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Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only Articles |

Antithrombotic and Thrombolytic Therapy for Ischemic StrokeAntithrombotic Therapy for Ischemic Stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Maarten G. Lansberg, MD, PhD; Martin J. O’Donnell, PhD; Pooja Khatri, MD; Eddy S. Lang, MDCM; Mai N. Nguyen-Huynh, MD; Neil E. Schwartz, MD, PhD; Frank A. Sonnenberg, MD; Sam Schulman, MD, PhD; Per Olav Vandvik, MD, PhD; Frederick A. Spencer, MD; Pablo Alonso-Coello, MD, PhD; Gordon H. Guyatt, MD, FCCP; Elie A. Akl, MD, MPH, PhD
Author and Funding Information

From the Stanford Stroke Center (Drs Lansberg and Schwartz), Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA; the HRB-Clinical Research Faculty (Dr O’Donnell), National University of Ireland Galway, Galway, Ireland; the Department of Neurology (Dr Khatri), University of Cincinnati, Cincinnati, OH; the University of Calgary (Dr Lang), Calgary, AB, Canada; the Department of Neurology (Dr Nguyen-Huynh), University of California, San Francisco, CA; the Division of General Internal Medicine (Dr Sonnenberg), UMDNJ/Robert Wood Johnson Medical School, New Brunswick, NJ; the Department of Medicine (Drs Schulman and Guyatt), McMaster University, ON, Canada; the Norwegian Knowledge Centre for the Health Services (Dr Vandvik), Oslo, Norway; St. Joseph’s Healthcare (Dr Spencer), Hamilton, ON, Canada; the Iberoamerican Cochrane Centre (Dr Alonso-Coello), CIBERESP-IIB Sant Pau, Barcelona, Spain; the State University of New York at Buffalo (Dr Akl), Buffalo, NY; and the Department of Clinical Epidemiology and Biostatistics (Drs Akl and Guyatt), McMaster University, Hamilton, ON, Canada.

Correspondence to: Elie A. Akl, MD, MPH, PhD, State University of New York at Buffalo, ECMC, DK Miller bldg C216, 462 Grider St, Buffalo, NY 14228; e-mail: elieakl@buffalo.edu


Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758]and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.

Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


Chest. 2012;141(2_suppl):e601S-e636S. doi:10.1378/chest.11-2302
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Objectives:  This article provides recommendations on the use of antithrombotic therapy in patients with stroke or transient ischemic attack (TIA).

Methods:  We generated treatment recommendations (Grade 1) and suggestions (Grade 2) based on high (A), moderate (B), and low (C) quality evidence.

Results:  In patients with acute ischemic stroke, we recommend IV recombinant tissue plasminogen activator (r-tPA) if treatment can be initiated within 3 h (Grade 1A) or 4.5 h (Grade 2C) of symptom onset; we suggest intraarterial r-tPA in patients ineligible for IV tPA if treatment can be initiated within 6 h (Grade 2C); we suggest against the use of mechanical thrombectomy (Grade 2C) although carefully selected patients may choose this intervention; and we recommend early aspirin therapy at a dose of 160 to 325 mg (Grade 1A). In patients with acute stroke and restricted mobility, we suggest the use of prophylactic-dose heparin or intermittent pneumatic compression devices (Grade 2B) and suggest against the use of elastic compression stockings (Grade 2B). In patients with a history of noncardioembolic ischemic stroke or TIA, we recommend long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended release dipyridamole (25 mg/200 mg bid), or cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B). Of the recommended antiplatelet regimens, we suggest clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or cilostazol (Grade 2C). In patients with a history of stroke or TIA and atrial fibrillation we recommend oral anticoagulation over no antithrombotic therapy, aspirin, and combination therapy with aspirin and clopidogrel (Grade 1B).

Conclusions:  These recommendations can help clinicians make evidence-based treatment decisions with their patients who have had strokes.

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommendations sections to indicate recommendations that are newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.

2.1.1. In patients with acute ischemic stroke in whom treatment can be initiated within 3 h of symptom onset, we recommend IV recombinant tissue plasminogen activator (r-tPA) over no IV r-tPA (Grade 1A).

2.1.2. In patients with acute ischemic stroke in whom treatment can be initiated within 4.5 h but not within 3 h of symptom onset, we suggest IV r-tPA over no IV r-tPA (Grade 2C).

2.1.3. In patients with acute ischemic stroke in whom treatment cannot be initiated within 4.5 h of symptom onset, we recommend against IV r-tPA (Grade 1B).

2.2.1. In patients with acute ischemic stroke due to proximal cerebral artery occlusions who do not meet eligibility criteria for treatment with IV r-tPA, we suggest intraarterial (IA) r-tPA initiated within 6 h of symptom onset over no IA r-tPA (Grade 2C).

2.2.2. In patients with acute ischemic stroke we suggest IV r-tPA over the combination IV/IA r-tPA (Grade 2C).

Remarks: Carefully selected patients who value the uncertain benefits of combination IV/IA thrombolysis higher than the associated risks may choose this intervention. Patients who prefer to avoid risk in the setting of uncertain benefits are more likely to choose IV r-tPA alone.

2.3. In patients with acute ischemic stroke, we suggest against the use of mechanical thrombectomy (Grade 2C).

Remarks: Carefully selected patients who value the uncertain benefits of mechanical thrombectomy higher than the associated risks may choose this intervention.

2.4. In patients with acute ischemic stroke or transient ischemic attack (TIA), we recommend early (within 48 h) aspirin therapy at a dose of 160 to 325 mg over no aspirin therapy (Grade 1A).

2.5. In patients with acute ischemic stroke or TIA, we recommend early (within 48 h) aspirin therapy with an initial dose of 160 to 325 mg over therapeutic parenteral anticoagulation (Grade 1A).

3.1.1. In patients with acute ischemic stroke and restricted mobility, we suggest prophylactic-dose subcutaneous heparin (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) or intermittent pneumatic compression devices over no prophylaxis (Grade 2B).

3.1.2. In patients with acute ischemic stroke and restricted mobility, we suggest prophylactic-dose LMWH over prophylactic-dose UFH (Grade 2B).

3.1.3. In patients with acute stroke and restricted mobility, we suggest against elastic compression stockings (Grade 2B).

Remarks: Pharmacologic and mechanical prophylaxis should be initiated as early as possible and should be continued throughout the hospital stay or until the patient has regained mobility. Mechanical devices should be temporarily removed as often as needed to allow for early mobilization and screening for skin complications.

Combining pharmacologic therapy with intermittent pneumatic compression devices may yield additional benefit in prevention of VTEs compared with either method used alone.

3.2.1. In patients with acute primary intracerebral hemorrhage and restricted mobility, we suggest prophylactic-dose subcutaneous heparin (UFH or LMWH) started between days 2 and 4 or intermittent pneumatic compression devices over no prophylaxis (Grade 2C).

3.2.2. In patients with acute primary intracerebral hemorrhage and restricted mobility, we suggest prophylactic-dose LMWH over prophylactic-dose UFH (Grade 2B).

3.2.3. In patients with primary intracerebral hemorrhage and restricted mobility, we suggest against elastic compression stockings (Grade 2B).

Remarks: Patients who prefer to avoid a theoretically increased risk of rebleeding with heparin would favor mechanical prophylaxis with intermittent pneumatic compression devices over pharmacologic prophylaxis.

Combining pharmacologic therapy with intermittent pneumatic compression devices may yield additional benefit in prevention of VTEs compared with either method used alone.

4.1.1. In patients with a history of noncardioembolic ischemic stroke or TIA, we recommend long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended-release dipyridamole (25 mg/200 mg bid), or cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B).

4.1.2. Of the recommended antiplatelet regimens, we suggest clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or cilostazol (Grade 2C).

Remarks: With long-term use ( > 5 y), the benefit of clopidogrel over aspirin in preventing major vascular events may be offset by a reduction in cancer-related mortality with regimens that contain aspirin.

4.2.1. In patients with a history of ischemic stroke or TIA and atrial fibrillation (AF), including paroxysmal AF, we recommend oral anticoagulation over no antithrombotic therapy (Grade 1A), aspirin (Grade 1B), or combination therapy with aspirin and clopidogrel (Grade 1B).

4.2.2. In patients with a history of ischemic stroke or TIA and atrial fibrillation, including paroxysmal AF, we suggest oral anticoagulation with dabigatran 150 mg bid over adjusted-dose VKA therapy (target International Normalized Ratio range, 2.0-3.0) (Grade 2B).

4.2.3. In patients with a history of ischemic stroke or TIA and atrial fibrillation, including paroxysmal AF, who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns about major bleeding), we recommend combination therapy with aspirin and clopidogrel over aspirin (Grade 1B).

Remarks: Patients should be treated (ie, bridged) with aspirin until anticoagulation has reached a therapeutic level.

Oral anticoagulation should generally be initiated within 1 to 2 weeks after stroke onset. Earlier anticoagulation can be considered for patients at low risk of bleeding complications (eg, those with a small infarct burden and no evidence of hemorrhage on brain imaging). Delaying anticoagulation should be considered for patients at high risk of hemorrhagic complications (eg, those with extensive infarct burden or evidence of significant hemorrhagic transformation on brain imaging).

Dabigatran is excreted primarily by the kidney. It has not been studied and is contraindicated in patients with severe renal impairment (estimated creatinine clearance of 30 mL/min or less).

4.3. In patients with a history of a symptomatic primary intracerebral hemorrhage (ICH), we suggest against the long-term use of antithrombotic therapy for the prevention of ischemic stroke (Grade 2C).

Remarks: Patients who might benefit from antithrombotic therapy are those at relatively low risk of recurrent ICH (eg, with deep hemorrhages) and relatively high risk ( > 7% per year) of thromboembolic events (eg, with mechanical heart valves or CHADS2 (Congestive heart failure, Hypertension, Age ≥ 75, Diabetes mellitus, Stroke or TIA) score ≥ 4 points).

5.1. In patients with cerebral venous sinus thrombosis, we suggest anticoagulation over no anticoagulant therapy during the acute and chronic phases (Grade 2C).

This article provides guidance for clinicians managing patients with stroke. The article covers three different stroke subpopulations: (1) patients with ischemic stroke or transient ischemic attacks (TIA), (2) patients with intracerebral hemorrhage (ICH), and (3) patients with cerebral venous sinus thrombosis.

The interventions of interest include both drug-based and device-based interventions. The drugs covered include antiplatelet agents, oral anticoagulants, parenteral anticoagulants, and thrombolytic agents. The devices covered include embolectomy devices used for the removal of blood clots from the cerebral circulation and devices used to prevent DVT formation in patients hospitalized for stroke.

Table 1 lists the clinical questions in PICO (population, intervention, comparator, and outcome) format. Recommendations for the primary prevention of stroke are addressed in the articles by Vandvik et al1 (coronary artery disease), Alonso-Coello et al2 (peripheral arterial disease), You et al3 (atrial fibrillation [AF]), and Whitlock et al4 (valvular disease) in this supplement. Recommendations on antithrombotic use for patients undergoing carotid endarterectomy are discussed in the article on peripheral artery disease by Alonso-Coello et al.2