Guideline 36: Antithrombotic Therapy

Antithrombotic Therapy
Section 7: Cerebrovascular disease

7.1 Acute stroke

7.1.1 INVESTIGATION

The SIGN guideline on Management of Patients with Stroke, part I: Assessment, investigation, immediate management and secondary prevention¹²⁴ recommends that all patients with acute stroke should undergo CT brain scanning as soon as possible-preferably within 48 hours-and no later than seven days. A local protocol for more urgent scans (e.g. patients receiving anticoagulant or recent thrombolytic therapy) should be available.

This recommendation is based on the following considerations:

Specific treatment of intracranial haemorrhage (e.g. neurosurgery, cessation/reversal of antithrombotic therapies) may be indicated if rapidly diagnosed.
There is conclusive evidence for the efficacy of antiplatelet or anticoagulant therapies in the secondary prevention of acute stroke, but they should be avoided in cases of haemorrhagic stroke.^{7, 17,
125, 126}
Clinical scoring systems have been found to be unreliable in distinguishing ischaemic and haemorrhagic stroke.¹²⁷

7.1.2 ACUTE PROPHYLAXIS OF FURTHER VASCULAR EVENTS

Since publication of part I of the SIGN guideline on management of patients with stroke,¹²⁴ a meta-analysis of three randomised trials of early treatment of acute ischaemic stroke with aspirin (160-300 mg/day) has shown modest, but definite (2P=0.001) net reduction in early death or non-fatal stroke: nine (SD 3) per 1,000.¹²⁶ This represents a balance between prevention of 11 (SD 3) per 1,000 ischaemic strokes or death and an increase in haemorrhagic strokes of two (SD 1) per 1,000. Application of these results to Scotland (about 10,000 acute strokes/year) would avoid about 90 early deaths, strokes or myocardial infarctions per year. Furthermore, early aspirin treatment in acute ischaemic stroke is likely to lead to more patients being sent home on long-term aspirin, further reducing morbidity and mortality (see section 7.2).¹²⁶ Early aspirin also reduced the risks of myocardial infarction and pulmonary embolism in patients with acute ischaemic stroke.¹²⁶ Evidence level Ia

Early treatment with aspirin (150-300 mg/day) is recommended in acute ischaemic stroke, starting as soon as intracranial haemorrhage is excluded by CT brain scanning, for risk reduction in death and cardiovascular events.

About one third of patients with acute stroke cannot swallow safely, and are at risk of aspiration. In such patients, aspirin may be given as a 300 mg suppository per rectum until swallowing recovers or a nasogastric or percutaneous gastrostomy tube is placed.

The International Stroke Trial¹²⁵ has shown that unfractionated heparin (either low dose or intermediate dose) did not improve clinical outcome in acute stroke, and increased the risk of intracranial haemorrhage, with a dose-dependent relationship. Evidence level Ib

Routine use of unfractionated or low molecular weight heparin (even at low doses) in acute stroke is not recommended.

In patients at increased risk of venous thromboembolism, additional prophylaxis with graduated elastic compression stockings should be considered in all immobile patients following acute stroke.

Based on extrapolation from RCTs in other patient groups⁵

Early institution or maintenance of anticoagulant therapy (with heparin or warfarin) in acute ischaemic stroke should be reserved for patients with a high risk of either venous thromboembolism (e.g. previous venous thromboembolism, thrombophilias) or recurrent thromboembolic stroke (e.g. rheumatic valve disease or mechanical heart valves, especially in the presence of atrial fibrillation) in whom these risks are judged to outweigh the increased risk of intracranial bleeding.¹²⁸

Based on extrapolation from RCTs in other patient groups⁵

Urgent CT brain scans are indicated in such patients, to exclude intracranial bleeding and predictors of haemorrhagic transformation such as major cerebral infarction. Careful control of both hypertension and the intensity of anticoagulants in such patients is also recommended to reduce the risk of intracranial bleeding.

Based on extrapolation from RCTs in other patient groups⁵

7.2 Secondary prevention after acute ischaemic stroke or transient cerebral ischaemic attack (TIA)

7.2.1 ASSESSMENT

The SIGN Guideline on Management of Patients with Stroke, Part I: Assessment, investigation, immediate management and secondary prevention,¹²⁴ recommends that local admissions policies should be agreed, as well as local protocols for referral to a fast-track assessment clinic for those with minor strokes or TIAs not requiring hospital admission, for identification and modification of risk factors and rapid administration of secondary prevention including antithrombotic treatments.

7.2.2 ASPIRIN

Meta-analyses of 22 randomised controlled trials have shown that antiplatelet drugs (usually aspirin) reduce the long term risk of cardiovascular events in patients with prior TIA or ischaemic stroke (absolute risk difference 4.5% over 30 months, see Table 1).^{7, 9} Medium dose aspirin therapy (75-300 mg/day) is the most widely tested; higher doses are associated with increased risk of adverse events.⁷ Evidence level Ia

Antiplatelet therapy-normally aspirin (75-300 mg/day)-should be prescribed as early as possible for secondary prevention of stroke and other vascular events in patients who have sustained an ischaemic stroke (or TIA). In acute ischaemic stroke, the starting dose should be 150-300 mg/day.

7.2.3 DIPYRIDAMOLE

One large randomised placebo-controlled trial in patients with ischaemic stroke has shown that dipyridamole in a sustained release preparation appears as effective as low dose aspirin (50 mg/day) in prevention of cardiovascular events, and that an additive effect is achieved in combination with this dose of aspirin for prevention of recurrent stroke.^{129, 130} Previous, smaller randomised trials of aspirin vs. dipyridamole and aspirin have not shown additive effects,⁷ and updated meta-analyses are awaited. Evidence level Ib

Dipyridamole (200 mg twice daily in a sustained release preparation) should be considered for prevention of cardiovascular events following ischaemic stroke:

as an alternative to aspirin in patients with contraindications to aspirin, or who are intolerant of aspirin; and

in addition to aspirin, especially in patients with recurrent stroke or TIA despite aspirin.

7.2.4 CLOPIDOGREL

Clopidogrel (75 mg/day) appears to be as effective as moderate dose aspirin (300 mg/day) for prophylaxis of cardiovascular events following ischaemic stroke.⁹³ Evidence level Ib

Clopidogrel (75 mg/day) should be considered as an alternative to aspirin in suitable patients with contraindications to aspirin, or who are intolerant of aspirin, for prevention of cardiovascular events following ischaemic stroke.

7.2.5 WARFARIN

In patients with atrial fibrillation, warfarin (target INR 2.5, range 2.0-3.0) should be used in preference to antiplatelet therapy to reduce the risk of a further ischaemic stroke because of its greater efficacy.¹⁷ (See section 3)

Warfarin should also be considered as secondary prophylaxis after cardioembolic stroke from valvular heart disease or recent myocardial infarction.¹²⁴ (See sections 3 and 4)

The balance of risk and benefit for warfarin (target INR 2.5, range 2.0-3.0) in secondary prevention in patients with TIA or ischaemic stroke who do not have atrial fibrillation or other cardiac source of embolism is not known reliably, and so is not recommended at present.¹³¹ A randomised trial of higher intensity warfarin (target INR 3.7, range 3.0-4.5) vs. aspirin was terminated early because of excessive intracranial bleeding.¹³²

7.3 Carotid endarterectomy

The SIGN Guideline on Management of Patients with Stroke, Part II: Management of carotid stenosis and carotid endarterectomy,¹³³ recommends that patients should continue on antiplatelet drugs throughout the perioperative period and should be heparinised during the procedure.