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Bivalirudin or unfractionated heparin in patients with acute coronary syndromes managed invasively with and without ST elevation (MATRIX): randomised controlled trial

BMJ 2016; 354 doi: (Published 27 September 2016) Cite this as: BMJ 2016;354:i4935
  1. Sergio Leonardi, clinician investigator1,
  2. Enrico Frigoli, study physician leader2,
  3. Martina Rothenbühler, statistician34,
  4. Eliano Navarese, consultant interventional cardiologist5,
  5. Paolo Calabró, associate professor6,
  6. Paolo Bellotti, interventional cardiologist7,
  7. Carlo Briguori, interventional cardiologist8,
  8. Marco Ferlini, interventional cardiologist1,
  9. Bernardo Cortese, interventional cardiologist9,
  10. Alessandro Lupi, interventional cardiologist10,
  11. Salvatore Lerna, interventional cardiologist11,
  12. Dennis Zavallonito-Parenti, interventional cardiologist12,
  13. Giovanni Esposito, associate professor13,
  14. Simone Tresoldi, interventional cardiologist14,
  15. Antonio Zingarelli, interventional cardiologist15,
  16. Stefano Rigattieri, interventional cardiologist16,
  17. Cataldo Palmieri, interventional cardiologist17,
  18. Armando Liso, interventional cardiologist18,
  19. Fabio Abate, interventional cardiologist19,
  20. Marco Zimarino, interventional cardiologist20,
  21. Marco Comeglio, interventional cardiologist21,
  22. Gabriele Gabrielli, interventional cardiologist22,
  23. Alaide Chieffo, interventional cardiologist23,
  24. Salvatore Brugaletta, interventional cardiologist24,
  25. Ciro Mauro, interventional cardiologist25,
  26. Nicolas M Van Mieghem, interventional cardiologist26,
  27. Dik Heg, statistician34,
  28. Peter Jüni, professor27,
  29. Stephan Windecker, professor28,
  30. Marco Valgimigli, professor of clinical research in interventional cardiology28
  31. for the MATRIX Investigators
  1. 1Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  2. 2EUSTRATEGY Association, Forli’, Italy
  3. 3CTU Bern, University of Bern, Switzerland
  4. 4Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland
  5. 5Policlinico Multimedica IRCSS, University of Milan, Milan, Italy
  6. 6Division of Cardiology, Department of Cardiothoracic Sciences, Second University of Naples, Naples, Italy
  7. 7Department of Cardiology, ASL3 Ospedale Villa Scassi, Genoa, Italy
  8. 8Clinica Mediterranea, Napoli, Italy
  9. 9Ospedale Fatebene Fratelli, Milano, Italy
  10. 10University Hospital Maggiore della Carità, Novara, Italy
  11. 11Ospedale Sirai–Carbonia, Carbonia, Italy
  12. 12Humanitas Research Hospital, IRCCS, Rozzano, Italy
  13. 13Division of Cardiology-Department of Advanced Biomedical Sciences, Federico II University of Naples
  14. 14A O Ospedale di Desio, Lombardia, Italy
  15. 15IRCCS San Martino-IST, Genoa, Italy
  16. 16Interventional Cardiology Sandro Pertini Hospital Rome, Italy
  17. 17Ospedale Pasquinucci, Massa, Italy
  18. 18Citta’ di Lecce Hospital, Lecce, Italy
  19. 19Ospedale Giovanni Paolo II, Sciacca, Italy
  20. 20Università degli Studi G d’Annunzio Chieti e Pescara, Chieti, Italy
  21. 21Ospedale San Jacopo, Pistoia, Italy
  22. 22Azienda Ospedali Riuniti-Presidio GM Lancisi, Ancona, Italy
  23. 23Ospedale San Raffaele IRCCS, Milano, Italy
  24. 24Hospital Clinic, Cardiovascular Institute, IDIBAPS, Barcelona, Spain
  25. 25AORN Cardarelli, Napoli, Italy
  26. 26Erasmus MC, Rotterdam, Netherlands
  27. 27Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital, and Department of Medicine, University of Toronto, Canada
  28. 28Swiss Cardiovascular Centre Bern, Bern University Hospital, CH-3010 Bern, Switzerland
  1. Correspondence to: M Valgimigli marco.valgimigli{at}
  • Accepted 2 September 2016


Objective To test the optimal antithrombotic regimen in patients with acute coronary syndrome.

Design Randomised controlled trial.

Setting Patients with acute coronary syndrome with and without ST segment elevation in 78 centres in Italy, the Netherlands, Spain, and Sweden.

Participants 7213 patients with acute coronary syndrome and planned percutaneous coronary intervention: 4010 with ST segment elevation and 3203 without ST segment elevation. The primary study results in the overall population have been reported previously.

Interventions Patients were randomly assigned, in an open label fashion, to one of two regimens: bivalirudin with glycoprotein IIb/IIIa inhibitors restricted to procedural complications or heparin with or without glycoprotein IIb/IIIa inhibitors.

Main outcome measures Primary endpoints were the occurrence of major adverse cardiovascular events, defined as death, myocardial infarction or stroke; and net adverse clinical events, defined as major bleeding or major adverse cardiovascular events, both assessed at 30 days. Analyses were performed by the principle of intention to treat.

Results Use of a glycoprotein IIb/IIIa inhibitor in patients assigned to heparin was planned at baseline in 30.7% of patients with ST segment elevation, in 10.9% without ST segment elevation, and in no patients assigned to bivalirudin. In patients with ST segment elevation, major adverse cardiovascular events occurred in 118 (5.9%) assigned to bivalirudin and 129 (6.5%) assigned to heparin (rate ratio 0.90, 95% confidence interval 0.70 to 1.16; P=0.43), whereas net adverse clinical events occurred in 139 (7.0%) patients assigned to bivalirudin and 163 (8.2%) assigned to heparin (0.84, 0.67 to 1.05; P=0.13). In patients without ST segment elevation, major adverse cardiovascular events occurred in 253 (15.9%) assigned to bivalirudin and 262 (16.4%) assigned to heparin (0.97, 0.80 to 1.17; P=0.74), whereas net adverse clinical events occurred in 262 (16.5%) patients assigned to bivalirudin and 281 (17.6%) assigned to heparin (0.93, 0.77 to 1.12; P=0.43).

Conclusions A bivalirudin monotherapy strategy compared with heparin with or without glycoprotein IIb/IIIa inhibitors, did not result in reduced major adverse cardiovascular events or net adverse clinical events in patients with or without ST segment elevation.

Trial Registration NCT01433627.


  • We thank the MATRIX patients and investigators who volunteered to help others.

  • Contributors: SL wrote the first draft of the manuscript and subsequent revision, and interpreted it in collaboration with the other authors. SL, EF, PC, PB, CB, MF, BC, AL, SI, DZ-P, GE, ST, AZ, SR CP, AL, FA, MZ, MC, GG, AC, SB, CM, NMvM, SW, and MV acquired data. MR, EN, DH, and PJ performed the analysis and interpreted it in collaboration with the other authors. MV conceived and designed the study and obtained funding. SL and MV had full access to the final data and 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. SL and MV are the guarantors.

  • Funding: The MATRIX programme was sponsored by the Italian Society of Invasive Cardiology (GISE), a non-profit organisation, and received grant support from The Medicines Company and 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.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare no support from any organisation for the submitted work. They declare the following financial relations: SL reports honorariums for advisory boards from The Medicines Company during the conduct of the study outside the submitted work; MF received honorariums 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; BC reports lecture fees from Abbott, AB Medica, Hexacath, Astra, Movi, and Concept Medicals and research grants from AB Medica, Aachen Resonance, and Movi, all outside the submitted work; MZ received honorariums as speaker at scientific congresses from Astra Zeneca and Pfizer, outside the submitted work; SR reports personal fees for advisory board participation from AstraZeneca; PJ 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; MV reports grants from the Medicines Company and Terumo during the conduct of the study. No other relationships or activities that could appear to have influenced the submitted work are reported.

  • Ethical approval: This study was approved by the ethics committee from each participating site.

  • Data sharing: No additional data available.

  • Transparency: The manuscript’s guarantors (SL and MV) 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.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

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