±24.5 83.4±25.6

eGFR<60 307 (15.4) 301 (15.3) 282 (17.7) 287 (17.9)

eGFR<30 20 (1.0) 25 (1.3) 18 (1.1) 15 (0.9)

Presented data are n (%) or mean (SD). P values were estimated using chi-square or Fisher’s exact test where appropriate or Student’s t-test. MI: myocardial infarction UFH: Unfractionated heparin; GPI: glycoprotein IIb/IIIa inhibitor; CAD: coronary artery disease; ARB: Angiotensin II receptor antagonist; BP: blood pressure; COPD: Chronic Obstructive Pulmonary Disease; LVEF: Left ventricular ejection fraction.

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Table 2. Pre-specified clinical outcomes at 30 days in patients with STEACS and NSTEACS.

STEACS NSTEACS

Bivalirudin UFH Rate Ratio (95% CI)

P value Bivalirudin UFH Rate Ratio (95% CI)

P value

(N=2012) (N=1998) (N=1598) (N=1605)

Coprimary composite–MACE 118 (5.9) 129 (6.5) 0.90 (0.70to1.16) 0.43 253 (15.9) 262 (16.4) 0.97 (0.80to1.17) 0.72

Coprimary composite–NACE 139 (7.0) 163 (8.2) 0.84 (0.67to1.05) 0.13 262 (16.5) 281 (17.6) 0.93 (0.77to1.12) 0.43

Alltocause mortality 42 (2.1) 61 (3.1) 0.68 (0.46to1.01) 0.053 17 (1.1) 22 (1.4) 0.77 (0.41to1.46) 0.43

Myocardial infarction 73 (3.7) 58 (3.0) 1.24 (0.88to1.76) 0.21 234 (14.7) 245 (15.3) 0.95 (0.78to1.16) 0.64

Stroke 5 (0.3) 14 (0.7) 0.35 (0.13to0.97) 0.035 8 (0.5) 2 (0.1) 4.04 (0.86to19.04) 0.057

BARC Type 3 or 5 Bleeding 33 (1.7) 54 (2.8) 0.60 (0.39to0.92) 0.019 16 (1.0) 34 (2.1) 0.47 (0.26to0.85) 0.012

Definite stent thrombosis 26 (1.3) 14 (0.7) 1.84 (0.96to3.52) 0.063 10 (0.6) 7 (0.4) 1.44 (0.55to3.77) 0.46

Acute ST 17 (0.8) 9 (0.5) 1.87 (0.83to4.20) 0.13 3 (0.2) 4 (0.3) 0.75 (0.17to3.38) 0.71

Subacute ST 9 (0.5) 5 (0.3) 1.78 (0.59to5.31) 0.30 7 (0.4) 3 (0.2) 2.35 (0.61to9.12) 0.20

Definite or probable stent thrombosis

32 (1.6) 20 (1.0) 1.58 (0.90to2.77) 0.11 13 (0.8) 15 (1.0) 0.87 (0.41to1.83) 0.71

Acute ST 19 (0.9) 10 (0.5) 1.88 (0.87to4.06) 0.10 3 (0.2) 6 (0.4) 0.50 (0.13to2.01) 0.32

Subacute ST 13 (0.7) 10 (0.5) 1.28 (0.56to2.93) 0.55 10 (0.6) 9 (0.6) 1.12 (0.45to2.75) 0.81

Percentages are cumulative incidence estimates. †Continuity corrected rate ratio (95% CI) with p value from Fisher’s test.

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