title: Will delays in treatment jeopardize the population benefit from extending the time window for stroke thrombolysis?
abstract: OBJECTIVE
  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.
authors.affiliation: University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK. martin.pitt@pms.ac.uk
authors.forename: Martin
authors.initials: M
authors.lastname: Pitt
authors.forename: Thomas
authors.initials: T
authors.lastname: Monks
authors.forename: Paritosh
authors.initials: P
authors.lastname: Agarwal
authors.forename: David
authors.initials: D
authors.lastname: Worthington
authors.forename: Gary A
authors.initials: GA
authors.lastname: Ford
authors.forename: Kennedy R
authors.initials: KR
authors.lastname: Lees
authors.forename: Ken
authors.initials: K
authors.lastname: Stein
authors.forename: Martin A
authors.initials: MA
authors.lastname: James
mesh_terms: D000933:Antifibrinolytic Agents / Q000008:administration & dosage*; D006801:Humans; D009010:Monte Carlo Method; D020521:Stroke / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D000933:Antifibrinolytic Agents; D010959:Tissue Plasminogen Activator