Chest
Volume 126, Issue 3, Supplement, September 2004, Pages 483S-512S
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Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

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This chapter about treatment and prevention of stroke is part of the 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al). Among the key recommendations in this chapter are the following: For patients with acute ischemic stroke (AIS), we recommend administration of IV tissue plasminogen activator (tPA), if treatment is initiated within 3 h of clearly defined symptom onset (Grade 1A). For patients with extensive and clearly identifiable hypodensity on CT, we recommend against thrombolytic therapy (Grade 1B). For unselected patients with AIS of > 3 h but < 6 h, we suggest clinicians not use IV tPA (Grade 2A). For patients with AIS, we recommend against streptokinase (Grade 1A) and suggest clinicians not use full-dose anticoagulation with IV or subcutaneous heparins or heparinoids (Grade 2B). For patients with AIS who are not receiving thrombolysis, we recommend early aspirin therapy, 160 to 325 mg qd (Grade 1A). For AIS patients with restricted mobility, we recommend prophylactic low-dose subcutaneous heparin or low molecular weight heparins or heparinoids (Grade 1A); and for patients who have contraindications to anticoagulants, we recommend use of intermittent pneumatic compression devices or elastic stockings (Grade 1C). In patients with acute intracerebral hematoma, we recommend the initial use of intermittent pneumatic compression (Grade 1C+). In patients with noncardioembolic stroke or transient ischemic attack (TIA) [ie, atherothrombotic, lacunar or cryptogenic], we recommend treatment with an antiplatelet agent (Grade 1A) including aspirin, 50 to 325 mg qd; the combination of aspirin and extended-release dipyridamole, 25 mg/200 mg bid; or clopidogrel, 75 mg qd. In these patients, we 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). For patients who are allergic to aspirin, we recommend clopidogrel (Grade 1C+). In patients with atrial fibrillation and a recent stroke or TIA, we recommend long-term oral anticoagulation (target international normalized ratio, 2.5; range, 2.0 to 3.0) [Grade 1A]. In patients with venous sinus thrombosis, we recommend unfractionated heparin (Grade 1B) or low molecular weight heparin (Grade 1B) over no anticoagulant therapy during the acute phase.

Section snippets

1.0. Acute Ischemic Stroke: Thrombolytic Therapy in Acute Stroke

The rationale for thrombolytic therapy is based on the recognition that the majority of ischemic strokes are caused by thrombotic or thromboembolic arterial occlusions.12 Pathologic and angiographic studies13 demonstrate the presence of occlusive clot in up to 80% of ischemic strokes. Thrombotic occlusion may also be responsible for a significant number of events in the 20% of patients without angiographic evidence of occlusion, as the thrombus may have lysed spontaneously prior to delayed

Recommendation

1.1.1. For eligible patients (see inclusion and exclusion criteria listed below), we recommend administration of IV tPA in a dose of 0.9 mg/kg (maximum of 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 h 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

Recommendation

1.1.2. For patients with extensive (greater than one third of the MCA territory) and clearly identifiable hypodensity on CT, we recommend against thrombolytic therapy (Grade 1B).

Remarks: Minor ischemic changes on CT are commonly present and subtle or small areas of hypodensity or loss of gray-white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery are not a contraindication to treatment.

1.2. For unselected patients with AIS of > 3 h but < 6 h, we 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.

Remark: Further data are required to identify patients in the 3- to 6-h treatment window who are most likely to benefit or be harmed by IV tPA.

Metaanalysis

The Cochrane analysis reported a significant increase in the number of symptomatic (including fatal) ICH

Recommendation

1.3. For patients with AIS, we recommend against streptokinase (Grade 1A).

Recommendations

1.4.1. For patients with angiographically demonstrated MCA occlusion and no signs of major early infarction on the baseline CT scan, who can be treated within 6 h of symptom onset, we suggest intra-arterial thrombolytic therapy with tPA (Grade 2C).

1.4.2. For patients with acute basilar artery thrombosis and without major CT/MRI evidence of infarction, we suggest intra-arterial thrombolysis with tPA (Grade 2C).

Remarks: Intra-arterial thrombolytic therapy has not received regulatory approval for

2.0. AIS: Patients not Eligible for Thrombolysis

For patients with acute cerebral infarction who are not eligible for IV or intra-arterial thrombolysis therapy, clinicians can consider a variety of antithrombotic agents. Clinical trials have evaluated several anticoagulants (heparin, low molecular weight heparins, and heparinoids) and aspirin. Other antiplatelet agents proven effective in the long-term reduction of recurrent ischemic events have not been adequately evaluated in the acute setting. The rationale for the use of antithrombotic

Recommendation

2.1. For patients with AIS, we suggest clinicians not use full-dose anticoagulation with IV, subcutaneous, or low molecular weight heparins or heparinoids (Grade 2B).

Remarks: Some experts recommend early anticoagulation for various specific stroke subgroups including cardioembolic stroke, progressing stroke, stroke due to large-artery atherosclerotic stenosis, documented intra-luminal thrombus, or arterial dissections. Clinical trials have not, however, adequately evaluated adjusted-dose IV

Recommendation

2.2. For patients with ischemic stroke who are not receiving thrombolysis, we recommend early aspirin therapy, 160 to 325 mg/d (Grade 1A).

Remarks: Aspirin should be started within 48 h of stroke onset, and may be used safely in combination with low doses of subcutaneous heparin for DVT prophylaxis. Aspirin is contraindicated among those with aspirin allergy or those with active GI bleeding.

Recommendations

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

Remarks: Low-dose heparin should be restricted for 24 h after administration of thrombolytic therapy. Low-dose heparin may be used safely in combination with aspirin.

2.3.2. For patients who have contraindications to anticoagulants, we recommend that clinicians use intermittent pneumatic compression devices or elastic

3.1 Heparin for DVT/PE prophylaxis in patients with ICH

Only one small study122 is available to address the risk of early prophylactic therapy with anticoagulants in patients with ICH. In this study, 22 patients with spontaneous ICH were treated with subcutaneous heparin beginning on the second day after the ICH. When compared with historical control subjects, early (day 2) low-dose heparin (5,000 U tid of subcutaneous heparin-sodium) significantly lowered the incidence of PE compared with delayed (day 4 or day 10) heparin therapy. No increase in

Recommendation

3.1. In patients with an acute ICH, we recommend the initial use intermittent pneumatic compression (Grade 1C+) for the prevention of DVT and PE. In stable patients, we 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.

The Antithrombotic Trialists' metaanalysis

Platelet antiaggregation drugs prevent strokes. Aspirin is the most widely studied antiplatelet drug and, until recently, it was the only drug used broadly for this purpose. Now, clinical trial results indicate that ticlopidine and clopidogrel are also effective for prevention of stroke and other vascular events in patients with cerebrovascular disease. Dipyridamole (particularly when combined with aspirin) also is effective for prevention of stroke. The selection of individual agents is

Recommendations

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

4.1.2. In patients receiving aspirin who are at moderate to high risk of bleeding complications, we recommend using low doses

Recommendations

4.2.1. For most patients with noncardioembolic stroke or TIA, we recommend antiplatelet agents over oral anticoagulation (Grade 1A).

4.2.2. For patients with noncardioembolic stroke with well-documented prothrombotic disorders, we suggest oral anticoagulation over antiplatelet agents (Grade 2C).

Recommendation

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

Recommendation

4.4.1. In patients with atrial fibrillation who have suffered a recent stroke or TIA, we recommend long-term oral anticoagulation (target INR, 2.5; range, 2.0 to 3.0) [Grade 1A].

Recommendation

4.4.2. For patients with cardioembolic stroke who have contraindications to anticoagulant therapy, we recommend aspirin (Grade 1A).

Recommendation

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

Recommendation

4.4.5. In patients with cryptogenic ischemic stroke and a PFO, we recommend antiplatelet therapy over no therapy (Grade 1C+), and suggest antiplatelet therapy over warfarin (Grade 2A).

Remark: For patients with evidence of DVT, we recommend anticoagulation.

Recommendation

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

5.0 Cerebral Venous Sinus Thrombosis

Cerebral venous sinus thrombosis (CVST) has diverse clinical presentations, which may include headache, focal neurologic deficits, seizures, alterations of consciousness, and papilledema with a sudden or progressive onset.197 Diagnosis of the thrombosed sinus, although frequently suspected on CT scan, is based on increased signal on both T1- and T2-weighted MRI and magnetic resonance angiography. Conventional angiography is rarely needed when MRI is available.198 Over 100 causes of CVST have

Recommendation

5.1. In patients with venous sinus thrombosis, we 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, we recommend use of vitamin K antagonists for 3 to 6 months (target INR, 2.5; range, 2.0 to 3.0) [Grade 1C]. For patients with venous sinus thrombosis associated with heparin-induced thrombocytopenia, see the chapter by

1.1 IV tPA for AIS within 3 h of symptom onset

1.1.1. For eligible patients (see inclusion and exclusion criteria listed in body of text), we recommend administration of IV tPA in a dose of 0.9 mg/kg (maximum of 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 h 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

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