Puck S S Fransen1, Olvert A Berkhemer2, Hester F Lingsma3, Debbie Beumer4, Lucie A van den Berg5, Albert J Yoo6, Wouter J Schonewille7, Jan Albert Vos8, Paul J Nederkoorn5, Marieke J H Wermer9, Marianne A A van Walderveen10, Julie Staals4, Jeannette Hofmeijer11, Jacques A van Oostayen12, Geert J Lycklama À Nijeholt13, Jelis Boiten14, Patrick A Brouwer15, Bart J Emmer15, Sebastiaan F de Bruijn16, Lukas C van Dijk17, L Jaap Kappelle18, Rob H Lo19, Ewoud J van Dijk20, Joost de Vries21, Paul L M de Kort22, J S Peter van den Berg23, Boudewijn A A M van Hasselt24, Leo A M Aerden25, René J Dallinga26, Marieke C Visser27, Joseph C J Bot28, Patrick C Vroomen29, Omid Eshghi30, Tobien H C M L Schreuder31, Roel J J Heijboer32, Koos Keizer33, Alexander V Tielbeek34, Heleen M den Hertog35, Dick G Gerrits36, Renske M van den Berg-Vos37, Giorgos B Karas38, Ewout W Steyerberg3, H Zwenneke Flach25, Henk A Marquering39, Marieke E S Sprengers40, Sjoerd F M Jenniskens41, Ludo F M Beenen40, René van den Berg40, Peter J Koudstaal42, Wim H van Zwam43, Yvo B W E M Roos5, Robert J van Oostenbrugge4, Charles B L M Majoie40, Aad van der Lugt15, Diederik W J Dippel42. 1. Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands2Department of Radiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands. 2. Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands3Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands. 3. Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands. 4. Department of Neurology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands. 5. Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands. 6. Texas Stroke Institute, Plano. 7. Department of Neurology, St Antonius Hospital, Nieuwegein, the Netherlands. 8. Department of Radiology, St Antonius Hospital, Nieuwegein, the Netherlands. 9. Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands. 10. Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands. 11. Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands. 12. Department of Radiology, Rijnstate Hospital, Arnhem, the Netherlands. 13. Department of Radiology, Medisch Centrum Haaglanden, the Hague, the Netherlands. 14. Department of Neurology, Medisch Centrum Haaglanden, the Hague, the Netherlands. 15. Department of Radiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands. 16. Department of Neurology, Haga Hospital, the Hague, the Netherlands. 17. Department of Radiology, Haga Hospital, the Hague, the Netherlands. 18. Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands. 19. Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands. 20. Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands. 21. Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands. 22. Department of Neurology, St Elisabeth Hospital, Tilburg, the Netherlands. 23. Department of Neurology, Isala Klinieken, Zwolle, the Netherlands. 24. Department of Radiology, Isala Klinieken, Zwolle, the Netherlands. 25. Department of Neurology, Reinier de Graaf Gasthuis, Delft, the Netherlands. 26. Department of Radiology, Reinier de Graaf Gasthuis, Delft, the Netherlands. 27. Department of Neurology, VU Medical Center, Amsterdam, the Netherlands. 28. Department of Radiology, VU Medical Center, Amsterdam, the Netherlands. 29. Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands. 30. Department of Radiology, University Medical Center Groningen, Groningen, the Netherlands. 31. Department of Neurology, Atrium Medical Center, Heerlen, the Netherlands. 32. Department of Radiology, Atrium Medical Center, Heerlen, the Netherlands. 33. Department of Neurology, Catharina Hospital, Eindhoven, the Netherlands. 34. Department of Radiology, Catharina Hospital, Eindhoven, the Netherlands. 35. Department of Neurology, Medical Spectrum Twente, Enschede, the Netherlands. 36. Department of Radiology, Medical Spectrum Twente, Enschede, the Netherlands. 37. Department of Neurology, St Lucas Andreas Hospital, Amsterdam, the Netherlands. 38. Department of Radiology, St Lucas Andreas Hospital, Amsterdam, the Netherlands. 39. Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands39Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands. 40. Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands. 41. Department of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands. 42. Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands. 43. Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands.
Abstract
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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. CONCLUSION AND RELEVANCE: 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. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1804.
RCT Entities:
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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. CONCLUSION AND RELEVANCE: 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. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1804.
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