March 16. http://dx.doi.org/10.1016/S0140-6736(15)60292-6. .... Table S7: Overview of randomised clinical trials comparing radial versus femoral access site in ..... the 99th percentile URL in at least one blood sample plus either new ...
Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Valgimigli M, Gagnor A, Calabró P, et al, for the MATRIX Investigators. Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial. Lancet 2015; published online March 16. http://dx.doi.org/10.1016/S0140-6736(15)60292-6.
Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised, multicentre trial Valgimigli et al.
MATRIX programme organisation: list of investigators .................................................................. 2 Funding .................................................................................................................................................. 4 MATRIX programme operator eligibility criteria ............................................................................ 4 MATRIX programme inclusion and exclusion criteria ..................................................................... 5 Clinical event committee procedures .................................................................................................. 6 MATRIX clinical outcome definitions ................................................................................................ 6 Table S1: Procedural characteristics in patients undergoing staged procedures ......................... 12 Table S2: Medications at hospital discharge .................................................................................... 13 Table S3: Sensitivity analyses of both co-primary endpoints and components of the co-primary endpoints .............................................................................................................................................. 14 Table S4: Estimated numbers-needed-to treat and numbers-needed-to-harm for both coprimary outcomes and components of the co-primary outcomes ................................................... 15 Table S5: Factors associated with deaths not directly attributed to a bleeding event in the nested case-control study of 137 cases and 1370 matched controls from univariable analysis................ 16 Table S6: Factors associated with deaths not directly attributed to a bleeding event in the nested case-control study of 137 cases and 1370 matched controls from multivariable analysis ............ 17 Table S7: Overview of randomised clinical trials comparing radial versus femoral access site in acute coronary syndrome patients used for the meta-analyses ...................................................... 19 Figure S1: Stratified analyses of all-cause mortality ....................................................................... 20 Figure S2: Stratified analyses of BARC 3 or 5 bleeding.................................................................. 21 References ............................................................................................................................................ 22
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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 (CoChair), 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 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),
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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.
MATRIX programme operator eligibility criteria Transradial intervention requires specific skills and dedicated training. Therefore, the scope of this study was not to investigate the learning curve of the technique, rather to assess the comparative efficacy and safety of radial versus femoral access and intervention, if indicated, in the context of fully trained interventional cardiologists having been properly exposed to both treatment options. Against this background, operators qualified for the study provided all three criteria below were met: i) They were familiar and had been exposed to transfemoral intervention as a senior cardiologist at least 2 years. ii) They had performed at least 50% of interventions in ACS transradially in the 12 months before site initiation. iii) At least 75 transradial coronary interventions had been performed in the 12 months before site initiation.
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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 triggerspecification 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 leftbundle 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 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.
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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 kinaseMB 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 infarction1 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 99th percentile URL in at least one blood sample plus either new pathological Q waves or new left bundlebranch 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. 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).
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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. 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.
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BARC classification2 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 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
