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Original Investigation | Clinical Trial

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke A Randomized Clinical Trial

Puck S. S. Fransen, MD1,2; Olvert A. Berkhemer, MD1,3; Hester F. Lingsma, PhD4; Debbie Beumer, MD5; Lucie A. van den Berg, MD6; Albert J. Yoo, MD7; Wouter J. Schonewille, MD, PhD8; Jan Albert Vos, MD, PhD9; Paul J. Nederkoorn, MD, PhD6; Marieke J. H. Wermer, MD, PhD10; Marianne A. A. van Walderveen, MD, PhD11; Julie Staals, MD, PhD5; Jeannette Hofmeijer, MD, PhD12; Jacques A. van Oostayen, MD, PhD13; Geert J. Lycklama à Nijeholt, MD, PhD14; Jelis Boiten, MD, PhD15; Patrick A. Brouwer, MD2; Bart J. Emmer, MD, PhD2; Sebastiaan F. de Bruijn, MD, PhD16; Lukas C. van Dijk, MD17; L. Jaap Kappelle, MD, PhD18; Rob H. Lo, MD19; Ewoud J. van Dijk, MD, PhD20; Joost de Vries, MD, PhD21; Paul L. M. de Kort, MD, PhD22; J. S. Peter van den Berg, MD, PhD23; Boudewijn A. A. M. van Hasselt, MD24; Leo A. M. Aerden, MD, PhD25; René J. Dallinga, MD26; Marieke C. Visser, MD, PhD27; Joseph C. J. Bot, MD, PhD28; Patrick C. Vroomen, MD, PhD29; Omid Eshghi, MD30; Tobien H. C. M. L. Schreuder, MD31; Roel J. J. Heijboer, MD32; Koos Keizer, MD, PhD33; Alexander V. Tielbeek, MD, PhD34; Heleen M. den Hertog, MD, PhD35; Dick G. Gerrits, MD36; Renske M. van den Berg-Vos, MD, PhD37; Giorgos B. Karas, MD, PhD, MBA38; Ewout W. Steyerberg, PhD4; H. Zwenneke Flach, MD25; Henk A. Marquering, PhD3,39; Marieke E. S. Sprengers, MD, PhD3; Sjoerd F. M. Jenniskens, MD, PhD40; Ludo F. M. Beenen, MD3; René van den Berg, MD, PhD3; Peter J. Koudstaal, MD, PhD1; Wim H. van Zwam, MD, PhD41; Yvo B.W. E. M. Roos, MD, PhD6; Robert J. van Oostenbrugge, MD, PhD5; Charles B. L. M. Majoie, MD, PhD3; Aad van der Lugt, MD, PhD2; Diederik W. J. Dippel, MD, PhD1 ; for the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) investigators
[+] Author Affiliations
1Department of Neurology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
2Department of Radiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
3Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands
4Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
5Department of Neurology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands
6Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands
7Texas Stroke Institute, Plano
8Department of Neurology, St Antonius Hospital, Nieuwegein, the Netherlands
9Department of Radiology, St Antonius Hospital, Nieuwegein, the Netherlands
10Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
11Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
12Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands
13Department of Radiology, Rijnstate Hospital, Arnhem, the Netherlands
14Department of Radiology, Medisch Centrum Haaglanden, the Hague, the Netherlands
15Department of Neurology, Medisch Centrum Haaglanden, the Hague, the Netherlands
16Department of Neurology, Haga Hospital, the Hague, the Netherlands
17Department of Radiology, Haga Hospital, the Hague, the Netherlands
18Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands
19Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands
20Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands
21Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands
22Department of Neurology, St Elisabeth Hospital, Tilburg, the Netherlands
23Department of Neurology, Isala Klinieken, Zwolle, the Netherlands
24Department of Radiology, Isala Klinieken, Zwolle, the Netherlands
25Department of Neurology, Reinier de Graaf Gasthuis, Delft, the Netherlands
26Department of Radiology, Reinier de Graaf Gasthuis, Delft, the Netherlands
27Department of Neurology, VU Medical Center, Amsterdam, the Netherlands
28Department of Radiology, VU Medical Center, Amsterdam, the Netherlands
29Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands
30Department of Radiology, University Medical Center Groningen, Groningen, the Netherlands
31Department of Neurology, Atrium Medical Center, Heerlen, the Netherlands
32Department of Radiology, Atrium Medical Center, Heerlen, the Netherlands
33Department of Neurology, Catharina Hospital, Eindhoven, the Netherlands
34Department of Radiology, Catharina Hospital, Eindhoven, the Netherlands
35Department of Neurology, Medical Spectrum Twente, Enschede, the Netherlands
36Department of Radiology, Medical Spectrum Twente, Enschede, the Netherlands
37Department of Neurology, St Lucas Andreas Hospital, Amsterdam, the Netherlands
38Department of Radiology, St Lucas Andreas Hospital, Amsterdam, the Netherlands
39Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands
40Department of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands
41Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands
JAMA Neurol. 2016;73(2):190-196. doi:10.1001/jamaneurol.2015.3886.
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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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Figure.
Effect of Time From Onset of Reperfusion (TOR) and Intra-arterial Treatment on Stroke Outcomes

A, The effect of time from the onset of stroke to reperfusion (TOR) on a good outcome (modified Thrombolysis in Cerebral Infarction [mTICI] score, 2b-3; range, 0 [no reperfusion] to 3 [complete reperfusion]) or the end of the procedure on the effect of intra-arterial therapy expressed as adjusted common odds ratio (acOR). B, The effect of TOR on a good outcome (modifed Rankin Scale [mRS] score, 0-2; range, 0 [no symptoms] to 6 [death]) expressed as the absolute risk difference. C, The association of TOR with the chances of a good outcome (mRS scale, 0-2) is plotted in the subset of patients who underwent thrombectomy only and achieved an mTICI score of 2b to 3.

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