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Original research
Influence of time metrics on the treatment effect of intravenous alteplase prior to endovascular treatment in MR CLEAN-NO IV
  1. Leon A Rinkel1,
  2. Kilian Maurizio Treurniet2,
  3. Manon Kappelhof2,
  4. Natalie E LeCouffe1,
  5. Agnetha A E Bruggeman2,
  6. Daan Nieboer3,
  7. Wim H van Zwam4,
  8. Maarten Uyttenboogaart5,6,
  9. Diederik W J Dippel7,
  10. Bart J Emmer2,
  11. Yvo B W E M Roos1,
  12. Charles B L M Majoie2,
  13. J M Coutinho1
  14. on behalf of the MR CLEAN-NO IV Investigators
  1. 1 Department of Neurology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
  2. 2 Department of Radiology and Nuclear Medicine, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
  3. 3 Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands
  4. 4 Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands
  5. 5 Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands
  6. 6 Department of Radiology and Nuclear Medicine, University Medical Center Groningen, Groningen, The Netherlands
  7. 7 Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
  1. Correspondence to Dr J M Coutinho, Neurology, Amsterdam UMC Locatie AMC, Amsterdam 1105 AZ, Netherlands; j.coutinho{at}


Background We assessed whether the treatment effect of intravenous alteplase (IVT) prior to endovascular treatment (EVT) on functional outcome is modified by time metrics.

Methods We used data from all patients included in MR CLEAN-NO IV, a randomized trial of IVT followed by EVT versus EVT alone in patients who presented directly to EVT-capable hospitals. The primary outcome was the modified Rankin Scale score at 90 days. We used ordinal regression with a multiplicative interaction term to assess if the effect of IVT is modified by onset-to-randomization (OTR), onset-to-IV-needle (OTN), door-to-groin (DTG) or needle-to-groin (NTG) times. Secondary outcomes included successful reperfusion (extended Thrombolysis In Cerebral Infarction Scale 2b–3) and symptomatic intracranial hemorrhage (sICH).

Results In 539 included patients (266 allocated to IVT+EVT and 273 to EVT alone), median workflow times were OTR: 93 (IQR 71–145) min; OTN: 98 (IQR 75–156) min; DTG: 64 (IQR 51–78) min; and NTG: 28 (IQR 20–41) min. There was a significant association between worse outcomes and longer time intervals for all metrics except NTG. We found no interaction between any of the time metrics and IVT for the effect on functional outcome (p values for interaction: OTR=0.40, OTN=0.39, DTG=0.61, NTG=0.56). We also did not observe any significant interaction for successful reperfusion or sICH.

Conclusion In MR CLEAN-NO IV, the effect of IVT prior to EVT was not modified by OTR, OTN, DTG or NTG times. Our results do not support the use of these metrics to guide IVT treatment decisions prior to EVT in comprehensive stroke centres.

Trial registration number ISRCTN80619088.

  • stroke
  • thrombectomy
  • thrombolysis

Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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  • Collaborators List of MR CLEAN-NO IV Investigators, Collaborators and Affiliations. Principal investigators: Yvo Roos,1 Charles Majoie.1 Study coordinators: Kilian Treurniet,1 Jonathan Coutinho,1 Bart Emmer,1 Natalie LeCouffe,1 Manon Kappelhof,1 Leon Rinkel,1 Agnetha Bruggeman.1 Local principal investigators: Bob Roozenbeek,2 Adriaan van Es,2 Inger de Ridder,4 Wim van Zwam,4 Bart van der Worp,5 Rob Lo,5 Koos Keizer,6 Rob Gons,6 Lonneke Yo,6 Jelis Boiten,7 Ido van den Wijngaard,7 Geert Lycklama à Nijeholt,7 Jeanette Hofmeijer,8 Jasper Martens,8 Wouter Schonewille,9 Jan Albert Vos,9 Anil Tuladhar,10 Floris Schreuder,10 Jeroen Boogaarts,10 Sjoerd Jenniskens,10 Karlijn de Laat,11 Lukas van Dijk,11 Heleen den Hertog,12 Boudewijn van Hasselt,12 Paul Brouwers,13 Emiel Sturm,13 Tomas Bulut,13 Michel Remmers,14 Anouk van Norden,14 Thijs de Jong,14 Anouk Rozeman,15 Otto Elgersma,15 Maarten Uyttenboogaart,16 Reinoud Bokkers,16 Julia van Tuijl,17 Issam Boukrab,17 Hans Kortman,17 Vincent Costalat,18 Caroline Arquizan,18 Robin Lemmens,19 Jelle Demeestere,19 Philippe Desfontaines,20 Denis Brisbois,20 Frédéric Clarençon,21 Yves Samson.21 Local trial collaborators: Executive and writing committee Yvo Roos,1 Charles Majoie,1 Adriaan van Es,2 Wim van Zwam,4 Jelis Boiten,7 Geert Lycklama à Nijeholt,7 Lonneke Yo,6 Koos Keizer,6 Jonathan Coutinho,1 Bart Emmer,1 Kilian Treurniet,1 Natalie LeCouffe,1 Manon Kappelhof.1 Data Safety Monitoring Board: Martin Brown22 – Chair, Phil White,23 John Gregson.24 Independent trial statistician: Daan Nieboer.2 CONTRAST clinical trial collaborators: Research leaders: Diederik Dippel,2 Charles Majoie.1 Consortium coordinator: Rick van Nuland.3 Imaging assessment committee: Charles Majoie1 – Chair (Amsterdam Medical Center, location AMC); Aad van der Lugt2 – Chair, Wim van Zwam,4 Linda Jacobi,4 René van den Berg,1 Ludo Beenen,1 Bart Emmer,1 Adriaan van Es,2 Pieter-Jan van Doormaal,2 Geert Lycklama,7 Ido van den Wijngaard,7 Albert Yoo,25 Lonneke Yo,6 Jasper Martens,8 Bas Hammer,11 Stefan Roosendaal,2 Anton Meijer,10 Menno Krietemeijer,6 Reinoud Bokkers,16 Anouk van der Hoorn,16 Dick Gerrits.13 Adverse event committee: Robert van Oostenbrugge4 – Chair, Bart Emmer,2 Jonathan Coutinho,1 Ben Jansen.17 Outcome assessment committee: Yvo Roos1 – Chair, Sanne Manschot,7 Diederik Dippel,2 Henk Kerkhof,15 Ido van den Wijngaard,7 Jonathan Coutinho,1 Peter Koudstaal,1 Koos Keizer.6 Data management group: Hester Lingsma,2 Diederik Dippel,2 Vicky Chalos,2 Olvert Berkhemer.2 Imaging data management: Aad van der Lugt,2 Charles Majoie,1 Adriaan Versteeg,2 Lennard Wolff,2 Jiahang Su,2 Manon Tolhuisen,1 Henk van Voorst.1 Biomaterials and translational group: Hugo ten Cate,4 Moniek de Maat,2 Samantha Donse-Donkel,2 Heleen van Beusekom,2 Aladdin Taha.2 Local collaborators: Vicky Chalos,2 Kilian Treurniet,1 Sophie van den Berg,1 Natalie LeCouffe,1 Rob van de Graaf,2 Robert-Jan Goldhoorn,4 Aladdin Taha,2 Samantha Donse-Donkel,2 Wouter Hinsenveld,4 Anne Pirson,4 Lotte Sondag,10 Manon Kappelhof,1 Rik Reinink,5 Manon Tolhuisen,1 Josje Brouwer,1 Lennard Wolff,2 Sabine Collette,16 Wouter van der Steen.2 Research nurses: Rita Sprengers,1 Martin Sterrenberg,2 Naziha El Ghannouti,2 Sabrina Verheesen,4 Wilma Pellikaan,9 Kitty Blauwendraat,9 Yvonne Drabbe,11 Joke de Meris,7 Michelle Simons,8 Hester Bongenaar,6 Anja van Loon,14 Eva Ponjee,12 Rieke Eilander,12 Suze Kooij,15, Marieke de Jong,16 Esther Santegoets,17 Suze Roodenburg,15 Ayla van Ahee,1,5 Marinette Moynier,18 Annemie Devroye,19 Evelyn Marcis,19 Ingrid Iezzi,20 Annie David,20 Atika Talbi.21 Study monitors: Leontien Heiligers,2 Yvonne Martens.2

    Affiliations:1Amsterdam University Medical Centers, location AMC, University of Amsterdam, Amsterdam the Netherlands; 2Erasmus MC University Medical Center, Rotterdam, the Netherlands; 3Lygature, Utrecht, the Netherlands; 4Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands; 5University Medical Center Utrecht, Brain Center Rudolf Magnus, Utrecht, the Netherlands; 6Catharina Hospital, Eindhoven, the Netherlands; 7Haaglanden Medical Center, the Hague, the Netherlands; 8Rijnstate Hospital, Arnhem, the Netherlands; 9St Antonius Hospital, Nieuwegein, the Netherlands; 10Radboud University Medical Center, Nijmegen, the Netherlands; 11HagaZiekenhuis, the Hague, the Netherlands; 12Isala Klinieken, Zwolle, the Netherlands; 13Medisch Spectrum Twente, Enschede, the Netherlands; 14Amphia Hospital, Breda, the Netherlands; 15Albert Schweitzer Hospital, Dordrecht, the Netherlands; 16University Medical Center Groningen, the Netherlands; 17Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands; 18Centre Hospitalier Universitaire de Montpellier, Montpellier, France; 19Universitair Ziekenhuis Leuven, Leuven, Belgium; 20Centre Hospitalier Chrétien, Liège, Belgium; 21Pitié-Salpêtrière Hospital, Paris, France; 22National Hospital for Neurology and Neurosurgery, London, UK; 23Institute of Neuroscience and Newcastle University Institute for Ageing, NewcastleUniversity, Newcastle, UK; 24London School of Hygiene & Tropical Medicine, London, UK; 25Texas Stroke Institute, Plano, Texas, USA.

  • Contributors All authors contributed to the design of the work and the acquisition, analysis, or interpretation of data. LAR drafted the manuscript, all other authors made critical revisions and substantial contributions and approved the final manuscript. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the manuscript are appropriately investigated and resolved. Guarantors: LAR and JMC.

  • Funding The MR CLEAN-NO IV trial was funded through the CONTRAST consortium, which acknowledges the support from the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation (CVON2015-01: CONTRAST), and from the Brain Foundation Netherlands (HA2015.01.06). The collaboration project is additionally financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships (LSHM17016). This work was funded in part through unrestricted funding by Stryker, Medtronic and Cerenovus. The funding sources were not involved in study design, monitoring, data collection, statistical analyses, interpretation of results, or manuscript writing.

  • Competing interests WHvZ reports speaker fees from Cerenovus, Stryker European Operations BV and NicoLab, paid to institution. DWJD reports grants for research from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra, Stryker European Operations BV, Medtronic, Thrombolytic Science and Cerenovus, all paid to institution. YBWEMR is a minor shareholder of Nico.lab. JMC received unrelated research support from The Netherlands Organisation for Health Research and Development, Dr C J Vaillant Foundation, Bayer, Boehringer, Portola. All fees were paid to his employer. CBLMM reports grants from TWIN Foundation, related to MR CLEAN Registry, paid to institution, and unrelated grants from CVON/Dutch Heart Foundation, European Commission, Dutch Health Evaluation Program, Stryker (all paid to institution), shareholder Nico-lab. BJE reports grants from Health Holland Top Sector Life Sciences & Health as well as from the Leading the Change Program (The Netherlands Organization for Health Research and Development), both paid to institution. NLC reports an honorarium for a short presentation at the American Academy of Neurology 2022. The other authors report no conflicts.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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