Matthew Edwardson, MD

Cronin CA, Langenberg P, Dutta TM, and Kittner SJ. Transition of European Cooperative Acute Stroke Study III Results to Clinical Practice: Ninety-Day Outcomes in a US Cohort. Stroke. 2013


The ECASS III trial provided strong evidence for the safety and efficacy of IV-TPA in the 3-4.5 hr time window post-stroke. After publication of ECASS III, the American Stroke Association endorsed the use of IV-TPA in the extended time window, but the U.S. FDA did not due to prior conflicting results from the ATLANTIS trial conducted in North America (ATLANTIS tested IV-TPA in the 3-5 hr window). What emerged is widespread off-label use of IV-TPA in the 3-4.5 hr window by U.S. physicians. Cronin and colleagues studied this practice by comparing outcomes in patients treated from 0-3 hrs and 3-4.5 hrs post-stroke.



The authors conducted a prospective cohort study enrolling 296 patients treated with IV-TPA at 18 primary stroke centers in Maryland. The authors found no difference between those treated from 0-3 and 3-4.5 hrs with regard to favorable outcome (mRS 0-1 or 0-2), mortality, or symptomatic ICH. Community hospitals were much less likely to treat patients in the extended time window (15.8%) than academic medical centers (38.3%). Regarding the additional ECASS III exclusion criteria for the extended time window, only age > 80 and combined history of prior stroke and diabetes influenced the number of patients treated.

It is difficult to draw hard conclusions from this study about the safety and efficacy of IV-TPA in the extended time window, but it does inform regarding the adoption of this practice in the U.S. The efficacy of IV-TPA decreases exponentially with time post-stroke, therefore one would expect worse outcomes in patients treated in the extended time window compared to the 0-3 hr time window. The fact that the authors did not see any difference in morbidity or mortality between groups is encouraging, however, those treated in the extended time window also had less severe strokes. What’s most interesting about this study is the reduced rate of IV-TPA treatment in community hospitals. This is not surprising considering the lack of FDA approval and that community hospitals often treat relative contraindications as absolute contraindications out of fear of litigation. This study corroborates the favorable results found in ECASS III and highlights reduced treatment rates in the extended time window in the U.S. Perhaps the time has come to resurrect a new version of the ATLANTIS trial testing the 3-4.5 hr time window so we can finally get our stroke patients the treatment they deserve.