Antithrombotic therapy for cerebrovascular disorders

Antiplatelet treatment

Aspirin is the only antiplatelet drug evaluated for the treatment of acute ischaemic stroke and is recommended early in the management at a dose of 160-325 mg daily. Two major randomised trials (the international stroke trial (IST) and the Chinese acute stroke trial (CAST)) have shown that starting daily aspirin promptly (< 48 hours after the start rather than the end of the hospital stay) in patients with suspected acute ischaemic stroke reduces the immediate risk of further stroke or death in hospital, and the overall risk of death and dependency at six months later. About 10 deaths or recurrent strokes are avoided in every 1000 patients treated with aspirin in the first few weeks after an ischaemic stroke.

The benefit of aspirin is seen in a wide range of patients irrespective of age, sex, atrial fibrillation, blood pressure, stroke subtype, and computed tomographic findings. In IST 300 mg of aspirin was used and in CAST 160 mg. Thus, the two studies show that giving aspirin early in acute stroke is safe, although side effects should always be considered. Other trials have shown that continuing treatment with low dose aspirin gives protection in the longer term. Until further evidence is available, however, aspirin should be withheld from patients receiving other forms of anticoagulant (except low dose heparin (5000 IU twice daily)) or thrombolytic treatment (and for 24 hours after finishing treatment).

Computed tomogram of the brain showing lacunar infarcts in the anterior limb of the left internal capsule

The results of the IST and CAST studies apply chiefly to patients who had a computed tomography scan to exclude intracranial haemorrhage. A meta-analysis of subgroups from the trials showed that aspirin was safe and beneficial. Even among patients who did not have a computed tomogram and patients with haemorrhagic stroke, aspirin treatment did not result in net hazard. Thus, aspirin can be started in patients with suspected ischaemic stroke even when computed tomography is not available immediately.

Anticoagulation treatment

Heparin is not routinely recommended for patients with acute ischaemic stroke. There are no randomised trials supporting the use of standard doses of heparin (for example > 10 000 IU daily) even in patients with acute stroke and risk factors for recurrent events. The risk:benefit ratio of heparin administration is narrow, ill defined, and probably depends on the pathophysiological subtype of stroke and the factors that predispose to haemorrhage. For patients with atrial fibrillation and acute ischaemic stroke, there seems to be no net benefit from standard dose heparin (aspirin should be given immediately, then warfarin started for secondary prevention as soon as the patient is medically stable). However, a subgroup analysis from IST showed that in acute ischaemic stroke low dose heparin (5000 IU twice daily) reduced death and recurrence, especially if combined with aspirin, and it is indicated if appreciable leg weakness is present for prevention of venous thromboembolism.

Thromboembolic and major haemorrhagic events in the International Stroke Trial. ICH=intracranial haemorrhage

• Download figure
• Open in new tab
• Download powerpoint

No particular benefit was observed in ischaemic stroke in the vertebrobasilar region with anticoagulation at six months. Trials with low molecular weight heparins or heparinoids have yielded contradictory (but generally negative) results, and they are not recommended for use at the moment.

Thrombolytic treatment

Thrombolytic treatment for acute ischaemic stroke has been in vogue since its immense benefit was seen with myocardial infarction. The National Institute of Neurological Disorders and Stroke (NINDS) rtPA Study Group trial showed that recombinant tissue plasminogen activator administered within three hours of onset of acute cerebral infarct at a dose of 0.9 mg/kg (maximum 90 mg) given over an hour under strict treatment protocols increased the likelihood of minimal or no disability at three months by at least 30%. This benefit was seen in all stroke patients. Recombinant tissue plasminogen activator is licensed for treating acute cerebral infarct in several countries. However, the risk:benefit ratio is narrow because of substantial risk of intracerebral haemorrhage, and the need to start treatment (after computed tomographic assessment) within three hours of stroke onset severely restricts the number of patients who can be treated.

Streptokinase is not approved for use in acute cerebral infarct because of the results of three large trials, which were terminated early due to excessive bleeding. These trials used streptokinase at a dose of 1.5 million units given more than three hours after stroke onset. Intra-arterial thrombolytic treatment for patients with large artery occlusions (such as of the internal carotid artery, middle cerebral artery, or basilarartery) remains investigational. In the United Kingdom, thrombolytic treatment is not licensed for treatment of stroke, pending results from ongoing clinical trials (for example, IST-3).

Antiplatelet agents

Among patients with vascular disorders (such as coronary artery disease, previous stroke or transient ischaemic attack, and peripheral vascular disease) antiplatelet agents substantially reduce the incidence of non-fatal stroke, non-fatal myocardial infarction, vascular mortality, and composite end point of stroke, myocardial infarction, and vascular death.

A variety of antiplatelet drugs with varying mechanisms of action are used to minimise stroke in patients at high risk. These include aspirin (irreversible inhibitor of cyclo-oxygenase), clopidogrel (which inhibits adenosine diphosphate induced platelet aggregation) and dipyridamole (precise mechanism of action not yet clear). Aspirin remains the most commonly used antiplatelet drug, partly because of its cost effectiveness.

Aspirin is effective for stroke prevention in doses ranging from 30 mg/day to 1300 mg/day. Its beneficial effect is seen in all age groups and sexes. The European stroke prevention study II (ESPS II) showed that a combination of aspirin and dipyridamole (sustained release 200 mg tablets twice daily) significantly reduced the risk of stroke and all vascular events compared with aspirin alone. An important ongoing trial (ESPRIT) is seeking to replicate these results.

Clopidogrel is a newer thienopyridine derivative without the adverse effect profile of ticlopidine. The CAPRIE (clopidogrel versus asprin in patients at risk of ischaemic events) study showed that clopidogrel is slightly more effective than aspirin in reducing the combined outcome of stroke, myocardial infarction, and vascular death among patients with atherosclerotic vascular disease. Although clopidogrel seems to be as safe as aspirin, it is considerably more expensive, and it remains to be seen whether its use in routine practice is cost effective. Its use is justified in patients who are intolerant to aspirin or who develop a stroke while taking aspirin.

Anticoagulation treatment

Anticoagulation in the form of warfarin has a role in a variety of cardiac disorders in primary and secondary prevention of stroke. Cardiac disorders that predispose to stroke and unequivocally seem to benefit from anticoagulation therapy include atrial fibrillation (with additional risk factors putting patients at moderate to high risk), mitral stenosis (with or without atrial fibrillation), and mechanical valve prosthesis. In contrast, recent randomised trials (SPIRIT, WARSS) did not show advantages of warfarin over aspirin for secondary prevention of non-cardioembolic brain ischaemia. At present, warfarin should not be used routinely for patients with common causes of non-cardioembolic stroke, pending results from ongoing randomised trials.