Contemporary Outcome Measures in Acute Stroke Research

Lees, Kennedy R.; Bath, Philip M.W.; Schellinger, Peter D.; Kerr, Daniel M.; Fulton, Rachael L.; Hacke, Werner; Matchar, David B.; Sehra, Ruchir; Toni, Danilo

doi:10.1161/strokeaha.111.641423

Cited by 196 publications

(165 citation statements)

References 59 publications

(55 reference statements)

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“…Ideally functional measures should include death, as does the modified Rankin Scale, the preferred outcome in acute stroke trials. 47 Eleventh, although both transient and permanent models of stroke were represented, all experimental protocols involved stroke induction with a monofilament. In general, it is better if experiments use a number of different systems for inducing ischemia.…”

Section: Discussionmentioning

confidence: 99%

Progesterone Treatment for Experimental Stroke: An Individual Animal Meta-Analysis

Wong

Renton

Gibson

et al. 2013

J Cereb Blood Flow Metab

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Preclinical studies suggest progesterone is neuroprotective after cerebral ischemia. The gold standard for assessing intervention effects across studies within and between subgroups is to use meta-analysis based on individual animal data (IAD). Preclinical studies of progesterone in experimental stroke were identified from searches of electronic databases and reference lists. Corresponding authors of papers of interest were contacted to obtain IAD and, if unavailable, summary data were obtained from the publication. Data are given as standardized mean differences (SMDs, continuous data) or odds ratios (binary data), with 95% confidence intervals (95% CIs). In an unadjusted analysis of IAD and summary data, progesterone reduced standardized lesion volume (SMD À 0.766, 95% CI À 1.173 to À 0.358, Po0.001). Publication bias was apparent on visual inspection of a Begg's funnel plot on lesion volume and statistically using Egger's test (P ¼ 0.001). Using individual animal data alone, progesterone was associated with an increase in death in adjusted analysis (odds ratio 2.64, 95% CI 1.17 to 5.97, P ¼ 0.020). Although progesterone significantly reduced lesion volume, it also appeared to increase the incidence of death after experimental stroke, particularly in young ovariectomized female animals. Experimental studies must report the effect of interactions on death and on modifiers, such as age and sex.

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Section: Discussionmentioning

confidence: 99%

Progesterone Treatment for Experimental Stroke: An Individual Animal Meta-Analysis

Wong

Renton

Gibson

et al. 2013

J Cereb Blood Flow Metab

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“…Because our analyses sought to predict death based on 3‐month mRS, patients with a 3‐month mRS of 6 were excluded. Disability at 3 months, 1 year, or 5 years was defined as mRS >2 (score of 3, 4, or 5, excluding 6, ie, death), as is often the case in acute stroke trials,16 at the respective follow‐up assessment.…”

Section: Methodsmentioning

confidence: 99%

“…The most commonly used primary outcome measure in acute stroke trials is the modified Rankin Scale (mRS),14, 15 at least partly because it is simple to administer, has good reproducibility, and avoids major floor or ceiling effects 16. Although most functional recovery poststroke happens in the first few months,17 recovery beyond 6 months does occur,18 but there are few published data on the relationship between early mRS and long‐term disability.…”

Section: Introductionmentioning

confidence: 99%

Time Course of Evolution of Disability and Cause‐Specific Mortality After Ischemic Stroke: Implications for Trial Design

Ganesh

Luengo-Fernández

Wharton

et al. 2017

JAHA

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BackgroundOutcome in stroke trials is often based on a 3‐month modified Rankin scale (mRS). How 3‐month mRS relates to longer‐term outcomes will depend on late recovery, delayed stroke‐related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3‐month mRS and death/disability at 1 and 5 years in a population‐based cohort study.Methods and ResultsIn 3‐month survivors of ischemic stroke (Oxford Vascular Study; 2002‐2014), we related 3‐month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index‐stroke‐related and nonstroke deaths in each poststroke year was categorized according to 3‐month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index‐stroke‐related deaths and 320 other deaths occurred during the subsequent 4866 patient‐years of follow‐up up to 5 years. Although 69/126 (54.8%) post‐3‐month index‐stroke‐related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88‐61.09, P<0.0001). Consequently, a 3‐month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16‐10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38‐3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3‐month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]).ConclusionsOur results reaffirm use of the 3‐month mRS outcome in stroke trials. Although later recovery does occur, extending follow‐up to 1 year would capture most long‐term stroke‐related disability. However, administrative mortality follow‐up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long‐term mortality without much erosion by non‐stroke‐related deaths.

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“…20 Our iterative work program has demonstrated the importance of reliable trial outcomes and a potential method to improve functional end point assessment.…”

Section: Implications For Future Practice and Researchmentioning

confidence: 99%

Improving the Efficiency of Stroke Trials

McArthur

Johnson

Quinn

et al. 2013

Stroke

Self Cite

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C linical trials in acute stroke are large and expensive, even with recent innovations in trial design.1 The modified Rankin scale (mRS) is the most commonly used outcome measure in stroke research. 2 The mRS is an ordinal scale of 7 categories describing full recovery, by increasing degrees of disability, to death.3 Typically, mRS assessment is based on a clinician's rating of a patient interview, and interobserver variability is common. 4 Meta-analysis suggests an overall reliability of κ=0.62 (κ w =0.9), 4 but this may be less (κ=0.25) in multicenter studies. 5 Mandatory training in mRS assessment is used in most trials to mitigate this, 6 but the problem persists. The end point misclassification inherent in this interobserver variability may affect trial power 7 and treatment effect size. 8 Central adjudication of trial end points is routinely used in a variety of settings but has been rarely used in stroke. Group adjudication of mRS has been based on review of written summaries 9 or telephone interview. 10,11 Advantages to a remote adjudication approach include the following: expert opinion and experience; quality control of mRS interviews and avoiding potential bias from use of mRS where local observers are not or cannot be blinded to treatment allocation. To date, remote functional assessment has been limited as a result of the difficulty in capturing a high-fidelity recording, suitable for off-line review. Furthermore, most trials are international, and culturally sensitive translation may also prove problematic. Our pilot data suggest that a video-based mRS assessment is a valid and reliable solution. 12Background and Purpose-Use of the modified Rankin scale (mRS) in multicenter trials may be limited by interobserver variability. We assessed the effect of this on trial power and developed a novel group adjudication approach. Methods-We generated power and sample size estimates from simulated trials modeled with varying mRS reliability.We conducted a virtual acute stroke trial across 14 UK sites to develop a group adjudication approach. Traditional mRS interviews, performed at local sites, were digitally recorded and scored by adjudication committee. We assessed the effect of translation by comparing scores in translated mRS interviews, originally conducted in English and Mandarin. Agreement was measured using κ and weighted κ (κ w ) statistics and intraclass correlation coefficient. Results-Statistical simulations suggest that improving mRS reliability from κ=0.25 to κ=0.5 or 0.7 may allow reductions in sample size of n=386 or 490 in a typical n=2000 study. Our virtual acute stroke trial included 370 participants and 563 mRS video assessments. We adjudicated mRS in 538 of 563 (96%) study visits. Methods Sample Size SimulationsWe performed simulations to demonstrate the effect of increasing mRS reliability and using multiple observers to assign mRS scores. We generated power estimates from simulated mRS studies under various combinations of sample size (N), effect size (δ), reliability (unweighted κ...

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Contemporary Outcome Measures in Acute Stroke Research

Cited by 196 publications

References 59 publications

Progesterone Treatment for Experimental Stroke: An Individual Animal Meta-Analysis

Progesterone Treatment for Experimental Stroke: An Individual Animal Meta-Analysis

Time Course of Evolution of Disability and Cause‐Specific Mortality After Ischemic Stroke: Implications for Trial Design

Improving the Efficiency of Stroke Trials

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