Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke

Anna M. M. Boers; Ivo G. H. Jansen; Scott Brown; Hester F. Lingsma; Ludo F. M. Beenen; Thomas G. Devlin; Luis San Roman; Ji-Hoe Heo; Marc Ribo; Mohammed A. Almekhlafi; David S. Liebeskind; Jeanne Teitelbaum; Patricia Cuadras; Richard du Mesnil de Rochemont; Marine Beaumont; Martin M. Brown; Albert J. Yoo; Geoffrey A. Donnan; Jean Louis Mas; Catherine Oppenheim; Richard J. Dowling; Thierry Moulin; Nelly Agrinier; Demetrius K. Lopes; Lucia Aja Rodriguez; Kars C. J. Compagne; Fahad S. Al-Ajlan; Jeremy Madigan; Gregory W. Albers; Sebastien Soize; Jordi Blasco; Stephen M. Davis; Raul G. Nogueira; Antoni Davalos; Bijoy K. Menon; Aad van der Lugt; Keith W. Muir; Yvo B. W. E. M. Roos; Phil White; Peter J. Mitchell; Andrew M. Demchuk; Wim H. van Zwam; Tudor G. Jovin; Robert J. van Oostenbrugge; Diederik W. J. Dippel; Bruce C. V. Campbell; Francis Guillemin; Serge Bracard; Michael D. Hill; Mayank Goyal; Henk A. Marquering; Charles B. L. M. Majoie

doi:10.1001/jamaneurol.2018.3661

Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke

Anna M. M. Boers^*, Ivo G. H. Jansen, Scott Brown, Hester F. Lingsma, Ludo F. M. Beenen, Thomas G. Devlin, Luis San Roman, Ji-Hoe Heo, Marc Ribo, Mohammed A. Almekhlafi, David S. Liebeskind, Jeanne Teitelbaum, Patricia Cuadras, Richard du Mesnil de Rochemont, Marine Beaumont, Martin M. Brown, Albert J. Yoo, Geoffrey A. Donnan, Jean Louis Mas, Catherine OppenheimRichard J. Dowling, Thierry Moulin, Nelly Agrinier, Demetrius K. Lopes, Lucia Aja Rodriguez, Kars C. J. Compagne, Fahad S. Al-Ajlan, Jeremy Madigan, Gregory W. Albers, Sebastien Soize, Jordi Blasco, Stephen M. Davis, Raul G. Nogueira, Antoni Davalos, Bijoy K. Menon, Aad van der Lugt, Keith W. Muir, Yvo B. W. E. M. Roos, Phil White, Peter J. Mitchell, Andrew M. Demchuk, Wim H. van Zwam, Tudor G. Jovin, Robert J. van Oostenbrugge, Diederik W. J. Dippel, Bruce C. V. Campbell, Francis Guillemin, Serge Bracard, Michael D. Hill, Mayank Goyal, Henk A. Marquering, Charles B. L. M. Majoie

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

IMPORTANCE The positive treatment effect of endovascular therapy (EVT) is assumed to be caused by the preservation of brain tissue. It remains unclear to what extent the treatment-related reduction in follow-up infarct volume (FIV) explains the improved functional outcome after EVT in patients with acute ischemic stroke.

OBJECTIVE To study whether FIV mediates the relationship between EVT and functional outcome in patients with acute ischemic stroke.

DESIGN, SETTING, AND PARTICIPANTS Patient data from 7 randomized multicenter trialswere pooled. These trials were conducted between December 2010 and April 2015 and included 1764 patients randomly assigned to receive either EVT or standard care (control). Follow-up infarct volume was assessed on computed tomography ormagnetic resonance imaging after stroke onset. Mediation analysis was performed to examine the potential causal chain in which FIV may mediate the relationship between EVT and functional outcome. A total of 1690 patients met the inclusion criteria. Twenty-five additional patients were excluded, resulting in a total of 1665 patients, including 821 (49.3%) in the EVT group and 844 (50.7%) in the control group. Data were analyzed from January to June 2017.

MAIN OUTCOME AND MEASURE The 90-day functional outcome via the modified Rankin Scale (mRS).

RESULTS Among 1665 patients, the median (interquartile range [IQR]) age was 68 (57-76) years, and 781 (46.9%) were female. The median (IQR) time to FIV measurement was 30 (24-237) hours. The median (IQR) FIV was 41 (14-120) mL. Patients in the EVT group had significantly smaller FIVs compared with patients in the control group (median [IQR] FIV, 33 [11-99] vs 51 [18-134] mL; P =.007) and lower mRS scores at 90 days (median [IQR] score, 3 [1-4] vs 4 [2-5]). Follow-up infarct volume was a predictor of functional outcome (adjusted common odds ratio, 0.46; 95% CI, 0.39-0.54; P

CONCLUSIONS AND RELEVANCE In this analysis, follow-up infarct volume predicted functional outcome; however, a reduced infarct volume after treatment with EVT only explained 12% of the treatment benefit. Follow-up infarct volume as measured on computed tomography and magnetic resonance imaging is not a valid proxy for estimating treatment effect in phase II and III trials of acute ischemic stroke.

Original language	English
Pages (from-to)	194-202
Number of pages	9
Journal	JAMA Neurology
Volume	76
Issue number	2
DOIs	https://doi.org/10.1001/jamaneurol.2018.3661
Publication status	Published - Feb 2019

Keywords

CT SCANS
THROMBECTOMY
RECANALIZATION
REPERFUSION
INSIGHTS
24-HOUR

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10.1001/jamaneurol.2018.3661

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Boers, A. M. M., Jansen, I. G. H., Brown, S., Lingsma, H. F., Beenen, L. F. M., Devlin, T. G., San Roman, L., Heo, J-H., Ribo, M., Almekhlafi, M. A., Liebeskind, D. S., Teitelbaum, J., Cuadras, P., de Rochemont, R. D. M., Beaumont, M., Brown, M. M., Yoo, A. J., Donnan, G. A., Mas, J. L., ... Majoie, C. B. L. M. (2019). Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke. JAMA Neurology, 76(2), 194-202. https://doi.org/10.1001/jamaneurol.2018.3661

@article{289a8f0a6a734e659b8d1d7f9e0ed053,

title = "Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke",

abstract = "IMPORTANCE The positive treatment effect of endovascular therapy (EVT) is assumed to be caused by the preservation of brain tissue. It remains unclear to what extent the treatment-related reduction in follow-up infarct volume (FIV) explains the improved functional outcome after EVT in patients with acute ischemic stroke.OBJECTIVE To study whether FIV mediates the relationship between EVT and functional outcome in patients with acute ischemic stroke.DESIGN, SETTING, AND PARTICIPANTS Patient data from 7 randomized multicenter trialswere pooled. These trials were conducted between December 2010 and April 2015 and included 1764 patients randomly assigned to receive either EVT or standard care (control). Follow-up infarct volume was assessed on computed tomography ormagnetic resonance imaging after stroke onset. Mediation analysis was performed to examine the potential causal chain in which FIV may mediate the relationship between EVT and functional outcome. A total of 1690 patients met the inclusion criteria. Twenty-five additional patients were excluded, resulting in a total of 1665 patients, including 821 (49.3%) in the EVT group and 844 (50.7%) in the control group. Data were analyzed from January to June 2017.MAIN OUTCOME AND MEASURE The 90-day functional outcome via the modified Rankin Scale (mRS).RESULTS Among 1665 patients, the median (interquartile range [IQR]) age was 68 (57-76) years, and 781 (46.9%) were female. The median (IQR) time to FIV measurement was 30 (24-237) hours. The median (IQR) FIV was 41 (14-120) mL. Patients in the EVT group had significantly smaller FIVs compared with patients in the control group (median [IQR] FIV, 33 [11-99] vs 51 [18-134] mL; P =.007) and lower mRS scores at 90 days (median [IQR] score, 3 [1-4] vs 4 [2-5]). Follow-up infarct volume was a predictor of functional outcome (adjusted common odds ratio, 0.46; 95% CI, 0.39-0.54; PCONCLUSIONS AND RELEVANCE In this analysis, follow-up infarct volume predicted functional outcome; however, a reduced infarct volume after treatment with EVT only explained 12% of the treatment benefit. Follow-up infarct volume as measured on computed tomography and magnetic resonance imaging is not a valid proxy for estimating treatment effect in phase II and III trials of acute ischemic stroke.",

keywords = "CT SCANS, THROMBECTOMY, RECANALIZATION, REPERFUSION, INSIGHTS, 24-HOUR",

author = "Boers, {Anna M. M.} and Jansen, {Ivo G. H.} and Scott Brown and Lingsma, {Hester F.} and Beenen, {Ludo F. M.} and Devlin, {Thomas G.} and {San Roman}, Luis and Ji-Hoe Heo and Marc Ribo and Almekhlafi, {Mohammed A.} and Liebeskind, {David S.} and Jeanne Teitelbaum and Patricia Cuadras and {de Rochemont}, {Richard du Mesnil} and Marine Beaumont and Brown, {Martin M.} and Yoo, {Albert J.} and Donnan, {Geoffrey A.} and Mas, {Jean Louis} and Catherine Oppenheim and Dowling, {Richard J.} and Thierry Moulin and Nelly Agrinier and Lopes, {Demetrius K.} and {Aja Rodriguez}, Lucia and Compagne, {Kars C. J.} and Al-Ajlan, {Fahad S.} and Jeremy Madigan and Albers, {Gregory W.} and Sebastien Soize and Jordi Blasco and Davis, {Stephen M.} and Nogueira, {Raul G.} and Antoni Davalos and Menon, {Bijoy K.} and {van der Lugt}, Aad and Muir, {Keith W.} and Roos, {Yvo B. W. E. M.} and Phil White and Mitchell, {Peter J.} and Demchuk, {Andrew M.} and {van Zwam}, {Wim H.} and Jovin, {Tudor G.} and {van Oostenbrugge}, {Robert J.} and Dippel, {Diederik W. J.} and Campbell, {Bruce C. V.} and Francis Guillemin and Serge Bracard and Hill, {Michael D.} and Mayank Goyal and Marquering, {Henk A.} and Majoie, {Charles B. L. M.}",

year = "2019",

month = feb,

doi = "10.1001/jamaneurol.2018.3661",

language = "English",

volume = "76",

pages = "194--202",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "2",

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Boers, AMM, Jansen, IGH, Brown, S, Lingsma, HF, Beenen, LFM, Devlin, TG, San Roman, L, Heo, J-H, Ribo, M, Almekhlafi, MA, Liebeskind, DS, Teitelbaum, J, Cuadras, P, de Rochemont, RDM, Beaumont, M, Brown, MM, Yoo, AJ, Donnan, GA, Mas, JL, Oppenheim, C, Dowling, RJ, Moulin, T, Agrinier, N, Lopes, DK, Aja Rodriguez, L, Compagne, KCJ, Al-Ajlan, FS, Madigan, J, Albers, GW, Soize, S, Blasco, J, Davis, SM, Nogueira, RG, Davalos, A, Menon, BK, van der Lugt, A, Muir, KW, Roos, YBWEM, White, P, Mitchell, PJ, Demchuk, AM, van Zwam, WH, Jovin, TG, van Oostenbrugge, RJ, Dippel, DWJ, Campbell, BCV, Guillemin, F, Bracard, S, Hill, MD, Goyal, M, Marquering, HA & Majoie, CBLM 2019, 'Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke', JAMA Neurology, vol. 76, no. 2, pp. 194-202. https://doi.org/10.1001/jamaneurol.2018.3661

TY - JOUR

T1 - Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke

AU - Boers, Anna M. M.

AU - Jansen, Ivo G. H.

AU - Brown, Scott

AU - Lingsma, Hester F.

AU - Beenen, Ludo F. M.

AU - Devlin, Thomas G.

AU - San Roman, Luis

AU - Heo, Ji-Hoe

AU - Ribo, Marc

AU - Almekhlafi, Mohammed A.

AU - Liebeskind, David S.

AU - Teitelbaum, Jeanne

AU - Cuadras, Patricia

AU - de Rochemont, Richard du Mesnil

AU - Beaumont, Marine

AU - Brown, Martin M.

AU - Yoo, Albert J.

AU - Donnan, Geoffrey A.

AU - Mas, Jean Louis

AU - Oppenheim, Catherine

AU - Dowling, Richard J.

AU - Moulin, Thierry

AU - Agrinier, Nelly

AU - Lopes, Demetrius K.

AU - Aja Rodriguez, Lucia

AU - Compagne, Kars C. J.

AU - Al-Ajlan, Fahad S.

AU - Madigan, Jeremy

AU - Albers, Gregory W.

AU - Soize, Sebastien

AU - Blasco, Jordi

AU - Davis, Stephen M.

AU - Nogueira, Raul G.

AU - Davalos, Antoni

AU - Menon, Bijoy K.

AU - van der Lugt, Aad

AU - Muir, Keith W.

AU - Roos, Yvo B. W. E. M.

AU - White, Phil

AU - Mitchell, Peter J.

AU - Demchuk, Andrew M.

AU - van Zwam, Wim H.

AU - Jovin, Tudor G.

AU - van Oostenbrugge, Robert J.

AU - Dippel, Diederik W. J.

AU - Campbell, Bruce C. V.

AU - Guillemin, Francis

AU - Bracard, Serge

AU - Hill, Michael D.

AU - Goyal, Mayank

AU - Marquering, Henk A.

AU - Majoie, Charles B. L. M.

PY - 2019/2

Y1 - 2019/2

N2 - IMPORTANCE The positive treatment effect of endovascular therapy (EVT) is assumed to be caused by the preservation of brain tissue. It remains unclear to what extent the treatment-related reduction in follow-up infarct volume (FIV) explains the improved functional outcome after EVT in patients with acute ischemic stroke.OBJECTIVE To study whether FIV mediates the relationship between EVT and functional outcome in patients with acute ischemic stroke.DESIGN, SETTING, AND PARTICIPANTS Patient data from 7 randomized multicenter trialswere pooled. These trials were conducted between December 2010 and April 2015 and included 1764 patients randomly assigned to receive either EVT or standard care (control). Follow-up infarct volume was assessed on computed tomography ormagnetic resonance imaging after stroke onset. Mediation analysis was performed to examine the potential causal chain in which FIV may mediate the relationship between EVT and functional outcome. A total of 1690 patients met the inclusion criteria. Twenty-five additional patients were excluded, resulting in a total of 1665 patients, including 821 (49.3%) in the EVT group and 844 (50.7%) in the control group. Data were analyzed from January to June 2017.MAIN OUTCOME AND MEASURE The 90-day functional outcome via the modified Rankin Scale (mRS).RESULTS Among 1665 patients, the median (interquartile range [IQR]) age was 68 (57-76) years, and 781 (46.9%) were female. The median (IQR) time to FIV measurement was 30 (24-237) hours. The median (IQR) FIV was 41 (14-120) mL. Patients in the EVT group had significantly smaller FIVs compared with patients in the control group (median [IQR] FIV, 33 [11-99] vs 51 [18-134] mL; P =.007) and lower mRS scores at 90 days (median [IQR] score, 3 [1-4] vs 4 [2-5]). Follow-up infarct volume was a predictor of functional outcome (adjusted common odds ratio, 0.46; 95% CI, 0.39-0.54; PCONCLUSIONS AND RELEVANCE In this analysis, follow-up infarct volume predicted functional outcome; however, a reduced infarct volume after treatment with EVT only explained 12% of the treatment benefit. Follow-up infarct volume as measured on computed tomography and magnetic resonance imaging is not a valid proxy for estimating treatment effect in phase II and III trials of acute ischemic stroke.

AB - IMPORTANCE The positive treatment effect of endovascular therapy (EVT) is assumed to be caused by the preservation of brain tissue. It remains unclear to what extent the treatment-related reduction in follow-up infarct volume (FIV) explains the improved functional outcome after EVT in patients with acute ischemic stroke.OBJECTIVE To study whether FIV mediates the relationship between EVT and functional outcome in patients with acute ischemic stroke.DESIGN, SETTING, AND PARTICIPANTS Patient data from 7 randomized multicenter trialswere pooled. These trials were conducted between December 2010 and April 2015 and included 1764 patients randomly assigned to receive either EVT or standard care (control). Follow-up infarct volume was assessed on computed tomography ormagnetic resonance imaging after stroke onset. Mediation analysis was performed to examine the potential causal chain in which FIV may mediate the relationship between EVT and functional outcome. A total of 1690 patients met the inclusion criteria. Twenty-five additional patients were excluded, resulting in a total of 1665 patients, including 821 (49.3%) in the EVT group and 844 (50.7%) in the control group. Data were analyzed from January to June 2017.MAIN OUTCOME AND MEASURE The 90-day functional outcome via the modified Rankin Scale (mRS).RESULTS Among 1665 patients, the median (interquartile range [IQR]) age was 68 (57-76) years, and 781 (46.9%) were female. The median (IQR) time to FIV measurement was 30 (24-237) hours. The median (IQR) FIV was 41 (14-120) mL. Patients in the EVT group had significantly smaller FIVs compared with patients in the control group (median [IQR] FIV, 33 [11-99] vs 51 [18-134] mL; P =.007) and lower mRS scores at 90 days (median [IQR] score, 3 [1-4] vs 4 [2-5]). Follow-up infarct volume was a predictor of functional outcome (adjusted common odds ratio, 0.46; 95% CI, 0.39-0.54; PCONCLUSIONS AND RELEVANCE In this analysis, follow-up infarct volume predicted functional outcome; however, a reduced infarct volume after treatment with EVT only explained 12% of the treatment benefit. Follow-up infarct volume as measured on computed tomography and magnetic resonance imaging is not a valid proxy for estimating treatment effect in phase II and III trials of acute ischemic stroke.

KW - CT SCANS

KW - THROMBECTOMY

KW - RECANALIZATION

KW - REPERFUSION

KW - INSIGHTS

KW - 24-HOUR

U2 - 10.1001/jamaneurol.2018.3661

DO - 10.1001/jamaneurol.2018.3661

M3 - Article

C2 - 30615038

VL - 76

SP - 194

EP - 202

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 2

ER -