Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial

Abstract

SummaryBackgroundBrain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase.MethodsIST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0–2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518.Findings3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55–0·81), large lesion (0·51, 0·38–0·68), swelling (0·59, 0·46–0·75), hyperattenuated artery (0·59, 0·47–0·75), atrophy (0·74, 0·59–0·94), and leukoaraiosis (0·72, 0·59–0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18–2·51), tissue hypoattenuation (1·54, 1·04–2·27), and hyperattenuated artery (1·54, 1·03–2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9–20·7; both signs absent, excess 3·2%, 1·4–5·1). However, no imaging findings—individually or combined—modified the effect of alteplase on independence or symptomatic intracranial haemorrhage.InterpretationSome early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke.FundingUK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental an...

Leukoaraiosis, Cerebral Hemorrhage, and Outcome After Intravenous Thrombolysis for Acute Ischemic Stroke

“…4, 6, 14, 15, 18, 19 The pooled incidence of poor outcome (defined as mRS>2 in three studies, 6, 14, 18 mRS≥2 in two studies 15, 19 ) was 47% (95%CI: 34%–60%) in the leukoaraiosis negative group compared to 64% (95%CI: 55%–74%) in the leukoaraiosis positive group. Pooled analysis of these studies demonstrated the odds of poor outcome at 3–6 month post-stroke to be significantly elevated in those with evidence of leukoaraiosis (OR: 2.02; 95%CI: 1.54–2.65, p<0.0001, Figure 3A), with significant statistical heterogeneity between studies (I 2 :73.5%, p=0.002).…”

“…4–6, 12–19 For the ECASS-1/−2 report (published only as an abstract), we contacted the lead authors to provide relevant data for the meta-analysis. 18 A summary of the characteristics of included studies, methodological key issues and quality indicators are noted in Table 1.…”

What are White Matter Hyperintensities Made of?

“…Furthermore, WMH increase risk of brain damage in the presence of other pathologies, for example, they associate with infarct growth and worse outcome after large artery stroke,60,61 and they predict poor functional stroke outcome 62–64…”

Effect of Right Insular Involvement on Death and Functional Outcome After Acute Ischemic Stroke in the IST-3 Trial (Third International Stroke Trial)

“…This study cohort included 2099 ischemic stroke patients showing unilateral acute ischemic changes in follow-up neuroimaging studies according to the expert central review ( Figure I in the online-only Data Supplement). 18 All scans were systematically assessed by neuroradiologists or stroke neurologists expert in stroke imaging, masked to all clinical data. 19 The definitions for cerebral infarcts involving the insular cortex, stroke severity, and lesion size are provided in the online-only Data Supplement.…”