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American Academy of Emergency Medicine

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 below.

Position Statement of the American Academy of Emergency Medicine on the Use of Intravenous Thrombolytic Therapy in the Treatment of Stroke
Submitted to AAEM by the Work Group on Thrombolytic Therapy in Stroke

Background
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 ischemic stroke.

Discussion

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

Conclusion
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.

References
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 2001; 37(4):S137-144.

4. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: The NINDS rt-PA stroke study. Neurology 2000;55:1649-1655.

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. JAMA 1999;282:2019-2026.

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. JAMA 2000;283:1151-1158. 

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, Rochester, MN

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