Infarct volume after ischemic stroke as a mediator of the effect of endovascular thrombectomy on early postprocedural neurologic deficit



      The beneficial effect of endovascular thrombectomy (EVT) on clinical outcome is assumed to be caused by reduced follow-up infarct volume (FIV), which could serve as an early imaging endpoint. However, the effect of EVT on the modified Rankin Scale (mRS) was poorly explained by FIV. NIHSS at 5-7 days could be a more specific measure of the effect of reperfusion therapy, as opposed to the mRS at 3 months. Therefore, we aimed to assess to what extent the effect of EVT on NIHSS is explained by FIV.

      Materials and methods

      We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; n = 500) trial to evaluate the mediating role of FIV within 1 week in the relationship between EVT and baseline adjusted NIHSS at 5–7 days.


      Larger FIVs were associated with higher NIHSS after treatment (adjusted beta-coefficient (aβ) 0.47;95%CI 0.39-0.55). EVT was associated with smaller FIVs (β -0.35;95%CI-0.64 to -0.06) and lower NIHSS (β -0.63;95%CI-0.90 to -0.35). After adjustment for FIV, the effect of EVT on NIHSS decreased (aβ -0.47;95%CI-0.72 to -0.23), indicating that effect of EVT on neurologic deficit is partially mediated by FIV. Reduction of FIV explained 34% (95%CI;5%–93%) of the effect of EVT on the NIHSS at 5–7 days.


      Larger FIV was significantly associated with larger neurological deficits after treatment. Reduced infarct volume after EVT explains one third of treatment benefit in terms of neurological deficit. This suggests that FIV is of interest as an imaging biomarker of stroke treatment effect.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Compagne K.C.J.
        • Boers A.M.M.
        • Marquering H.A.
        • et al.
        Follow-up infarct volume as a mediator of endovascular treatment effect on functional outcome in ischaemic stroke.
        Eur Radiol. 2019; 29: 736-744
        • Boers A.M.M.
        • Jansen I.G.H.
        • Brown S.
        • et al.
        Mediation of the relationship between endovascular therapy and functional outcome by follow-up infarct volume in patients with acute ischemic stroke.
        JAMA Neurol. 2019; 76: 194-202
        • Goyal M.
        • Ospel J.M.
        • Menon B.
        • et al.
        Challenging the ischemic core concept in acute ischemic stroke imaging.
        Stroke. 2020; 51: 3147-3155
        • Brott T.
        • Adams Jr., H.P.
        • Olinger C.P.
        • et al.
        Measurements of acute cerebral infarction: a clinical examination scale.
        Stroke. 1989; 20: 864-870
        • Chalos V.
        • van der Ende N.A.M.
        • Lingsma H.F.
        • et al.
        National institutes of health stroke scale: an alternative primary outcome measure for trials of acute treatment for ischemic stroke.
        Stroke. 2020; 51: 282-290
        • Kerr D.M.
        • Fulton R.L.
        • Lees K.R.
        • et al.
        Seven-day NIHSS is a sensitive outcome measure for exploratory clinical trials in acute stroke: evidence from the virtual international stroke trials archive.
        Stroke. 2012; 43: 1401-1403
        • Al-Ajlan F.S.
        • Al Sultan A.S.
        • Minhas P.
        • et al.
        Posttreatment infarct volumes when compared with 24hour and 90-day clinical outcomes: insights from the REVASCAT randomized controlled trial.
        AJNR Am J Neuroradiol. 2018; 39: 107-110
        • Berkhemer O.A.
        • Fransen P.S.
        • Beumer D.
        • et al.
        A randomized trial of intraarterial treatment for acute ischemic stroke.
        N Engl J Med. 2015; 372: 11-20
        • Boers A.M.
        • Marquering H.A.
        • Jochem J.J.
        • et al.
        Automated cerebral infarct volume measurement in follow-up noncontrast CT scans of patients with acute ischemic stroke.
        AJNR Am J Neuroradiol. 2013; 34: 1522-1527
        • Bucker A.
        • Boers A.M.
        • Bot J.C.J.
        • et al.
        Associations of ischemic lesion volume with functional outcome in patients with acute ischemic stroke: 24hour versus 1-week imaging.
        Stroke. 2017; 48: 1233-1240
        • Vickers A.J.
        • Altman D.G.
        Statistics notes: analysing controlled trials with baseline and follow up measurements.
        BMJ. 2001; 323: 1123-1124
        • Baron R.M.
        • Kenny DA.
        The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations.
        J Pers Soc Psychol. 1986; 51: 1173-1182
        • Vanderweele T.J.
        • Vansteelandt S.
        Odds ratios for mediation analysis for a dichotomous outcome.
        Am J Epidemiol. 2010; 172: 1339-1348
        • Prentice R.L.
        Surrogate endpoints in clinical trials: definition and operational criteria.
        Stat Med. 1989; 8: 431-440
        • Valeri L.
        • Vanderweele TJ.
        Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros.
        Psychol Methods. 2013; 18: 137-150
        • Freedman L.S.
        • Graubard B.I.
        • Schatzkin A.
        Statistical validation of intermediate endpoints for chronic diseases.
        Stat Med. 1992; 11: 167-178
        • Moons K.G.
        • Donders R.A.
        • Stijnen T.
        • et al.
        Using the outcome for imputation of missing predictor values was preferred.
        J Clin Epidemiol. 2006; 59: 1092-1101
        • Vanderweele T.J.
        • Vansteelandt S.
        • Robins JM.
        Marginal structural models for sufficient cause interactions.
        Am J Epidemiol. 2010; 171: 506-514
        • Ernst M.
        • Boers A.M.M.
        • Forkert N.D.
        • et al.
        Impact of ischemic lesion location on the mRS score in patients with ischemic stroke: a voxel-based approach.
        AJNR Am J Neuroradiol. 2018; 39: 1989-1994
        • Phan T.G.
        • Chen J.
        • Donnan G.
        • et al.
        Development of a new tool to correlate stroke outcome with infarct topography: a proof-of-concept study.
        Neuroimage. 2010; 49: 127-133
        • Rabinstein A.A.
        • Albers G.W.
        • Brinjikji W.
        • et al.
        Factors that may contribute to poor outcome despite good reperfusion after acute endovascular stroke therapy.
        Int J Stroke. 2019; 14: 23-31
      1. R.A.S.N van de Graaf. Predictors of poor outcome despite successful endovascular treatment for ischemic stroke: results from the MR CLEAN Registry. Submitted 2021.

        • McLeod C.
        • Norman R.
        • Litton E.
        • et al.
        Choosing primary endpoints for clinical trials of health care interventions.
        Contemp Clin Trials Commun. 2019; 16100486
        • Boers A.M.M.
        • Jansen I.G.H.
        • Beenen L.F.M.
        • et al.
        Association of follow-up infarct volume with functional outcome in acute ischemic stroke: a pooled analysis of seven randomized trials.
        J Neurointerv Surg. 2018; 10: 1137-1142
        • Konduri P.
        • van Voorst H.
        • Bucker A.
        • et al.
        Posttreatment ischemic lesion evolution is associated with reduced favorable functional outcome in patients with stroke.
        Stroke. 2021; (STROKEAHA120032331)
        • Liu S.H.
        • Ulbricht C.M.
        • Chrysanthopoulou S.A.
        • et al.
        Implementation and reporting of causal mediation analysis in 2015: a systematic review in epidemiological studies.
        BMC Res Notes. 2016; 9: 354
        • VanderWeele TJ.
        Mediation analysis: a practitioner's guide.
        Annu Rev Public Health. 2016; 37: 17-32