primary prevention of a first event (ischaemic or haemorrhagic stroke),
About one-third of strokes are recurrent. The recurrence rate for ischaemic stroke is about 3–7% per year for individuals who are in sinus rhythm and about 12% per year for those in atrial fibrillation.
Primary prevention of ischaemic stroke
Blood pressure reduction. Hypertension is the single most powerful predictor of stroke. Pooled trial results indicate that a reduction in diastolic blood pressure by 5–6 mmHg reduces the risk of stroke by about 40% (Ch. 6). For isolated systolic hypertension, a similar reduction in risk has been shown after an average 11 mmHg reduction in systolic blood pressure.
Smoking cessation. The risk of ischaemic stroke is reduced by up to 40% by 2–5 years after smoking cessation. This is probably due to slower progression of arterial atherothrombotic disease.
Reduced platelet aggregation. Low-dose aspirin has not been shown to prevent a first ischaemic stroke when taken by healthy individuals who are in sinus rhythm. For people with atrial fibrillation, aspirin produces a modest reduction in the risk of a first ischaemic stroke by about one-quarter. However, aspirin is much less effective than warfarin (or other oral anticoagulants) for stroke reduction in atrial fibrillation (Ch. 8).
Inhibition of blood clotting. Oral anticoagulation (Chs 8 and 11) in people with atrial fibrillation reduces the risk of a first ischaemic stroke by 70%. Warfarin, at a dosage giving an international normalised ratio (INR) of 2–3, or one of the newer anticoagulants such as apixaban, dabigatran or rivaroxaban, can be used. There is no advantage of warfarin over aspirin for people in sinus rhythm. Warfarin reduces the risk of stroke following myocardial infarction if there is intracardiac clot associated with an akinetic area of the left ventricular wall.
Cholesterol reduction. Reduction of a raised plasma cholesterol with a statin (Ch. 48) produces a 25% reduction in the risk of a first stroke, although much of the evidence for this effect derives from trials in people who already have clinical evidence of vascular disease or who have diabetes mellitus.
Treatment of acute ischaemic stroke
Fibrinolytic therapy with recombinant tissue plasminogen activator (rt-PA, alteplase; Ch. 11) can reduce the long-term neurological deficit after an ischaemic stroke. If treatment is started within 3 h of the onset of symptoms, thrombolysis reduces the risk of death or dependency at 3 months, with greater benefit the earlier that treatment is given. Overall, 7% more people who are given thrombolysis after ischaemic stroke will have no or minimal disability 3 months later. However, more than half of those who are treated with an intravenous fibrinolytic drug do not have complete or near-complete recovery. There is an increased risk of intracerebral haemorrhage after thrombolysis, particularly in those with a blood pressure above 185/110 mmHg or when treatment is delayed, which can outweigh the benefit from neuronal salvage. About 6% of people who are treated will have a symptomatic intracranial haemorrhage.
Meta-analysis of several studies shows that intravenous alteplase is moderately effective from 3 h until 4.5 h after the event. Intra-arterial alteplase is effective in large ischaemic strokes up to 6 h after the onset of symptoms.
Indications and usual contraindications for thrombolytic therapy in acute stroke are shown in Box 9.1. Anticoagulants or antiplatelet drugs should not be given for 24 h after thrombolysis.
Box 9.1 Usual indications and contraindications for thrombolysis in acute ischaemic stroke
| Indications for thrombolysis | Potential contraindications to thrombolysis |
| Clinical diagnosis of ischaemic stroke causing measurable neurological deficit for at least 30 min Onset of symptoms less than 4.5 h before beginning treatment The patient and family understand the potential risks and benefits of therapy Intracranial haemorrhage excluded by CT or MR head scan | Severe stroke deficit on clinical assessment Head trauma or prior stroke in past 3 months Any previous stroke with concomitant diabetes mellitus Gastrointestinal or genitourinary hemorrhage in previous 21 days Arterial puncture in non-compressible site during previous 7 days Major surgery in previous 14 days History of previous intracranial haemorrhage Evidence of acute trauma or haemorrhage Taking an oral anticoagulant (or, if so, INR greater than 1.4 when treating in under 3 h) Heparin within 48 h, unless a normal activated partial thromboplastin time Seizure at the onset of the stroke Systolic blood pressure above 185 mmHg or diastolic blood pressure above 110 mmHg Platelet count of less than 100 × 109 L−1 Blood glucose less than 2.7 mmol⋅L−1 |
There have been many recent advances in treatment of acute ischaemic stroke. These include the use of mechanical thrombectomy devices to reduce the size of the thrombus, and ultrasonography to improve penetration of the fibrinolytic drug into the thrombus. However, a major advance may be the use of sensitive brain imaging to identify those who have potentially recoverable neurological injury from those with irreversible infarction.
Secondary prevention of recurrent ischaemic stroke
Many treatments are similar to those used for primary prevention of ischaemic stroke (see above).
Blood pressure reduction. Lowering blood pressure after a stroke will reduce the risk of recurrence by 30–40%. There is considerable reluctance to reduce blood pressure in the first few days after a stroke, because of concern that cerebral perfusion pressure may fall too much if the normal cerebral arterial autoregulation has been disturbed by the stroke. However, there is some evidence that early treatment (after the first 24 h) may be advantageous.
Reduced platelet aggregation. Low-dose aspirin with dipyridamole can be used following a TIA for people who are in sinus rhythm. The combination reduces the risk of a subsequent non-fatal stroke by about 35%, and is more effective than aspirin alone. This combination is recommended for up to 2 years after a TIA, when the risk of recurrent stroke is highest, after which aspirin is often used alone. Clopidogrel alone (Ch. 11) is as effective as aspirin and dipyridamole after ischaemic stroke, and is now the preferred treatment. By contrast, the combination of aspirin and clopidogrel is no more effective than aspirin alone for long-term prevention (unlike in acute coronary syndromes; see Ch. 5), and increases the risk of serious bleeds. However, there may be some benefit from the combination for short-term treatment (7–30 days) immediately after a stroke or TIA in those at high risk of recurrence. Warfarin has no role in preventing recurrent stroke in people who are in sinus rhythm.
Inhibition of blood clotting. After a first stroke in people with atrial fibrillation, oral anticoagulation reduces the risk of a further stroke by two-thirds. In contrast, aspirin has no protective effect in this situation (see Ch. 11).
Cholesterol reduction. Cholesterol reduction with a statin is effective in secondary prevention of ischaemic stroke, reducing recurrent stroke by 21% for every 1 mmol⋅L−1 reduction in low-density lipoprotein (LDL) cholesterol. However, the greatest advantage of cholesterol reduction in this situation is in the prevention of ischaemic cardiac events, since coronary artery disease often coexists with atheromatous cerebrovascular disease.
Carotid endarterectomy or stenting. This reduces the risk of recurrent stroke if there have already been transient focal neurological symptoms in the cerebral territory served by a diseased carotid artery. If the stenosis is ≥70% of the vessel diameter (but without near total occlusion), then endarterectomy reduces the risk of recurrent stroke by about two-thirds over the subsequent 2 years (despite a perioperative risk of stroke or death of 3–5%). There is no benefit from surgery if the occlusion is less than 50%, and only marginal benefit if the occlusion is between 50 and 69%, unless the surgery is carried out soon after the event (usually within 2 weeks), when the risk of recurrence is highest.Secondary prevention of recurrent haemorrhagic stroke
Blood pressure reduction. Lowering blood pressure after a haemorrhagic stroke will reduce the risk of recurrence by up to 40%. The reduction in risk from treating hypertension is greater than for ischaemic stroke, and even lowering a ‘normal’ blood pressure may be effective. As for ischaemic stroke, treatment is usually delayed to allow return of autoregulation of cerebral blood flow, unless the blood pressure exceeds 185/105 mmHg.Subarachnoid haemorrhage
Most subarachnoid haemorrhages are caused by rupture of a saccular (or berry) aneurysm on an intracranial artery, usually on or close to the circle of Willis. These aneurysms are acquired during life and the cause is unknown, although there is an association with hypertension and conditions that increase cerebral blood flow such as arteriovenous malformations. About 5% of all strokes are caused by subarachnoid haemorrhage. Sudden onset of severe occipital headache is the most common presenting symptom, but focal neurological signs or progressive confusion and impaired consciousness can occur. Rebleeding is a significant cause of disability and death, and early surgical intervention in survivors of the initial bleed reduces this risk. A more common cause of permanent neurological disability or later death is delayed cerebral ischaemia. This is produced by cerebral vasospasm, which develops in about 25% of cases, usually at least 3 days after the haemorrhage. The mechanism is poorly understood, but involves activation of voltage-dependent L-type Ca2+ channels in intracranial arteries. It presents with confusion, decreased consciousness and new focal neurological deficit.
Drugs for subarachnoid haemorrhage
Nimodipine is a dihydropyridine L-type calcium channel blocker (for mechanism of action see Ch. 5) that is an arterial vasodilator with some selectivity for cerebral arteries. It reduces the risk of vasospasm following subarachnoid haemorrhage, but probably produces most of its benefits by protecting ischaemic neurons from Ca2+ overload. There is a theoretical risk that cerebral vasodilation may actually facilitate further bleeding, but this does not appear to be a problem in practice.
Pharmacokinetics: Nimodipine is well absorbed from the gut and undergoes extensive first-pass metabolism in the liver and gut wall. It has a half-life of 8–9 h, and is eliminated by metabolism in the liver.
Unwanted effects: These are mainly caused by arterial dilation:
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