Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials

Lancet. 2004 Mar 6;363(9411):768-74. doi: 10.1016/S0140-6736(04)15692-4.


Background: Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment.

Methods: We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage.

Findings: Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0.005). Odds were 2.8 (95% CI 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2) for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min in favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p<0.0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002).

Interpretation: The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.

Publication types

  • Meta-Analysis
  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Brain Ischemia / drug therapy
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Middle Aged
  • Placebos
  • Randomized Controlled Trials as Topic
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / therapeutic use
  • Stroke / drug therapy*
  • Tissue Plasminogen Activator / administration & dosage
  • Tissue Plasminogen Activator / therapeutic use*
  • Treatment Outcome


  • Placebos
  • Recombinant Proteins
  • Tissue Plasminogen Activator