Cases & Commentaries

Hold the tPA

Commentary By Susan C. Fagan, PharmD, BCPS, FCCP

The Case

A 74-year-old woman with a history of atrial
fibrillation on warfarin therapy came to the emergency department
(ED) 1 hour after the sudden onset of aphasia and right-sided
weakness. A non-contrast CT scan of the brain revealed blurring of
the left gray-white junction with no hemorrhage, consistent with an
acute left middle cerebral artery ischemic stroke. Less than 3
hours had elapsed since the onset of her symptoms, making her a
potential candidate for thrombolysis. There were no
contraindications to tissue plasminogen activator (tPA)
administration at the time, but laboratory results, including a
complete blood count (CBC) and coagulation studies, were

In order to expedite treatment (crucial because
research finds benefit for thrombolysis in acute stroke only if
administered in the first 3 hours; see below), the ED physician
wrote an order for an appropriate dose of intravenous (IV) tPA and
asked a nurse to obtain the dose from the pharmacy. The nurse
returned from the pharmacy and placed the medication at the
patient’s bedside. A second ED nurse caring for the patient
read the order in the patient’s chart and administered the
tPA bolus. Five minutes later, the lab results returned—the
INR was elevated at 4.5, an absolute contraindication to
thrombolytic therapy.

The patient was transferred to the neurological
ICU. She underwent serial CT scanning, which did not show
hemorrhagic conversion of her ischemic stroke. She didn’t
suffer any other bleeding complications, but she was unable to
receive many elements of standard ischemic stroke care, such as
permissive hypertension. Eventually, she died of stroke-related

The Commentary

The use of tPA in acute ischemic stroke patients
has been shown to improve the likelihood of an excellent outcome
(ie, minimal or no disability) at 90 days by 30%.(1) In clinical
practice, the benefits have been shown to be similar, as long as a
strict protocol is followed.(2) The therapy
is recommended for ischemic stroke patients meeting criteria and
presenting early enough to be treated within 3 hours of the onset
of symptoms.(3,4) After that
narrow window of time, the potential benefits of thrombolysis are
thought to be outweighed by the real risk of hemorrhage (up to 15%
or more).(5,6) This means
that “time is brain” in the management of acute
stroke—clinicians have only a short time to assess a
patient’s symptoms, confirm that they are due to stroke and
that the patient is eligible for thrombolysis, and rule out any
condition, such as coagulopathy or preexisting bleeding, that would
be a thrombolysis contraindication.

This patient appears to have met criteria for the
administration of tPA and might well have benefited from treatment.
However, in the rush to administer the tPA in the 3-hour time
window, she was given the tPA before her coagulation studies were
known. Luckily, she did not suffer any obvious or immediate
consequences, but the administration of tPA to a patient whose INR
was supratherapeutic (above 3) undoubtedly placed her at increased
risk for bleeding complications.

Because weighing the risks and benefits of tPA
administration in acute ischemic stroke is complex,
institution-specific protocols have been developed, based on the
published clinical trial demonstrating efficacy.(1)
Unfortunately, protocol deviations occur commonly in the
community—in more than 50% of patients treated in some early
series.(2,5,6) When
examined in a meta-analysis of studies of tPA in routine clinical
practice, high rates of protocol deviations were associated with
increased in-hospital mortality.(2) The most
common protocol deviations were treatment beyond the 3-hour window,
use of antithrombotic therapy within 24 hours of tPA
administration, and failure to follow blood pressure parameters or
monitoring schedule.(5,6) In one
study, 10% of the violations involved tPA administered to patients
with a “bleeding diathesis,” like the patient in this

Thrombolysis in the setting of acute stroke is an
urgent, essential, and yet risky intervention for eligible
patients. The Institute of Safe Medication Practices (ISMP)
considers tPA a “high-alert” medication (7)—one
that bears a heightened risk of causing significant patient harm
when it is used in error. A recent commentary proposed
recommendations to limit errors associated with these medications,
focusing on thrombolysis.(8) The
principles are listed in the Table.

Is there any way to improve patient safety in the
area of acute stroke management? The good news is that instituting
a quality improvement effort in acute stroke care, involving
education and streamlining processes of care, can drastically
reduce protocol violations and improve both the numbers and safety
of patients treated.(9) In a recent
study, a community-wide quality improvement effort reduced protocol
violations from 50% to 19% in a year-long effort.(9) The specific
interventions that were effective included improving documentation
and communication. Standardized orders and checklists were used
(see Figure), with inclusion and exclusion criteria. Most
high-volume EDs utilize tPA “kits,” which include order
forms, inclusion and exclusion criteria, and the medication. As
well, many institutions use a dedicated “stroke team.”
Stroke teams consist of nurses practicing in emergency, critical
care, and specialized neurological or stroke units; general
neurologists; emergency physicians; radiologists; speech-language,
physical, and occupational therapists; clinical pharmacists; and
nutrition support dietitians. Ongoing, intensive education of
providers involved in the care of acute stroke patients is

Unfortunately, the incidence of medication errors
in EDs has been estimated to be 12.6% of elderly patients
(10) and up to
17% of pediatric emergency patients.(11)
Although involvement of a clinical pharmacist in a
multidisciplinary team has been shown to reduce adverse events and
reduce mortality (12), this
tactic is not practical in all ED settings. Diligent attention to
the systems of care for administration of a risky, but highly
beneficial, medication in a narrow population, such as tPA for
stroke, can maximize the benefit to patients.

Take-Home Points

  • Thrombolysis for acute stroke can be an
    effective and safe treatment if strict medication protocols are
  • The safe administration of tPA to
    patients with acute ischemic stroke depends on a well-functioning
    team that has the necessary tools and has practiced and perfected
    their roles, both individually and collectively.
  • Institutions should utilize standardized
    orders and checklists with inclusion and exclusion criteria in the
    care of acute stroke patients.

Susan C. Fagan, PharmD
Professor of Pharmacy
University of Georgia


1. Tissue plasminogen activator for acute
ischemic stroke. The National Institute of Neurological Disorders
and Stroke rt-PA Stroke Study Group. N Engl J Med.
[ go to PubMed ]

2. Graham GD. Tissue plasminogen activator
for acute ischemic stroke in clinical practice: a meta-analysis of
safety data. Stroke. 2003;34:2847-50.
[ go to PubMed ]

3. Albers GW, Amarenco P, Easton JD, Sacco
RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic
stroke: the Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest. 2004;126:483S-512S.
[ go to PubMed ]

4. Adams HP Jr, Adams RJ, Brott T, et al.
Guidelines for the early management of patients with ischemic
stroke: a scientific statement from the Stroke Council of the
American Stroke Association. Stroke. 2003;34:1056-83.
[ go to PubMed ]

5. Bravata DM, Kim N, Concato J, Krumholz
HM, Brass LM. Thrombolysis for acute stroke in routine clinical
practice. Arch Intern Med. 2002;162:1994-2001.
[ go to PubMed ]

6. Katzan IL, Furlan AJ, Lloyd LE, et al.
Use of tissue-type plasminogen activator for acute ischemic stroke:
the Cleveland area experience. JAMA. 2000;283:1151-8.
[ go to PubMed ]

7. ISMP’s list of high-alert
medications. ISMP Web site. December 2003. Available at: [
go to related site ]. Accessed February 10, 2005.

8. Paparella S. Thrombolytic therapy: no
room for error. J Emerg Nurs. 2004;30:348-50.
[ go to PubMed ]

9. Katzan IL, Hammer MD, Furlan AJ, et al.
Quality improvement and tissue-type plasminogen activator for acute
ischemic stroke: a Cleveland update. Stroke. 2003;34:799-800.
[ go to PubMed ]

10. Caterino JM, Emond JA, Camargo CA Jr.
Inappropriate medication administration to the acutely ill elderly:
a nationwide emergency department study, 1992-2000. J Am Geriatr
Soc. 2004;52:1847-55.
[ go to PubMed ]

11. Kozer E, Seto W, Verjee Z, et al.
Prospective observational study on the incidence of medication
errors during simulated resuscitation in a paediatric emergency
department. BMJ. 2004;329:1321.
[ go to PubMed ]

12. Position paper on critical care pharmacy
services. Society of Critical Care Medicine and American College of
Clinical Pharmacy. Pharmacotherapy. 2000;20:1400-6.
[ go to PubMed ]


Table. Recommendations to limit errors
associated with thrombolysis.

  • Standardize and simplify: Reduce the
    number of similar agents used and develop preprinted order
  • Perform analyses of systems to identify
    potential sources of error before they occur.
  • Improve communication among all
    necessary practitioners. Ideally, a pharmacist should review all
    emergency department orders (usually not done).
  • Clearly label different
    “kits” for myocardial infarction and ischemic
  • Apply bold auxiliary labels to patient
    charts with inclusion and exclusion checklists, time of
    administration, etc.
  • Obtain a thorough patient history for
    contraindications and ensure all providers have easy access to this
  • Perform an independent double-check
    prior to administration, similar to those performed before blood
    transfusions and chemotherapy.
  • Avoid abbreviations.
  • Maintain and promote staff competency
    and education.


Figure. Sample stroke history and checklist.
Available at

Click on the thumbnail for a full
view of the figure.