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

Puck S. S. Fransen; Olvert A. Berkhemer; Hester F. Lingsma; Debbie Beumer; Lucie A. van den Berg; Albert J. Yoo; Wouter J. Schonewille; Jan Albert Vos; Paul J. Nederkoorn; Marieke J. H. Wermer; Marianne A. A. van Walderveen; Julie Staals; Jeannette Hofmeijer; Jacques A. van Oostayen; Geert J. Lycklama a Nijeholt; Jelis Boiten; Patrick A. Brouwer; Bart J. Emmer; Sebastiaan F. de Bruijn; Lukas C. van Dijk; L. Jaap Kappelle; Rob H. Lo; Ewoud J. van Dijk; Joost de Vries; Paul L. M. de Kort; J. S. Peter van den Berg; Boudewijn A. A. M. van Hasselt; Leo A. M. Aerden; Rene J. Dallinga; Marieke C. Visser; Joseph C. J. Bot; Patrick C. Vroomen; Omid Eshghi; Tobien H. C. M. L. Schreuder; Roel J. J. Heijboer; Koos Keizer; Alexander V. Tielbeek; Heleen M. den Hertog; Dick G. Gerrits; Renske M. van den Berg-Vos; Giorgos B. Karas; Ewout W. Steyerberg; H. Zwenneke Flach; Henk A. Marquering; Marieke E. S. Sprengers; Sjoerd F. M. Jenniskens; Ludo F. M. Beenen; Rene van den Berg; Peter J. Koudstaal; Wim H. van Zwam; Multictr Randomized Clin Trial End

doi:10.1001/jamaneurol.2015.3886

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

Puck S. S. Fransen, Olvert A. Berkhemer, Hester F. Lingsma, Debbie Beumer, Lucie A. van den Berg, Albert J. Yoo, Wouter J. Schonewille, Jan Albert Vos, Paul J. Nederkoorn, Marieke J. H. Wermer, Marianne A. A. van Walderveen, Julie Staals, Jeannette Hofmeijer, Jacques A. van Oostayen, Geert J. Lycklama a Nijeholt, Jelis Boiten, Patrick A. Brouwer, Bart J. Emmer, Sebastiaan F. de Bruijn, Lukas C. van DijkL. Jaap Kappelle, Rob H. Lo, Ewoud J. van Dijk, Joost de Vries, Paul L. M. de Kort, J. S. Peter van den Berg, Boudewijn A. A. M. van Hasselt, Leo A. M. Aerden, Rene J. Dallinga, Marieke C. Visser, Joseph C. J. Bot, Patrick C. Vroomen, Omid Eshghi, Tobien H. C. M. L. Schreuder, Roel J. J. Heijboer, Koos Keizer, Alexander V. Tielbeek, Heleen M. den Hertog, Dick G. Gerrits, Renske M. van den Berg-Vos, Giorgos B. Karas, Ewout W. Steyerberg, H. Zwenneke Flach, Henk A. Marquering, Marieke E. S. Sprengers, Sjoerd F. M. Jenniskens, Ludo F. M. Beenen, Rene van den Berg, Peter J. Koudstaal, Wim H. van Zwam, Multictr Randomized Clin Trial End

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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.

Original language	English
Pages (from-to)	190-196
Number of pages	7
Journal	Jama neurology
Volume	73
Issue number	2
DOIs	https://doi.org/10.1001/jamaneurol.2015.3886
Publication status	Published - Feb-2016

Keywords

INTRAVENOUS T-PA
ENDOVASCULAR TREATMENT
ANGIOGRAPHIC REPERFUSION
IMAGING SELECTION
THROMBECTOMY
THERAPY
INTERVENTION
COMPLEXITY
OUTCOMES

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Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke
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Fransen, P. S. S., Berkhemer, O. A., Lingsma, H. F., Beumer, D., van den Berg, L. A., Yoo, A. J., Schonewille, W. J., Vos, J. A., Nederkoorn, P. J., Wermer, M. J. H., van Walderveen, M. A. A., Staals, J., Hofmeijer, J., van Oostayen, J. A., Nijeholt, G. J. L. A., Boiten, J., Brouwer, P. A., Emmer, B. J., de Bruijn, S. F., ... Multictr Randomized Clin Trial End (2016). Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial. Jama neurology, 73(2), 190-196. https://doi.org/10.1001/jamaneurol.2015.3886

@article{4676fc1353d44500952609fa4aef792b,

title = "Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial",

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.",

keywords = "INTRAVENOUS T-PA, ENDOVASCULAR TREATMENT, ANGIOGRAPHIC REPERFUSION, IMAGING SELECTION, THROMBECTOMY, THERAPY, INTERVENTION, COMPLEXITY, OUTCOMES",

author = "Fransen, {Puck S. S.} and Berkhemer, {Olvert A.} and Lingsma, {Hester F.} and Debbie Beumer and {van den Berg}, {Lucie A.} and Yoo, {Albert J.} and Schonewille, {Wouter J.} and Vos, {Jan Albert} and Nederkoorn, {Paul J.} and Wermer, {Marieke J. H.} and {van Walderveen}, {Marianne A. A.} and Julie Staals and Jeannette Hofmeijer and {van Oostayen}, {Jacques A.} and Nijeholt, {Geert J. Lycklama a} and Jelis Boiten and Brouwer, {Patrick A.} and Emmer, {Bart J.} and {de Bruijn}, {Sebastiaan F.} and {van Dijk}, {Lukas C.} and Kappelle, {L. Jaap} and Lo, {Rob H.} and {van Dijk}, {Ewoud J.} and {de Vries}, Joost and {de Kort}, {Paul L. M.} and {van den Berg}, {J. S. Peter} and {van Hasselt}, {Boudewijn A. A. M.} and Aerden, {Leo A. M.} and Dallinga, {Rene J.} and Visser, {Marieke C.} and Bot, {Joseph C. J.} and Vroomen, {Patrick C.} and Omid Eshghi and Schreuder, {Tobien H. C. M. L.} and Heijboer, {Roel J. J.} and Koos Keizer and Tielbeek, {Alexander V.} and {den Hertog}, {Heleen M.} and Gerrits, {Dick G.} and {van den Berg-Vos}, {Renske M.} and Karas, {Giorgos B.} and Steyerberg, {Ewout W.} and Flach, {H. Zwenneke} and Marquering, {Henk A.} and Sprengers, {Marieke E. S.} and Jenniskens, {Sjoerd F. M.} and Beenen, {Ludo F. M.} and {van den Berg}, Rene and Koudstaal, {Peter J.} and {van Zwam}, {Wim H.} and {Multictr Randomized Clin Trial End}",

year = "2016",

month = feb,

doi = "10.1001/jamaneurol.2015.3886",

language = "English",

volume = "73",

pages = "190--196",

journal = "Jama neurology",

issn = "2168-6149",

publisher = "AMER MEDICAL ASSOC",

number = "2",

}

Fransen, PSS, Berkhemer, OA, Lingsma, HF, Beumer, D, van den Berg, LA, Yoo, AJ, Schonewille, WJ, Vos, JA, Nederkoorn, PJ, Wermer, MJH, van Walderveen, MAA, Staals, J, Hofmeijer, J, van Oostayen, JA, Nijeholt, GJLA, Boiten, J, Brouwer, PA, Emmer, BJ, de Bruijn, SF, van Dijk, LC, Kappelle, LJ, Lo, RH, van Dijk, EJ, de Vries, J, de Kort, PLM, van den Berg, JSP, van Hasselt, BAAM, Aerden, LAM, Dallinga, RJ, Visser, MC, Bot, JCJ, Vroomen, PC, Eshghi, O, Schreuder, THCML, Heijboer, RJJ, Keizer, K, Tielbeek, AV, den Hertog, HM, Gerrits, DG, van den Berg-Vos, RM, Karas, GB, Steyerberg, EW, Flach, HZ, Marquering, HA, Sprengers, MES, Jenniskens, SFM, Beenen, LFM, van den Berg, R, Koudstaal, PJ, van Zwam, WH & Multictr Randomized Clin Trial End 2016, 'Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial', Jama neurology, vol. 73, no. 2, pp. 190-196. https://doi.org/10.1001/jamaneurol.2015.3886

TY - JOUR

T1 - Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke

T2 - A Randomized Clinical Trial

AU - Fransen, Puck S. S.

AU - Berkhemer, Olvert A.

AU - Lingsma, Hester F.

AU - Beumer, Debbie

AU - van den Berg, Lucie A.

AU - Yoo, Albert J.

AU - Schonewille, Wouter J.

AU - Vos, Jan Albert

AU - Nederkoorn, Paul J.

AU - Wermer, Marieke J. H.

AU - van Walderveen, Marianne A. A.

AU - Staals, Julie

AU - Hofmeijer, Jeannette

AU - van Oostayen, Jacques A.

AU - Nijeholt, Geert J. Lycklama a

AU - Boiten, Jelis

AU - Brouwer, Patrick A.

AU - Emmer, Bart J.

AU - de Bruijn, Sebastiaan F.

AU - van Dijk, Lukas C.

AU - Kappelle, L. Jaap

AU - Lo, Rob H.

AU - van Dijk, Ewoud J.

AU - de Vries, Joost

AU - de Kort, Paul L. M.

AU - van den Berg, J. S. Peter

AU - van Hasselt, Boudewijn A. A. M.

AU - Aerden, Leo A. M.

AU - Dallinga, Rene J.

AU - Visser, Marieke C.

AU - Bot, Joseph C. J.

AU - Vroomen, Patrick C.

AU - Eshghi, Omid

AU - Schreuder, Tobien H. C. M. L.

AU - Heijboer, Roel J. J.

AU - Keizer, Koos

AU - Tielbeek, Alexander V.

AU - den Hertog, Heleen M.

AU - Gerrits, Dick G.

AU - van den Berg-Vos, Renske M.

AU - Karas, Giorgos B.

AU - Steyerberg, Ewout W.

AU - Flach, H. Zwenneke

AU - Marquering, Henk A.

AU - Sprengers, Marieke E. S.

AU - Jenniskens, Sjoerd F. M.

AU - Beenen, Ludo F. M.

AU - van den Berg, Rene

AU - Koudstaal, Peter J.

AU - van Zwam, Wim H.

AU - Multictr Randomized Clin Trial End

PY - 2016/2

Y1 - 2016/2

N2 - 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.

AB - 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.

KW - INTRAVENOUS T-PA

KW - ENDOVASCULAR TREATMENT

KW - ANGIOGRAPHIC REPERFUSION

KW - IMAGING SELECTION

KW - THROMBECTOMY

KW - THERAPY

KW - INTERVENTION

KW - COMPLEXITY

KW - OUTCOMES

U2 - 10.1001/jamaneurol.2015.3886

DO - 10.1001/jamaneurol.2015.3886

M3 - Article

C2 - 26716735

SN - 2168-6149

VL - 73

SP - 190

EP - 196

JO - Jama neurology

JF - Jama neurology

IS - 2

ER -

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

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