Brain CT signs and the effect of alteplase after stroke
The third International Stroke Trial (IST-3) is the largest (n=3035) randomised controlled trial of intravenous alteplase for acute ischaemic stroke to date. 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. The proportional benefit from alteplase increased with earlier treatment but was not modified by age. 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.3 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.3
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.4 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.5
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.6, 7 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.
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