The Case

A 71-year-old woman arrives to the ED by EMS with right-sided weakness beginning 3 hours prior. Immediate neuroimaging demonstrates she does not qualify for endovascular clot retrieval. She has a National Institutes of Health Stroke Scale (NIHSS) score of 12 and no contraindications for systemic thrombolysis.

Clinical Question

Is tissue plasminogen activator (tPA) safe and effective 3–4.5 hours after onset of symptoms in patients with acute ischemic stroke (AIS)?

Background

One of the most debated subjects in EM over the years is the use of thrombolytics in AIS. The controversy goes back to 1995 when the National Institute of Neurological Disorders and Stroke (NINDS) trial was published.¹ This was the first randomized controlled trial (RCT) to claim efficacy for tPA in patients presenting with stroke symptoms of less than 3 hours. The authors of NINDS reported a 12 percent absolute benefit (good neurological outcome on the modified Rankin Scale [mRS]) at 90 days, with a 6 percent absolute increase in harm (bleeding).

A reanalysis of the NINDS data published in 2009 revealed that a baseline imbalance in stroke severity at presentation likely led to the difference in outcomes.² After controlling for these baseline differences, the claimed efficacy of tPA was no longer statistically significant.

There’s only one other RCT claiming benefit for the primary outcome of thrombolytics in AIS—the ECASS-III trial that gave tPA 3–4.5 hours after stroke symptom onset.³ ECASS-I and -II did not show a benefit with thrombolysis but did find an increase in harm (7 percent increase in mortality and 7 percent increase in intracranial hemorrhage, respectively).

The ECASS-III trial reported a 7 percent absolute benefit of improved mRS at 90 days compared to placebo, 9 percent increase in intracranial hemorrhage, 2 percent increase in symptomatic intracranial hemorrhage, and no significant difference in mortality.

NINDS and ECASS-III informed the ACEP clinical policy statement on the issue.⁴ The policy looked at the less than 3-hour time frame and the 3–4.5-hour time frame and made no level A recommendations, but it did make level B and C recommendations:

• Is IV tPA safe and effective for patients with AIS if given within 3 hours of symptom onset?
  • Level B Recommendations: With a goal to improve functional outcomes, IV tPA should be offered and may be given to selected patients with AIS within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication. The increased risk of symptomatic intracerebral hemorrhage (sICH) should be considered when deciding whether to administer IV tPA to patients with AIS.
  • Level C Recommendations: When feasible, shared decision-making between the patient (and/or their surrogate) and a member of the health care team should include a discussion of potential benefits and harms prior to deciding whether to administer IV tPA for AIS. (Consensus recommendation.)
• Is IV tPA safe and effective for patients with AIS treated between 3–4.5 hours after symptom onset?
  • Level B Recommendations: Despite the known risk of sICH and the variability in the degree of benefit in functional outcomes, IV tPA may be offered and may be given to carefully selected patients with AIS within 3–4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication.
  • Level C Recommendations: When feasible, shared decision-making between the patient (and/or their surrogate) and a member of the care team should include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA for AIS. (Consensus recommendation.)

Now, 12 years after the publication of ECASS-III, a reanalysis of the RCT—similar to the reanalysis of the NINDS trial 14 years after it was published—has been published.

Reference: Alper BS, Foster G, Thabane L, et al. Thrombolysis with alteplase 3–4.5 hours after acute ischemic stroke: trial reanalysis adjusted for baseline imbalances [published online ahead of print May 19, 2020]. BMJ Evid Based Med.