While working on the Neurocritical care service, I have enjoyed seeing the teamwork between neurologists and emergency medicine physicians. Neurologists rely on the EM physician to inform them of potential stroke patients in the ED, while EM physicians use the neurologist as a guide in treatment management; however, in my short time on the service, I have seen a vast array of opinions on the administration of tPA. Tissue plasminogen activator or alteplase is a fantastic drug that saves lives when used in the right patient population. That is where the controversy lies. What is the right patient population and how do we avoid wasting valuable resources on non-stroke patients?

We have all heard the saying “time is brain.” Current recommendations state that tPA should be used in “eligible patients” within the first 3 hours (or 4.5 depending on who you ask). Who is an “eligible patient?” Inclusion criteria include a “clinical diagnosis” of ischemic stroke causing measurable neurologic deficit, onset of symptoms less than 4.5 (or maybe 3) hours before treatment, and age older than 18. Exclusion criteria are much more intricate, but almost all of them involve bleeding risk. The interesting part of the inclusion criteria is that administration of tPA requires only a clinical diagnosis of ischemic stroke. This means that as long as the CT scan shows no evidence of hemorrhage, anyone having stroke-like symptoms is an ischemic stroke until proven otherwise. EM physicians are tasked with trying to clinically diagnose an ischemic stroke in three hours, usually less since patients do not immediately present to the ED after symptoms begin.

Several disorders can mimic stroke including seizures, complex migraines, and conversion disorder. All of these would technically fit the eligibility criteria and thus could potentially receive tPA. Many studies have been performed on the risks of hemorrhage in actual stroke patients. These include the CASES study which showed a 4.6 percent risk of hemorrhage, the STARS study which showed 3.3 percent risk, and the SITS-MOST study which showed 7.3 percent risk. But what does the literature state on the opposite situation? Not much data has been reported. Does tPA increase the risk of bleed in patients not experiencing a stroke?

Dr. Cheryshev, et. al at the University of Texas in Houston performed a retrospective study on 512 patients who received tPA at their institution from 2004 to 2008. On follow-up imaging, it was found that 21% of these patients did not have an infarct. One third of these patients were determined to have stroke mimics (SM), i.e. complicated migraines, conversion disorder, etc. The other two thirds had neuroimaging negative cerebral ischemia (NNCI), i.e. TIA, cocaine vasospasm, etc. It was found that none of the patients with either a stroke mimic or NNCI had systemic hemorrhage, intracerebral hemorrhage, or angioedema. This is a pretty substantial finding as it shows the safety of the patient should not be the concern when deciding whether to administer tPA to a non-stroke patient. Though this may be true, the paper fails to mention that SM patients tend to be younger, healthier patients than those who have actual acute ischemic strokes. These patients by nature are probably less prone to bleed; however, the paper does mention that the use of tPA in STEMI patients causes less than one percent to have a hemorrhage. These patients tend to be of the same health as stroke patients and require a higher dose of tPA than stroke patients. Lastly, the paper does not take into account the cost of tPA. Alteplase is given at the dose of 0.9 mg/kg for acute ischemic strokes. For the average size man the cost of tPA needed is $7,829.50 according to Lexicomp. According to one of my Neurocritical care attendings, this price is actually closer to $15,000 for one dose; however, the cost of stroke to society according to the CDC is $36.5 billion per year. Although the cost of a patient’s life is immeasurable, the limitations of the data and the cost of tPA should still be taken into account when viewing the data on the safety of tPA administration.


  1. “Alteplase: Drug Information.” Lexicomp. UpToDate. <>
  2. “Reperfusion Therapy for Acute Ischemic Stroke.” Oliveria-Filho M.D. et. al. UpToDate. <>
  3. “Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia.” Chernyshev, M.D. et. al. Neurology. April 27, 2010.

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