Thrombolysis in Acute Stroke


Ever wonder where the the current American Heart Association and American Stroke Association (AHA/ASA) guidelines for thrombolysis in acute ischemic stroke come from?   Included is a summary of the landmark studies that have contributed to these recommendations (NINDS& ECASS III) as well as a review of IST-3. 

t-PA Inclusion Criteria

t-PA Absolute Exclusion Criteria

t-PA Relative Exclusion Criteria

Summary of Major Trials:

 NINDS (1995):

Study Question:

  • Does tPA reduce M&M in pt’s with ischemic stroke?


  • 2-part, multicenter (8 US centers), double-blinded, randomized placebo-controlled

  • N=624

    • NINDS I: 291
    • NINDS II: 333
  • Inclusion: acute ischemic strokes presenting <3 h from symptom onset

Results (Bottom Line):

  • In patients w/ acute ischemic stroke, administration of tPA w/in 3 h from symptom onset demonstrated improved neurologic outcome at 90 days (NNT= 8-9); however, it did not demonstrate mortality benefit.

  • Despite greater numbers of symptomatic intracranial hemorrhages in the tPA group, mortality rate was not statistically significant between the groups.

 ECASS-III (2008):

Study Question:

  • Is administration of tPA in acute stroke 3-4.5 h after symptom onset safe and effective?


  • RCT, n=821

  • Same inclusion/exclusion as NINDS, but with additional exclusions below:

    • baseline NIHSS score >25
    • age >80
    • use of any oral anticoagulant
    • combined history of DM and prior stroke

Results (Bottom Line):

  • IV tPA demonstrated improved neurologic outcome at 90 days when given within 3-4.5 h after symptom onset (NNT= 14).

  • Despite a greater incidence of intracranial hemorrhage in the tPA group (NNH=11), there was no significant difference in mortality between groups.


I IST-3 (2012):

  • Largest RCT of tPA use in acute stroke to date (3035 pts).
  • Inclusion criteria broadened to include pts > 80 yo and a wider BP range (SBP 90-220; DBP 40-130)

Results (Bottom Line):

  • Administration of IV tPA in acute stroke within 6 hours from symptom onset did not demonstrate improved functional neurologic outcome at 6 months.

  • There was a high incidence of symptomatic intracranial hemorrhage in the tPA group.

  • Despite an increased 7-day mortality rate in the tPA group, mortality at 6 months was the same between groups.



Hacke, W, Kaste, M, Fieschi, C et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet.1998; 352: 1245–1251

Huff, JS, Perron, AD. Neurologic Examination. In: Tintinalli JE, Stapczynski J, Ma O, Yealy DM, Meckler GD, Cline DM. eds.Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e. New York, NY: McGraw-Hill; 2016.Jauch et al.Guidelines for the early management of patients with acute ischemic stroke: A Guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947.

The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-2363.

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.