Should Tissue Plasminogen Activator (tPA) Administration be Considered for the 3 to 4.5 Hours Range?

FEBRUARY 16, 2018
The CDC estimates that stroke kills 140,000 Americans per year, which is approximately 1 of every 20 deaths in the United States.1 Another alarming fact is that someone in the US has a stroke every 40 seconds, but fewer than half of 911 calls for stroke events were made within 1 hour of symptom onset2,3 It is common for institutions to limit the administration of tPA to within 3 hours of acute ischemic stroke onset. However, clinical evidence supports the use of tPA for the 3-4.5 hour range in defined situations. Let’s take a look at the clinical studies relevant to tPA administration in patients with Acute Ischemic Stroke.
Stroke can be either ischemic or hemorrhagic, and they are treated differently.4,5 Ischemic stroke results from occlusion of cerebral artery which leads to severe reduction in cerebral blood flow leading to infarction. Continued ischemic state results in neuronal damage and accumulation of prostaglandins, leukotrienes, and free radicals. The free radicals induce intracellular acidosis which subsequently leads to cell death. This process takes approximately 2-3 hours.

Hemorrhagic stroke is not only less common than ischemic stroke, but we also have limited understanding of the disease. Intracranial hemorrhage (ICH), especially in the brain parenchyma, produces damages to surrounding tissue through mass effect.5,6 About 30% of ICH enlarge predominantly within the first 4 hours and continue over the 24 hours period.7 Hemorrhage volumes of more than 60 milliliters are associated with 71% to 93% mortality within 30 days.6
Clinical Presentation
The patient may experience cognitive or verbal deficit, weakness on one side of the body, vision changes with both ischemic and hemorrhagic stroke. Severe headache is usually unique to hemorrhagic stroke.5 The National Stroke Association recommends using FAST (Face, Arms, Speech, and Time) acronym to identify stoke8:

Face: does one side of the face droop?
Arms: When the person lifts two arms, does one arm drift downward?
Speech: Is the person’s speech slurred or strange?
Time: If you observe any of the above signs, call 911 immediately
The 2013 AHA/ASS Guidelines for the Early Management of Patients with Acute Ischemic Stroke recommends utilizing National Institutes of Health Stroke Scale (NIHSS) to quantify impairment caused by stroke (0: no stroke symptoms, 1-4 minor stroke, 5-15 moderate stroke, 16-20 moderate to severe stroke 21-42 severe stroke).

The National Institute of Neurological Disorders and Stroke's tPA Stroke Trial was a two part trial that evaluated 624 subjects with ischemic stroke.11 The subjects were given either intravenous tPA or placebo within 3 hours of symptom onset. The first part of the trial’s primary end point was ≥4 point improvement in the NIHSS score or complete recovery (NIHSS score 0).12 There was no significant difference between the intravenous tPA and placebo. The second part of the trial’s primary end point was favorable outcome defined as minimal or no disability using 4 stroke assessment scales: barthel index (score 95≤), modified rankin score (Score ≤1), glasgow outcome scale (score=1), and NIHSS (score ≤1). The results of all four scales demonstrated functional and neurological improvements.

A meta-analysis of of ECASS I, ECASS II, ATLANTIS A, and ATLANTIS B trials suggest a benefit of 3 to 4.5 hour window of tPAadministration.13 The outcome is based on global outcome measure and the modified rankin scale without adversely affecting 90 day mortality. Although none of the 4 trials individually demonstrated clinical benefit of 3 to 4.5 hour window of tPA administration, a pooled analysis of the 4 trials showed improved outcome in post-stoke disability. ECASS III trial was conducted to study the benefit of 3 to 4.5 hour window of tPA administration. The outcome showed tPA’s excellent 90-day outcome on the mRS disability scale (0-1) in comparison to placebo. The EPITHET study looked at whether the tPA administration during the 3 to 6 hour window would promote perfusion as well as attenuate infarct for those who had a mismatch between perfusion weighed and diffusion weighed MRI. IV tPA was statistically significantly associated with increased perfusion but insignificantly associated with lower infarct growth.14

The AHA/ASS guideline lists exclusion criteria for 3 to 4.5 hour administration of tPA: >80 years of age, anticoagulant use regardless of INR, NIHSS score >25, imaging evidence of ischemic injury more than 1/3 of MCA territory, and history of both diabetes mellitus and stroke.9 Inclusion criteria is similar to that of 3 hour administration window. 
Although administration of tPA during the 3 to 4.5 hour of acute ischemic stroke onset may not be widely practiced, it is an option that can be considered for patients who meet the inclusion criteria.
  1. Vital Signs: Recent trends in stroke death rates—United States, 2000-2015. The Centers for Disease Control and Prevention. MMWR. 2017;66
  2. Benjamin EJ, Blaha MJ, Chiuve SE, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135:e229-e445.
  3. Mosley I, Nicol M, Donnan G, Patrick I, Dewey H. Stroke symptoms and the decision to call for an ambulance. Stroke. 2007;38:361–366
  4. Xing C, Arai K, Lo EH, Hommel M. Pathophysiologic cascades in ischemic stroke. Int J Stroke 2012;7:378–385.  
  5. Fagan SC, Hess DC. Chapter 10. Stroke. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014.
  6. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral hemorrhage. Lancet 2009;373:1632–1644.§ionid=45310472. Accessed January 05, 2018.
  7. Gregson BA, Broderick JP, Auer LM, et al. Individual patient data subgroup meta analysis of surgery for spontaneous supratentorial intracerebral hemorrhage. Stroke 2012;43:1496–1504
  8. Accessed January 6th 2017
  9. The 2013 AHA/ASS Guidelines for the Early Management of Patients with Acute Ischemic Stroke
  10. Hage V (2011). "The NIH stroke scale: a window into neurological status". Nursing Spectrum. 24 (15): 44–49.
  11. Chong JY. Intravenous Tissue Plasminogen Activator (IV tPA) Treatment for Acute Ischemic Stroke. Cerebrovascular Disease. 2013:1-6. doi:10.1093/med/9780199907878.003.0001.
  12. Activase [Prescribing Information]. South San Francisco, CA: Genentech, Inc; January 2017.
  13. Lansberg MG, Bluhmki E, Thijs VN. Efficacy and Safety of Tissue Plasminogen Activator 3 to 4.5 Hours After Acute Ischemic Stroke: A Metaanalysis. Stroke. 2009;40(7):2438-2441. doi:10.1161/strokeaha.109.552547.
  14. Norrving, Bo. Faculty of 1000 evaluation for effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-Controlled randomised trial. F1000—Post-Publication peer review of the biomedical literature, 2008, doi:10.3410/f.1103191.558324.

David Kim, PharmD
David Kim, PharmD
Dr. Kim is a graduate of MCPHS University in Boston, MA. He is currently serving his country as a Pharmacy Specialist in the United States Army Reserve. He is a certified immunizer and holds other APhA certifications such as Medication Therapy Management and Diabetes Care. The views expressed in his publications do not reflect the views of the United States Army, Department of Defense, or the United States Government.