title: Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known.
  
  
  OBJECTIVE
  To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT.
  
  
  METHODS
  The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015.
  
  
  METHODS
  Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion.
  
  
  RESULTS
  Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours.
  
  
  CONCLUSIONS
  For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion.
  
  
  BACKGROUND
  trialregister.nl Identifier: NTR1804.
authors.affiliation: Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands2Department of Radiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Puck S S
authors.initials: PS
authors.lastname: Fransen
authors.affiliation: Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands3Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Olvert A
authors.initials: OA
authors.lastname: Berkhemer
authors.affiliation: Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Hester F
authors.initials: HF
authors.lastname: Lingsma
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Debbie
authors.initials: D
authors.lastname: Beumer
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Lucie A
authors.initials: LA
authors.lastname: van den Berg
authors.affiliation: Texas Stroke Institute, Plano.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Yoo
authors.affiliation: Department of Neurology, St Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: Schonewille
authors.affiliation: Department of Radiology, St Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Vos
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Nederkoorn
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Wermer
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marianne A A
authors.initials: MA
authors.lastname: van Walderveen
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Julie
authors.initials: J
authors.lastname: Staals
authors.affiliation: Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hofmeijer
authors.affiliation: Department of Radiology, Rijnstate Hospital, Arnhem, the Netherlands.
authors.forename: Jacques A
authors.initials: JA
authors.lastname: van Oostayen
authors.affiliation: Department of Radiology, Medisch Centrum Haaglanden, the Hague, the Netherlands.
authors.forename: Geert J
authors.initials: GJ
authors.lastname: Lycklama À Nijeholt
authors.affiliation: Department of Neurology, Medisch Centrum Haaglanden, the Hague, the Netherlands.
authors.forename: Jelis
authors.initials: J
authors.lastname: Boiten
authors.affiliation: Department of Radiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Brouwer
authors.affiliation: Department of Radiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Emmer
authors.affiliation: Department of Neurology, Haga Hospital, the Hague, the Netherlands.
authors.forename: Sebastiaan F
authors.initials: SF
authors.lastname: de Bruijn
authors.affiliation: Department of Radiology, Haga Hospital, the Hague, the Netherlands.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: van Dijk
authors.affiliation: Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: L Jaap
authors.initials: LJ
authors.lastname: Kappelle
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rob H
authors.initials: RH
authors.lastname: Lo
authors.affiliation: Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ewoud J
authors.initials: EJ
authors.lastname: van Dijk
authors.affiliation: Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: de Vries
authors.affiliation: Department of Neurology, St Elisabeth Hospital, Tilburg, the Netherlands.
authors.forename: Paul L M
authors.initials: PL
authors.lastname: de Kort
authors.affiliation: Department of Neurology, Isala Klinieken, Zwolle, the Netherlands.
authors.forename: J S Peter
authors.initials: JS
authors.lastname: van den Berg
authors.affiliation: Department of Radiology, Isala Klinieken, Zwolle, the Netherlands.
authors.forename: Boudewijn A A M
authors.initials: BA
authors.lastname: van Hasselt
authors.affiliation: Department of Neurology, Reinier de Graaf Gasthuis, Delft, the Netherlands.
authors.forename: Leo A M
authors.initials: LA
authors.lastname: Aerden
authors.affiliation: Department of Radiology, Reinier de Graaf Gasthuis, Delft, the Netherlands.
authors.forename: René J
authors.initials: RJ
authors.lastname: Dallinga
authors.affiliation: Department of Neurology, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Marieke C
authors.initials: MC
authors.lastname: Visser
authors.affiliation: Department of Radiology, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Joseph C J
authors.initials: JC
authors.lastname: Bot
authors.affiliation: Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Vroomen
authors.affiliation: Department of Radiology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Omid
authors.initials: O
authors.lastname: Eshghi
authors.affiliation: Department of Neurology, Atrium Medical Center, Heerlen, the Netherlands.
authors.forename: Tobien H C M L
authors.initials: TH
authors.lastname: Schreuder
authors.affiliation: Department of Radiology, Atrium Medical Center, Heerlen, the Netherlands.
authors.forename: Roel J J
authors.initials: RJ
authors.lastname: Heijboer
authors.affiliation: Department of Neurology, Catharina Hospital, Eindhoven, the Netherlands.
authors.forename: Koos
authors.initials: K
authors.lastname: Keizer
authors.affiliation: Department of Radiology, Catharina Hospital, Eindhoven, the Netherlands.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Tielbeek
authors.affiliation: Department of Neurology, Medical Spectrum Twente, Enschede, the Netherlands.
authors.forename: Heleen M
authors.initials: HM
authors.lastname: den Hertog
authors.affiliation: Department of Radiology, Medical Spectrum Twente, Enschede, the Netherlands.
authors.forename: Dick G
authors.initials: DG
authors.lastname: Gerrits
authors.affiliation: Department of Neurology, St Lucas Andreas Hospital, Amsterdam, the Netherlands.
authors.forename: Renske M
authors.initials: RM
authors.lastname: van den Berg-Vos
authors.affiliation: Department of Radiology, St Lucas Andreas Hospital, Amsterdam, the Netherlands.
authors.forename: Giorgos B
authors.initials: GB
authors.lastname: Karas
authors.affiliation: Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.affiliation: Department of Neurology, Reinier de Graaf Gasthuis, Delft, the Netherlands.
authors.forename: H Zwenneke
authors.initials: HZ
authors.lastname: Flach
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands39Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Henk A
authors.initials: HA
authors.lastname: Marquering
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Marieke E S
authors.initials: ME
authors.lastname: Sprengers
authors.affiliation: Department of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Sjoerd F M
authors.initials: SF
authors.lastname: Jenniskens
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Ludo F M
authors.initials: LF
authors.lastname: Beenen
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: van den Berg
authors.affiliation: Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Koudstaal
authors.affiliation: Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Wim H
authors.initials: WH
authors.lastname: van Zwam
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Yvo B W E M
authors.initials: YB
authors.lastname: Roos
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: van Oostenbrugge
authors.affiliation: Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Charles B L M
authors.initials: CB
authors.lastname: Majoie
authors.affiliation: Department of Radiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Aad
authors.initials: A
authors.lastname: van der Lugt
authors.affiliation: Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Diederik W J
authors.initials: DW
authors.lastname: Dippel
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000175:diagnosis / Q000188:drug therapy / Q000601:surgery*; D057510:Endovascular Procedures / Q000379:methods; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015424:Reperfusion; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy / Q000601:surgery*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator