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 Román, Ji Hoe Heo, Marc Ribó, 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, Lucía Aja Rodríguez, Kars C.J. Compagne, Fahad S. Al-Ajlan, Jeremy Madigan, Gregory W. Albers, Sebastien Soize, Jordi Blasco, Stephen M. Davis, Raul G. Nogueira, Antoni Dávalos, 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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 trials were 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 or magnetic 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 <.001). Follow-up infarct volume partially mediated the relationship between treatment type with mRS score, as EVT was still significantly associated with functional outcome after adjustment for FIV (adjusted common odds ratio, 2.22; 95% CI, 1.52-3.21; P <.001). Treatment-reduced FIV explained 12% (95% CI, 1-19) of the relationship between EVT and functional outcome. 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 languageEnglish
Pages (from-to)194-202
Number of pages9
JournalJAMA Neurology
Volume76
Issue number2
DOIs
Publication statusPublished - 2019 Feb

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Stroke
Therapeutics
Group Psychotherapy
Odds Ratio
Tomography
Magnetic Resonance Imaging
Tissue Preservation
Feline Immunodeficiency Virus
Control Groups
Proxy
Multicenter Studies
Outcome Assessment (Health Care)

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Boers, A. M. M., Jansen, I. G. H., Brown, S., Lingsma, H. F., Beenen, L. F. M., Devlin, T. G., ... 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
Boers, Anna M.M. ; Jansen, Ivo G.H. ; Brown, Scott ; Lingsma, Hester F. ; Beenen, Ludo F.M. ; Devlin, Thomas G. ; Román, Luis San ; Heo, Ji Hoe ; Ribó, Marc ; Almekhlafi, Mohammed A. ; Liebeskind, David S. ; Teitelbaum, Jeanne ; Cuadras, Patricia ; Du Mesnil De Rochemont, Richard ; Beaumont, Marine ; Brown, Martin M. ; Yoo, Albert J. ; Donnan, Geoffrey A. ; Mas, Jean Louis ; Oppenheim, Catherine ; Dowling, Richard J. ; Moulin, Thierry ; Agrinier, Nelly ; Lopes, Demetrius K. ; Aja Rodríguez, Lucía ; Compagne, Kars C.J. ; Al-Ajlan, Fahad S. ; Madigan, Jeremy ; Albers, Gregory W. ; Soize, Sebastien ; Blasco, Jordi ; Davis, Stephen M. ; Nogueira, Raul G. ; Dávalos, Antoni ; Menon, Bijoy K. ; Van Der Lugt, Aad ; Muir, Keith W. ; Roos, Yvo B.W.E.M. ; White, Phil ; Mitchell, Peter J. ; Demchuk, Andrew M. ; Van Zwam, Wim H. ; Jovin, Tudor G. ; Van Oostenbrugge, Robert J. ; Dippel, Diederik W.J. ; Campbell, Bruce C.V. ; Guillemin, Francis ; Bracard, Serge ; Hill, Michael D. ; Goyal, Mayank ; Marquering, Henk A. ; Majoie, Charles B.L.M. / Mediation of the Relationship between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients with Acute Ischemic Stroke. In: JAMA Neurology. 2019 ; Vol. 76, No. 2. pp. 194-202.
@article{4cc60b94f4e74b6d9be8752017081793,
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 trials were 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 or magnetic 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 <.001). Follow-up infarct volume partially mediated the relationship between treatment type with mRS score, as EVT was still significantly associated with functional outcome after adjustment for FIV (adjusted common odds ratio, 2.22; 95{\%} CI, 1.52-3.21; P <.001). Treatment-reduced FIV explained 12{\%} (95{\%} CI, 1-19) of the relationship between EVT and functional outcome. 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..",
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 Rom{\'a}n, {Luis San} and Heo, {Ji Hoe} and Marc Rib{\'o} and Almekhlafi, {Mohammed A.} and Liebeskind, {David S.} and Jeanne Teitelbaum and Patricia Cuadras and {Du Mesnil De Rochemont}, Richard 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 Rodr{\'i}guez}, Luc{\'i}a 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 D{\'a}valos 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 = "2",
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, Román, LS, Heo, JH, Ribó, M, Almekhlafi, MA, Liebeskind, DS, Teitelbaum, J, Cuadras, P, Du Mesnil De Rochemont, R, Beaumont, M, Brown, MM, Yoo, AJ, Donnan, GA, Mas, JL, Oppenheim, C, Dowling, RJ, Moulin, T, Agrinier, N, Lopes, DK, Aja Rodríguez, L, Compagne, KCJ, Al-Ajlan, FS, Madigan, J, Albers, GW, Soize, S, Blasco, J, Davis, SM, Nogueira, RG, Dávalos, 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

Mediation of the Relationship between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients with Acute Ischemic Stroke. / Boers, Anna M.M.; Jansen, Ivo G.H.; Brown, Scott; Lingsma, Hester F.; Beenen, Ludo F.M.; Devlin, Thomas G.; Román, Luis San; Heo, Ji Hoe; Ribó, Marc; Almekhlafi, Mohammed A.; Liebeskind, David S.; Teitelbaum, Jeanne; Cuadras, Patricia; Du Mesnil De Rochemont, Richard; Beaumont, Marine; Brown, Martin M.; Yoo, Albert J.; Donnan, Geoffrey A.; Mas, Jean Louis; Oppenheim, Catherine; Dowling, Richard J.; Moulin, Thierry; Agrinier, Nelly; Lopes, Demetrius K.; Aja Rodríguez, Lucía; Compagne, Kars C.J.; Al-Ajlan, Fahad S.; Madigan, Jeremy; Albers, Gregory W.; Soize, Sebastien; Blasco, Jordi; Davis, Stephen M.; Nogueira, Raul G.; Dávalos, Antoni; Menon, Bijoy K.; Van Der Lugt, Aad; Muir, Keith W.; Roos, Yvo B.W.E.M.; White, Phil; Mitchell, Peter J.; Demchuk, Andrew M.; Van Zwam, Wim H.; Jovin, Tudor G.; Van Oostenbrugge, Robert J.; Dippel, Diederik W.J.; Campbell, Bruce C.V.; Guillemin, Francis; Bracard, Serge; Hill, Michael D.; Goyal, Mayank; Marquering, Henk A.; Majoie, Charles B.L.M.

In: JAMA Neurology, Vol. 76, No. 2, 02.2019, p. 194-202.

Research output: Contribution to journalArticle

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 - Román, Luis San

AU - Heo, Ji Hoe

AU - Ribó, Marc

AU - Almekhlafi, Mohammed A.

AU - Liebeskind, David S.

AU - Teitelbaum, Jeanne

AU - Cuadras, Patricia

AU - Du Mesnil De Rochemont, Richard

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 Rodríguez, Lucía

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 - Dávalos, 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 trials were 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 or magnetic 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 <.001). Follow-up infarct volume partially mediated the relationship between treatment type with mRS score, as EVT was still significantly associated with functional outcome after adjustment for FIV (adjusted common odds ratio, 2.22; 95% CI, 1.52-3.21; P <.001). Treatment-reduced FIV explained 12% (95% CI, 1-19) of the relationship between EVT and functional outcome. 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..

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 trials were 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 or magnetic 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 <.001). Follow-up infarct volume partially mediated the relationship between treatment type with mRS score, as EVT was still significantly associated with functional outcome after adjustment for FIV (adjusted common odds ratio, 2.22; 95% CI, 1.52-3.21; P <.001). Treatment-reduced FIV explained 12% (95% CI, 1-19) of the relationship between EVT and functional outcome. 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..

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DO - 10.1001/jamaneurol.2018.3661

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JO - JAMA Neurology

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