Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?


  • Conflict of interest: KH reports fees or expenses from Boehringer Ingelheim, D-Pharm, and Lundbeck. RLF declares no conflicts of interest. HCD reports received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Abbott, Allergan, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, Daichii-Sankyo, D-Pharm, EV3, Fresenius, GlaxoSmithKline, Janssen Cilag, Knoll, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Thrombogenics, Wyeth, and Yamanouchi. Financial support for research projects was provided by Astra/Zeneca, GSK, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis and Talecris. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation, and Heinz-Nixdorf Foundation. HCD has no ownership interest and does not own stocks of any pharmaceutical company. HCD served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerznews, Stroke News, and the Treatment Guidelines of the German Neurological Society, as coeditor of Cephalalgia and on the editorial board of Lancet Neurology, European Neurology and Cerebrovascular Disorders. KRL reports fees or expenses from Archemix, American Stroke Association, Astellas, Asubio, Bayer, Boehringer Ingelheim, Co-Axia, D-Pharm, EVER, Ferrer, GlaxoSmithKline, infill, Johnson & Johnson, Lundbeck, Merck Sharpe and Dhome, Mitsubishi, Photothera, Quintiles, Sanofi-Aventis, Servier, Solvay, Talecris, and Wyeth.
  • Funding: VISTA has received financial support from the European Stroke Organisation in the form of an unrestricted grant and contributions toward data extraction and capacity building from the Universities of Glasgow, California San Diego, Nottingham, Edmonton, Calgary, Texas, and Massachusetts; from commercial groups including Brainsgate, Novartis, Boehringer Ingelheim, and the Vertical Group; and from grant agencies and charities including the UK Stroke Association. KH is supported by an educational grant from the European Stroke Organisation for young scientists and physicians. RFL was partly funded by a Research Scholarship from Wyeth and Johnson & Johnson.



Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale.


We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran–Mantel–Haenszel test.


Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43–1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18–1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90–1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients.


Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.