Background

Stroke is one of the leading causes of death in the United States. Approximately 87% of all strokes are ischemic. Available therapies are limited and include thrombolysis and thrombectomy. There is a known risk of hemorrhagic conversion of acute ischemic strokes with the use of thrombolytics. Of the 12 clinical trials comparing thrombolysis vs. either placebo or no treatment for acute ischemic stroke, only two favored thrombolysis (NINDS-2 and ECASS-III). In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) group established a 3-hour window for the use of alteplase, reporting that patients who received alteplase within this window had more favorable neurological outcomes. The European Cooperative Acute Stroke Study (ECASS) investigators aimed to demonstrate the advantage of thrombolysis over placebo using an extended window of 3-4.5 hours after symptom onset, while also investigating the safety profile of alteplase.

Clinical Question

In adult patients presenting with acute ischemic stroke, does the administration of alteplase between 3-4.5 hours of symptom onset reduce disability at 90 days?

Population

Adult patients diagnosed with acute ischemic stroke presenting to 130 sites in 19 European countries.

  • Inclusion Criteria
    • 18 to 80 years old
    • Diagnosis of acute ischemic stroke
    • Able to receive alteplase within 3 to 4.5 hours after onset of symptoms
    • Stroke symptoms present for at least 30 minutes with no significant improvement before treatment

Intervention

0.9 mg of alteplase per kilogram, administered intravenously (with an upper limit of 90 mg)

Control

Placebo

Outcomes

  • Primary
    • Disability at 90 days defined using the modified Rankin scale (mRS), dichotomized as a favorable outcome (score of 0-1) or an unfavorable outcome (score of 2-6).
  • Secondary
    • Global outcome analysis of four neurologic and disability scores at day 90, defined as:
      • 0 or 1 on mRS
      • >95 on Barthel index
      • 0 or 1 on NIHSS
      • 1 on Glasgow Outcome Scale
    • Safety endpoints
      • Mortality at 90 days
      • Symptomatic intracranial hemorrhage (defined in ECASS-III as any apparently extravascular blood in the brain or within the cranium associated with clinical deterioration, defined by an increase of 4 points or more on the NIHSS or that led to death and that was identified as the predominant cause of the neurologic deterioration)
      • Symptomatic edema
      • Other serious adverse events

Design

Multicenter, randomized, double-blinded, placebo-controlled trial

Excluded

  • Intracranial hemorrhage
  • Severe stroke (NIHSS >25 or involving more than 1/3 of the MCA territory)
  • Time of symptom onset unknown
  • Symptoms rapidly improving or only minor before start of infusion
  • Seizure at the onset of stroke
  • Stroke or serious head trauma within the previous 3 months
  • Combination of previous stroke and DM
  • Administration of heparin within 48 hours preceding onset of stroke, with a PTT exceeding the upper limit of normal
  • Platelet count of <100,000
  • Systolic BP >185 or diastolic BP >110, or aggressive IV meds needed to reduce BP to these limits
  • FS <50 or >400
  • Symptoms suggestive of SAH
  • Oral anticoagulant treatment
  • Major surgery or severe trauma within the previous 3 months
  • Other major disorders associated with an increased risk of bleeding

Primary Results

  • Primary Results
    • A total of 821 patients were enrolled
    • Median time for administration of alteplase was 3 hours and 59 minutes
    • More patients had a favorable outcome with alteplase than placebo (52.4% vs. 45.2%, OR 1.34, P = 0.04)
    • The incidence of symptomatic intracranial hemorrhage was higher with alteplase than placebo (2.4% vs. 0.2%; P=0.008)
    • There was no mortality difference between alteplase and placebo (7.7% and 8.4%, P = 0.68)
    • There was no significant difference in the rate of other serious adverse events
  • Critical Findings
    • The alteplase group had less severe strokes at baseline (mean 10.7 vs. 11.6, P=0.03)
    • If the primary outcome is changed to include a score of 2 on the mRS as a favorable outcome, there benefit to alteplase is no longer significant (OR 1.3, P=0.11).

Strengths

  • This was a multicenter, randomized, double-blinded, placebo-controlled trial
  • There was a large sample size (n=821)

Limitations

  • The primary outcome of disability at 90 days was dichotomized on the mRS, considering a score of 2 (unable to carry out all previous activities but able to look after own affairs without assistance) equivalent to a 6 (death).
  • The alteplase group had less severe strokes, creating an imbalance between the groups at baseline.
  • The study protocol was changed during the trial (from a window of 3-4 hours to a window of 3-4.5 hours) secondary to slow rate of patient recruitment.
  • Patients with severe strokes were excluded.
  • The trial was funded by Boehringer Ingelheim, the makers of alteplase.

Author's Conclusions

“As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage.”

Our Conclusions

There may be a benefit to administering alteplase in patients with acute ischemic stroke between 3 and 4.5 hours after symptom onset. However, this benefit is defined using a dichotomized scale that has a wide range of outcomes considered to be unfavorable. This is one of only two positive trials for tPA out of the 12 trials to date. Alteplase also has no mortality benefit while carrying a significant risk of intracranial hemorrhage.

Potential Impact To Current Practice

Based on the data in this study, ACEP gives a Level B recommendation to the use of tPA between 3 to 4.5 hours after symptom onset. The risk of administering tPA should be carefully weighed against the potential benefit. Shared decision-making with the patient and obtaining informed consent is essential when considering tPA for acute ischemic stroke.

Bottom Line

In adult patients presenting with acute ischemic stroke between 3 and 4.5 hours after symptom onset, alteplase may reduce disability at 90 days while there is no mortality benefit and a significant risk of symptomatic intracranial hemorrhage.

Read More

EMCrit: The tPA for Ischemic Stroke Debate

EMCrit: Ischemic Stroke 2013

LITFL: Stroke Thrombolysis

REBEL EM: Ischemic Stroke Treatment Archive

ACEP Policies: Intravenous tPA for Acute Ischemic Stroke

EM Lit of Note: The Wholesale Revision of ACEP’s tPA Clinical Policy

References

  • Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Dávalos, A., Guidetti, D., … & Schneider, D. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. New England Journal of Medicine, 359(13), 1317-1329.
  • National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. (1995). Tissue plasminogen activator for acute ischemic stroke. New England Journal of Medicine, 333(24), 1581-1588.
  • “Stroke Facts.” Centers for Disease Control and Prevention. 2017. www.cdc.gov/stroke/facts.htm.