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.

• Population: Adult patients age 18–80 years with at least 30 minutes of AIS symptoms presenting between 3–4.5 hours after onset of symptoms with no significant improvement.
  • Main Exclusion: Multiple exclusions were listed in the manuscript.
• Intervention: tPA 0.9 mg/kg;initial 10 percent bolus, remainder given over 60 min.
• Comparison: Placebo.
• Outcomes:
  • Primary: mRS score 0–1 (favorable) versus 2–6 (unfavorable) at 90 days.
  • Secondary: Global outcome measure combining 90-day outcomes of mRS 0–1, ≥95 Barthel Index, NIHSS score 0–1, score of 1 Glasgow Outcome Scale; mortality at 90 days; any ICH, sICH, symptomatic edema, and other serious adverse events.

Authors’ Conclusions

“Reanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3–4.5 hours after stroke onset.”

Key Results

ECASS-III included 821 patients with a mean age of 65 years and 60 percent male. After adjusting for baseline imbalances, multiple methods failed to find statistically significant benefits with thrombolysis given 3–4.5 hours after stroke onset and confirmed the significant increase in harm.

Evidence-Based Medicine Commentary

1. Inter-rater reliability (IRR): The outcome assessment used mRS. The IRR for mRS is moderate at best.^5,6 A clinical trial has internal validity only if imbalances between groups and bias in the assessment of outcome and chance have been excluded as possible explanations for the observed difference in outcomes.

2. Fragility index (FI): The FI is another way to represent the data, and it’s statistically reproducible.⁷ FI is the minimum number of patients who would need to have a different outcome to change the P value from <0.05 to >0.05, although the 0.05 threshold as a measure of statistical significance has its own problems.⁸ A low FI means only a small number of patients would need to have their outcome change for the trial to lose statistical significance. The FI of the original ECASS-III data is 1, meaning only one patient would need to have a different outcome to change the result. This is consistent with the reanalysis study by Alper et al, which found no significant benefit for tPA.

Other data for this time window support the fragility of ECASS-III data. IST-3 was the largest RCT investigating tPA for AIS in treated patients up to 6 hours.9 It didn’t show a benefit for its primary outcome. The pre-specified 3–4.5-hour subgroup was around double that of ECASS-III (n=1,177 versus n=821). IST-3 had a significant decrease in good neurologic outcome in patients randomized to tPA (32 percent) versus placebo (38 percent).

3. Baseline imbalances: A strong predictor of stroke outcome is severity of symptoms at presentation. There was an important baseline imbalance in stroke between the two groups in the ECASS-III trial. Those randomized to placebo had a worse median and mean baseline NIHSS score.

Another difference between the two groups was that double the number of patients with a history of a previous stroke (7.7 percent tPA versus 14.1 percent placebo; P = 0.003) appeared in the placebo arm. Recurrent strokes have a worse outcome than first strokes. The statistical difference in outcome favoring tPA over placebo could be explained by the baseline imbalance.

Bottom Line

Reanalysis of the original ECASS-III data does not support a patient-oriented benefit of tPA given 3–4.5 hours after onset of stroke symptoms and confirms the known potential harm.

Summary of Thrombolytics for AIS

There are 13 RCTs of thrombolytics for AIS (see Table 1). Four were stopped early for harm (bleeding) or futility, and all 13 failed to show a statistical benefit after the reanalysis of NINDS-2 and ECASS-III.

Table 1: Trials Involving Thrombolytics for Acute Ischemic Stroke

* Reanalysis of NINDS-2, ** Reanalysis of ECASS-III , Red indicates trials that were stopped before completion.

The table does not include two newer RCTs looking at extending the therapeutic window to 4.5–9 hours. These newer trials were done with more advanced brain imaging, selecting patients with a perfusion mismatch. Both RCTs were stopped early, which can introduce bias toward efficacy. In addition, the majority of patients included in these trials would now qualify for endovascular therapy (EVT) clot retrieval. EVT has more evidence for efficacy than systemic thrombolysis and a recent RCT has shown that EVT alone is noninferior to EVT plus tPA.

Case Resolution

You provide the patient with the latest information on thrombolytics for stroke. Her mental status is intact and she clearly understands the information as presented. She elects not to move forward with systemic tPA administration.

Thank you to Prof. Daniel Fatovich, an emergency physician at Royal Perth Hospital in western Australia and the head of the Centre for Clinical Research in EM, for his help with this review.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References

1. 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(24):1581-1587.
2. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med. 2009;54(3):329-336.
3. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
4. Brown MD, Burton JH, Nazarian DJ, et al. Clinical policy: use of intravenous tissue plasminogen activator for the management of acute ischemic stroke in the emergency department. Ann Emerg Med. 2015;66:322-333.
5. Quinn TJ, Dawson J, Walters MR, et al. Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009;40(10): 3393-3395.
6. Wilson JT, Hareendran A, Hendry A, et al. Reliability of the modified Rankin Scale across multiple raters: Benefits of a structured interview. Stroke 2005;36(4):777-781.
7. Farkas J. What is the fragility index of the NINDS trial? PulmCrit (EMCrit) website. Accessed Aug. 24, 2020.
8. Wasserestin RL, Lazar NA. The ASA’s statement on p-values: Context, process, and purpose. Am Stat. 2016;70(2):129-133.
9. IST-3 collaborative group, Sandercock P, Wardlaw JM, et al. 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.