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 and philanthropic national funders.
Highlights
Prompt treatment with intravenous alteplase improves independent survival after acute ischaemic stroke.[1,2] concerns about the risk of symptomatic intracranial haemorrhage and whether patients with early signs of ischaemia on CT should receive alteplase could be deterring use of this treatment.[3]Early signs of ischaemia on non-enhanced brain CT include tissue hypoattenuation, lesion swelling, and arterial hyperattenuation from occlusive thrombus
Experts who were unaware of the random allocation assessed scans for early signs of ischaemia and pre-existing signs
Symptomatic intracranial haemorrhage was predicted by old infarct, tissue hypoattenuation (1∙54, 1∙04–2∙27), and hyperattenuated artery (1∙54, 1∙03–2∙29)
Summary
Signs of ischaemia on non-enhanced brain CT include tissue hypoattenuation, lesion swelling, and arterial hyperattenuation from occlusive thrombus. Tissue hypoattenuation might represent irreversible tissue damage[4] and has been associated with increased risk of symptomatic intracranial haemorrhage in some,[5] but not all,[6,7] studies. These signs are rarely seen alone, www.thelancet.com/neurology Vol 14 May 2015. For more on IST-3 see http://www.ist3.com but the association between combinations of signs and prognosis after stroke or their interaction with alteplase is unknown. In some alteplase trials, patients with specific findings (eg, extensive tissue hypoattenuation) were excluded.[5,8]
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