title: 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: BACKGROUND
  Brain 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.
  
  
  METHODS
  IST-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.
  
  
  RESULTS
  3017 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.
  
  
  CONCLUSIONS
  Some 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.
  
  
  BACKGROUND
  UK 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.
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D003627:Data Interpretation, Statistical; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011859:Radiography; D016037:Single-Blind Method; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
references.citation: Int J Stroke. 2006 Aug;1(3):172-6
references.pmid: 18706043
references.citation: N Engl J Med. 2008 Sep 25;359(13):1317-29
references.pmid: 18815396
references.citation: Cerebrovasc Dis. 2009;27(1):51-9
references.pmid: 19018138
references.citation: Ageing Res Rev. 2011 Jan;10(1):104-14
references.pmid: 20850567
references.citation: PLoS One. 2010;5(12):e15757
references.pmid: 21209901
references.citation: Int J Stroke. 2012 Apr;7(3):186-7
references.pmid: 22405276
references.citation: Lancet. 2012 Jun 23;379(9834):2364-72
references.pmid: 22632907
references.citation: Lancet. 2012 Jun 23;379(9834):2352-63
references.pmid: 22632908
references.citation: Stroke. 2012 Nov;43(11):2904-9
references.pmid: 22996959
references.citation: Stroke. 2012 Nov;43(11):2992-7
references.pmid: 23010678
references.citation: Lancet Neurol. 2013 Aug;12(8):768-76
references.pmid: 23791822
references.citation: Neurology. 2013 Sep 24;81(13):1130-3
references.pmid: 23946306
references.citation: Stroke. 2014 Feb;45(2):444-9
references.pmid: 24335227
references.citation: Cochrane Database Syst Rev. 2014;7:CD000213
references.pmid: 25072528
references.citation: Lancet. 2014 Nov 29;384(9958):1929-35
references.pmid: 25106063
references.citation: Stroke. 2007 Apr;38(4):1250-6
references.pmid: 17347470
references.citation: CMAJ. 2005 Aug 30;173(5):489-95
references.pmid: 16129869
references.citation: Stroke. 2005 Oct;36(10):2110-5
references.pmid: 16166579
references.citation: Stroke. 2006 Apr;37(4):973-8
references.pmid: 16497977
references.citation: Radiology. 2005 May;235(2):444-53
references.pmid: 15858087
references.citation: Lancet. 1998 Oct 17;352(9136):1245-51
references.pmid: 9788453
references.citation: Radiology. 1997 Nov;205(2):327-33
references.pmid: 9356611
references.citation: N Engl J Med. 1995 Dec 14;333(24):1581-7
references.pmid: 7477192
references.citation: JAMA. 1995 Oct 4;274(13):1017-25
references.pmid: 7563451
references.citation: AJNR Am J Neuroradiol. 1994 Nov;15(10):1933-9
references.pmid: 7863945
references.citation: Lancet. 1991 Jun 22;337(8756):1521-6
references.pmid: 1675378
references.citation: JAMA. 1999 Dec 1;282(21):2003-11
references.pmid: 10591382
references.citation: Stroke. 2000 Jul;31(7):1555-60
references.pmid: 10884453
references.citation: Lancet. 2000 May 13;355(9216):1670-4
references.pmid: 10905241
references.citation: Stroke. 2001 Feb;32(2):438-41
references.pmid: 11157179
references.citation: Radiology. 2001 Apr;219(1):95-100
references.pmid: 11274542
references.citation: Can J Neurol Sci. 2001 May;28(2):113-9
references.pmid: 11383934
references.citation: Stroke. 2001 Jun;32(6):1318-22
references.pmid: 11387493
references.citation: JAMA. 2001 Dec 12;286(22):2830-8
references.pmid: 11735758
references.citation: Mech Ageing Dev. 2002 Sep;123(11):1457-60
references.pmid: 12425952
references.citation: Stroke. 2003 Aug;34(8):1925-31
references.pmid: 12843342
references.citation: AJR Am J Roentgenol. 1987 Aug;149(2):351-6
references.pmid: 3496763
references.citation: Stroke. 1989 Jun;20(6):828
references.pmid: 2728057
references.citation: J Neurol Neurosurg Psychiatry. 1990 Jan;53(1):16-22
references.pmid: 2303826
references.citation: J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1080-3
references.pmid: 2292703