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What is the effect of time to treatment of ischemic stroke with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk?

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Best Evidence in Emergency Medicine Answer

  • Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W; ECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group, Allen K, Mau J, Meier D, del Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C, Bladin C, Byrnes G. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010 May 15;375(9727):1695-703. (
  • This pooled analysis is of a predetermined selection of RCTs to be included and so does not qualify as a systematic review. Furthermore, these trials differ significantly in their protocols and exclusion criteria (see Carpenter CR, et al. Thrombolytic therapy for acute ischemic stroke beyond three hours, J Emerg Med 2010) and this "macro-heterogeneity" suggests that these trials not be combined into a pooled analysis. However, the studies selected are also those most likely to be included in a sensitivity analysis of a full systematic review. The data from the 3,670 patients confirm that intravenous alteplase does not provide any therapeutic benefit to the vast majority of patients suffering from stroke and that the greatest benefit is seen early after symptom onset. Although there appears to be greater mortality associated with alteplase after 4.5 hours, there is no evidence that risk of serious or fatal symptomatic haemorrhage increases with later initiation of treatment.
  • Thrombolytic treatment of ischemic stroke needs to be given early. Treatment after 4.5 hours will likely do more harm than good.


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