Anticoagulants and antiplatelet agents in
acute ischemic stroke
Report of the Joint Stroke Guideline Development
Committee of the American Academy of Neurology and
the American Stroke Association (a Division of the
American Heart Association)
B.M. Coull, MD; L.S. Williams, MD; L.B. Goldstein, MD; J.F. Meschia, MD; D. Heitzman, MD;
S. Chaturvedi, MD; K.C. Johnston, MD; S. Starkman, MD; L.B. Morgenstern, MD; J.L. Wilterdink, MD;
S.R. Levine, MD; and J.L. Saver, MD
Stroke remains a common and costly problem world-
wide, but substantial advances have been made in
recent decades in understanding stroke mechanisms,
risk factors, and therapies. Because thrombosis plays
an important role in the pathogenesis of ischemic
stroke, drugs that interfere with hemostasis and clot
formation such as anticoagulants and platelet anti-
aggregants commonly are used in the management
of cerebrovascular disease. Considerable evidence
supports the use of certain antithrombotic drugs in
stroke prevention. However, because of limited sup-
portive data, the use of these agents in patients with
acute ischemic stroke remains controversial.
In this report, we examine the published evidence
relevant to the effects of anticoagulants and anti-
platelet agents on acute ischemic stroke mortality,
morbidity, and recurrence rates as well as associated
ancillary benefits and risks of those treatments on the
rates of deep vein thrombosis, pulmonary embolus, and
cardiovascular complications. As part of these analy-
ses, we also sought to determine whether there was
evidence supporting differential efficacy of these drugs
according to ischemic stroke subtypes.
rologists with a special interest in stroke diagnosis
and management were appointed by the Quality
Standards Subcommittee (QSS) and the Therapeu-
tics and Technology Assessment (TTA) Subcommit-
tee of the American Academy of Neurology, and the
Stroke Council and Science Advisory and Coordinat-
ing Committee (SACC) of the American Heart Asso-
ciation (AHA). The QSS, TTA, Stroke Council and
SACC are each charged with the responsibility of
preparing evidence-based reports pertaining to med-
ical practice issues including stroke.
To facilitate the process of joint guideline develop-
ment, a Steering Committee, chaired by representa-
tives ofthe AAN and
Association of the AHA, was appointed to discuss
potential topics of wide interest to the stroke commu-
nity. Choosing the role of anticoagulants and anti-
platelet agents in acute ischemic stroke as the first
topic, a Joint Writing Committee was appointed with
equal representation from each organization.
The Joint Writing Committee first conducted a
To prepare this report, experienced neu-
the American Stroke
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Con-
tents for the July 9 issue to find the title link for this article.
See page 21 for a listing of the members of the Joint Stroke Guideline Development Committee.
From the Department of Neurology (Dr. Coull), Arizona Health Science Center, Tucson, AZ; Department of Neurology (Dr. Williams), Indiana University
School of Medicine, Research Scientist, Regenstrief Institute for Health Care, Indianapolis, IN; Department of Neurology (Dr. Goldstein), Duke Center for
Cerebrovascular Disease, Duke Center for Clinical Health Policy Research, and Durham VA Medical Center, Durham, NC; Department of Neurology (Dr.
Meschia), Mayo Clinic/Jacksonville, FL; Texas Neurology, PC (Dr. Heitzman), Dallas, TX; Department of Neurology (Dr. Chaturvedi), Wayne State
University, Detroit, MI; Departments of Neurology and Health (Dr. Johnston), Evaluation Sciences, University of Virginia, Charlottesville; Departments of
Emergency Medicine and Neurology (Dr. Starkman), UCLA, and Department of Neurology (Dr. Saver), UCLA School of Medicine, Los Angeles, CA;
Departments of Neurology & Epidemiology (Dr. Morgenstern), University of Texas, Houston; Department of Clinical Neurosciences (Dr. Winterdink), Brown
Medical School, Providence, RI; and Department of Neurology (Dr. Levine), Mount Sinai School of Medicine, New York, NY.
Approved by the AAN Quality Standards Subcommittee December 8, 2001. Approved by the AAN Practice Committee January 31, 2002. Approved by the
AAN Board of Directors February 23, 2002.
Address correspondence and reprint requests to American Academy of Neurology, 1080 Montreal Ave., St. Paul, MN 55116.
Copyright © 2002 by AAN Enterprises, Inc.
structured literature review with the assistance of a
professional medical research librarian based at the
University of Minnesota (see Acknowledgment). The
literature review was based on MEDLINE searches
from 1966 through February 2001. In addition, Cur-
rent Contents and International Pharmaceutical Ab-
stracts databases were searched from 1985 to
February 2001. The search strategy, available online
at www.aan.com, included controlled clinical trials
and large-scale cohort studies.
The committee also searched the Cochrane Data-
base for pertinent randomized clinical trials and sys-
tematic reviews. Cochrane Reviews typically consist
of formal meta-analyses of published and unpub-
lished trials, not all of which are indexed in MED-
LINE. These reviews were used to identify any
relevant studies that may not have been found in the
other searches. In addition, to help ensure that all
pertinent studies were considered, a letter request-
ing relevant articles was sent to an international
group of stroke experts who, in the opinion of the
Joint Writing Committee, were considered authori-
ties in the field of antithrombotic treatment of acute
ischemic stroke (see Acknowledgment).
The treatments selected by the Joint Writing
Committee for review included unfractionated hepa-
rin, low molecular weight (LMW) heparin, hepari-
noids, aspirin, ticlopidine, clopidogrel, dipyridamole,
hirudin, and glycoprotein IIb/IIIa antagonists. Re-
ports of thrombolytics and fibrinogenolytics identi-
fied in the search were excluded because they are
neither antiplatelet agents nor anticoagulants. Pros-
tacyclin and pentoxifylline were also excluded be-
cause they have major vascular effects other than
antiplatelet actions. Case reports, studies of primary
intracranial hemorrhages, studies that included only
patients with TIA, and studies of dural sinus or cere-
bral vein thrombosis were also excluded.
To be considered for analysis, a study had to be a
controlled clinical trial that tested an anticoagulant
or antiplatelet agent in patients with ischemic
stroke. In addition, the drug must have been given
within 48 hours of symptom onset. Clinical end-
points had to be clearly defined before the study
started. Studies that included patients in whom
treatment could be delayed after 48 hours were con-
sidered only if results were also separately reported
on a well defined subgroup of patients treated within
48 hours of symptom onset. A number of excellent
and comprehensive articles on acute stroke manage-
ment have been published recently, such as the rec-
ommendations from the European Stroke Initiative,1
but these reports did not meet our criteria for inclu-
sion because they were based on reviews of other
studies and expert opinion rather than primary
source clinical trials.
Each study considered was rated using the evi-
dence classification system of the QSS and approved
by the AAN and AHA (Appendix A). This evidence-
based classification scheme excludes review articles,
letters, comments, editorials, and articles based
solely on expert opinion.
Abstracts of all identified articles were indepen-
dently reviewed by two members of the committee,
and accepted articles were read and independently
abstracted by two committee members according to
the Data Abstraction Form, available online at www.
aan.com. This form was designed to address the key
questions listed in table 1. These key questions were
designed to critically assess the major issues involved
in the efficacy of anticoagulants and antiplatelet
agents in the outcome of patients with acute ischemic
stroke. For each of these questions, the quality of the
evidence was rated and recommendations formulated
and assigned a grade of A, B, or C based on the quality
of evidence as outlined in Appendix A.
2372 abstracts. There were no disagreements among
the reviewers regarding inclusion or exclusion of in-
dividual studies. This review process yielded 310 ar-
ticles to be read in full and reviewed by the
committee members in detail. Of the total reviewed,
only 10 articles satisfied all inclusion criteria.2-11De-
spite the apparently common use of anticoagulation
for progressing stroke or vertebrobasilar stroke, we
found no Class I or II evidence addressing these spe-
cific clinical situations. None of the included studies
that fulfilled the prespecified inclusion criteria and
addressed the review’s key questions (see table 1)
examined the use of hirudin, dipyridamole, ticlopi-
dine, or clopidogrel in the setting of acute ischemic
stroke. Table 2 summarizes the results.
The structured literature search yielded
1. Do antithrombotic agents reduce stroke mortal-
ity and stroke-related morbidity?
Neither stroke-related mortality nor all-cause
mortality was used as the primary endpoint in any of
the studies included in this document. Stroke-related
impairment was difficult to compare among the stud-
ies because different outcome scales were used and
the interval after onset of the stroke at which stroke-
related morbidity was assessed varied. The thera-
peutic agents used in the studies in which mortality
Table 1 Key questions
1. Do antithrombotic agents reduce stroke-related morbidity and
2. Do antithrombotic agents reduce early stroke recurrence?
3. Do antithrombotic agents vary in efficacy according to stroke
4. Do antithrombotic agents reduce systemic thrombotic
complications such as DVT/PE?
5. What are the risks of hemorrhage associated with
6. Do antithrombotic agents alter acute cardiovascular
DVT/PE ? deep vein thrombosis/pulmonary emboli.
July (1 of 2) 2002
9. The Abciximab in Ischemic Stroke Investigators. Abciximab in
acute ischemic stroke: a randomized, double-blind, placebo-
controlled, dose-escalation study. Stroke 2000;31:601–609.
10. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low
molecular-weight heparin versus aspirin in patients with
acute ischaemic stroke and atrial fibrillation: a double-blind
randomised study. HAEST Study Group Heparin in Acute
Embolic Stroke Trial. Lancet 2000;355:1205–1210.
11. Diener HC, Ringelstein EB, von Kummer R, et al. Treatment
of acute ischemic stroke with the low-molecular-weight hepa-
rin certoparin. Results of the TOPAS Trial. Stroke 2001;32:
12. Chen ZM, Sandercock P, Pan HC, et al. Indications for early
aspirin use in acute ischemic stroke: a combined analysis of
40,000 randomized patients from the chinese acute stroke
trial and the international stroke trial. On behalf of the CAST
and IST collaborative groups. Stroke 2000;31:1240–1249.
13. Hommel M, FISS bis Investigators Group. Fraxiparine in
Ischemic Stroke Study (FISS bis). Cerebrovasc Dis 1998;
8(suppl 4):19A. Abstract.
14. EAFT Study Group. Secondary prevention in non-rheumatic
atrial fibrillation after transient ischaemic attack or minor
stroke. Lancet 1993;342:1255–1262.
15. Gubitz G, Counsell C, Sandercock P, et al. Anticoagulants for
acute ischemic stroke (Cochrane Review). In: The Cochrane
Library, Issue 1, 2000. Oxford.
16. Counsell C, Sandercock P. Low-molecular-weight heparins or
heparinoids versus standard unfractionated heparin for acute
ischemic stroke. In: The Cochrane Library, Issue 1, 2000. Ox-
17. Gubitz G, Sandercock P, Counsell C. Antiplatelet therapy for
acute ischemic stroke. In: The Cochrane Library, Issue 1, 2000.
18. Ciuffetti G, Aisa G, Mercuri M, et al. Effects of ticlopidine on
the neurologic outcome and the hemorheologic pattern in the
postacute phase of ischemic stroke: a pilot study. Angiology
19. Bath PMW, Lindenstrom E, Boysen G, et al. Tinzaparin in
acute ischaemic stroke (TAIST): a randomized aspirin-
controlled trial. Lancet 2001;358:702–710.
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