Ischemic stroke is an emergent and devastating neurologic disorder, and is a leading cause of both death and disability in the United States. With each minute of brain ischemia, two million neurons are irreversibly damaged. Total ischemic time is linked to functional outcome, and therefore, the role of the Emergency Department is paramount in the management of these patients. Fibrinolytic therapy has become a mainstay of therapy for acute stroke, but guidelines for the use of tPA are dynamic, and often even controversial. When you identify someone with symptoms of stroke, what is your approach to determining if a patient should receive tPA?

Based on data from the landmark National Institute of Neurological Disorders and Stroke (NINDS) trial in 1995, IV tPA has become the standard of care in the treatment of acute ischemic stroke. Despite the favorable outcomes suggested in this trial, tPA administration is associated with an increased risk of intracerebral hemorrhage. In addition, questions regarding timing of tPA administration, route of tPA administration, and exclusion criteria for tPA administration continue to be actively investigated and debated. When evaluating a patient with ischemic stroke for tPA, the following considerations can guide your decision-making.

1. Time is brain

For patients who present within 3 hours of symptom onset, the original NINDS data demonstrated not only improved outcome for patients who received the IV tPA, but suggested that outcomes were better for patients who received tPA earlier. This was particularly robust for those patients who received tPA within 90 minutes of symptom onset. 1 Subsequent pooled analysis of the NINDS data and 5 other large trials of IV tPA for acute stroke confirmed a time-dependent benefit of IV tPA if given within 3 hours of symptom onset. 2,3  Most recently, data from over 58,000 patients also confirmed this time-to-treatment benefit for patients presenting up to 4.5 hours from symptoms onset, both in terms of functional recovery and mortality. 4 Administration of tPA as soon as possible is a Level 1A recommendation of the American Heart Association (AHA), with a door-to-needle goal of less than 60 minutes. This is also a Level A Recommendation by ACEP. 5,6

2. Timing of IV tPA

Notably, although the NINDS trial only enrolled patients with symptoms <3 hours in duration, other major randomized-controlled trials have enrolled patients with symptoms up to 6 hours. Pooled analysis of these studies not only confirmed benefit of IV tPA until 3 hours from symptom onset but also suggested benefit of IV tPA until 4.5 hours from symptom onset. This finding was confirmed in a prospective RCT in 2008 (ECASS III), as well as subsequent meta-analysis in 2009. 2,3,7  Opponents of IV tPA in the extended time period cite the increased risk of ICH seen in the ECASS III trial, though the combined data demonstrated improved outcomes with no change in mortality. Though IV tPA is only FDA approved up to 3 hours from symptom onset, its use up to 4.5 hours is widely accepted and is a Level 1B recommendation of the American Heart Association (AHA). It is a Level B recommendation by ACEP.

 3. Less is more

When considering IV tPA, focus on expediting essential interventions to confirm the diagnosis of stroke and evaluate for potential exclusion criteria. All efforts should be made to obtain a non-contrast CT of the brain as soon as possible after ED arrival, as tPA cannot be given without brain imaging. The AHA goal for door-to-CT time is less than 25 minutes. Without specific clinical indication (e.g. patient on anticoagulation), neither CT nor administration of tPA should be delayed by adjunctive testing. That means ECG, CXR, and most basic laboratory values, including coagulation studies, should not delay CT or tPA administration. According to the AHA guidelines, blood glucose evaluation is the only routine lab that must precede the administration of IV tPA. This is a Level 1B recommendation by the AHA.

4. If it looks like a stroke, it’s OK to treat it like one

Although stroke is the most common cause of acute focal neurologic deficit, other neurologic conditions can mimic stroke symptoms. Nonetheless, presence of a stroke mimic does not need to deter nor delay consideration of IV tPA. Retrospective data suggest that anywhere from 3-21% of patients treated with IV tPA do not have ischemic stroke, but rather complicated migraine, seizure or conversion disorder. 8–10  In these cohorts, no patients experienced symptomatic hemorrhagic complications after receiving IV tPA. Though further research is needed, this data suggests that IV tPA is not harmful to patients with stroke mimics. Given the time-dependent benefit for patients with ischemic stroke, IV tPA merits careful consideration even in the face of diagnostic uncertainty.

5. Not all exclusion criteria are created equal

The exclusion criteria for the administration of IV tPA were largely dictated by the exclusion criteria chosen by the investigators in the original NINDS trial.  Since 1995, data suggests that IV tPA may hold benefit for subsets of patients with traditional exclusion criteria. These include advanced age, surgery or trauma within 3 months, prior stroke, recent MI, low initial NIHSS and the presence of rapidly improving stroke symptoms (RISS). Patients with RISS have been the focus of recent debate, as data suggests that these patients may be at risk for further deterioration. A recent consensus statement from the original NINDS investigators supports treatment of patients with RISS, and that:

“all neurological deficits present at the time of the treatment decision should be considered in the context of individual risk and benefit, as well as the patient’s baseline functional status.” 11

View and download the 2013 Stroke exclusion criteria list in PV Card form. 1

6. Plan for advanced intervention early

Although IV tPA is a mainstay of treatment in the ED, some patients with acute ischemic stroke may benefit from additional interventions such as intra-arterial (IA) tPA or direct clot retrieval. Studies regarding the efficacy and safety of IA treatment and combination IV/IA treatment are ongoing, but preparation for the potential of further intervention should be considered in the ED. This includes further imaging, including CTA, and early involvement of interventional radiologists. Further imaging should not delay IV tPA.

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Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-774. [PubMed]
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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. [PubMed]
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Chernyshev O, Martin-Schild S, Albright K, et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology. 2010;74(17):1340-1345. [PubMed]
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Re-examining A, Levine S, Khatri P, et al. Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke. 2013;44(9):2500-2505. [PubMed]
Todd A. Seigel, MD

Todd A. Seigel, MD

ALiEM Featured Contributor
Clinical Fellow in Critical Care Medicine
University of California, San Francisco (UCSF)
Todd A. Seigel, MD

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