This is the current release of the guideline.

According to the guideline developer, this guideline has been reviewed and is still considered to be current as of October 2005. This review involved new literature searches of electronic databases followed by expert committee review of new evidence that has emerged since the original publication date.

Acute ischemic stroke (cardioembolic, large vessel atherosclerotic, vertebrobasilar, or "progressing" stroke)

Assessment of Therapeutic Effectiveness
Management
Prevention
Treatment

Critical Care
Emergency Medicine
Neurology

Not stated

• To examine the published evidence relevant to the effects of anticoagulants and antiplatelet agents on acute ischemic stroke mortality, morbidity, and recurrence rate as well as associated ancillary benefits and risks of those treatments on the rate of deep vein thrombosis, pulmonary embolus, and cardiovascular complications
• To determine if there is evidence supporting the differential efficacy of anticoagulants and antiplatelet agents according to ischemic stroke subtype
• To offer evidence-based recommendations on the management of acute ischemic stroke

Patients with acute ischemic stroke

1. Platelet antiaggregants (aspirin)
2. Unfractionated heparin (intravenously or subcutaneously)
3. Low molecular weight (LMW) heparin/heparinoids, such as ORG 10172, nadroparin calcium, danaparoid, dalteparin, certoparin, Fraxiparine

Notes:

• The platelet glycoprotein IIb/IIIa inhibitor abciximab was considered but data were insufficient to make any recommendations on its use in the setting of acute ischemic stroke.
• Guideline developers intended to consider hirudin, dipyridamole, ticlopidine, or clopidogrel but were unable to do so because none of the studies that fulfilled the prespecified inclusion criteria addressed the reviewer's key questions.
• Guideline developers did not consider prostacyclin and pentoxifylline because these agents have major vascular effects other than antiplatelet actions.

• Stroke-related morbidity and mortality
• Stroke recurrence
• Systemic thrombotic complications, such as deep vein thrombosis (DVT)/pulmonary embolism (PE)
• Risks of hemorrhage
• Acute cardiovascular complications

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

• 2372 abstracts found
• 310 articles read in full and reviewed by the committee members in detail
• 10 articles satisfied all of the inclusion criteria

Weighting According to a Rating Scheme (Scheme Given)

The following evidence classification system of the Quality Standards Subcommittee (QSS) was approved by the American Academy of Neurology (AAN) and the American Heart Association (AHA).

Levels of Evidence

Class I: Evidence provided by a prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required:

• Primary outcome(s) is/are clearly defined.
• Exclusion/inclusion criteria are clearly defined.
• Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias.
• Relevant baseline characteristics are presented and substantially equivalent among treatment groups, or there is appropriate statistical adjustment for differences.

Class II: Evidence provided by a prospective, matched cohort study in a representative population with masked outcome assessment that meets all of the above OR a randomized controlled trial in a representative population that lacks one of the above criteria.

Class III: Evidence provided by all other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, in which outcome assessment is independent of patient treatment.

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.

Systematic Review with Evidence Tables

Not stated

Grades of Recommendation

Grade A. At least one convincing Class I study or at least two consistent, convincing Class II studies.

Grade B. At least one convincing Class II study or at least three convincing Class III studies.

Grade C. At least two convincing and consistent Class III studies.

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Draft guidelines were reviewed for accuracy, quality, and thoroughness by the American Academy of Neurology (AAN) members, topic experts, and pertinent physician organizations.

Final guidelines were approved by the American Academy of Neurology Quality Standards Subcommittee on December 8, 2001, the American Academy of Neurology Practice Committee on January 31, 2002, and the American Academy of Neurology Board of Directors on February 23, 2002. A report was published in Neurology 2002;59:13-22.

Definitions of the levels of evidence (Class I-IV) and grades of recommendation (Grade A-C) are provided at the end of the Major Recommendations field.

1. Patients with acute ischemic stroke presenting within 48 hours of symptom onset should be given aspirin (160 to 325 mg/day) to reduce stroke mortality and decrease morbidity, provided contraindications such as allergy and gastrointestinal bleeding are absent, and the patient has not been or will not be treated with recombinant tissue type plasminogen activator (Grade A). The data are insufficient at this time to recommend the use of any other platelet antiaggregant in the setting of acute ischemic stroke.
2. Subcutaneous unfractionated heparin, low molecular weight (LMW) heparins, and heparinoids may be considered for deep vein thrombosis (DVT) prophylaxis in at-risk patients with acute ischemic stroke, recognizing that nonpharmacologic treatments for DVT prevention also exist (Grade A). A benefit in reducing the incidence of pulmonary embolism (PE) has not been demonstrated. The relative benefits of these agents must be weighed against the risk of systemic and intracerebral hemorrhage.
3. Although there is some evidence that fixed-dose, subcutaneous, unfractionated heparin reduces early recurrent ischemic stroke, this benefit is negated by a concomitant increase in the occurrence of hemorrhage. Therefore, use of subcutaneous unfractionated heparin is not recommended for decreasing the risk of death or stroke-related morbidity or for preventing early stroke recurrence (Grade A).
4. A. Dose-adjusted, unfractionated heparin is not recommended for reducing morbidity, mortality, or early recurrent stroke in patients with acute stroke (i.e., in the first 48 hours) because the evidence indicates it is not efficacious and may be associated with increased bleeding complications (Grade B).

4. B. High-dose LMW heparin/heparinoids have not been associated with either benefit or harm in reducing morbidity, mortality, or early recurrent stroke in patients with acute stroke and are, therefore, not recommended for these goals (Grade A).
5. Intravenous (IV), unfractionated heparin or high dose LMW heparin/heparinoids are not recommended for any specific subgroup of patients with acute ischemic stroke that is based on any presumed stroke mechanism or location (e.g., cardioembolic, large vessel atherosclerotic, vertebrobasilar, or "progressing" stroke) because data are insufficient (Grade U). Although the LMW heparin dalteparin at high doses may be efficacious in patients with atrial fibrillation, it is not more efficacious than aspirin in this setting. Because aspirin is easier to administer, it, rather than dalteparin, is recommended for the various stroke subgroups (Grade A).

Definitions:

Levels of Evidence

Class I: Evidence provided by a prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required:

• Primary outcome(s) is/are clearly defined.
• Exclusion/inclusion criteria are clearly defined.
• Adequate accounting for drop outs and crossovers with numbers sufficiently low to have minimal potential for bias.
• Relevant baseline characteristics are presented and substantially equivalent among treatment groups, or there is appropriate statistical adjustment for differences.

Class II: Evidence provided by a prospective, matched cohort study in a representative population with masked outcome assessment that meets all of the above OR a randomized controlled trial in a representative population that lacks one of the above criteria.

Class III: Evidence provided by all other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, in which outcome assessment is independent of patient treatment.

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.

Grade of Recommendation

Grade A. At least one convincing Class I study or at least two consistent, convincing Class II studies.

Grade B. At least one convincing Class II study or at least three convincing Class III studies.

Grade C. At least two convincing and consistent Class III studies.

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Potential Overall Benefits:

• These guidelines may assist physicians in making appropriate clinical decisions regarding the use of anticoagulant and antiplatelet agents in the management of patients with acute ischemic stroke.

Potential Specific Benefits:

• Aspirin (160 mg or 325 mg daily) results in a small but statistically significant reduction in death and disability when given within 48 hours after ischemic stroke, as indicated by a combined analysis of available studies.
• Anticoagulants (but not antiplatelet agents) reduce the frequency of deep vein thrombosis (DVT) in acute stroke.

There is an increase in both systemic and central nervous system (CNS) hemorrhage in patients treated with aspirin, subcutaneous unfractionated heparin, or low molecular weight (LMW) heparin/heparinoids.

Contraindications to aspirin include allergy, gastrointestinal bleeding, and plans to be treated with recombinant tissue type plasminogen activator.

• None of the studies included for review by the guideline developers that fulfilled the prespecified inclusion criteria and addressed the review’s key questions examined the use of hirudin, dipyridamole, ticlopidine or clopidogrel in the setting of acute ischemic stroke.
• This statement is provided as an educational service of the American Stroke Association of the American Heart Association (AHA) and the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurological problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative method of care. The American Academy of Neurology and American Heart Association recognize that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.

An implementation strategy was not provided.

Getting Better
Staying Healthy

Effectiveness
Safety
Timeliness

Not applicable: The guideline was not adapted from another source.

2002 Jul (reviewed 2005 Oct)

American Academy of Neurology - Medical Specialty Society
American Stroke Association - Disease Specific Society

American Academy of Neurology (AAN)

Joint Stroke Guideline Development Committee

Joint Stroke Guideline Development Committee: Milton Alter, MD, PhD (Co-Chair, American Academy of Neurology); George J. Hademenos, PhD (Co-Chair, American Heart Association); Larry B. Goldstein, MD; Philip B. Gorelick, MD, MPH; Chung Y. Hsu, MD, PhD; Jose Biller, MD; and Wendy Edlund

Not stated

This is the current release of the guideline.

According to the guideline developer, this guideline has been reviewed and is still considered to be current as of October 2005. This review involved new literature searches of electronic databases followed by expert committee review of new evidence that has emerged since the original publication date.

None available

This summary was completed by ECRI on February 6, 2004. This summary was updated by ECRI Institute on June 22, 2007 following the U.S. Food and Drug Administration (FDA) advisory on heparin sodium injection. This summary was updated by ECRI Institute on March 13, 2008 following the updated FDA advisory on heparin sodium injection.

This NGC summary is based on the original guideline, which is copyrighted by the American Academy of Neurology.