When the landmark NINDS trial was published in 1995, there was no reference to early ischemic change (EIC) on CT. The concept of increased hemorrhagic risk with tPA in patients with EIC was popularized by von Kummer and the ECASS investigators, based substantially on longer time window data (mainly 3 to 6 hours). Interestingly, a further analysis of the NINDS data set, adjusting for confounding variables, did not substantiate a relationship between EIC and symptomatic hemorrhage. The Australian Streptokinase Trial was the only other thrombolytic trial to use a comparatively short time window (4 hours). Interestingly, the investigators also found no link.1 One might therefore conclude that the time window is the important factor to be considered. We agree with Lyden that CT has some value as a “tissue clock” and that major ischemic change may suggest earlier stroke onset than realized.
Then came ASPECTS. In this phase IV Canadian study in which a semi-quantitative scoring system was used, the investigators found a strong relationship among sub-3 hour tPA, EIC, and hemorrhage. How do we reconcile these findings, when confronted with a potential candidate for tPA in the emergency room? As both our contributors mention, subtle or undefined EIC should not necessarily preclude use of tPA. We certainly endorse the view of Lyden that tPA is too often not administered because of doubtful exclusion criteria.
Given the ASPECTS findings, we consider that enough doubt now remains to err on the side of caution and to continue to exclude patients for thrombolytic therapy based on early CT findings of major ischemia (more than one third of MCA territory) or an ASPECTS score of ≤7. We consider that with any area of uncertainty, more evidence is required from both randomized trials and phase IV studies. Certainly, the presence of early CT changes is likely to reflect the severity of ischemia (a product of the duration and level of hypoperfusion) and should alert the clinician to re-evaluate the time of stroke onset.2
Gilligan A, Markus R, Read S, Srikanth V, Hirano T, Fitt G, Arends M, Chambers BR, Davis SM, Donnan GA, Australian Streptokinase Trial (ASK) Investigators. Baseline blood pressure and not early CT changes predict major hemorrhage after streptokinase in acute ischemic stroke. Stroke. 2002; 33: 2236–2242.
Donnan GA, Davis SM. Neuroimaging: the ischaemic penumbra and selection of patients for acute stroke therapy. Lancet Neurol. In press.