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BACKGROUND AND PURPOSE: Pooled analyses show benefits of intravenous alteplase (recombinant tissue-type plasminogen activator) treatment for acute ischemic stroke up to 4.5 hours after onset despite marketing approval for up to 3 hours. However, the benefit from thrombolysis is critically time-dependent and if extending the time window reduces treatment urgency, this could reduce the population benefit from any extension. METHODS: Based on 3830 UK patients registered between 2005 to 2010 in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR), a Monte Carlo simulation was used to model recombinant tissue-type plasminogen activator treatment up to 4·5 hours from onset and assess the impact (numbers surviving with little or no disability) from changes in hospital treatment times associated with this extended time window. RESULTS: We observed a significant relation between time remaining to treat and time taken to treat in the UK SITS-ISTR data set after adjustment for censoring. Simulation showed that as this "deadline effect" increases, an extended treatment time window entails that an increasing number of patients are treated at a progressively lower absolute benefit to a point where the population benefit from extending the time window is entirely negated. CONCLUSIONS: Despite the benefit for individual patients treated up to 4.5 hours after onset, the population benefit may be reduced or lost altogether if extending the time window results in more patients being treated but at a lower absolute benefit. A universally applied reduction in hospital arrival to treatment times of 8 minutes would confer a population benefit as large as the time window extension.

Original publication




Journal article



Publication Date





2992 - 2997


Antifibrinolytic Agents, Humans, Monte Carlo Method, Stroke, Thrombolytic Therapy, Time Factors, Tissue Plasminogen Activator