title: Unwitnessed stroke: impact of different onset times on eligibility into stroke trials.
abstract: BACKGROUND
  Patients with unwitnessed stroke represent >25% of all strokes. Clinical trials enrolling patients with unwitnessed stroke onset have conservatively used last known normal (LKN) as the time of stroke onset. We explored the impact of alternative methods of selecting onset time in unwitnessed strokes on eligibility into an acute stroke therapeutic trial using a representative sample of acute stroke subjects.
  
  
  METHODS
  We analyzed data on 641 consecutive patients with suspected stroke presenting to our hospital between January 2007 and July 2008. Time of onset was calculated by 3 methods: (1) LKN, (2) first known abnormal (FKA), and (3) midpoint between LKN and FKA. Subjects with incomplete data or a final diagnosis of nonischemic stroke were excluded. Rates of trial eligibility based on different onset times were compared for several inclusion time windows.
  
  
  RESULTS
  Onset time was known in 440 subjects (69%). Of the remaining 201 patients with unwitnessed onset, 114 (57%) were "wake-up" strokes. Among unwitnessed stroke subjects, eligibility increased from 18% using LKN to 57% using FKA at 4.5 hours and 42% to 81% at 9 hours (P < .001), respectively. Overall enrollment eligibility for the full cohort increased from 36% to 48% at 4.5 hours and 61% to 73% at 9 hours (P < .001), respectively.
  
  
  CONCLUSIONS
  Given potential advantages in safety evaluation and the historical inadequate enrollment rates in acute stroke trials, alternative onset time definitions, perhaps in combination with advanced neuroimaging methods (e.g., fluid-attenuated inversion recovery-diffusion-weighted imaging mismatch), should be considered for early-phase trials.
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. mbmaas@northwestern.edu
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Maas
authors.forename: Aneesh B
authors.initials: AB
authors.lastname: Singhal
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D004608:Eligibility Determination; D006801:Humans; D018579:Patient Selection; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries; D020521:Stroke / Q000175:diagnosis* / Q000628:therapy; D013997:Time Factors; D061665:Time-to-Treatment