Position Statement on the Use of Intravenous Thrombolytic Therapy in the Treatment of Stroke
AAEM statements are not to be construed as dictating an exclusive course of action nor are they intended to replace the medical judgment of healthcare professionals. The unique circumstances of individual patients and environments are to be taken into account in any diagnosis and treatment plan. AAEM statements reflect clinical and scientific advances as of the date of their publication and are subject to change.
Link to AAEM Educational Tool:
tPA for Stroke – Potential Benefit,Risk and Alternatives (PDF) (5/3/07)
AAEM Comment by Robert McNamara, MD, FAAEM
This AAEM position statement has been met with a great deal of support
from our primary constituency, the practicing emergency clinician. However,
some in academic centers are not happy with this statement because of
their opinion that the NINDs trial is definitive. AAEM expected both reactions
and understands each view point. We are aware of lawsuits against community
emergency physicians alleging a deviation from the standard of care for
failure to administer thrombolytics in stroke. This statement should assist
in such matters. It is important to note that AAEM is not the first organization
to cast doubt on the widespread use of thrombolytics in stroke. The Canadian
Association of Emergency Physicians in their position statement make several
recommendations including having an expert in neuroradiology read the
CT scan first, having a neurologist directly involved and recommend use
only within an approved research protocol or formal clinical practice
protocol with tight adherence to the NINDs criteria. For those in academic
or other centers who are currently using this treatment, the AAEM statement
should not inhibit their practice as "use" is also not considered
a standard of care issue.
How can we further reconcile this divergence on this
matter? First off, AAEM is always open to member input on any position
it takes and as always will be responsive to the members. I have already
engaged a few of the critics of this statement and have left the door
open for them to submit comments, modifications to the board for consideration.
However, in reviewing such submissions the board will be acutely aware
that its primary constituency, the EP at the bedside has not been convinced
by those promoting this therapy. The rank and file accepted thrombolytics
for MI despite its risks because there was clear evidence to them of the
significant benefits. The challenge to those who are critical of this
statement is to convince the EM community as was done for MI that this
should be the standard of care. It may be difficult to do that without
further research. Certainly, there needs to be recognition that the circumstances
and resources surrounding a funded, major research trial cannot be easily
duplicated by the average center. This document will certainly not be
welcomed by the makers of tPA. Fortunately, the Academy has carefully
developed itself in a manner that has precluded its dependence on funding
from outside sources. We therefore are able to speak to what we feel best
serves the majority of the membership. This position statement was passed
with that intent. We look forward to your input. Thanks for your support.
On its January 9, 2002, conference call, the AAEM Board
of Directors adopted an official position statement on whether the use
of tPA should be regarded as the standard of care for the treatment of
eligible patients with acute ischemic stroke. The board adopted its position
after reviewing the report submitted by the AAEM workgroup established
to study this issue. The full report and position statement are included
Position Statement of the American Academy of Emergency
Medicine on the Use of Intravenous Thrombolytic Therapy in the Treatment
Submitted to AAEM by the Work Group on Thrombolytic Therapy
For many years physicians have been frustrated by the lack of an effective
treatment for ischemic stroke. Thus, the introduction of tPA therapy for
acute ischemic stroke was met with considerable enthusiasm. Following
the favorably reported results of the 1995 National Institute of Neurological
Disorders and Stroke (NINDS) trial1 the Food and Drug Administration approved
tPA use for stroke. This therapy was subsequently endorsed by several
medical professional societies, including the American Heart Association
(AHA) and the American Academy of Neurology. In 2000, the AHA upgraded
its recommendation on the use of tPA for acute ischemic stroke from a
Class IIb ('optional') to a Class I ('definitely recommended') intervention.2,3
Despite these endorsements, debate about the efficacy, safety, and applicability
of tPA has limited its widespread use. Nonetheless, an increasing number
of liability suits are emerging against physicians for not administering
tPA based on the assumption that it represents a standard of care. Because
of these continuing concerns, the American Academy of Emergency Medicine
established a workgroup to study whether or not tPA should be regarded
as the standard of care for the treatment of eligible patients with acute
Efficacy concerns. The NINDS trial was a randomized
controlled study evaluating the efficacy and safety of tPA when administered
to carefully selected stroke patients within 180 minutes of symptom onset.1
It reported an 11% absolute increase in the number of patients recovering
without significant disability at 90 days (number needed to treat = 9).
Though these results appeared promising, the NINDS trial
has been criticized for two potential methodological flaws. First, the
trial selectively enrolled an equal number of patients treated within
0-90 and 91-180 minutes of stroke onset, with greater benefit shown for
those in the former group.4 Such selective enrollment likely skewed the
participants toward earlier treatment than would be encountered in clinical
practice so that overall results were rendered poorly generalizable. Second,
stroke severity in the group treated in the later time strata was greater
in the placebo than in the tPA group, again potentially biasing the results
in favor of treatment.4,5
Other thrombolytic trials have demonstrated less encouraging
results. To date, seven randomized controlled studies have evaluated the
efficacy of thrombolytic therapy for stroke. With the exception of the
NINDS trial, none have shown benefit in any of their primary outcome measures.1,6,7,8,9,10,11
Safety concerns. Three trials have evaluated streptokinase
for acute ischemic stroke. Each was prematurely terminated due to excessive
deaths in the treatment group.6,7,8 Four trials have evaluated tPA for
stroke. Each showed higher rates of intracranial hemorrhage and increases
in either short-term or long-term mortality with treatment.1,9,10,11 In
the NINDS trial, treated patients had a 10-fold increase in the incidence
of symptomatic intracranial hemorrhage with an absolute increase in risk
of 5.8% (number needed to harm = 17). One in 34 tPA-treated patients died
as a result of intracranial hemorrhage.
Applicability concerns. The NINDS trial was conducted
in expert settings with dedicated stroke teams, designated laboratory,
and rapid radiologic imaging resources. This infrastructure allowed rapid
identification both of patients having strokes and of those with contraindications
to thrombolytic therapy. Issues regarding the need for such resources
to ensure appropriate patient selection must be addressed.
Two studies have shown that patients with stroke mimics
were frequently misdiagnosed with strokes.12,13 Administration of tPA
to such patients would carry all of the bleeding risks without any of
the potential benefits. A separate study assessing clinicians' ability
to interpret CT scans showed an alarming rate of misread CT's, with emergency
physicians identifying only 73% of hemorrhages.14 Only 52% of radiologists
in this study were able to identify all cases of hemorrhage on five cranial
CT scans. Post-marketing registries and regional databases have yielded
conflicting results regarding the effectiveness of this therapy in clinical
practice, making it difficult to determine the true impact of widespread
implementation of thrombolytic protocols.15,16
It is the position of the American Academy of Emergency Medicine that
objective evidence regarding the efficacy, safety, and applicability of
tPA for acute ischemic stroke is insufficient to warrant its classification
as standard of care. Until additional evidence clarifies such controversies,
physicians are advised to use their discretion when considering its use.
Given the cited absence of definitive evidence, AAEM believes it is inappropriate
to claim that either use or non-use of intravenous thrombolytic therapy
constitutes a standard of care issue in the treatment of stroke.
1. The National Institute of Neurological Disorders and Stroke rt-PA
Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med 1995;333:1581-1587.
2. Guidelines 2000 for Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care. Part 7: The era of reperfusion: section
2: acute stroke. The American Heart Association in collaboration with
the International Liaison Committee on Resuscitation. Circulation 2000;102(8):1204-1216.
3. Kothari RU, Hacke W, Brott T, et al. Cardiopulmonary
resuscitation and emergency cardiovascular care. Stroke. Ann Emerg Med
4. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment
associated with better outcome: The NINDS rt-PA stroke study. Neurology
5. Koroshetz WJ. Tissue plasminogen activator for acute
ischemic stroke. N Engl J Med 1996;334:1405-1406.
6. Multicenter Acute Stroke Trial-Italy (MAST-I) Study Group.
Randomized controlled trial of streptokinase, aspirin, and combination
of both in treatment of acute ischemic stroke. Lancet 1995;346:1509-1514.
7. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase
for acute ischemic stroke with relationship to time of administration:
Australian Streptokinase (ASK) Trial Study Group. JAMA 1996;276:961-966.
8. The Multicenter Acute Stroke Trial-Europe (MAST-E) Group.
Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl
J Med 1996;335:145-150.
9. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis
with recombinant tissue plasminogen activator for acute hemispheric stroke.
The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-1025.
10. Hacke W, Kaste M, Fieschi C, et al. Randomized double-blind
placebo-controlled trial of thrombolytic therapy with intravenous alteplase
in acute ischemic stroke (ECASS II). Second European-Australasian Acute
Stroke Study Investigators. Lancet 1998;352:1245-1251.
11. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type
plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after
symptom onset. The ATLANTIS Study: A randomized controlled trial. Alteplase
Thrombolysis for Acute Non-interventional Therapy in Ischemic Stroke.
12. Libman R, Wirkowski E, Alvir J, et al. Conditions that
mimic stroke in the Emergency Department: Implications for acute stroke
trials. Arch Neurol 1995;52:1119-1122.
13. Allder SJ, Moody AR, Martel AL, et al. Limitations of
clinical diagnosis in acute stroke. Lancet 1999;354:1523.
14. Schriger D, Kalafut M, Starkman S, et al. Cranial computed
tomography interpretation in acute stroke: Physician accuracy in determining
eligibility for thrombolytic therapy. JAMA 1998;279(16):1293-1297.
15. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type
plasminogen activator for treatment of acute stroke: The Standard Treatment
with Alteplase to Reverse Stroke (STARS) Study. JAMA 2000;283(9):1145-1150.
16. Katzan I, Furlan A, Lloyd L, et al. Use of tissue-type
plasminogen activator for acute ischemic stroke: The Cleveland area experience.
AAEM Work Group on Thrombolytic Therapy in Stroke:
Deepi G. Goyal, MD, Chair of Work Group
Assistant Program Director, Mayo Emergency Medicine Residency
Assistant Professor, Mayo Graduate School of Medicine
Senior Associate Consultant, Department of Emergency Medicine, Mayo Clinic,
James Li, MD
Division of Emergency Medicine; Harvard Medical School
Jeffrey Mann, MD
Emergency Physician. Salt Lake City
David L. Schriger, MD MPH
Professor, UCLA School of Medicine