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## Complete Summary

#### GUIDELINE TITLE

Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh
ACCP Conference on Antithrombotic and Thrombolytic Therapy.

#### BIBLIOGRAPHIC SOURCE(S)

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 Sep;126(3
Suppl):483S-512S. \[202 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15383482)

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Albers GW, Amarenco P, Easton
JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for
ischemic stroke. Chest 2001 Jan;119(1 Suppl):300S-320S.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [February 28, 2008, Heparin Sodium
    Injection](http://www.fda.gov/medwatch/safety/2008/safety08.htm#HeparinInj2):
    The U.S. Food and Drug Administration (FDA) informed the public that
    Baxter Healthcare Corporation has voluntarily recalled all of their
    multi-dose and single-use vials of heparin sodium for injection and
    their heparin lock flush solutions. Alternate heparin manufacturers
    are expected to be able to increase heparin production sufficiently
    to supply the U.S. market. There have been reports of serious
    adverse events including allergic or hypersensitivity-type
    reactions, with symptoms of oral swelling, nausea, vomiting,
    sweating, shortness of breath, and cases of severe hypotension.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Acute ischemic stroke

-   Cerebral venous sinus thrombosis

#### GUIDELINE CATEGORY

Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Cardiology\
Critical Care\
Emergency Medicine\
Family Practice\
Internal Medicine\
Neurology\
Pulmonary Medicine

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

-   To make recommendations for the use of antithrombotic and
    thrombolytic therapy in the management and treatment of ischemic
    stroke for the purpose of reducing mortality, disability, and
    complications of ischemic stroke

-   To make recommendations for the use of antithrombotic therapy in the
    prevention of ischemic stroke

#### TARGET POPULATION

-   Adults with or at risk of acute ischemic stroke

-   Adults with cerebral venous sinus thrombosis

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Management/Treatment**

*Treatment of Acute Ischemic Stroke (AIS)*

1.  Thrombolytic therapy:

    -   Intravenous (IV) recombinant tissue plasminogen activator (tPA)
        with strict adherence to eligibility criteria for use

    -   In selected patients, intra-arterial thrombolytic therapy

2.  Antithrombotic therapy:

    -   Anticoagulation in selected patients

    -   Early aspirin therapy

    -   Aspirin therapy in combination with low doses of subcutaneous
        heparin

> **Note**: The following agents are considered but not recommended for
> the treatment of acute ischemic stroke: streptokinase (except within
> the confines of a clinical trial), full-dose anticoagulation,
> subcutaneous heparin and low-molecular-weight heparins or heparinoids.

*Secondary Prevention of Deep Venous Thrombosis (DVT)/Pulmonary Embolism
(PE) in Ischemic Stroke Patients*

1.  Low-dose subcutaneous heparin

2.  Low-molecular-weight heparins

3.  The heparinoid danaparoid

4.  Nonpharmacologic measures:

    -   Intermittent pneumatic compression devices

    -   Elastic stockings

*Prevention of Strokes*

1.  Aspirin therapy

2.  Aspirin in combination with extended-release dipyridamole

3.  Clopidogrel for patients allergic to aspirin

**Note**: Aspirin in combination with ticlopidine is considered, but not
recommended.

*Treatment of Cerebral Venous Sinus Thrombosis*

1.  Unfractionated heparin or low-molecular-weight heparin

2.  Oral anticoagulation

**Monitoring**

1.  International normalized ratio (INR)

2.  Computed tomography (CT)

3.  Magnetic resonance imaging (MRI)

#### MAJOR OUTCOMES CONSIDERED

Efficacy and safety of treatment, as defined by the following:

-   Rates of mortality and disability from ischemic stroke

-   Functional status

-   Rates of deep vein thrombosis (DVT) and pulmonary embolism (PE)
    secondary to ischemic stroke

-   Rates of adverse events from treatment, such as intracerebral
    hemorrhages (ICH)

-   Relative risk reduction of recurrent stroke and other vascular
    events (*prevention*)

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

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

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Process of Searching for Evidence**

Defining the clinical question provided the framework for formulating
eligibility criteria that guided the search for relevant evidence. Prior
to searching for the evidence, methodological experts and librarians
reviewed each question to ensure that the librarians could derive a
comprehensive search strategy.

In specifying eligibility criteria, authors not only identified
patients, interventions, and outcomes, but also methodological criteria.
For most therapeutic studies, authors restricted eligibility to
randomized controlled trials (RCTs).

For many questions, RCTs did not provide sufficient data, and article
authors also included observational studies. This was also true when
randomized trials were not the most appropriate design to use for
addressing the research question. In particular, randomized trials are
not necessarily the best design to understand risk groups (e.g., the
baseline or expected risk of a given event for certain subpopulations).
Because there are no interventions examined in questions about
prognosis, one replaces interventions by the exposure, which is time.

**Identifying the Evidence**

To identify the relevant evidence, a team of librarians at the
University at Buffalo conducted comprehensive literature searches. For
each question the authors provided, the librarians developed sensitive
(but not specific) search strategies, including all languages, and
conducted separate searches for systematic reviews, RCTs, and, if
applicable, observational studies. The librarians searched the Cochrane
Database of Systematic Reviews, the Database of Abstracts of Reviews of
Effectiveness and Cochrane Register of Controlled Trial, the ACP Journal
Club, MEDLINE, and Embase for studies published between 1966 and June
2002 in any language. To filter MEDLINE and Embase search results for
RCT evidence, the librarians used the search strategy developed by the
Cochrane Collaboration (full strategy available in Appendix online at:
<http://www.chestjournal.org/content/vol126/3_suppl_1>).

For observational studies, they restricted their searches to human
studies. Searches were not further restricted in terms of methodology.
While increasing the probability of identifying all published studies,
this sensitive approach resulted in large number of citations for many
of the defined clinical questions. Therefore, trained research
assistants screened the citation list developed from the search and
removed any apparently irrelevant citations. These irrelevant citations
included press news, editorials, narrative reviews, single case reports,
animal studies (any nonhuman studies), and letters to the editor.
Authors included data from abstracts of recent meetings if reporting was
transparent and all necessary data for the formulation of a
recommendation were available. The guideline developers did not
explicitly use Internet sources to search for research data.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

The rating scheme framework captures the trade-off between benefits and
risks (1 or 2) (and the methodological quality of the underlying
evidence (A, B, C+, or C). See \"Rating Scheme for the Strength of the
Recommendations.\"

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

**Summarizing Evidence**

The electronic searches also included searching for systematic reviews.
If authors were satisfied with a recent high-quality systematic review,
evidence from that review provided a foundation for the relevant
recommendation.

Pooled analyses from high-quality systematic reviews formed, wherever
possible, the evidence base of the recommendations. Pooling offers the
advantage of obtaining more precise estimates of treatment effects and
allows for a greater generalizability of results. However, pooling also
bears the risk of spurious generalization. In general, the summary
estimates of interest were the different types of outcomes conveying
benefit and downsides (i.e., risk, burden, and cost).

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Consensus Development Conference)

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The strength of any recommendation depends on the following two factors:
the trade-off between the benefits and the risks, burdens, and costs;
and the strength of the methodology that leads to the treatment effect.
The guideline developers grade the trade-off between benefits and risks
in the two categories: 1, in which the trade-off is clear enough that
most patients, despite differences in values, would make the same
choice; and 2, in which the trade-off is less clear, and individual
patients´ values will likely lead to different choices.

When randomized trials provide precise estimates suggesting large
treatment effects, and the risks and costs of therapy are small,
treatment for average patients with compatible values and preferences
can be confidently recommended.

If the balance between benefits and risks is in doubt, methodologically
rigorous studies providing **Grade A** evidence and recommendations may
still be weak (**Grade 2**). Uncertainty may come from less precise
estimates of benefit, harm, or costs, or from small effect sizes.

There is an independent impact of validity and consistency, and the
balance of positive and negative impacts of treatment on the strength of
recommendations. In situations in which there is doubt about the value
of the trade-off, any recommendation will be weaker, moving from **Grade
1** to **Grade 2**.

**Grade 1** recommendations can only be made when there is a relatively
clear picture of both the benefits and the risks, burdens, and costs,
and when the balance between the two clearly favors recommending or not
recommending the intervention for the typical patient with compatible
values and preferences. A number of factors can reduce the strength of a
recommendation, moving it from **Grade 1** to **Grade 2**. Uncertainty
about a recommendation to treat may be introduced if the following
conditions apply: (1) the target event that is trying to be prevented is
less important (confident recommendations are more likely to be made to
prevent death or stroke than asymptomatic deep vein thrombosis); (2) the
magnitude of risk reduction in the overall group is small; (3) the
probability of the target event is low in a particular subgroup of
patients; (4) the estimate of the treatment effect is imprecise, as
reflected in a wide confidence interval (CI) around the effect; (5)
there is substantial potential harm associated with therapy; or (6)
there is an expectation for a wide divergence in values even among
average or typical patients. Higher costs would also lead to weaker
recommendations to treat.

The more balanced the trade-off between benefits and risks, the greater
the influence of individual patient values in decision making. Virtually
all patients, if they understand the benefits and risks, will take
aspirin after experiencing a myocardial infarction (MI) or will comply
with prophylaxis to reduce the risk of thromboembolism after undergoing
hip replacement. Thus, one way of thinking about a **Grade 1**
recommendation is that variability in patient values is unlikely to
influence treatment choice in average or typical patients.

When the trade-off between benefits and risks is less clear, individual
patient values may influence treatment decisions even among patients
with average or typical preferences.

**Grade 2** recommendations are those in which variation in patient
values or individual physician values will often mandate different
treatment choices, even among average or typical patients. An
alternative, but similar, interpretation is that a **Grade 2**
recommendation suggests that clinicians conduct detailed conversations
with patients to ensure that their ultimate recommendation is consistent
with the patient\'s values.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

  ------------------------------------------------------------------------------
  **Grade of         **Clarity of     **Methodological   **Implications**
  Recommendation**   Risk/Benefit**   Strength of        
                                      Supporting         
                                      Evidence**         
  ------------------ ---------------- ------------------ -----------------------
  **1A**             Clear            Randomized         Strong recommendation;
                                      controlled trials  can apply to most
                                      (RCTs) without     patients in most
                                      important          circumstances without
                                      limitations        reservation

  **1C+**            Clear            No RCTs, but       Strong recommendation;
                                      strong RCT results can apply to most
                                      can be             patients in most
                                      unequivocally      circumstances
                                      extrapolated, or   
                                      overwhelming       
                                      evidence from      
                                      observational      
                                      studies            

  **1B**             Clear            RCTs with          Strong recommendation;
                                      important          likely to apply to most
                                      limitations        patients
                                      (inconsistent      
                                      results,           
                                      methodological     
                                      flaws\*)           

  **1C**             Clear            Observational      Intermediate-strength
                                      studies            recommendation; may
                                                         change when stronger
                                                         evidence is available

  **2A**             Unclear          RCTs without       Intermediate-strength
                                      important          recommendation; best
                                      limitations        action may differ
                                                         depending on
                                                         circumstances or
                                                         patients\' or societal
                                                         values

  **2C+**            Unclear          No RCTs, but       Weak recommendation;
                                      strong RCT results best action may differ
                                      can be             depending on
                                      unequivocally      circumstances or
                                      extrapolated, or   patients\' or societal
                                      overwhelming       values
                                      evidence from      
                                      observational      
                                      studies            

  **2B**             Unclear          RCTs with          Weak recommendation;
                                      important          alternative approaches
                                      limitations        likely to be better for
                                      (inconsistent      some patients under
                                      results,           some circumstances
                                      methodological     
                                      flaws\*)           

  **2C**             Unclear          Observational      Very weak
                                      studies            recommendation; other
                                                         alternatives may be
                                                         equally reasonable
  ------------------------------------------------------------------------------

*\*These situations include RCTs with both lack of blinding and
subjective outcomes, where the risk of bias in measurement of outcomes
is high, or RCTs with large loss to follow-up.*

#### COST ANALYSIS

While conference participants agreed that recommendations should reflect
economic considerations, incorporating costs is fraught with difficult
challenges. For most recommendations, formal economic analyses are
unavailable. Even when analyses are available, they may be
methodologically weak or biased. Furthermore, costs differ radically
across jurisdictions, and even sometimes across hospitals within
jurisdictions.

Because of these challenges, the guideline developers consider economic
factors only when the costs of one therapeutic option over another are
substantially different within major jurisdictions in which clinicians
make use of these recommendations. As a result, in jurisdictions in
which resource constraints are severe, alternative allocations may serve
the health of the public far better than some of the interventions that
are designated as **Grade 1A**. This will likely be true for all less
industrialized countries and, with the increasing promotion of expensive
drugs with marginal benefits, may be increasingly true for wealthier
nations. Furthermore, recommendations change (either in direction or
with respect to grade) only when the guideline developers believe that
costs are high in relation to benefits. Instances in which costs have
influenced recommendations are labeled in the \"values and preferences\"
statements associated with the recommendation.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guideline authors formulated draft recommendations prior to the
conference that served as the foundation for authors to work together
and critique the recommendations. Drafts of all articles including draft
recommendations were available for review during the conference. A
representative of each article presented potentially controversial
issues in their recommendations at plenary meetings. Article authors met
to integrate feedback, to consider related recommendations in other
articles, and to revise their own guidelines accordingly. Authors
continued this process after the conference until they reached agreement
within their groups and with other author groups who had provided
critical feedback. Finally, the editors of this supplement harmonized
the articles and resolved remaining disagreements through facilitated
discussion.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The rating scheme is defined at the end of the \"Major Recommendations\"
field.

**[Acute Ischemic Stroke (AIS): Thrombolytic Therapy in Acute
Stroke]{.underline}**

**Intravenous (IV) Tissue Plasminogen Activator (tPA) for AIS within 3
hours of Symptom Onset**

1.  For eligible patients (see inclusion and exclusion criteria listed
    below), the guideline developers recommend administration of IV tPA
    in a dose of 0.9 mg/kg (maximum 90 mg), with 10% of the total dose
    administered as an initial bolus, and the remainder infused over 60
    min, provided that treatment is initiated within 3 hours of clearly
    defined symptom onset (**Grade 1A**).

> *Underlying values and preferences*: This recommendation assumes a
> relatively higher value on long-term functional improvement and a
> relatively lower value on minimizing the risk of intracranial
> hematomas (ICH) in the immediate peristroke period.

2.  For patients with extensive (more than one third of the middle
    cerebral artery \[MCA\] territory) and clearly identifiable
    hypodensity on CT, the guideline developers recommend **against**
    thrombolytic therapy (**Grade 1B**).

**IV tPA for AIS between 3 to 6 hours of Symptom Onset**

1.  For unselected patients with AIS of \>3 hours but \<6 hours, the
    guideline developers suggest clinicians **not** use IV tPA (**Grade
    2A**).

> *Underlying values and preferences*: This recommendation assumes a
> relatively low value on small increases in long-term functional
> improvement, a relatively high value on avoiding acute ICH and death,
> and a relatively high degree of risk aversion.

**IV Streptokinase for AIS between 0 and 6 hours of Symptom Onset**

1.  For patients with AIS, the guideline developers recommend
    **against** streptokinase (**Grade 1A**).

**Intra-Arterial Thrombolysis for AIS**

1.  For patients with angiographically demonstrated middle cerebral
    artery (MCA) occlusion and no signs of major early infarction on the
    baseline CT scan, who can be treated within 6 hours of symptom
    onset, the guideline developers suggest use of intra-arterial
    thrombolytic therapy with tPA (**Grade 2C**).

2.  For patients with acute basilar artery thrombosis and without major
    CT/magnetic resonance imaging (MRI) evidence of infarction, the
    guideline developers suggest intra-arterial thrombolysis with tPA
    (**Grade 2C**).

**[AIS: Patients Not Eligible for Thrombolysis]{.underline}**

**Anticoagulants for Altering Outcomes among Acute Stroke in Patients
Not Eligible for Thrombolysis**

1.  For patients with AIS, the guideline developers suggest clinicians
    **not** use full-dose anticoagulation with IV, subcutaneous, or low
    molecular weight heparin or heparinoids (**Grade 2B**).

**Antiplatelet Agents for Altering Outcomes in Acute Stroke in Patients
Not Eligible for Thrombolysis**

1.  For patients with ischemic stroke who are not receiving
    thrombolysis, the guideline developers recommend early aspirin
    therapy, 160 to 325 mg/day (**Grade 1A**).

**Antithrombotic Therapy for Prevention of Deep Vein Thrombosis (DVT)
and Pulmonary Embolism (PE) in AIS**

1.  For acute stroke patients with restricted mobility, the guideline
    developers recommend prophylactic low-dose subcutaneous heparin or
    low molecular weight heparins or heparinoids (**Grade 1A**).

2.  For patients who have contraindications to anticoagulants, the
    guideline developers recommend use of intermittent pneumatic
    compression devices or elastic stockings (**Grade 1C**).

**[DVT/PE Prophylaxis in Patients with ICH]{.underline}**

**Heparin for DVT/PE Prophylaxis in Patients with ICH**

1.  In patients with an acute ICH, the guideline developers recommend
    the initial use of intermittent pneumatic compression (**Grade
    1C+**). In stable patients, the guideline developers suggest
    low-dose subcutaneous heparin may be initiated as soon as the second
    day after the onset of the hemorrhage (**Grade 2C**).

> *Underlying values and preferences*: The recommendation for
> subcutaneous heparin assumes a relatively low degree of risk aversion.

**[Stroke Prevention]{.underline}**

**Prevention of Cerebral Ischemic Events in Patients with
Noncardioembolic Transient Ischemic Attack (TIA) or Stroke: Antiplatelet
Drugs vs. Placebo or vs. an Alternative Antiplatelet Drug**

1.  In patients who have experienced a noncardioembolic stroke or TIA
    (i.e., atherothrombotic, lacunar, or cryptogenic), the guideline
    developers recommend treatment with an antiplatelet agent (**Grade
    1A**). Aspirin at a dose of 50 to 325 mg daily (qd); the combination
    of aspirin, 25 mg, and extended-release dipyridamole, 200 mg twice a
    day (bid); or clopidogrel, 75 mg qd, are all acceptable options for
    initial therapy.

2.  In patients receiving aspirin who are at moderate-to-high risk of
    bleeding complications, the guideline developers recommend using low
    doses of aspirin, 50 to 100 mg/day (**Grade 1C+**).

3.  In patients who have experienced a noncardioembolic stroke or TIA,
    the guideline developers suggest use of the combination of aspirin
    and extended-release dipyridamole, 25/200 mg bid, over aspirin
    (**Grade 2A**), and clopidogrel over aspirin (**Grade 2B**).

> *Underlying values and preferences*: This recommendation to use the
> combination of aspirin and extended-release dipyridamole or
> clopidogrel over aspirin places a relatively high value on a small
> absolute risk reduction in stroke rates, and a relatively low value on
> minimizing drug expenditures.

4.  For patients who are allergic to aspirin, the guideline developers
    recommend clopidogrel (**Grade 1C+**).

**Prevention of Noncardioembolic Cerebral Ischemic Events: Oral
Anticoagulants**

1.  For most patients with noncardioembolic stroke or TIA, the guideline
    developers recommend antiplatelet agents over oral anticoagulation
    (**Grade 1A**).

2.  For patients with well-documented prothrombotic disorders, the
    guideline developers suggest oral anticoagulation over antiplatelet
    agents (**Grade 2C**).

**Prevention of Cerebral Ischemic Events in Patients Undergoing Carotid
Endarterectomy: Antiplatelet Agents**

1.  In patients undergoing carotid endarterectomy, the guideline
    developers recommend aspirin, 81 to 325 mg/d, prior to and following
    the procedure (**Grade 1A**).

**Prevention of Cardioembolic Cerebral Ischemic Events**

*Patients with Stroke with Underlying Atrial Fibrillation:
Anticoagulation*

1.  In patients with atrial fibrillation who have had a recent stroke or
    TIA, the guideline developers recommend long-term oral
    anticoagulation (target INR, 2.5; range, 2.0 to 3.0) \[**Grade
    1A**\].

*Patients with Stroke with Underlying Atrial Fibrillation: Antiplatelet
Agents*

1.  For patients with cardioembolic stroke who have contraindications to
    anticoagulant therapy, the guideline developers recommend aspirin
    (**Grade 1A**).

*Patients with Aortic Atheromata*

1.  In patients with stroke associated with aortic atherosclerotic
    lesions, the guideline developers recommend antiplatelet therapy
    over no therapy (**Grade 1C+**). For patients with cryptogenic
    stroke associated with mobile aortic arch thrombi, the guideline
    developers suggest either oral anticoagulation or antiplatelet
    agents (**Grade 2C**).

*Patients with Patent Foramen Ovale (PFO)*

1.  In patients with cryptogenic ischemic stroke and a patent foramen
    ovale, the guideline developers recommend antiplatelet therapy over
    no therapy (**Grade 1C+**), and suggest antiplatelet agents over
    anticoagulation (**Grade 2A**).

*Mitral Valve Strands and Prolapse*

1.  In patients with mitral valve strands or prolapse, who have a
    history of TIA or stroke, the guideline developers recommend
    antiplatelet therapy (**Grade 1C+**).

**[Cerebral Venous Sinus Thrombosis]{.underline}**

**Anticoagulation for Cerebral Venous Sinus Thrombosis**

1.  In patients with venous sinus thrombosis, the guideline developers
    recommend that clinicians use unfractionated heparin (**Grade 1B**)
    or low molecular weight heparin (**Grade 1B**) over no anticoagulant
    therapy during the acute phase, even in the presence of hemorrhagic
    infarction. In these patients, the guideline developers recommend
    oral anticoagulation for 3 to 6 months (target INR, 2.5; range, 2.0
    to 3.0) \[**Grade 1C**\].

**[Definitions]{.underline}**

  ------------------------------------------------------------------------------
  **Grade of         **Clarity of     **Methodological   **Implications**
  Recommendation**   Risk/Benefit**   Strength of        
                                      Supporting         
                                      Evidence**         
  ------------------ ---------------- ------------------ -----------------------
  **1A**             Clear            Randomized         Strong recommendation;
                                      controlled trials  can apply to most
                                      (RCTs) without     patients in most
                                      important          circumstances without
                                      limitations        reservation

  **1C+**            Clear            No RCTs, but       Strong recommendation;
                                      strong RCT results can apply to most
                                      can be             patients in most
                                      unequivocally      circumstances
                                      extrapolated, or   
                                      overwhelming       
                                      evidence from      
                                      observational      
                                      studies            

  **1B**             Clear            RCTs with          Strong recommendation;
                                      important          likely to apply to most
                                      limitations        patients
                                      (inconsistent      
                                      results,           
                                      methodological     
                                      flaws\*)           

  **1C**             Clear            Observational      Intermediate-strength
                                      studies            recommendation; may
                                                         change when stronger
                                                         evidence is available

  **2A**             Unclear          RCTs without       Intermediate-strength
                                      important          recommendation; best
                                      limitations        action may differ
                                                         depending on
                                                         circumstances or
                                                         patients\' or societal
                                                         values

  **2C+**            Unclear          No RCTs, but       Weak recommendation;
                                      strong RCT results best action may differ
                                      can be             depending on
                                      unequivocally      circumstances or
                                      extrapolated, or   patients\' or societal
                                      overwhelming       values
                                      evidence from      
                                      observational      
                                      studies            

  **2B**             Unclear          RCTs with          Weak recommendation;
                                      important          alternative approaches
                                      limitations        likely to be better for
                                      (inconsistent      some patients under
                                      results,           some circumstances
                                      methodological     
                                      flaws\*)           

  **2C**             Unclear          Observational      Very weak
                                      studies            recommendation; other
                                                         alternatives may be
                                                         equally reasonable
  ------------------------------------------------------------------------------

*\*These situations include RCTs with both lack of blinding and
subjective outcomes, where the risk of bias in measurement of outcomes
is high, or RCTs with large loss to follow-up.*

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

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

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Therapeutic strategies designed to restore cerebral perfusion in a
    timely fashion have the potential to limit the cellular,
    biochemical, and metabolic consequences of cerebral ischemia that
    ultimately lead to irreversible brain injury.

-   Appropriate use of antithrombotic and thrombolytic agents in
    ischemic stroke patients may reduce the rates and relative risk of
    ischemic stroke.

#### POTENTIAL HARMS

The primary risk of thrombolytic therapy is cerebral hemorrhage. In one
study, symptomatic intracerebral hemorrhage occurred in 6.4% of patients
receiving tissue plasminogen activator (tPA) versus 0.6% of the
placebo-treated patients (p \< 0.001). Despite the increased risk of
hemorrhage, patients with severe strokes were more likely to have
favorable outcomes if treated with tissue plasminogen activator
(adjusted odds ratio, 4.3; 95% confidence interval, 1.6 to 11.9).

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   Aspirin is contraindicated among those with aspirin allergy or those
    with active gastrointestinal (GI) bleeding.

-   Thrombolytic therapy is contraindicated in patients with computed
    tomography (CT) signs of intracranial hematoma (ICH), a history of
    ICH, seizure at stroke onset, stroke or serious head injury within 3
    months, major surgery or serious trauma within 2 weeks,
    gastrointestinal (GI) or urinary tract hemorrhage within 3 weeks,
    systolic blood pressure \>185 mm Hg, diastolic blood pressure \>110
    mm Hg, aggressive treatment required to lower blood pressure (BP),
    glucose level \< 50 mg/dL or \>400 mg/dL, symptoms of subarachnoid
    hemorrhage, arterial puncture at a noncompressible site or lumbar
    puncture within 1 week, platelet count \<100,000
    platelets/microliters, heparin therapy within 48 hours associated
    with elevated activated partial thromboplastin time, clinical
    presentation suggesting post-myocardial infarction (MI)
    pericarditis, pregnant or lactating women, and current use of oral
    anticoagulants (prothrombin time \> 15 seconds, international
    normalized ratio \[INR\] \>1.7).

-   For patients with extensive (more than one third of the middle
    cerebral artery \[MCA\] territory) and clearly identifiable
    hypodensity on computed tomography (CT), the guideline developers
    recommend **against** thrombolytic therapy.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

**Interpreting the Recommendations**

Clinicians, third-party payers, institutional review committees, or the
courts should not construe these guidelines in any way as absolute
dictates. In general, anything other than a **Grade 1A** recommendation
indicates that the article authors acknowledge that other
interpretations of the evidence, and other clinical policies, may be
reasonable and appropriate. Even **Grade 1A** recommendations will not
apply to all circumstances and all patients. For instance, the guideline
developers have been conservative in their considerations of cost and
have seldom downgraded recommendations from **Grade 1** to **Grade 2**
on the basis of expense. As a result, in jurisdictions in which resource
constraints are severe, alternative allocations may serve the health of
the public far better than some of the interventions that are designated
as **Grade 1A**. This will likely be true for all less industrialized
countries and, with the increasing promotion of expensive drugs with
marginal benefits, may be increasingly true for wealthier nations.

Similarly, following **Grade 1A** recommendations will at times not
serve the best interests of patients with atypical values or preferences
or of those whose risks differ markedly from those of the usual patient.
For instance, consider patients who find anticoagulant therapy extremely
aversive, either because it interferes with their lifestyle (e.g.,
prevents participation in contact sports) or because of the need for
monitoring. Clinicians may reasonably conclude that following some
**Grade 1A** recommendations for anticoagulation therapy for either
group of patients will be a mistake. The same may be true for patients
with particular comorbidities (e.g., a recent gastrointestinal bleed or
a balance disorder with repeated falls) or other special circumstances
(e.g., very advanced age) that put them at unusual risk.

The guideline developers trust that these observations convey their
acknowledgment that no recommendations or clinical practice guidelines
can take into account the often compelling and unique features of
individual clinical circumstances. No clinician, and no body charged
with evaluating a clinician´s actions, should attempt to apply these
recommendations in a rote or blanket fashion.

**Limitations of Guideline Development Methods**

The limitations of these guidelines include the possibility that some
authors followed this methodology more closely than others, although the
development process was centralized and supervised by the editors.
Second, it is possible that the guideline developers missed relevant
studies despite the comprehensive searching process. Third, the
guideline developers did not centralize the methodological evaluation of
all studies to facilitate uniformity in the validity assessments of the
research incorporated into these guidelines. Fourth, if high-quality
meta-analyses were unavailable, the guideline developers did not
statistically pool primary study results using meta-analysis. Finally,
sparse data on patient preferences and values, resources, and other
costs represent additional limitations that are inherent to most
guideline development methods.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

**Guideline Implementation Strategies**

A full review of implementation strategies for practice guidelines is
provided in the companion document titled \"Antithrombotic and
Antithrombolytic Therapy: From Evidence to Application.\" The review
suggests that there are few implementation strategies that are of
unequivocal, consistent benefit, and that are clearly and consistently
worth resource investment. The following is a summary of the
recommendations (see \"Major Recommendations\" for a definition of the
recommendation grades).

To encourage uptake of guidelines, the guideline developers recommend
that appreciable resources be devoted to distribution of educational
material (**Grade 2B**).

They also suggest that:

-   Few resources be devoted to educational meetings (**Grade 2B**)

-   Few resources be devoted to educational outreach visits (**Grade
    2A**)

-   Appreciable resources be devoted to computer reminders (**Grade
    2A**)

-   Appreciable resources be devoted to patient-mediated interventions
    to encourage uptake of the guidelines (**Grade 2B**)

-   Few resources be devoted to audit and feedback (**Grade 2B**)

#### IMPLEMENTATION TOOLS

Patient Resources\
Personal Digital Assistant (PDA) Downloads\
Quick Reference Guides/Physician Guides\
Resources\
Slide Presentation\
Tool Kits

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

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 Sep;126(3
Suppl):483S-512S. \[202 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15383482)

#### ADAPTATION

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

#### DATE RELEASED

2001 Jan (revised 2004 Sep)

#### GUIDELINE DEVELOPER(S)

American College of Chest Physicians - Medical Specialty Society

#### SOURCE(S) OF FUNDING

Funding was provided through an unrestricted educational grant by
AstraZeneca LP, Aventis Pharmaceuticals, GlaxoSmithKline, Bristol-Myer
Squibb/Sanofi-Synthelabo Partnership, and Organon Sanofi-Synthelabo LLC.

#### GUIDELINE COMMITTEE

American College of Chest Physicians Consensus Panel on Antithrombotic
and Thrombolytic Therapy

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Primary Authors*: Gregory W. Albers, MD (Chair); Pierre Amarenco, MD;
J. Donald Easton, MD; Ralph L. Sacco, MD; Philip Teal, MD

*Committee Co-Chairs*: Jack Hirsh, MD, FCCP (Chair); Gregory W. Albers,
MD; Gordon H. Guyatt, MD, MSc; Holger J. Schünemann, MD, MSc, PhD, FCCP

*Participants*: Giancarlo Agnelli, MD; Amin Al-Ahmad, MD; Pierre
Amarenco, MD; Jack E. Ansell, MD; Shannon M. Bates, MD; Richard C.
Becker, MD; Peter B. Berger, MD; David Bergqvist, MD, PhD, FRCS; Rebecca
J. Beyth, MD, MSc; Stewart Brower, MLIS; Harry R. Buller, MD; Henry I.
Bussey, PharmD, FCCP; Christopher P. Cannon, MD, FACC; Elizabeth A.
Chalmers, MB, ChB, MD, MRCP(UK). FRCPath; Anthony K.C. Chan, MD; G.
Patrick Clagett, MD; Barry Coller, MD; Clifford W. Colwell, MD; Deborah
Cook, MD, MSc; James E. Dalen, MD, MPH, FCCP; J. Donald Easton, MD;
Michael Ezekowitz, MD; Garret A. Fitzgerald, MD; William H. Geerts, MD,
FCCP; Jeffrey S. Ginsberg, MD, FCCP; Alan S. Go, MD; Shaun D. Goodman,
MD, FACC; Ian A. Greer, MD, FRCP, FRCOG; Andreas Greinacher, MD; Jeremy
Grimshaw, MD, PhD; Cindy Grines, MD; Jonathan L. Halperin, MD; Robert A.
Harrington, MD; John Heffner, MD, MPH; John A. Heit, MD; Judith S.
Hochman, MD, FACC; Dieter Horstkotte, MD, FESC; Russell D. Hull, MBBS,
MSc, FCCP; Elaine Hylek, MD; Thomas M. Hyers, MD, FCCP; Mark R. Jackson,
MD; Alan Jacobson, MD; Roman Jaeschke, MD, MSc; Ajay Kakkar BSc, PhD;
Clive Kearon, MD, PhD, FCCP; Matthew Kraay; Michael R. Lassen, MD; Mark
N. Levine, MD, MSc; Alessandro Liberati, MD; Gregory YH Lip, MD, FESC,
FACC; Warren J. Manning, MD; M. Patricia Massicotte, MD, MSc, FRCPC,
MSc; Thomas W. Meade, MD; Venu Menon, MD, FACC; Alan D. Michelson, MD;
Nancy Miller, RN; Paul Monagle, MBBS, MSc, MD, FRACP, FRCPA, FCCP;
Heather Munger, MLS; Christopher M. O´Connor, MD; Martin O´Donnell, MD;
E. Magnus Ohman, MD, FCCP; Carlo Patrono, MD; Stephen G. Pauker, MD;
Graham F. Pineo, MD; Leon Poller, MD; Jeffrey J. Popma, MD; Martin H.
Prins, MD; Robert Raschke, MD, MS; Gary Raskob, PhD; Joel G. Ray, MD,
MSc; Gerald Roth, MD; Ralph L. Sacco, MD; Deeb N. Salem, MD, FCCP; Meyer
M. Samama, MD; Andrew Schafer; Sam Schulman, MD, PhD; Daniel Singer, MD;
Michael Sobel, MD; Paul D. Stein, MD, FCCP; Marco Tangelder, MD; Victor
F. Tapson, MD, FCCP; Philip Teal, MD; Raymond Verhaeghe, MD; David A.
Vorchheimer, MD; Theodore E. Warkentin, MD; Jeffrey Weitz, MD; Robert G.
Wilcox, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Dr. Albers has received research support and honoraria as a consultant
from AstraZeneca, Bristol- Myers Squibb, Boehringer Ingelheim, Genentech
and Sanofi-Arganon.

Dr. Easton has received honoraria for his participation on advisory
boards or as a speaker at educational events from Boehringer Ingelheim,
Bristol- Myers Squibb, and Sanofi-Synthelabo.

Dr. Sacco has received research funding from GlaxoSmithKline and Pfizer,
and has received honoraria for his participation as a consultant on
advisory boards, data and safety monitoring boards and/or as a speaker
at educational events from Boehringer Ingelheim, sanofi-Synthelabo,
Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, and Texas
Biotechnology.

Dr. Teal has received honoraria for participation on advisory boards
and/or as a speaker at medical education events supported by
Boehringer-Ingelheim, Sanofi-Synthelabo and Bayer, Servier, Aventis,
PAION, AstraZeneca, and Hoffman-LaRoche. He has served on research
steering committees for clinical trials conducted by
Boehinger-Ingelheim, Bayer, ONO Pharmaceuticals and Pfizer and
Eli-Lilly, EKOS, GlaxoSmithKline, and Yamaguichi.

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Albers GW, Amarenco P, Easton
JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for
ischemic stroke. Chest 2001 Jan;119(1 Suppl):300S-320S.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [Chest - The Cardiopulmonary and
Critical Care
Journal](http://www.chestjournal.org/content/vol126/3_suppl/).

Print copies: Available from the American College of Chest Physicians,
Products and Registration Division, 3300 Dundee Road, Northbrook IL
60062-2348.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   The Seventh ACCP Conference on Antithrombotic and Thrombolytic
    Therapy. Evidence-based guidelines. Northbrook, IL: ACCP, 2004 Sep.

-   Methodology for guideline development for the Seventh American
    College of Chest Physicians Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Applying the grades of recommendation for antithrombotic and
    thrombolytic therapy: The Seventh ACCP Conference on Antithrombotic
    and Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Hemorrhagic complications of anticoagulant treatment: The Seventh
    ACCP Conference on Antithrombotic and Thrombolytic Therapy.
    Northbrook, IL: ACCP, 2004 Sep.

-   Antithrombotic and thrombolytic therapy: from evidence to
    application: The Seventh ACCP Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Platelet-active drugs: the relationships among dose, effectiveness,
    and side effects: The Seventh ACCP Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

Electronic copies: Available from the [Chest - The Cardiopulmonary and
Critical Care Journal Web
site](http://www.chestjournal.org/content/vol126/3_suppl/).

Print copies: Available from the American College of Chest Physicians
(ACCP), Products and Registration Division, 3300 Dundee Road, Northbrook
IL 60062-2348.

The following is also available:

-   Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy:
    Evidence-based guidelines; quick reference guide. Northbrook, IL:
    ACCP, 2004 Sep. Personal Digital Assistant (PDA) download available
    at [ACCP Web site](http://accp.apprisor.com/dlselect.cfm).

Additional implementation tools are also available:

-   Clinical resource: antithrombotic and thrombolytic therapy.
    Northbrook, IL. ACCP, 2004. Ordering information: Available from the
    [ACCP Web
    site](http://www.chestnet.org/education/guidelines/products.php).

#### PATIENT RESOURCES

The following is available:

-   A patient\'s guide to antithrombotic and thrombolytic therapy. In:
    Clinical resource: antithrombotic and thrombolytic therapy.
    Northbrook (IL): American College of Chest Physicians (ACCP). 2004.

Ordering information is available from the [ACCP Web
site](http://www.chestnet.org/education/guidelines/products.php).

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This summary was completed by ECRI on July 30, 2001. The information was
verified by the guideline developer on September 27, 2001. This NGC
summary was updated by ECRI on December 9, 2004. The updated information
was verified by the guideline developer on January 12, 2005. 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 14, 2008
following the updated FDA advisory on heparin sodium injection.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
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Guidelines represented on the NGC Web site are submitted by guideline
developers, and are screened solely to determine that they meet the NGC
Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
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Readers with questions regarding guideline content are directed to
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Date Modified: 11/10/2008