Alteplase beyond Three Hours in Ischemic Stroke: Do We Know Enough?

Abstract

Alteplase (tPA) remains the only approved treatment for stroke that has a beneficial functional outcome if used within 3 h of an ischemic event. The results of the recently published European Cooperative Stroke Study III trial (1) and the Safe Implementation of Thrombolysis in Stroke-International Stroke Register (2) study suggest that the time window during which alteplase could be safely administered in stroke patients may extend up to 4 5 h. In these studies and previous tPA trials, the focus of outcome measures has been on physical disability and dependence in basic activities of daily living assessed via the NIH stroke scale, modified Rankin, Barthel, and Glasgow outcome scales (1, 2). An evaluation of the instrumental and cognitive outcomes, however, has been overlooked. It would seem to be important to assess cognitive outcomes since almost onefourth of stroke patients develop poststroke dementia within 3 months of the event (3). Thus far, the cognitive and instrumental outcomes have only been studied by Nys and colleagues, who showed that tPA administration within 3 h of stroke did not have a beneficial cognitive outcome. They suggested that either the reduction in the volume of the ischemic region by tPA is not sufficient to have an effect on cognitive outcomes or that the focal cognitive improvement by tPA is countered by a global cognitive decline that could potentially result from tPA treatment (4). It has been suggested that tPA could be deleterious to neurons through a number of mechanisms involving excitotoxicity, activation of microglia, and degradation of extracellular matrix components (5). N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is a key pathway leading to neuronal cell death during ischemic stroke. Glutamate is the main trigger of NMDA-mediated excitotoxicity and its parenchymal levels increase with the duration of the ischemic insult (6). tPA has been shown to potentiate NMDA-mediated excitotoxicity by increasing the calcium influx and production of nitric oxide. Mouse models deficient in tPAwere shown to be resistant to the NMDA-mediated excitotoxic neuronal death, whereas exogenous administration of tPA reinstated excitotoxicity in these animals (5). A delayed administration of tPA in patients with ischemic stroke, given the greater concentration and geographic localization of glutamate with the passage of time might as well provide a greater substrate for the tPA potentiating of excitotoxicity. Perhaps, it would seem appropriate to assess the patients treated with alteplase in the ongoing International Stroke Trial III and any subsequent trials for more comprehensive clinical outcome including cognition and instrumental functioning. That might be the best way we assure ourselves that the thrombolytic benefits of tPA continue to outweigh the risk of neurotoxicity associated with it, even outside the conventional 3-h time window.