Brain CT signs and the effect of alteplase after stroke
Authors: Vincent Larrue
Journal: The Lancet Neurology (2015)

The third International Stroke Trial (IST-3) is the largest (n=3035) randomised controlled trial of intravenous alteplase for acute ischaemic stroke to date.1The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar Participants in IST-3 were older than in previous trials: 1617 (53%) were older than 80 years of age, whereas only 112 patients of this age were included in eight previous similar trials.2Emberson J Lees KR Lyden P et al.for the Stroke Thrombolysis Trialists' Collaborative GroupEffect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384: 1929-1935Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar In IST-3, participants could be treated up to 6 h after stroke onset, but 849 (28%) were treated within 3 h. No significant effect of alteplase was reported on the IST-3 primary endpoint—independence at 6 months (defined as an Oxford Handicap Scale score of 0–2). However, in a prespecified ordinal analysis, a significant shift was noted in functional outcome, in favour of alteplase.1The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar A meta-analysis of individual patient data from nine randomised trials (including IST-3) showed that intravenous alteplase improved outcome when administered up to 4·5 h after stroke onset.2Emberson J Lees KR Lyden P et al.for the Stroke Thrombolysis Trialists' Collaborative GroupEffect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384: 1929-1935Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar The proportional benefit from alteplase increased with earlier treatment but was not modified by age.2Emberson J Lees KR Lyden P et al.for the Stroke Thrombolysis Trialists' Collaborative GroupEffect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384: 1929-1935Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar IST-3 is a landmark study because the effects of alteplase could be assessed reliably in older patients with acute ischaemic stroke.Joanna Wardlaw and colleagues in the IST-3 collaborative group report in The Lancet Neurology their findings on brain imaging.3IST-3 collaborative groupAssociation 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.Lancet Neurol. 2015; (published online March 27.)http://dx.doi.org/10.1016/S1474-4422(15)00012-5Google Scholar They sought to establish whether early ischaemic or pre-existing CT signs were associated with the effect of alteplase on several outcomes, including symptomatic intracerebral haemorrhage and independence at 6 months. All images were reviewed centrally. Early ischaemic changes were classified as hyperattenuated artery, tissue hypoattenuation, and ischaemic lesion swelling, and infarct extent was also assessed; pre-existing signs were classified as old infarcts, leukoaraiosis, and brain atrophy. Diminished independent survival was associated with all early ischaemic changes (including tissue hypoattenuation [odds ratio 0·66, 95% CI 0·55–0·81]), leukoaraiosis (0·72, 0·59–0·87), and atrophy (0·74, 0·59–0·94). Risk of symptomatic intracerebral haemorrhage was increased by the presence of old infarcts (odds ratio 1·72, 95% CI 1·18–2·51), hypoattenuation (1·54, 1·04–2·27), and a hyperattenuated artery (1·54, 1·03–2·29). Multivariate logistic regression models including seven imaging signs showed that hyperattenuated arteries, large lesion, and leukoaraiosis each reduced the chance of a good outcome by 25–30%. Old infarcts and hyperattenuated arteries were significant predictors of symptomatic intracerebral haemorrhage. However, the effect of alteplase on symptomatic intracerebral haemorrhage or functional outcome was not modified by any of these CT variables.3IST-3 collaborative groupAssociation 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.Lancet Neurol. 2015; (published online March 27.)http://dx.doi.org/10.1016/S1474-4422(15)00012-5Google ScholarWhen interpreting these findings, the characteristics of patients included in IST-3 should be considered. The prevalence of tissue hypoattenuation might have been lower than in previous studies because of the large number of patients older than 80 years of age. Indeed, findings from the present analysis confirm a negative association between tissue hypoattenuation and age. Moreover, the relation between age and symptomatic intracerebral haemorrhage could be more complex than initially thought. The Safe Implementation of Thrombolysis in Stroke (SITS) registry has shown that the rate of symptomatic intracerebral haemorrhage increases with age up to 70 years, but not beyond.4Ford GA Ahmed N Azevedo E et al.Intravenous alteplase for stroke in those older than 80 years old.Stroke. 2010; 41: 2568-2574Crossref PubMed Scopus (135) Google Scholar Such a ceiling effect could account for why IST-3 could not confirm the association of age with symptomatic intracerebral haemorrhage reported in previous trials that included younger patients.5Whiteley WN Slot KB Fernandes P Sandercock P Wardlaw J Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies.Stroke. 2012; 43: 2904-2909Crossref PubMed Scopus (214) Google ScholarCompared with other trials, the relatively high proportion of patients treated within 3 h in IST-3 is another likely explanation for the lack of association between tissue hypoattenuation and symptomatic intracerebral haemorrhage in multivariate analysis, because tissue hypoattenuation becomes more discernible with time from stroke onset. The association between tissue hypoattenuation and symptomatic intracerebral haemorrhage was significant in previous European Cooperative Acute Stroke Study (ECASS) trials, in which patients were included up to 6 h after symptom onset, but not in the National Institute of Neurological Disorders and Stroke (NINDS) trial, in which patients were included within 3 h of symptom onset.6Larrue V von Kummer RR Müller A Bluhmki E Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II).Stroke. 2001; 32: 438-441Crossref PubMed Scopus (776) Google Scholar, 7Patel SC Levine SR Tilley BC et al.Lack of clinical significance of early ischemic changes on computed tomography in acute stroke.JAMA. 2001; 286: 2830-2836Crossref PubMed Scopus (320) Google Scholar Wardlaw and colleagues did analyses by time windows, which suggested that hypoattenuation was associated with symptomatic intracerebral haemorrhage in patients treated 4·5–6 h after stroke but not in those treated earlier, but these findings must be interpreted cautiously because of small samples and wide CIs.Wardlaw and colleagues from the IST-3 collaborative group have identified some CT imaging findings that might help to estimate the risk of symptomatic intracerebral haemorrhage and reduced independence for the individual patient. However, no imaging findings, either alone or in combination, were associated with a modified treatment effect of alteplase. The primary findings in IST-3 have contributed to the justification of extending treatment to patients older than 80 years in clinical practice. This new analysis suggests that patients who can be treated within 4·5 h might be considered for treatment irrespective of CT findings, as long as intracranial haemorrhage and established cerebral infarction have been excluded, although further studies will be needed to confirm these findings.VL has received grants from Boehringer Ingelheim, outside the submitted work, and has served as a member of the steering committee in several studies supported by Boehringer Ingelheim: ECASS II, ECASS III, and SITS Monitoring Study. The third International Stroke Trial (IST-3) is the largest (n=3035) randomised controlled trial of intravenous alteplase for acute ischaemic stroke to date.1The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar Participants in IST-3 were older than in previous trials: 1617 (53%) were older than 80 years of age, whereas only 112 patients of this age were included in eight previous similar trials.2Emberson J Lees KR Lyden P et al.for the Stroke Thrombolysis Trialists' Collaborative GroupEffect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384: 1929-1935Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar In IST-3, participants could be treated up to 6 h after stroke onset, but 849 (28%) were treated within 3 h. No significant effect of alteplase was reported on the IST-3 primary endpoint—independence at 6 months (defined as an Oxford Handicap Scale score of 0–2). However, in a prespecified ordinal analysis, a significant shift was noted in functional outcome, in favour of alteplase.1The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar A meta-analysis of individual patient data from nine randomised trials (including IST-3) showed that intravenous alteplase improved outcome when administered up to 4·5 h after stroke onset.2Emberson J Lees KR Lyden P et al.for the Stroke Thrombolysis Trialists' Collaborative GroupEffect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384: 1929-1935Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar The proportional benefit from alteplase increased with earlier treatment but was not modified by age.2Emberson J Lees KR Lyden P et al.for the Stroke Thrombolysis Trialists' Collaborative GroupEffect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384: 1929-1935Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar IST-3 is a landmark study because the effects of alteplase could be assessed reliably in older patients with acute ischaemic stroke. Joanna Wardlaw and colleagues in the IST-3 collaborative group report in The Lancet Neurology their findings on brain imaging.3IST-3 collaborative groupAssociation 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.Lancet Neurol. 2015; (published online March 27.)http://dx.doi.org/10.1016/S1474-4422(15)00012-5Google Scholar They sought to establish whether early ischaemic or pre-existing CT signs were associated with the effect of alteplase on several outcomes, including symptomatic intracerebral haemorrhage and independence at 6 months. All images were reviewed centrally. Early ischaemic changes were classified as hyperattenuated artery, tissue hypoattenuation, and ischaemic lesion swelling, and infarct extent was also assessed; pre-existing signs were classified as old infarcts, leukoaraiosis, and brain atrophy. Diminished independent survival was associated with all early ischaemic changes (including tissue hypoattenuation [odds ratio 0·66, 95% CI 0·55–0·81]), leukoaraiosis (0·72, 0·59–0·87), and atrophy (0·74, 0·59–0·94). Risk of symptomatic intracerebral haemorrhage was increased by the presence of old infarcts (odds ratio 1·72, 95% CI 1·18–2·51), hypoattenuation (1·54, 1·04–2·27), and a hyperattenuated artery (1·54, 1·03–2·29). Multivariate logistic regression models including seven imaging signs showed that hyperattenuated arteries, large lesion, and leukoaraiosis each reduced the chance of a good outcome by 25–30%. Old infarcts and hyperattenuated arteries were significant predictors of symptomatic intracerebral haemorrhage. However, the effect of alteplase on symptomatic intracerebral haemorrhage or functional outcome was not modified by any of these CT variables.3IST-3 collaborative groupAssociation 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.Lancet Neurol. 2015; (published online March 27.)http://dx.doi.org/10.1016/S1474-4422(15)00012-5Google Scholar When interpreting these findings, the characteristics of patients included in IST-3 should be considered. The prevalence of tissue hypoattenuation might have been lower than in previous studies because of the large number of patients older than 80 years of age. Indeed, findings from the present analysis confirm a negative association between tissue hypoattenuation and age. Moreover, the relation between age and symptomatic intracerebral haemorrhage could be more complex than initially thought. The Safe Implementation of Thrombolysis in Stroke (SITS) registry has shown that the rate of symptomatic intracerebral haemorrhage increases with age up to 70 years, but not beyond.4Ford GA Ahmed N Azevedo E et al.Intravenous alteplase for stroke in those older than 80 years old.Stroke. 2010; 41: 2568-2574Crossref PubMed Scopus (135) Google Scholar Such a ceiling effect could account for why IST-3 could not confirm the association of age with symptomatic intracerebral haemorrhage reported in previous trials that included younger patients.5Whiteley WN Slot KB Fernandes P Sandercock P Wardlaw J Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies.Stroke. 2012; 43: 2904-2909Crossref PubMed Scopus (214) Google Scholar Compared with other trials, the relatively high proportion of patients treated within 3 h in IST-3 is another likely explanation for the lack of association between tissue hypoattenuation and symptomatic intracerebral haemorrhage in multivariate analysis, because tissue hypoattenuation becomes more discernible with time from stroke onset. The association between tissue hypoattenuation and symptomatic intracerebral haemorrhage was significant in previous European Cooperative Acute Stroke Study (ECASS) trials, in which patients were included up to 6 h after symptom onset, but not in the National Institute of Neurological Disorders and Stroke (NINDS) trial, in which patients were included within 3 h of symptom onset.6Larrue V von Kummer RR Müller A Bluhmki E Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II).Stroke. 2001; 32: 438-441Crossref PubMed Scopus (776) Google Scholar, 7Patel SC Levine SR Tilley BC et al.Lack of clinical significance of early ischemic changes on computed tomography in acute stroke.JAMA. 2001; 286: 2830-2836Crossref PubMed Scopus (320) Google Scholar Wardlaw and colleagues did analyses by time windows, which suggested that hypoattenuation was associated with symptomatic intracerebral haemorrhage in patients treated 4·5–6 h after stroke but not in those treated earlier, but these findings must be interpreted cautiously because of small samples and wide CIs. Wardlaw and colleagues from the IST-3 collaborative group have identified some CT imaging findings that might help to estimate the risk of symptomatic intracerebral haemorrhage and reduced independence for the individual patient. However, no imaging findings, either alone or in combination, were associated with a modified treatment effect of alteplase. The primary findings in IST-3 have contributed to the justification of extending treatment to patients older than 80 years in clinical practice. This new analysis suggests that patients who can be treated within 4·5 h might be considered for treatment irrespective of CT findings, as long as intracranial haemorrhage and established cerebral infarction have been excluded, although further studies will be needed to confirm these findings. VL has received grants from Boehringer Ingelheim, outside the submitted work, and has served as a member of the steering committee in several studies supported by Boehringer Ingelheim: ECASS II, ECASS III, and SITS Monitoring Study. 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 trialSome 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. Full-Text PDF Open Access