The Evidence Supports Thrombolytics & Stroke @ 4.5 Hours

July 2009

The Evidence Supports Thrombolytics & Stroke @ 4.5 Hours

Search Strategy: Since this is a therapy question, you first turn to the Cochrane Database of Systematic Reviews and quickly locate three high-quality randomized controlled trials since 1995. To ensure that more recent trials have not been published since the latest Cochrane Review (2003), you conduct a PUBMED Clinical Query (narrow/specific) for therapy using the search term “acute ischemic stroke thrombolysis” and net 99 citations which does indeed include one publication from 2008.

July 1. Residency transitions occur every year at the same time, but the bustle of excited apprehensive faces is never repetitious. This year’s first case is a 68 year old right-handed female arriving from home with expressive aphasia and right-sided weakness beginning 2.5 hours ago. The communications center astutely initiated the “stroke pager” as the emotional patient and her husband are wheeled back to their room. The Neurologist arrives in the room at the same time as the Emergency Medicine (EM) physician, quickly communicating with patient and husband to complete the NINDS-stroke check list. As labs are sent and the patient transported across the hall for her emergent CT, the nervous new Neurology resident and EM team confirm that no thrombolysis exclusion criteria have yet been identified.

Labs and CT-imaging are available within 25-minutes, pushing your patient to (but not across) the 3-hour no-thrombolysis threshold as Neurology and Emergency Medicine concurrently decide to administer t-PA. Shortly thereafter, your patient leaves the ED for the Neuro-ICU and you decide to explore the evidence supporting stroke thrombolysis.

PICO Question

Population: Emergency Department patients with acute ischemic stroke

Intervention: t-PA administration plus routine care

Comparison: Placebo plus routine care

Outcome: Intracranial hemorrhage, mortality, short- and long-term functional outcomes


First years: Tissue plasminogen activator for acute ischemic stroke, NEJM 1995; 333: 1581-1587. (

Second years: Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II), Lancet 1998; 352: 1245-1251. (

Third years: Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset: The ATLANTIS study, a randomized controlled trial, JAMA 1999; 282: 2019-2026. (

Fourth years: Thrombolysis with alteplast 3 to 4.5 hours after acute ischemic stroke, NEJM 2008; 359: 1317-1329. (


Article 1: Tissue Plasminogen Activator for Acute Ischemic Stroke NEJM 1995; 333:1581-1587

Article 2: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II), Lancet 1998; 352:1245-1251

Article 3: Recombinant Tissue – Type Plasminogen Activator (Alteplase) for Ischemic Stroke 3 to 5 Hours after Symptom Onset — The ATLANTIS Study: A Randomized Controlled Trial, JAMA 1999; 282: 2019-2026

Article 4: Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke, NEJM 2008; 359:1317-1329

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Bottom Line

The Succinct Answer

In university-affiliated United States hospital, the NINDS trials demonstrated that t-PA within 3-hours of symptom onset to highly select patients significantly reduces functional deficit at 24-hours and 3-months (NNT = 8). These benefits are associated with a significantly increased risk of symptomatic ICH within 36 hours (6% vs. 0%; NNH = 18), but no overall increase (or decrease) in 3-month mortality. Lacking other effective interventions for acute ischemic stroke the NNT, NNH, and limitations of this single study should be discussed with patients in collectively deciding upon the best option for an individual. Unfortunately, ECASS-II demonstrated that t-PA within 6-hours of symptom onset yielded a non-significant trend towards improved outcomes while significantly increasing the risk of ICH within 7-days – a finding replicated in the 3- to 5-hour window by ATLANTIS

ECASS-III has now demonstrated that intravenous alteplase (0.9 mg/kg with 10% bolus over 1-2-minutes and remainder over 1-hour) administered from 3 – 4.5 hours after symptom onset for ischemic stroke in select patients (see exclusion criteria below) in a research environment is associated with a clinically significant improvement in the proportion of patients with functionally independent favorable outcomes (NNT = 14; 95% CI 7 – 255) without increasing mortality or symptomatic ICH rates (NNH = 47; 95% CI 39-161). Patients who can be treated within 3 hours should not have their treatment delayed. Optimally, these results will be expeditiously replicated in future studies, but this currently represents the best-evidence by which to treat (otherwise untreatable) ischemic strokes and ought to be discussed with patients and families in conjunction with a local neurological protocol.

ECASS III Exclusion Criteria

  • Age < 18 or > 80 years
  • Onset of stroke > 4.5 hours before drug administration or symptom onset unknown
  • Stroke symptoms present < 30 minutes or significantly improving before treatment
  • Intracranial hemorrhage
  • Severe stroke as defined by NIHSS > 25 or imaging (CT or MRI) displaying > 1/3 of middle cerebral artery territory involved
  • Seizure at the onset of stroke
  • Stroke or serious head trauma within the previous 3-months
  • Combination of previous stroke and diabetes mellitus
  • Heparin within the preceding 48 hours with PTT above normal limit
  • Platelet count < 100,000 mm3
  • Systolic blood pressure > 185 mm Hg or diastolic > 110 mm Hg or aggressive treatment (intravenous medication) to reduce blood pressure to these limits
  • Glucose < 50 mg/dL or > 400 mg/dL
  • Symptoms suggestive of subarachnoid hemorrhage even if CT normal
  • Oral anticoagulation therapy
  • Major surgery or severe trauma within 3-months
  • Other major disorders with an increased risk of bleeding