Stroke Prevention by the Practitioner 2nd, revised edition
Editor
J. Bogousslavsky, Lausanne on behalf of the European Stroke Initiative (EUSI)
2 figures and 11 tables, 2003
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Vol. 15, Supplement 2, 2003
Contents
Chapter 6
IV Contributors V Preface
37 Other Risk Factors Olsen, T.S. (Hellerup)
Chapter 1 1 Introduction to Stroke and Its Management Michel, P. (Lausanne)
Chapter 7 43 Antiplatelet Therapy in Stroke Prevention Ringleb, P.A.; Hacke, W. (Heidelberg)
Chapter 2 11 Ten Questions to Stroke Units Lyrer, P. (Basel)
Chapter 8 49 Anticoagulant Therapy Chamorro, A.; Obach, V. (Barcelona)
Chapter 3 19 Hypertension and Lowering Blood Pressure Perren, F.; Bogousslavsky, J. (Lausanne)
Chapter 9 57 Stroke Prevention in Carotid Stenosis Kaste, M. (Helsinki)
Chapter 4 25 Diabetes and Stroke Nedeltchev, K.; Mattle, H.P. (Bern)
Chapter 10 63 Stroke Services Brainin, M. (Maria Gugging)
Chapter 5 31 High Cholesterol and Its Management Olsen, T.S. (Hellerup)
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71 Subject Index
Contributors
Prof. Dr. Julien Bogousslavsky Service de Neurologie CHUV BH 10 CH–1011 Lausanne (Switzerland)
Dr. H.P. Mattle Department of Neurology Inselspital CH–3010 Bern (Switzerland)
Prof. Michael Brainin Donau-Universität und Donauklinikum Maria Gugging A–3400 Maria Gugging (Austria)
Dr. Patrik Michel Service de Neurologie CHUV CH–1011 Lausanne (Switzerland)
Dr. Angel Chamorro Neurology Service Hospital Clinic 170 Villaroel E–08036 Barcelona (Spain)
Dr. Krassen Nedeltchev Department of Neurology Inselspital CH– 3010 Bern (Switzerland)
Prof. Dr. Werner Hacke Department of Neurology University of Heidelberg Im Neuenheimer Feld 400 D–69120 Heidelberg (Germany) Prof. Markku Kaste Department of Neurology Helsinki University Central Hospital University of Helsinki PO Box 340 FIN–00029 Helsinki (Finland) Dr. Philippe Lyrer Neurologische Universitätsklinik Abteilung für Zerebrale Ultraschalldiagnostik und Zerebrovaskuläre Sprechstunde Kantonsspital Basel Petersgraben 4 CH–4031 Basel (Switzerland)
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Dr. V. Obach Neurology Service Hospital Clinic 170 Villaroel E–08036 Barcelona (Spain) Dr. Tom Skyhøj Olsen Department of Neurology Gentofte University Hospital DK–2900 Hellerup (Denmark) Dr. Fabienne Perren Service de Neurologie CHUV BH 13 CH–1011 Lausanne (Switzerland) Dr. P.A. Ringleb Department of Neurology University of Heidelberg Im Neuenheimer Feld 400 D–69120 Heidelberg (Germany)
Preface
Stroke prevention is one of the most important aspects of the fight against the burden of stroke. Besides, it is also a critical step in the general management of patients with atherothrombotic risk. In Europe, nearly one million individuals suffer a stroke every year, and the same is true for North America. However, stroke is also a major problem in the developing world. Stroke affects young people, old people, women and men of all races and backgrounds, and its costs – functional, emotional and financial – are huge. Preventing stroke occurrence is the best means to avoid these consequences, both in people at risk (who have not yet had a stroke), and in patients who have already had one. The general practitioner plays a key role in this task, and his or her interaction with stroke specialists should be emphasized and encouraged. Because of the success of the first version of ‘Stroke Prevention by the Practitioner’ a few years ago, a new edition, totally reworked and rewritten, has been prepared by European stroke experts. The European Stroke Initiative is happy to present this revised version on behalf of the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies. J. Bogousslavsky, MD
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Chapter 1 Cerebrovasc Dis 2003;15(suppl 2):1–10 DOI: 10.1159/000069674
Introduction to Stroke and Its Management P. Michel
Question 1
2
Question 7
What Is a Stroke?
5
Question 2
2
Which Are the Risk Factors for Stroke? Question 8
What Types of Stroke Are There?
5
How Do You Make the Diagnosis of Stroke in the Emergency Setting?
Question 3
3
Question 9
How Frequent Are Strokes? 7 Question 4
3
Which Are the Warning Symptoms of Stroke? Question 5
3
4
Question 10
8
What Should a Practitioner Do if He Suspects a TIA or Minor Stroke? Question 6
ABC
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How Do You Treat a Patient with Acute Stroke? Question 11
9
What Are the Manifestations of Stroke?
Which Tests Can Help in the Search for Stroke Aetiology?
What to Do to Prevent Stroke?
Question 1
Question 2
What Is a Stroke?
What Types of Stroke Are There?
Stroke (or ‘brain attack’) is defined as a sudden neurological deficit of the central nervous system due to ischaemia or haemorrhage. The definition includes ischaemic stroke (about 80%), intracerebral haemorrhages (15%) and subarachnoid haemorrhages (5%). In ischaemic stroke, neurons start malfunctioning and clinical deficits appear if arterial blood flow in brain tissue falls below a critical level. If this hypoperfusion is sufficiently severe and protracted, neuronal death occurs in the core of the ischaemic region. The surrounding area, called ‘penumbra’, may also be transformed into infarction within minutes to hours unless blood flow is restored by reperfusion or collateral circulation or effective neuroprotection is initiated. Intracerebral haemorrhages (ICH) and subarachnoid haemorrhages (SAH) lead to tissue damage by mechanical factors (local disruption and shearing of cerebral tissue) as well as by molecular, biochemical, and inflammatory mechanisms related to blood degradation and parenchymal necrosis. Stroke symptoms and signs that disappear completely within 24 h are called ‘transient ischemic attacks’ (TIAs). The 24-hour threshold was chosen arbitrarily and most TIAs disappear in less than 1 h (see question 4). Like TIA, stroke or ‘brain attack’ are clinical terms. Many TIAs lasting longer than 1 h and most strokes leave pathological evidence of infarction and abnormal signals on brain imaging (especially MRI). An abnormality on brain imaging (CT, MRI or other) is not required to make a diagnosis of stroke, however. There are many other disorders of intracranial circulation which do not necessarily present as strokes and are not discussed here: cerebral vein and sinus thrombosis, subdural and epidural haematomas, diffuse vascular leucoencephalopathy (leucoaraiosis), vascular malformations, anoxic encephalopathy after cardio-respiratory arrest, brief hypoperfusion due to vasovagal or orthostatic hypotension and arrhythmias.
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Cerebrovasc Dis 2003;15(suppl 2):1–10
The pathophysiological mechanism of a stroke should be thoroughly searched as it influences acute treatment, secondary prevention and prognosis. Furthermore, multiple potential stroke causes are present in 15–30% of patients, and recurrent strokes may be of a different pathogenesis in a similar number of patients. Ischemic strokes can roughly be divided into four, similarly frequent categories (table 1): 1. Large artery arteriosclerosis (or ‘macroangiopathy’) may affect extracerebral (aorta, brachiocephalic, carotid, vertebral) or intracranial arteries (anterior cerebral artery, ACA; middle cerebral artery, MCA; posterior cerebral artery, PCA; vertebral and basilar arteries). In each case, arteriosclerosis of one of these vessels may cause strokes by local thrombosis, by embolization of thrombotic material (artery-to-artery embolization), or by a reduction of the blood flow between two arterial territories (haemodynamic mechanism).
Table 1. Stroke pathogenesis
Ischaemic stroke (80%) Large vessel arteriosclerosis (macroangiopathy) Large artery thrombosis Artery-to-artery embolization (including aorta) Haemodynamic stroke (borderzone stroke) Cardiogenic embolus (including paradoxical embolus) Structural pathologies Arrhythmias Small vessel occlusion (lacunar stroke, microangiopathy) Unidentified and rare mechanisms (e.g. dissection, vasculitis, hypercoagulable states, and migrainous stroke) Haemorrhagic stroke (20%) Intracerebral haemorrhage Hypertensive arteriolopathy (deep, lobar or brainstem haemorrhages) Cerebral amyloid angiopathy (lobar haemorrhages) Vascular malformations Rare and unidentified mechanisms Subarachnoid haemorrhage Saccular aneurysms Rare mechanisms
Michel
2. Cardiogenic stroke may be caused by embolization of abnormal material (mostly intracardiac thrombi), arrhythmia and haemodynamic failure. Frequent causes are atrial fibrillation, valvular heart disease, prosthetic valves, mural thrombus in acute or chronic ischaemic heart disease, dilated cardiomyopathy, and interatrial septum defects. The risk is particularly high if such cardiac abnormalities occur simultaneously or in combination with other risk factors. Occasionally, cardioembolic occlusion of a large artery can also lead to a haemodynamic pattern of infarct. 3. Small vessel occlusion leads to lacunar infarcts, pathologically defined as being inferior to 15 mm in diameter. They usually cause lacunar stroke syndromes (table 3) and are localised in deep brain structures in the territories of perforating arteries. The cause for the occlusion is usually lipohyalinosis due to hypertension and diabetes. Another mechanism is an unstable plaque in a parent vessel obstructing the orifice of the perforating artery. 4. There is a long list of rare causes of ischaemic strokes, including extra- or intracranial arterial dissection, vasculitis, vasospasms after subarachnoid haemorrhages, medications or recreational drugs, and haematological conditions such as polycythemia, antiphospholipid antibody syndrome, genetic procoagulant states, or sickle cell anaemia. ICHs are roughly divided in deep (basal ganglia, thalamus, brainstem and cerebellum) and lobar localisations (cortical and near-cortical). The former is mainly caused by a hypertensive arteriolopathy and the latter may be related to hypertension, cerebral amyloid angiopathy or vascular malformations (mainly arterio-venous malformations and cavernous haemangiomas). Anticoagulation facilitates all types of intracranial haemorrhages, but an underlying cause is usually present. In SAH, bleeding occurs primarily into the meninges. It is associated in about 85% with a ruptured saccular aneurysm of the main intracranial arteries. Secondary ischaemic infarction may occur due to vasospasms several days after the bleed. Table 2. Warning symptoms of stroke
Sudden weakness, numbness or loss of control of the face, arm, or leg on one side of the body Sudden dimness or loss of vision in one or both eyes Loss of speech, or trouble talking or understanding speech Unexplained dizziness, unsteadiness or sudden falls Sudden difficulty in swallowing Sudden onset, unusual and severe headache (SAH)
Introduction to Stroke and Its Management
Question 3
How Frequent Are Strokes?
Strokes are frequent: they are the third leading cause of death (after cardiovascular causes and cancer), and the most frequent cause of acquired disability in adults. It occurs in about 150 patients per 1,000,000 inhabitants per year in industrialised countries; 15–30% die within 30 days and even more remain disabled. After age 45, stroke incidence doubles every 10–15 years and remains higher for men than for women (cf. chapter 6). Despite a slow decrease of mortality from stroke in many industrialised nations, the emotional, social and economic impact of stroke remains enormous.
Question 4
Which Are the Warning Symptoms of Stroke?
Short-lasting warning symptoms are in fact TIAs (table 2; see question 1); about 20–30 % of strokes are preceded by TIAs or minor strokes. They are frequently not recognised or not taken seriously, either because of inattention or wrong interpretation by the patient or the physician (‘slept on the arm’, ‘hypertensive episode’, ‘gastroenteritis’). Although a TIA is often thought to be ‘less severe’ than a stroke, its significance as a risk factor for stroke is immense. They require an identical work-up to strokes and, if recognised, are a great opportunity for the physician to offer secondary prevention. Primary care physicians should routinely ask and patients (especially at-risk patients) should be taught about the warning symptoms listed in table 2.
Question 5
What Should a Practitioner Do if He Suspects a TIA or Minor Stroke?
Whether recognised within minutes, hours or days, symptoms and signs suggestive of TIAs or stroke (table 2, 3) should prompt immediate referral to the next casualty or stroke centre. Antithrombotics or anticoagulation should not be given until a brain imaging excludes haemorrhage. If several days or weeks have passed before the symptoms come to the attention of the physician, semi-urgent referral to a neurologist or stroke centre is appropriate.
Cerebrovasc Dis 2003;15(suppl 2):1–10
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Question 6
What Are the Manifestations of Stroke?
Both in the acute and the chronic phases, stroke may affect higher (cognitive) cerebral functions, such as motivation, judgement, language, affect, emotions, memory, spatial attention, pattern recognition, and complex motor function. It may cause paralysis of cranial nerves or extremities and it might affect arousal, the visual system, speech and swallowing, sensation, sphincter function, coordination, balance and gait. Ischaemic strokes cause classical constellations of symptoms and signs that usually allow the identification of a specific vascular territory (table 3, 4). The value of recognising a vascular syndrome lies in differentiating vascular from non-vascular diseases (migraines, seizures, syncopies), in suggesting a stroke mechanism (and thus a potential cause of the stroke) and in directing further work-up and management accordingly. Briefly, the anterior circulation consists of the common and internal carotid arteries branching into the ophthalmic artery (supplying the optic nerve and retina), the
MCA (supplying the frontal, parietal, and lateral temporal lobes, basal ganglia and internal capsule) and the ACA (supplying the paramedian part of the frontal and parietal lobes and part of the internal capsule). The posterior circulation takes its origin in the vertebral arteries (medulla, lower cerebellum), which join to form the basilar artery (supplying the pons, the mesencephalon, and the upper cerebellum) and then branch into the PCA (supplying most of the thalamus, occipital lobes and medial temporal lobes).
Table 4. Correlation vascular territories – stroke syndromes (simpli-
fied) Deficit Anterior circulation MCA-left
Sensitivo-motor facio-brachial, aphasia, acalculia, homonymous hemianopsia, eye deviation, ideomotor apraxia, rare hemineglect
MCA-right
Sensitivo-motor facio-brachial, hemineglect, homonymous hemianopsia, eye deviation, constructive and dressing apraxia, confusion
ACA
Sensitivo-motor crural, frontal signs (primitive reflexes, apathy, mutism, desinhibition)
Internal carotid
See MCA and ACA, plus monocular blindness (often transient)
Table 3. Correlation stroke syndromes – vascular territories (simpli-
fied) Deficit Sensorimotor crural paresis Sensorimotor faciobrachial hemiparesis Aphasia, ideomotor apraxias, acalculia Neglect, constructional apraxias Conjugate eye deviation and contralateral signs Conjugate eye deviation and ipsilateral signs Diplopia, disconjugate gaze deficits, nystagmus Homonymous hemianopsia or quadranopsia Bilateral signs Crossed signs (cranial nerves vs. body) Decreased level of vigilance Hemi-ataxia without paresis Dizziness, vertigo, nausea, hearing loss Lacunar syndromes Pure motor hemiparesis Ataxic hemiparesis Dysarthria-clumsy hand Pure sensory stroke Sensory-motor stroke
冧
Territory ACA MCA MCA (left) MCA (mainly right)
VA (lateral medulla)
Vertigo, nausea, hiccup, ipsilateral facial sensation loss, ataxia, palatal and tongue paresis, Horner’s syndrome. Contralateral bodily sensory deficits
Mid-BA (pons)
Unilateral or bilateral ataxic hemiparesis (‘locked-in syndrome‘), dysarthria, horizontal gaze paresis, ipsilateral cranial nerve V–VII deficits
High-BA (midbrain, thalamus, ev. PCA)
Decreased vigilance, vertical gaze paralysis, often also PCA signs
Cerebellar (VA or BA or cerebellar arteries)
Vertigo, nystagmus, ipsilateral ataxia of extremities, ataxia while sitting or walking, often other posterior circulation signs
PCA
Homonymous or bilateral hemianopsia, quadranopsia or sectoranopsia, alexia (right), sensory aphasia (left), visual perception deficits (agnosia), amnesia (thalamus or medial temporal lobe), confusion, sensitive hemisyndrome (lateral thalamus)
MCA BA (pons) VA, BA (brainstem) PCA, MCA BA (brainstem) or ACAS (paraparesis) VB, BA (brainstem) BA (upper brainstem, thalamus) VB, BA (cerebellum) VB, BA (brainstem)
internal capsule, pons, corona radiata
冧 thalamus, corona radiata
VA = Vertebral artery; BA = basilar artery.
4
Posterior circulation
Cerebrovasc Dis 2003;15(suppl 2):1–10
VA = Vertebral artery; BA = basilar artery.
Michel
ICHs can be clinically indistinguishable from ischaemic strokes, although a combination of signs, such as prominent headaches, a decreased level of consciousness, and certain risk factors (anticoagulation, previous ICH) should raise suspicion of haemorrhage. A necessary, reliable, and quick way to ascertain the diagnostic is a cranial CT scan. SAHs are characterised by an unusual persistent headache of very sudden onset, often in a bilateral cervico-
occipital distribution. On examination, meningismus, a decreased level of consciousness, signs of intracranial hypertension (nausea, yawning, 6th nerve palsy) and focal (sometimes fleeting) neurological signs are often present. Stroke-like presentations of non-vascular disorders may be caused by migraine with aura, complicated migraine, epileptic seizure, persistent deficits after epileptic seizures (‘Todd’s paralysis’), a multiple sclerosis plaque, a conversion disorder, or by unmasking of an old and sometimes silent brain infarction due to a toxic-metabolic encephalopathy.
Table 5. Risk factors for ischaemic strokes
Non-modifiable risk factors Increasing age Male gender Ethnicity Family history of vascular disease Inherited diseases and risk factors Previous TIAs and strokes Silent cerebral infarctions Modifiable risk factors Arterial hypertension Diabetes mellitus Hyperlipidemia Smoking Cardiac diseases Atrial fibrillation Valvular disease Prosthetic valves Coronary artery disease Recent myocardial infarction Low cardiac ejection fraction Others Carotid artery stenosis Peripheral artery disease Obesity Physical inactivity Alcohol abuse Uncommon, emerging and probable risk factors Isolated systolic hypertension Cardiac, aortic, and carotid angiography and interventions Patent foramen ovale, atrial septum defect Hypercoagulable states, especially antiphospholipid antibodies Hyperhomocysteinaemia Cerebral amyloid angiopathy Oral contraception Pregnancy and peripartum state Migraine Drug abuse Nutrition Certain medications Chronic systemic inflammation Recent infection Sleep apnea
Introduction to Stroke and Its Management
Question 7
Which Are the Risk Factors for Stroke?
The individual stroke risk varies greatly and can approximately be calculated by tables distributed by national stroke organisations. They take into account age, gender, markers of arterial disease and other risk factors. The risk of ischaemic stroke increases with age and after previous TIAs or strokes. Others risk factors are listed in table 5 and are discussed in chapter 6. For ICH, risk factors partially overlap with the ones for ischaemic stroke (see chapter 6). For non-traumatic SAH, the main risk factor is the presence of an intracranial saccular aneurysm, especially if it is bigger than 10 mm. Other risk factors for SAH are increasing age, ethnicity, probably female gender, arterial hypertension, smoking, alcohol overuse and drug abuse; most of these factors act probably as triggers for rupture of the aneurysm.
Question 8
How Do You Make the Diagnosis of Stroke in the Emergency Setting?
The most valuable tools are a precise history taking, which should include questioning of the family or caregivers, and a basic neurological exam (table 6). This information helps to differentiate stroke from stroke-like manifestations of non-vascular disorders. TIAs and strokes are characterised by their rapid onset over seconds to minutes, and by a typical constellation of signs and symptoms that can be attributed to a specific vascular territory (table 3, 4). Loss of consciousness is rarely caused by TIAs or strokes and should lead to a search for epileptic seizures, hypoglycaemia, orthostatic hypotension, and cardiac ar-
Cerebrovasc Dis 2003;15(suppl 2):1–10
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Table 6. Basic neurological exam of the patient with suspected
Table 7. Emergent exams in the patient with suspected stroke
stroke General Vital signs, including cardiac rhythm Cardiac and carotid bruits, meningismus Cognitive Level of consciousness Orientation, attention (digit span), hemineglect of space Language (fluency, comprehension, repetition) Behaviour, primitive reflexes (grasping, lack of initiative, perseveration) Short-term memory (3 words after 5 min) Cranial nerves Ptosis, pupillary reaction to light, visual fields to confrontation Ocular pursuit, nystagmus Facial paralysis and sensation to pinprick Tongue and palate deviation, dysarthria Extremities Bilateral arm and leg raising and strength Ataxia (finger-to-nose and heel-to-shin) Sensation (asymmetry of pinprick and vibration) Reflexes (asymmetry of tendon reflexes, cutaneous plantar reflexes)
rhythmias. Precise history taking is also extremely helpful in identifying previous TIAs or other undiagnosed risk factors, triggers of stroke (medications, drugs, recent infection, head and neck trauma) and associated diseases. A minimal neurological exam (table 6) should be performed by the non-neurologist and usually permits a rapid orientation between territorial and lacunar syndromes (table 4). It needs to be remembered that a ‘non-focal’ exam does neither rule out TIAs nor stroke. The most frequently missed ‘non-focal’ signs of stroke are hemi- and quadranopsias (because they are not tested), mild aphasias (missed or mistaken as confusional states), mild confusional states due, for example, to right hemispheric or thalamic strokes, somnolence and upward gaze paresis due to midbrain strokes (not recognised), and bilateral ptosis in right hemispheric or midbrain strokes (they are often not recognised or mistaken as somnolence). As discussed in question 4, rapid disappearance of symptoms and a normal exam is characteristic of TIAs and should in no way undermine the urgency and thoroughness of a cerebrovascular work-up. In addition to the history and clinical exam, acute brain and arterial imaging and some basic laboratory tests (table 7) are essential aids to the diagnosis of acute stroke.
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Brain imaging (at least one of the following): Cranial CT with contrast Brain MRI Imaging of cervical and intracranial arteries (at least one of the following): CT angiography Doppler and duplex ultrasonography MR angiography Conventional or digital subtraction angiograpy (if intra-arterial thrombolysis is an option) Laboratory Complete blood count, INR, aPTT, blood glucose, sodium, potassium, creatinine, CK, CK-MB, CRP Others 12-Lead electrocardiogram Lumbar puncture (if SAH is suspected and CT is normal or if meningo-vascular infection is suspected)
Acute brain imaging (cranial CT with contrast or MRI with contrast, diffusion, perfusion, FLAIR and T2* susceptibility sequences) distinguishes immediately and reliably ischaemic stroke from ICH. After a large ischaemic stroke involving the cortex or basal ganglia, early abnormalities on CT appear within 1–3 h. Small and brainstem strokes may not be visualised for 12–24 h on CT, they may actually never show up on CT. They are occasionally missed on MRI, too. Clinical information such as suspected stroke localisation as well as joint visualisation of images by the clinician and radiologist is very helpful in interpreting subtle abnormalities on brain imaging. In acute stroke, the advantages of MRI [higher resolution, faster appearance of abnormalities (diffusion MRI), better brainstem imaging] are offset by its limited availability and more complicated monitoring of the stroke patient. Acute ICHs are immediately visible on the non-contrast CT (hyperdense) and on MRI (especially on T2* susceptibility sequences). If there is a clinical suspicion of SAH but the cranial CT or MRI is negative (as in less than 10% of cases in the first 24 h), lumbar puncture is necessary to rule out this diagnosis. Acute imaging of cervical and intracranial arteries is highly recommended for ischaemic stroke. Which imaging modality is used depends mainly on local availability and expertise. CT angiography using spiral CT technique is rapid and practical, but experience is still limited. Acute Doppler and duplex ultrasonography with transportable equipment is practical and easily repeatable. On the other hand, it depends on the availability of a trained examiner and may give limited intracranial information. MR angi-
Michel
ography, if available, is a reliable and validated method for extra- and intracranial arterial imaging. Cerebral conventional (or digital subtraction) angiography is the preferred method in the acute phase if intra-arterial thrombolysis is considered. Cerebral blood flow measurements (by perfusion CT, perfusion MRI or Xenon-enhanced CT) are currently limited to specialised stroke centres. Basic laboratory tests (table 7) help exclude a number of metabolic causes of neurological signs (for example hypoglycaemia) and screen for contraindications to thrombolysis.
Question 9
Which Tests Can Help in the Search for Stroke Aetiology?
Following initial brain, cervical and cerebral artery imaging (cf. table 7), the subsequent work-up should be tailored individually to exclude non-stroke conditions (for example EEG in suspected partial epileptic seizure), to clarify stroke pathogenesis and cause, prevent and manage complications, identify risk factors and to plan rehabilitation. Ideally, the work-up (table 8) follows a stepwise hypothesis testing of stroke pathogenesis, but costs and limited length of hospitalisation may force the clinician into making an early choice based on the clinical information and the initial exams. A neurological consultation should be obtained in most patients with stroke or TIA. Ischemic stroke patients should be observed for at least 24 h in an acute stroke unit, with frequent neurological examinations. Monitoring of vital signs, behaviour and sleep is often very helpful in the identification of stroke pathogenesis and the early detection of complications. If not available in the acute phase, cervical and cerebral arterial imaging by Doppler and duplex ultrasonography, MR or CT angiography should be obtained. A cardiac work-up (CK-MB, 24-hour rhythm monitoring, echocardiography) is indicated in all patients with non-lacunar strokes. A search for a patent foramen ovale (PFO) by intravenous injection of microbubbles is recommended in younger patients without other obvious causes. Transoesophageal echocardiography is indicated if no sufficient explanation has been found by the initial work-up and cardioembolic or aortic plaques are possible mechanisms, or if unclear findings on transthoracic echocardiography need to be further explored (especially atrial or valvular abnormalities).
Introduction to Stroke and Its Management
Table 8. Additional exams potentially useful to determine stroke aetiology and acute complications of stroke
Evaluation by a neurologist or stroke team (if not done on emergency admission) Twenty-four-hour monitoring of Vital signs (arrhythmia, hypo- and hypertension, fever) Neurological signs (neurological complications of stroke) Oxymetry and breathing (sleep apnea, aspiration) Early medical complications (infection, cardiac problems, deep venous thrombosis) Chest radiography Echocardiography Transthoracic Transoesophageal Intravenous injection of microbubbles to detect cardiac shunt Cervical and transcranial Doppler and duplex Brain MRI and angio MRI of cervical and cerebral arteries (if not done on emergency admission) With diffusion and perfusion images With susceptibility and FLAIR images (recent or old haemorrhages) Conventional cervical and cerebral angiography (mostly digital subtraction arteriography) Electroencephalography (to identify epilepsy or encephalopathy) Neuropsychological testing Laboratory tests in all patients Sedimentation rate, lipid profile, TSH, liver function tests Laboratory tests in selected patients Total proteins, serum or immunoprotein electrophoresis, fibrinogen, blood viscosity, serum osmolarity, differentiation of leucocytes, erythrocyte morphology (sickle cells), syphilis serology, homocysteine, antiphospholipid antibodies, antinuclear antibodies, rheumatoid factor and other auto-antibodies, proteins C and S, anti-thrombin-III, plasminogen and tPA deficiency, activated protein C resistance, search for mutations of prothrombin-II, factor V Leiden, notch-3 gene (CADASIL) and mitochondrial DNA (e.g. MELAS) Lumbar puncture Urinary sediment Biopsy of temporal arteries or meninges and cortex (suspicion of vasculitis)
In ICH, laboratory evaluation may reveal predisposing conditions (thrombocytopenia, liver disease, alcoholism, and haematological neoplasms). A control CT with contrast or an MRI with MR angiography 2–3 months after the initial haemorrhage is recommended as it may detect previous silent ICHs (MR susceptibility images), an underlying cerebral metastasis or a vascular malformation. Suspicion of the latter usually calls for conventional cerebral angiography. In subarachnoid haemorrhage, imaging by MR or CT angiography may initially be used to detect an underlying
Cerebrovasc Dis 2003;15(suppl 2):1–10
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saccular aneurysm in the main intracranial arteries. This initial information is usually completed by conventional (DS) angiography in order to better define the anatomy of the aneurysm, to search for multiple or very small aneurysms, and to detect other vascular malformations.
Question 10
How Do You Treat a Patient with Acute Stroke?
If symptoms are recognised within minutes or hours, the patient is immediately referred to the next casualty or stroke centre by ambulance. If thrombolysis is considered, referral to a stroke centre should not be delayed by a CT scan and antithrombotic drugs should be withheld. Other reasons for a transfer to a stroke centre are recurrent or progressive deficits, an anticipated high risk for complications, need of specialised diagnostic tests or neurosurgical evaluation. Acute ischaemic stroke can be treated with thrombolysis (table 9). Given within 3 h of onset, i.v. rtPA has been shown to reduce disability by 20–30% without changing the 90-day mortality. Intra-arterial thrombolysis can be prescribed up to 6 h and in some cases even later. The risk for bleeding increases with extensive hypodensity on the native CT scan, severe hypertension at the time of thrombolysis, higher age (175–80 years), hyperglycaemia and with concomitant antiplatelet treatment or anticoagulation. Patients not thrombolysed benefit from early treatment with aspirin (100–300 mg/day). Administration of low dose subcutaneous heparin, low molecular weight heparin, or heparinoids may be beneficial for prophylaxis of venous thrombosis and pulmonary embolism, but not for the stroke itself. Other antiplatelet agents (including platelet glycoprotein IIb/IIIa antagonists), haemodilution, cooling and neuroprotective agents have not yet shown convincing benefit in acute stroke treatment.
Table 9. Drug treatment of acute ischaemic stroke
Intravenous thrombolysis up to 3 h Intra-arterial thrombolysis up to 6 h (rarely longer in basilar occlusions) Aspirin 100–300 mg/d all patients not eligible for thrombolysis after initial brain imaging thrombolysed patients not before 24 h Intravenous heparine rarely indicated
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Early anticoagulation after ischaemic stroke has not shown an overall benefit and increases the risk for haemorrhage. It may only be considered (without a bolus) in patients with TIAs or minor strokes who have a moderate to high risk of early stroke recurrence, such as in atrial fibrillation, intracardiac thrombi, severely depressed ejection fraction, acute myocardial infarction, symptomatic extracranial or intracranial stenosis with recurrent TIAs or progressive strokes, floating thrombi in the aortic arch or cervical arteries, and symptomatic dissection of extracranial arteries. In patients with moderate to large size infarction for whom anticoagulation is indicated for secondary prevention (cf. question 11), this treatment should only be initiated after 5–10 days to avoid facilitating haemorrhagic transformation. Admission to a stroke unit has been shown to reduce handicap and mortality, probably because of better prevention and treatment of neurological (brain oedema, haemorrhagic transformation, seizures) and medical complications (bronchoaspiration, cardiac and metabolic problems, infections, deep venous thrombosis and pulmonary embolism). Thus aggressive treatment of hyper- and hypoglycaemia, hypoxaemia, other metabolic disturbances, fever and infections, and prevention of aspiration are recommended. Mild to moderate hypertension (up to 220/120 mm Hg) is desirable in the first days after ischaemic stroke, rapid decrease of hypertension should be avoided and hypotension should be treated promptly if the neurologic status worsens (fluids, rarely adrenergic drugs). Craniotomy for impending herniation due to brain oedema (‘malignant’ MCA infarction or large cerebellar infarcts) can be lifesaving in ischaemic stroke and ICH and should be considered in younger patients, especially in the case of right hemispheric or posterior fossa infarcts. In ICH, prompt treatment of coagulation deficits and avoidance of moderate and severe hypertension (above 160/100 mm Hg) may limit ongoing bleeding. Neurosurgical evacuation of blood clots may be considered for lobar haemorrhages with important mass effect; reduction of mortality and handicap remains unproven for other indications. Ventricular drainage may be necessary for acute hydrocephalus. In SAH, treatment in a stroke unit or neurosurgical intensive care unit is recommended. Specific attention is paid to early detection, prevention (nifedipine) and treatment of secondary vasospasm and ischaemic infarction. In ICH and SAH, prevention and treatment of other neurological and medical complications is similar to ischaemic stroke.
Michel
Question 11
What to Do to Prevent Stroke?
Effective primary and secondary prevention (table 10) seems to be responsible for a decrease in stroke mortality in many industrialised countries over the last 30 years. Optimally used, it can decrease first and recurrent stroke by 30–60%. Primary Prevention The primary prevention of ischaemic stroke is aimed at the modifiable risk factors mentioned in table 5 and is discussed in chapters 3–6. There is currently no sufficient evidence that antithrombotic drugs or anticoagulation reduce the risk of stroke in asymptomatic patients, with the following exceptions: 1. Patients with chronic and intermittent atrial fibrillation. They should receive oral long-term anticoagulation with an INR of 2.0–3.0 if one of the following conditions is present: valvular disease, hypertension, diabetes mellitus, low ejection fraction, age 165 years. 2. Patients with mechanical valve prosthesis benefit from chronic anticoagulation with a target INR between 3.0 and 4.0. 3. Anticoagulation has also been shown to reduce stroke risk after recent transmural (especially anterior) MI, and may be beneficial for patients with very low ejection fraction. The benefit of carotid endarterectomy for asymptomatic stenosis of 60% is marginal and depends on a life expectancy of at least 5 years and a complication rate of !3%. Therefore the decision to undertake such an intervention needs to be individualised. The most important measure to reduce the risk of ICH is strict control of hypertension.
Table 10. Role of the general practitioner in stroke prevention and
treatment Recognise and tightly control hypertension, diabetes, hypercholesterolaemia Educate and insist on lifestyle changes (smoking cessation, drug consumption, obesity, physical inactivity) Introduce and assure effective anticoagulation in most atrial fibrillation patients and certain other cardiac diseases Recognise and promptly investigate possible TIAs, minor strokes, and carotid bruits Refer acute stroke patient urgently to the next casualty or stroke centres Control/supervise secondary prevention after TIAs and strokes
Introduction to Stroke and Its Management
Primary prevention of SAH by treating asymptomatic intracranial saccular aneurysms remains controversial as randomised studies regarding the frequency of radiological follow-up and the benefit-risk ratio of an intervention are not yet published. Secondary Prevention Beside tight control of the other modifiable risk factors (see table 5), blood pressure lowering may be initiated after several days or a few weeks, and normal values should be achieved progressively over 1–3 months. Rapid lowering of hypertension should be avoided in the acute phase of ischaemic strokes or TIAs (see question 9), especially if a symptomatic arterial stenosis is documented. It is possible that blood pressure lowering decreases stroke recurrence even in normotensive patients. Anticoagulation. If a TIA or ischaemic stroke is considered to be due to a cardioembolic mechanism and the risk for recurrence is considered to be moderate or high, oral anticoagulation with a target INR of 2.0–3.0 is recommended. Examples are strokes attributed to atrial fibrillation, rheumatic valvular heart disease, low ejection fraction, acute myocardial infarction, intracardiac thrombi, and a PFO associated with a hypercoagulable state. Rarely, efficiently anticoagulated patients present recurrent cardioembolic strokes. In such patients, an increase of the INR, followed by the addition of a low-dose antiaggregant may be considered. Such an association considerably increases the risk of haemorrhage. Antiaggregant Drugs. Virtually all patients not requiring anticoagulation and having no contraindication should receive one form of antiaggregant drug after a TIA or stroke, for example 100–300 mg aspirin per day. The combination of aspirin and dipyridamole has been shown in one large study to be superior to aspirin alone. Clopidogrel has been shown to be more effective than aspirin for secondary prevention if all atherothrombotic events are combined. It may be given to patients with a high overall atherothrombotic risk, if aspirin is not tolerated (e.g. gastrointestinal bleeding), and in those who have a new ischaemic event while treated with aspirin. A combination treatment with different antiplatelet drugs is currently being studied. Carotid Endarterectomy (CEA). CEA is recommended for symptomatic stenosis 170%; because of an increased risk of neurological complications, the operation should be delayed 3–4 weeks after a moderate to large stroke (but not necessarily after a TIA or minor stroke) but should be undertaken no more than 6 months after the symptoms. In order to compensate the stroke and cardiac risk of the
Cerebrovasc Dis 2003;15(suppl 2):1–10
9
intervention, life expectancy should be at least 3–5 years, and the surgeon’s perioperative complication rate less than 6%. Male patients with recent hemispheric symptoms may also benefit if the degree of stenosis is between 50 and 69%. Endarterectomy or bypass grafting for acute or chronic occlusion of the carotid artery is probably not beneficial. Percutaneous Transluminal Angioplasty (PTA). Safety and benefits of PTA with stenting is being evaluated in randomised studies; it currently may be considered in patients with contraindications to CEA and in patients with stenosis at surgically inaccessible sites. The optimal treatment for vertebrobasilar and intracranial stenosis is still unknown as no randomised study has compared PTA, anticoagulation and antiaggregants. Treatment of PFO. The secondary prevention of strokes attributed to an isolated small- or moderate-size PFO is highly controversial, mainly because of a low recurrence rate and the absence of randomised studies. Aspirin and treatment of other risk factors may be sufficient in this scenario. Large-size PFO, recurrent ischaemic events, and an associated aneurysm of the interauricular septum seem to increase the recurrence risk. In the presence of these factors, anticoagulation or surgical (su-
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ture) or percutaneous closure (interatrial ‘umbrella’) weeks to months after a stroke may be justified, especially if other stroke causes have not been found. The efficacy of these interventions has not been tested in a randomised fashion, however, and specific recommendations cannot be given. Secondary Prevention of ICH and SAH. After ICH, the most important preventive step is aggressive and chronic lowering of blood pressure, maybe even in normotensive patients. Although many ICH patients also have coronary artery disease or ischaemic strokes, antiplatelet medications and anticoagulation are not desirable, though the relative risk of further ischaemic and haemorrhagic events in these patients has not been studied rigorously. AVMs are usually followed by a multidisciplinary team that will decide about surgery, endovascular treatments, or focal radiation. Currently, no effective treatment of cerebral amyloid angiopathy is known. After SAH, clipping or coiling the saccular aneurysms constitutes a highly effective means to avoid a recurrent haemorrhage. The necessity and frequency of a radiological follow-up to detect new aneurysms in these patients remains unknown.
Michel
Chapter 2 Cerebrovasc Dis 2003;15(suppl 2):11–17 DOI: 10.1159/000069675
Ten Questions to Stroke Units P. Lyrer
Question 1
Question 7
12 What Is a Stroke Unit? Question 2
13 How Should a Stroke Service or Unit Be
Organised?
15 How Many Diagnostic Tests (Excluding
Standard Laboratory Tests) Should the ‘Average’ Stroke Patient Get until Final Diagnosis? Question 8
15 What Are the Issues That Make Stroke Unit
Question 3
13 What Is the Minimum Infrastructure Needed
to Run a Stroke Unit?
Treatment Cost Effective? Question 9
16 Should Access to Stroke Services Be Limited
Question 4
14 What Is the Importance of Having a
Neurologist Performing Diagnosis of Stroke Syndromes in the Early Stage of Stroke?
by Age, Clinical Syndromes or Aetiological Factors? Question 10
16 Is Stroke Unit Care Clinically Effective?
Question 5
14 What Type of Other Health Care Professionals
Should Take Part in a Stroke Service or Unit? Question 6
14 Which Type of Hospital Should Run a Stroke
Unit?
ABC
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Question 1
What Is a Stroke Unit?
It is crucial to outline the different existing types of stroke care, which range from services providing acute stroke care during the first days after stroke to those providing rehabilitation only. The various aspects of stroke care include one or all of the following items: E a location of the stroke treatment within the hospital: emergency ward, intensive care unit, specialised ward, general ward E consistency of the diagnostic and treatment process E expertise of the treating physicians and staff members E availability of diagnostic facilities and general infrastructure E clearly focused services, e.g. emergency treatment only, rehabilitation only, comprehensive treatment covering all needs E social and political requirements or commitments Different opinions regarding stroke treatment pathways and infrastructure exist. The maximum solution may consist of a comprehensive stroke care facility providing treatment covering the whole period from the acute phase to the end of rehabilitation [1–4]. The minimum but not necessarily the least effective option is community-based home treatment [5]. A recent systematic meta-analysis identified several types of stroke services. The most important finding was that all services should provide organised care and use defined pathways [6]. So-called dedicated stroke units can be distinguished as follows. Acute Stroke Unit and Acute Stroke Intensive Care Unit This setting is defined by clearly marked/restricted wards, where stroke patients are admitted and cared for. This category includes the ‘acute intensive stroke unit’ or ‘acute stroke intensive care unit’, which accepts patients acutely but discharges early, i.e. usually within 7 days. Acute stroke units seem to improve care by providing examinations as well as secondary prevention, thus reducing length of stay [7].
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Acute Stroke Team The formation of so-called acute stroke teams, also referred to as ‘stroke code teams’ in analogy to cardiac code teams, is one approach to reducing the in-hospital delays by obtaining specialised medical care and providing acute stroke care. This is a common approach in the US [8] and in some hospitals in the UK [9]. Different specialists collaborate and are available on request to advise on specific stroke-related issues. The team is thus based on organisation, not on a specified locality within the institution and, in the most extreme case, the patients may be treated on any ward of any appropriate hospital. Stroke Rehabilitation Units Stroke rehabilitation units only accept patients after the acute phase of the disease, i.e. with a delay of usually 7 days or more, and focus exclusively on rehabilitation. Comprehensive Stroke Units Comprehensive stroke units combine acute and rehabilitation stroke care. Here, patients may also be treated for a prolonged time [6]. References 1 Warlow C, Dennis M, van Gijn J, Hankey GJ, Sandercock P, Bamford J, et al: The organization of stroke services; in Warlow C, Dennis M, van Gijn J, Hankey GJ, Sandercock P, Bamford J, et al. (eds): Stroke. A Practical Guide to Management, ed 2. Oxford, Blackwell Science, 2001, pp 723– 761. 2 Helsingborg Conference: Stroke Management in Europe. The Helsingborg Declaration. Essential Principles for Good Practice. Delegates’ draft. Helsingborg, WHO, 1995. 3 Aboderin I, Venables G: Stroke Management in Europe. Pan European Consensus Meeting on Stroke Management. J Intern Med 1996;240:173– 180. 4 Kaste M, Skyhoj OT, Orgogozo J, Bogousslavsky J, Hacke W: Organization of stroke care: Education, stroke units and rehabilitation. European Stroke Initiative (EUSI). Cerebrovasc Dis 2000;10(suppl 3):1–11. 5 Bhalla A, Dundas R, Rudd AG, Wolfe CD: Does admission to hospital improve the outcome for stroke patients? Age Ageing 2001;30:197–203. 6 Stroke Unit Trialists’ Collaboration: Organised inpatient (stroke unit) care for stroke (Cochrane Review); in The Cochrane Library (ed): The Cochrane Library (2001/3). Oxford, Update Software, 1998, pp 1–15. 7 Bath PMW, Soo J, Butterworth RJ, Kerr JE: Do Acute Stroke Units Improve Care? Cerebrovasc Dis 1996;6:346–349. 8 Alberts MJ, Chaturvedi S, Graham G, Hughes RL, Jamieson DG, Krakowski F, et al: Acute stroke teams: Results of a national survey. National Acute Stroke Team Group. Stroke 1998;29:2318–2320. 9 Kalra L, Evans A, Perez I, Knapp M, Donaldson N, Swift CG: Alternative strategies for stroke care: A prospective randomised controlled trial. Lancet 2000;356:894–899.
Lyrer
Question 2
How Should a Stroke Service or Unit Be Organised?
Different types of stroke unit organisation can be identified. Several models have been described and few have been evaluated. Stroke units are far from being homogenous. As outlined in question one, there are acute stroke units [1] or intensive stroke care units [2] to provide care for patients in the acute phase only, these units do not focus on rehabilitation. Their aim is to avoid systemic complications and to rapidly detect deteriorating stroke as the patient’s condition often changes in the early hours after stroke onset. On the other hand there are non-intensive stroke units, also called stroke rehabilitation units, which concentrate their efforts on rehabilitation. These units are usually discrete stroke wards. All of these types of stroke units are beneficial, regardless of their organisational form [3]. Furthermore, there are stroke wards taking care of patients in the acute phase until full rehabilitation. Another approach is to create mobile stroke teams in acute care as well as in rehabilitation hospitals with the aim of providing skilled treatment at every stage of the illness. This form of organisation is clearly less effective [3, 4]. Every stroke unit should, in any case, be dedicated to provide [2]: E a comprehensive assessment of the patient’s illness and disability E development and implementation of a collaborative policy for stroke management E identification and awareness of the objectives of rehabilitation E close multidisciplinary collaboration E education and research activity Another important point to consider is that patients must have easy access to a stroke service. Furthermore, it may be important to shorten in-hospital delay of stroke treatment by adequate measures, e.g. by establishing a phone call system [5]. References 1 Levine SR: Acute cerebral ischemia in a critical care unit. A review of diagnosis and management. Arch Intern Med 1989;149:90–96. 2 Langhorne P, Dennis MS, Williams BO: Stroke units: Their role in acute stroke management. Vasc Med Rev 1995;6:33–44. 3 Stroke Unit Trialists’ Collaboration: Organised inpatient (stroke unit) care for stroke (Cochrane Review); in The Cochrane Library (ed): The Cochrane Library (2001/3). Oxford, Update Software, 1998, pp 1–15. 4 Kalra L, Evans A, Perez I, Knapp M, Donaldson N, Swift CG: Alternative strategies for stroke care: A prospective randomised controlled trial. Lancet 2000;356:894–899.
Ten Questions to Stroke Units
5 Gomez CR, Malkoff MD, Sauer CM, Tulyapronchote R, Burch CM, Banet GA: Code stroke. An attempt to shorten inhospital therapeutic delays. Stroke 1994;25:1920–1923.
Question 3
What Is the Minimum Infrastructure Needed to Run a Stroke Unit?
The required infrastructure is strongly correlated to the goal of the institution. For acute care, an emergency room should be available 24 h/day, as strokes may occur at any time and are to be considered a medical emergency; the focus must be on patients who might benefit from acute treatment. The rapid assessment of patients and close monitoring must be warranted. The following diagnostic tools should be available on site 24 h/day: cranial computer tomography (CCT) or magnetic resonance (MR) scanning facilities, neurosonological examination, routine laboratory tests, cerebral angiography and an intensive care unit. Emergency CCT diagnosis is mandatory to exclude intracerebral haemorrhage, especially before intended thrombolytic treatment. Neurosonology examinations are needed to check for large artery disease and to monitor arterial occlusions. Laboratory facilities are required to detect electrolyte, haematologic and metabolic disturbances. The possibility to transfer a patient to an intensive care ward is important to avoid early systemic complications and to closely monitor impairment as well as cardiovascular functions. For further treatment and diagnosis, a wide range of diagnostic facilities are mandatory, such as MR imaging, a nuclear medicine department, laboratories for rheumatologic, haematologic and rheologic tests, a cardiology department, etc. It is also important to organise the teamwork within the institution. The introduction of a pager system is a possible step towards an organised, comprehensive management [1]. For live-saving procedures neurosurgical facilities should be readily available. Stroke units with rehabilitation as the primary goal will not need the diagnostic facilities but will instead focus on therapeutic modalities. They will need instruments for activities of daily living, workshops, outdoor training facilities, etc. They also need access to laboratory testing for anticoagulation, antidiabetic, and anti-infective treatment and to imaging modalities in cases of deterioration. Every institution involved should assess the quality of care in a register that requires data processing tools as well as corresponding knowledge [2].
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References
Question 5
1 Gomez CR, Malkoff MD, Sauer CM, Tulyapronchote R, Burch CM, Banet GA: Code stroke. An attempt to shorten inhospital therapeutic delays. Stroke 1994;25:1920–1923. 2 Aboderin I, Venables G: Stroke management in Europe. Pan European Consensus Meeting on Stroke Management. J Intern Med 1996;240:173–180.
Question 4
What Is the Importance of Having a Neurologist Performing Diagnosis of Stroke Syndromes in the Early Stage of Stroke?
This issue has not yet been addressed systematically. At present, no single group of medical specialists can claim to be exclusively responsible for stroke patients. The most appropriate professional group can vary from place to place. Therefore only a personal opinion can be transmitted at the present time. In a recently published textbook there is no specification about what kind of physician is the best to treat stroke patients. It is stated that the physician should have a broad knowledge of the pathology underlying stroke as well as of the functional problems related to the disease [1]. It is considered important to have a person within a stroke team who has a special interest in neurology [2, 3]. The neurologist may provide knowledge on clinical diagnosis, interpretation of syndromes and consequences of neurological impairment, and he may be more aware of stroke in the posterior fossa than an untrained physician [4]. A report comparing neurologists to other specialists treating stroke patients demonstrated that treatment by neurologists is correlated with a better outcome, as mortality was lower. But treatment by neurologists was more expensive [5]. The most important factors contributing to the effectiveness of stroke units are their organisation and the involvement of a multidisciplinary team.
What Type of Other Health Care Professionals Should Take Part in a Stroke Service or Unit?
The answer to this question depends on the organisational type of the stroke unit or service and the severity of the stroke syndrome. In the emergency room, the emergency physician, the neurologist and the neuroradiologist may play an important role [1]. After the acute phase of treatment, a core stroke team should include a physician, nurses, physiotherapists, occupational therapists, speech therapists and social workers. As stroke patients have a broad range of problems, their care requires input from several disciplines. Depending on the problems, further specialists may be consulted, such as clinical psychologists, psychiatrists, neurosurgeons, vascular surgeons, radiologists, rheumatologists, orthopaedic surgeons, ophthalmologists, dieticians, dentists and pharmacists [2]. A focus on neurological knowledge is evident, therefore the medical staff should, in our opinion, include a neurologist as the responsible or consulting physician. The most important issue is an interest in and specialist knowledge of stroke management as well as good communication within the team [3]. In the UK, physicians in geriatric medicine play a major role in stroke treatment but neurologists are also involved, especially in younger patients, while in continental Europe neurologists frequently manage stroke patients [3]. References 1 Schweikert K, Engelter S, Lyrer Ph, et al: Introduction of a comprehensive stroke program in a university hospital (abstract). Cerebrovasc Dis 1996;6: 131. 2 Warlow C, Dennis M, van Gijn J, et al: A practical approach to the management of stroke patiens; in Warlow C, Dennis M, van Gijn J, et al (eds): Stroke. A Practical Guide to Management, ed 2. Oxford, Blackwell Science, 2001, pp 723–761. 3 Langhorne P, Dennis MS, Williams BO: Stroke units: Their role in acute stroke management. Vasc Med Rev 1995;6:33–44.
References 1 Warlow C, Dennis M, van Gijn J, Hankey GJ, Sandercock P, Bamford J, et al: The organization of stroke services; in Warlow C, Dennis M, van Gijn J, et al (eds): Stroke. A Practical Guide to Management, ed 2. Oxford, Blackwell Science, 2001, pp 723–761. 2 Aboderin I, Venables G: Stroke management in Europe. Pan European Consensus Meeting on Stroke Management. J Intern Med 1996;240:173–180. 3 Helsingborg Conference: Stroke Management in Europe. The Helsingborg Declaration. Essential Principles for Good Practice. Delegates’ draft. Helsingborg, WHO, 1995. 4 Lyrer Ph, Ebnöther E, Operschall C, Rickenbacher P, Steck AJ: The effect of introducing a comprehensive stroke program on primary diagnostic evaluation in stroke patients (abstract). Cerebrovasc Dis 1996;6(suppl 2):153. 5 Mitchell JB, Ballard DJ, Whisnant JP, Ammering CJ, Samsa G, Matchar DB: What role do neurologists play in determining the costs and outcomes of stroke patients? Stroke 1996;27:1937–1943.
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Question 6
Which Type of Hospital Should Run a Stroke Unit?
Hospitals treating stroke patients should at least provide neurological expertise to be able to offer thrombolytic treatment (if appropriate) themselves or to refer patients to a hospital with such treatment options. A hospital offering thrombolytic treatment should have the neces-
Lyrer
sary experienced staff and be able to deal with the possible complications of thrombolytic treatment, which requires a neuroimaging unit, access to laboratory facilities for determining haemostatic values and direct access to neurosurgery treatments. It makes little sense to run a stroke unit in a small hospital where only few patients a year are hospitalised for stroke. As multidisciplinary care is required, it is probably more reasonable to leave this kind of complex care to larger hospitals (serving populations of about 100,000–200,000 people) [1]. This will generate approximately 10–20 acute stroke cases to be treated by thrombolysis a year. As estimates of stroke incidence vary considerably from country to country, such hospitals have to evaluate their annual stroke admissions themselves. Large numbers of patients make it worthwhile to establish a dedicated stroke unit, team, or service. Smaller hospitals should be encouraged to take part in larger networks of stroke management centres. An independent criterion, however, is that hospitals accepting stroke patients should be able to perform a work-up of acute stroke patients on a 24-hour basis. At present it is largely up to the authorities to decide which type of care should be provided and who warrant the minimum infrastructure necessary for stroke treatment.
tect patent foramen ovale. Twenty-four-hour ECG monitoring can be provided in specialised stroke units during the first hours of hospitalisation and will not be required later. A basic examination set would be routine blood tests, chest X-ray, ECG, 24-h ECG monitoring, CCT and follow-up CCT, neurosonology and cardiac sonologic examination. Angiography is only mandatory in those few cases where the diagnosis cannot be made with the above mentioned tests. In conclusion, a minimum work-up comprises basic admission tests, carotid ultrasound, ECG and extended cardiac monitoring. Additional work-up comprises echocardiography, transcranial Doppler ultrasound, MRI/ MRA, tests for coagulopathies and cerebral angiography [1]. One must be aware that the optimal work-up depends on the patient’s age, risk factors and clinical presentation. By a stepwise approach, the most evident stroke cause is sought first and tests for less likely causes are reserved for cases with persistent diagnostic uncertainty. At present, there are no tried and tested diagnostic algorithms. Therefore stroke diagnostic plans are individualised. It seems reasonable that a clear diagnosis of the underlying pathology and the patient’s risk factors is important, as secondary prevention has proven effective in many cases [1]. Reference
Reference 1 Laaser U, Breckenkamp J, Niermann U: Kosten-Wirksamkeits-Analyse kurativer Interventionen bei Patienten mit Schlaganfall in Deutschland unter besonderer Berücksichtigung von Schlaganfallstationen (‘Stroke Units’). Gesundheit Oekon Qualitaetsmanag 1999;4:176–183.
1 Adams RJ: Management issues for patients with ischemic stroke. Neurology 1995;45:15–18.
Question 8 Question 7
How Many Diagnostic Tests (Excluding Standard Laboratory Tests) Should the ‘Average’ Stroke Patient Get until Final Diagnosis?
What Are the Issues That Make Stroke Unit Treatment Cost Effective?
In emergencies, patients will usually first get a CCT scan to exclude cerebral haemorrhage. The affected vascular territory can be estimated by clinical examination. Further CCT or MRI might be indicated to detect the cause of an ischaemic stroke. Neurosonologic examination as well as cardiac ultrasound and chest X-ray give clues about cardioembolic and atherothrombotic stroke. With these examinations most aetiologic factors can be detected. In cases of unusual aetiology, further laboratory exams may be necessary to evaluate the coagulation system, diagnose vascular rheumatologic disorders and de-
Until now a systematic assessment of costs arising from a stroke unit has not been performed. Supplied drugs and investigations are unlikely to be of major influence. Remedial therapy, such as physiotherapy or occupational therapy, may increase costs in stroke unit care. Staff and in-hospital accommodation account for the majority of costs of the acute phase. They strongly depend on hospital structure and organisation. Treatment in specialised stroke units shortens the overall hospitalisation time. Further, more patients can be discharged to their homes compared to patients treated in general wards. Therefore it may be postulated that long-term costs for stroke unit care are lower than for the care provided by non-specialised wards. Though the costs for acute stroke treatment by neurologists may be higher, but
Ten Questions to Stroke Units
Cerebrovasc Dis 2003;15(suppl 2):11–17
15
this might be outweighed by the above-mentioned advantages [1]. On the other hand, the implementation of an acute stroke program leads to significantly lower costs in acute stroke. By reducing length of stay from 7.0 to 4.6 days, costs fell from USD 14,000 to 10,800 [2]. Costs may also be lowered by a higher amount of patients discharged home [3, 4]. It will be much more difficult to estimate community costs as greater awareness and recognition of stroke will increase costs. To elaborate the specific quality improvement for patients treated in stroke units will be an issue of further studies. Neurologists were found to have significantly higher expenses (USD 16,000 per hospitalisation), whereas internists and family practitioners were cheaper [1]. These costs included the hospitalisation itself, inpatient physician services and post-acute care for 90 days.
The aetiology of stroke is not definitively known when a patient enters the emergency room. Therefore aetiological factors cannot be taken as a basis for the decision whether the patient needs to be transferred to the stroke unit. Aetiological diagnosis is essential for secondary prevention. Stroke units have proved effective in terms of reduced mortality, hospitalisation time and improved follow-up (less and less severe disability) [3]. No randomised trial has yet investigated the above-mentioned conditions and their influence on post-stroke disability, therefore it will be impossible to deny stroke unit treatment to patients of old age on the basis of a specific aetiology or clinical syndrome alone. At present each individual patient should receive the best available treatment in order to reduce disability as much as possible. References
References 1 Mitchell JB, Ballard DJ, Whisnant JP, Ammering CJ, Samsa G, Matchar DB: What role do neurologists play in determining the costs and outcomes of stroke patients? Stroke 1996;27:1937–1943. 2 Wentworth DA, Atkinson P: Implementation of an acute stroke program decreases hospitalization costs and length of stay. Stroke 1996;27:1040– 1043. 3 Jorgensen HS, Nakayama H, Raaschou HO, Larsen K, Hübbe P, Olsen TS: The effect of a stroke unit: Reductions in mortality, discharge rate to nursing home, length of hospital stay, and cost. A community-based study. Stroke 1995;26:1178–1182. 4 Spieler JF, Lanoe JL, Amarenco P: Socioeconomic aspects of postacute care for patients with brain infarction in France. Cerebrovasc Dis 2002;13: 132–141.
1 Kalra L: Does age affect benefits of stroke unit rehabilitation? Stroke 1994; 25:346–351. 2 Bamford J, Sandercock P, Dennis M, Burn J, Warlow C: Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991;337:1521–1526. 3 Langhorne P, Dennis MS, Williams BO: Stroke units: Their role in acute stroke management. Vasc Med Rev 1995;6:33–44.
Question 10
Is Stroke Unit Care Clinically Effective?
Question 9
Should Access to Stroke Services Be Limited by Age, Clinical Syndromes or Aetiological Factors?
It is known that elderly people may have poorer outcome after stroke [1], but there are no data to suggest that stroke is more severe in elder than in younger patients. Outcome is mainly determined by factors such as marital status, comorbidity, and stroke recurrence. Prognosis may vary considerably between different clinical syndromes [2]. One could consider giving priority to patients with certain stroke syndromes. At present there is no clear evidence which neurological syndrome should be treated in stroke units, although patients with lacunar syndromes and some posterior circulation infarcts may be less disabled compared to patients with cortical syndromes. The course of the disease cannot be predicted at entry.
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Specifically Established Pathways for Stroke Care With the aim of establishing a meta-analysis for stroke care, the Stroke Unit Trialists’ Collaboration identified the following stroke pathways [1]. Controlled Randomised Trials Several controlled randomised trials aimed at showing the efficacy of different types of stroke unit care. The results of each trial give a very heterogeneous picture, and no definite conclusion can be drawn. For a few years, the Stroke Trialists’ Collaboration has provided data from meta-analysis of all available data on stroke unit care. Data has been extracted from more than 25 controlled randomised trials, enabling the following efficacy estimate [1]. Effect on Death In the cited meta-analysis, data from 20 trials on the principal outcome of death at final review were available. This analysis is based on the service comparisons within
Lyrer
the original trials, where a novel intervention was compared with contemporary conventional care. Case fatality recorded at final review (median follow-up 12 months; range 1.5–12 months) was lower in the organised (stroke unit) care in 15 of the 20 trials. The overall estimate gives an odds ratio of 0.83 (95% CI 0.71–0.97). The odds of death were not considerably changed when the analysis was restricted to trials where scheduled follow-up was continued for a fixed period of 6 months or 1 year [1]. Effect on Death or Institutional Care The second outcome examined was the odds ratio of death or a condition requiring institutional care at the end of follow-up (median 1 year after stroke). Institutional care is an important outcome as it may be unbiased. The summary result was highly significant (odds ratio 0.77, 95% CI 0.68–0.88; p ! 0.0001), but some heterogeneity existed between trials that had a very short or variable period of follow-up. Trials with a fixed prolonged period of follow-up showed a significant reduction in death or institutionalisation and less heterogeneity [1].
Effect on Death or Dependency The third outcome examined in the meta-analysis was the combined adverse outcome of being dead or dependent for activities of daily living at the end of follow-up. The overall odds ratio for being dead or dependent after organised (stroke unit) care rather than conventional care was 0.75 (95% CI 0.65–0.87; p ! 0.0001), and the summary result showed some minor heterogeneity. The main reason for this may lie in the nature of the control group. The results were less heterogeneous and the odds ratio remained significant when organised (stroke unit) care was compared to conventional care provided in a general medical ward. The conclusions were not altered by the exclusion of trials with a variable follow-up period or informal randomisation procedure. The main methodological difficulty when using dependency as an outcome was the degree of blinding at final assessment and the potential for bias when the assessor is aware of treatment allocation [1]. Reference 1 Stroke Unit Trialists’ Collaboration: Organised inpatient (stroke unit) care for stroke (Cochrane Review); in The Cochrane Library (ed): The Cochrane Library (2001/3). Oxford, Update Software, 1998, pp 1–15.
Ten Questions to Stroke Units
Cerebrovasc Dis 2003;15(suppl 2):11–17
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Chapter 3 Cerebrovasc Dis 2003;15(suppl 2):19–23 DOI: 10.1159/000069676
Hypertension and Lowering Blood Pressure F. Perren J. Bogousslavsky
Question 1
20 What Is the Role of Hypertension in Stroke? Question 2
20 Primary Prevention of Stroke in Hypertension: What, When and
for Whom? Question 3
21 What Is the Course of Blood Pressure in Acute Stroke? Question 4
21 Should Anti-Hypertensive Therapies Be Given to Patients with
Acute Ischaemic Stroke? Question 5
22 Is There a Relationship between Blood Pressure Variations and
Neurological Deficits? Question 6
22 Hypertension as a Risk Factor in Secondary Prevention:
How Do You Treat It?
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Stroke is one of the leading factors of morbidity and mortality worldwide. It represents the third most common cause of death in many industrialised countries and it is the most important cause of morbidity and long-term disability in Europe. Hypertension is the most important risk factor in the development of stroke and is also the risk factor most amenable to treatment.
Question 1
What Is the Role of Hypertension in Stroke?
Hypertension is the major risk factor in ischaemic and haemorrhagic stroke and in subarachnoidal haemorrhage. It affects predominantly small arteries and arterioles. This form of microangiopathy may lead to lacunar infarcts (small ischaemic infarcts occurring especially in the white matter and the basal ganglia) or to subcortical arteriosclerotic encephalopathy. Hypertension also leads to macroangiopathy in the form of atherosclerotic plaques and stenosis at the bifurcations of brain arteries and of the aortic arch. It may also provoke cardiac injury leading to arrhythmia, in particular atrial fibrillation. Furthermore, it constitutes a major risk factor for intracerebral haemorrhages. More than 50% of stroke patients with intracerebral bleeding suffer from hypertension. In most instances the cause is a ruptured microaneurysm. Moreover, with ageing, arteries progressively stiffen. This is reflected by an age-related, disproportionate increase in systolic compared to diastolic blood pressure and, consequently, by a rise in pulse pressure [1]. Stroke risk is rising continuously with elevated systolic and diastolic pressure in every age group. Several studies conducted in over 400,000 patients over more than 10 years of observation have shown a significant correlation between hypertension and primary stroke incidence. Reference 1 Safar ME: Carotid artery stiffness with applications to cardiovascular pharmacology. Gen Pharmacol 1996;27(8):1293–1302.
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Question 2
Primary Prevention of Stroke in Hypertension: What, When and for Whom?
Hypertension is the most prevalent and modifiable risk factor for stroke. Its treatment substantially reduces the risk of stroke. Many studies have demonstrated that antihypertensive therapy effectively reduces morbidity and mortality of stroke in hypertensive subjects, including elderly patients with isolated systolic hypertension [1–5]. A meta-analysis of 14 randomised trials showed that a decrease of only 5–6 mm Hg in systolic blood pressure leads to a 42%, significant reduction of stroke in treated patients [2]. Nevertheless, the optimal blood pressure is still not known, and there is some concern that too great a reduction in blood pressure might be associated with recurrence of stroke and cardiovascular morbidity, i.e. myocardial infarction [6, 7]. In older patients with advanced arteriosclerosis and stiff arterial walls, excessive lowering of blood pressure may reduce brain perfusion, resulting in syncope or even stroke [8]. Furthermore, in patients suffering from occlusive carotid disease, concern might be to lower systemic blood pressure too much and thereby increase the risk of ischaemic stroke on the ipsilateral side of the stenosis [9]. In this particular case it is wise to avoid over-treatment. Nevertheless, it is important to treat not only patients with severe or moderate hypertension but also those with mild or isolated systolic hypertension and patients 175 years in whom hypertension develops. Antihypertensive treatment based on a low-dose thiazide diuretic is effective for the primary prevention of stroke, particularly in old patients. In the Systolic Hypertension in the Elderly Program (SHEP) trial, active treatment for 5 years with a diuretic and/or a betablocker reduced the total rate of stroke and myocardial infarction by 35 and 27% (p ! 0.05 vs. placebo), respectively. Diabetics, who are at a higher risk of stroke, also benefit from low-dose thiazide diuretics and ACE inhibitors. In those with isolated systolic hypertension, long-acting dihydropyridine calcium antagonists in addition to low-dose thiazide diuretics have also been shown to significantly reduce stroke risk. Furthermore, in order to
Perren/Bogousslavsky
obtain a sufficiently lower blood pressure and most effectively reduce stroke risk (140/80 mm Hg), combination therapy will probably be required. In conclusion, good and safe control of blood pressure is particularly important for the prevention of stroke. References 1 Bronner LL, Kanter DS, Manson JE: Primary prevention of stroke. N Engl J Med 1995;333:1392–1400. 2 Collins R, Peto R, Goldwin J, Mac Mahon S: Blood pressure and coronary heart disease. Lancet 1990;336:370–371. 3 Perry HM Jr, Davis BR, Price TR, Applegate WB, Fields WS, Guralnik JM, Kuller L, Pressel S, et al: Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). JAMA 2000;284: 465–471. 4 Insua JT, Sacks HS, Lau TS, Reitman D, Pagano D, Chalmers TC: Drug treatment of hypertension in the elderly: a meta-analysis. Ann Intern Med 1994;121:355–362. 5 Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757– 764. 6 Irie K, Yamaguchi T, Minematsu K, Omae T: The J-curve phenomenon in stroke recurrence. Stroke 1993;24:1844–1849. 7 Minami J, Kawano Y, Nonogi H, Ishimitsu T, Matsuoka H, Takishita S: Blood pressure and other risk factors before the onset of myocardial infarction in hypertensive patients. J Hum Hypertens 1998;12:713–718. 8 Friday G, Alter M, Lai SM: Control of hypertension and risk of stroke recurrence. Stroke 2002;33:2652–2657. 9 Dobkin BH: Orthostatic hypotension as a risk factor for symptomatic occlusive cerebrovascular disease. Neurology 1989;39:30–34.
Question 3
What Is the Course of Blood Pressure in Acute Stroke?
Abnormally elevated blood pressure is seen in approximately 70–80% of acute stroke patients [1]. Several mechanisms, including activation of sympathetic nerve activity secondary to brain damage, impaired autoregulatory vasodilatation and decreased perfusion in the ischaemic border zone of the cerebral lesion, might be responsible for this. Hypertension and enhanced blood pressure lability can also be induced by specific lesions, typically those affecting the nucleus solitary tract. Since cerebral autoregulation is impaired during the early phase of stroke, blood pressure should not be lowered too much in the first few days otherwise cerebral blood flow could become insufficient. Only patients presenting with intracerebral haemorrhage and extreme hypertension should be cautiously treated with antihypertensive drugs in order to avoid early re-bleeding. The natural course of blood pressure is to
Hypertension and Lowering Blood Pressure
decline within a few days following acute stroke. Ten days after onset no more than one third of the patients are expected to still have elevated blood pressure. Reference 1 Powers WJ: Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology 1993;43:461–467.
Question 4
Should Anti-Hypertensive Therapies Be Given to Patients with Acute Ischaemic Stroke?
The increase in systemic blood pressure in the acute phase of stroke is a uniform response to ischaemia per se and may be a physiological response to decreased blood flow in the ischaemic penumbra. Other factors such as age, gender, ischaemic heart disease, atrial fibrillation, known hypertension and type of stroke (haemorrhage/ infarct) may influence blood pressure in the acute phase of stroke [1]. Autoregulation of cerebral blood pressure is then momentarily interrupted and the viability of the neurons in the affected area is dependent on the systemic blood pressure [1, 2]. However, blood pressure variations appear to be unrelated to stroke severity. Although hypertension is common during the acute phase of stroke, its management remains controversial. The optimal treatment of hypertension in acute stroke has not yet been subject to controlled studies. There are yet no accepted guidelines. The attitude depends on the clinical situation. Elevated or strongly elevated blood pressure values are measured on admission in three quarters of acute stroke patients, about half of whom have a history of hypertension [3]. Blood pressure diminishes spontaneously in the first week after stroke onset and returns to pre-stroke levels in two thirds of patients. This initially elevated blood pressure is even more marked in patients suffering from hypertension prior to stroke. Many studies showed that high blood pressure in the acute phase of stroke is associated with poor outcome [4, 5]. However, a drastic lowering of blood pressure in the acute phase leads to a fall in cerebral blood flow with concomitantly lesions in the ischaemic ‘penumbra’ because of the failing cerebral autoregulation. There are only a few indications for immediate antihypertensive therapy in the first hours after symptom onset. Treatment may be appropriate in the setting of (1) acute myocardial ischaemia, (2) cardiac insufficiency/failure, (3) acute renal failure, or
Cerebrovasc Dis 2003;15(suppl 2):19–23
21
(4) acute hypertensive encephalopathy. Lowering blood pressure in the acute phase of stroke should only be initiated in case of severe hypertension (1240/120 mm Hg), acute myocardial infarction, aortic dissection, hypertensive encephalopathy, severe left ventricular failure, and in cases of non-ischaemic stroke such as in subarachnoid or intracerebral haemorrhage. If indicated, blood pressure should then be lowered gradually. Oral calcium antagonists such as sublingual nifedipin, still frequently used, should be avoided because of their potential rapid and excessive effect. Oral captopril (6.25–12.5 mg) should be used instead. Moreover, in patients who are candidates for thrombolytic therapy, blood pressure over 180/ 105 mm Hg should be lowered. Urapidil or clonidin are the drugs of first choice. Drugs like sodium nitroprussiate with important side-effects (reflex tachycardia, coronary artery ischaemia), nitroglycerin, verapamil and nicardipin should not be used to avoid the potential risk of elevating pre-existing increased intracranial pressure. Therefore the risk of doing harm by pharmacological lowering of blood pressure, together with the lack of evidence of associated benefits, suggests that unless there are comorbid conditions that require antihypertensive treatment, high blood pressure in the acute phase of stroke should not be treated. References 1 Jorgensen HS, Nakayama H, Christensen HR, Raaschou HO, Kampmann JP, Olsen TS: Blood pressure in acute stroke. The Copenhagen Stroke Study. Cerebrovasc Dis 2002;13:204–209. 2 Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA: Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002;33:1315– 1320. 3 Carlberg B, Asplund K, Hagg E: The prognostic value of admission blood pressure in patients with acute stroke. Stroke 1993;24:1372–1375. 4 Dandapani BK, Suzuki S, Kelley RE, Reyes-Iglesias Y, Duncan RC: Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke 1995;26:21–24. 5 Robinson T, Potter J: Cardiopulmonary and arterial baroreflex-mediated control of forearm vasomotor tone is impaired after acute stroke. Stroke 1997;28:2357–2362.
Question 5
Is There a Relationship between Blood Pressure Variations and Neurological Deficits?
Under normal circumstances, autoregulation of cerebral blood flow occurs immediately and even large falls in systemic blood pressure do not lead to cerebral symptoms. Nevertheless, focal ischaemia can occur without acute vessel occlusion, simply due to low flow. This usual-
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ly occurs distal to a highly stenosed or occluded internal carotid artery, in which case the vascular bed is maximally dilated and the brain is particularly vulnerable to any fall in perfusion pressure. Under these circumstances, a small drop in systemic blood pressure is likely to provoke symptoms of focal ischaemia without any occlusive event. If TIA or ischaemic stroke occur in an upright position, after getting up quickly, after a heavy meal, at high surrounding temperatures, during a hot bath, on exercising or during a Valsalva manoeuvre, transient falls in systemic blood pressure should be suspected. The same is true if there was an episode of arrhythmia, operative hypotension or if the patient has recently been started on antihypertensive drugs or when these drugs have recently been increased (vasodilators, calcium channel blockers).
Question 6
Hypertension as a Risk Factor in Secondary Prevention: How Do You Treat It?
The natural tendency for elevated blood pressure is to decline within 1 or 2 weeks after stroke [1]. Nevertheless patients with sustained increased blood pressure after stroke are at higher risk of early mortality. The severity of hypertension on admission and the clinical outcome are, however, unrelated, and there is no correlation either to lesion or to lesion size. After stroke or TIA, patients suffering from hypertension are more at risk of early death. In a meta-analysis of nine studies, the occurrence of a new stroke, fatal or non-fatal, was significantly reduced (p ! 0.001) in treated patients compared to untreated controls, with a relative risk of 0.72 [2]. It therefore appears mandatory to normalise blood pressure in hypertensive stroke survivors. Several studies have confirmed that antihypertensive treatment with different anti-hypertensive drugs significantly reduced the number of subsequent strokes (fatal or non-fatal) [3–5]. The Acute Candesartan Cilexetil Evaluation in Stroke Survivors (ACCESS) tested whether anti-hypertensive treatment during acute stroke could immediately improve prognosis [6]. After one year of treatment there was a significant reduction of 47.5% in total mortality and cerebrovascular events in all patients who received candesartan cilexetil in the first 30 h following acute stroke. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was designed to determine the effects of lowering blood pressure in hypertensive and non-hypertensive patients with a history of stroke or TIA. It has been shown that blood pressure-low-
Perren/Bogousslavsky
ering regimens reduced the risk of stroke in hypertensive and non-hypertensive individuals with a history of stroke or TIA. Combination therapy with perindopril and indapamide produced greater blood pressure reductions and greater risk reductions than did monotherapy with perindopril [3]. In the unique Heart Outcomes Prevention Evaluation (HOPE) trial, which was performed in patients with a high prevalence of chronic heart disease (80%), ramipril (an ACE inhibitor) has been shown to have a blood pressure-independent protective effect not only for cardiac events but also for strokes. In comparison to placebo, ramipril reduced the absolute stroke risk for 5 years by 6% and the relative risk reduction was 36% [4]. However, in both of these trials it has still not been clarified how soon after stroke antihypertensive therapy should be started.
Hypertension and Lowering Blood Pressure
References 1 Christensen H, Meden P, Overgaard K, Boysen G: The course of blood pressure in acute stroke is related to the severity of the neurological deficits. Acta Neurol Scand 2002;106:142–147. 2 Gueyffier F, Boissel JP, Boutite F, Pocock S, Coope J, Cutler J, et al: Effect of antihypertensive treatment in patients having already suffered from stroke. Gathering the evidence. The INDANA (INdividual Data Analysis of Antihypertensive intervention trials) Project Collaborators. Stroke 1997; 28:2557–2562. 3 Mc Mahon S, Peto J, Cutler J, et al: Blood pressure, stroke and coronary heart disease. Part I: Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765–774. 4 Mc Mahon S, et al: The effects of antihypertensive treatment on vascular disease: reappraisal of the evidence. J Vasc Med Biol 1993;4:265–271. 5 Mc Mahon S, et al: Blood pressure and the prevention of stroke. J Hypertens 1996;14(suppl 6):39–46. 6 Schrader J, Röthenmeyer M, Lüders S, et al: Hypertension and stroke – rationale behind the ACCESS trial. Basic Res Cardiol 1998;93(suppl 2): 69–78.
Cerebrovasc Dis 2003;15(suppl 2):19–23
23
Chapter 4 Cerebrovasc Dis 2003;15(suppl 2):25–30 DOI: 10.1159/000069677
Diabetes and Stroke Krassen Nedeltchev Heinrich P. Mattle
Question 1
26 Does Diabetes Increase the Risk of Stroke? Question 2
26 Is Stroke More Severe in Diabetic Patients? Question 3
27 Does Diabetes Lead to an Early Occurrence of Stroke? Question 4
27 Are There Any Differences in the Frequency and Severity of
Stroke in Type I and Type II Diabetic Patients? Question 5
27 Is Hyperglycaemia Itself a Risk Factor for Stroke? Question 6
28 What Is the Role of Coexisting Risk Factors for Stroke
Frequently Found in Diabetics? Question 7
28 Can Good Metabolic Control Lead to a Decrease in the Risk of
Stroke? Question 8
29 How Can We Identify Diabetic Patients at Risk of Stroke? Question 9
29 What Can Decrease the Risk of Stroke in Diabetic Patients? Question 10
30 Does the Correction of Hyperglycaemia Decrease Stroke
Severity?
ABC
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Diabetes is on the rise in developed and developing countries, in children and adolescents as well as in adults. Its prevalence ranges from 20% of middle-aged adults to 35% of the older population when some form of abnormal glucose tolerance is considered. High body mass index and obesity, especially with a high waist-to-hip ratio, are associated with hyperinsulinaemia, insulin resistance and overt diabetes mellitus. They mostly reflect the lifestyle of the affected individual. Since the incidence and mortality of all forms of cardiovascular disease are 2- to 8-fold higher in individuals with diabetes than in non-diabetics, diabetes is a major health issue.
Question 1
Does Diabetes Increase the Risk of Stroke?
Ischaemic stroke incidence increases with diabetes and elevated fasting insulin concentrations, and it is also greater in persons with increased waist-to-hip ratios. This indicates that the risk increases with the severity of diabetes. In the Atherosclerosis Risk in Communities Study (ARIC), type II diabetics with fasting glucose levels 6140 mg/dl (67.77 mmol/l) were at increased risk, contrary to those with values of 126–140 mg/dl (6.99– 7.77 mmol/l) or with lesser degrees of glycaemia. The association between diabetes and stroke is strong, with relative risks of 2.0–4.0 [1, 2]. At the 30-year follow-up of the Framingham Study, blood glucose level was an independent risk factor for stroke in women but not men [3]. Diabetes, however, increased the risk in diabetic men and women. In the Nurses Health Study the age-adjusted risk of stroke of diabetic versus non-diabetic women was 4.1 (95% CI 2.8–6.1), 5.0 for fatal and 3.8 for non-fatal strokes [4]. Taking into account the prevalence of diabetes in ARIC (approximately 10%) and a relative risk of 3.7, the population-attributable risk (i.e. the proportion of stroke cases potentially preventable by eliminating diabetes) is 21%. Patients with diabetes are at increased risk of cardiovascular disease (CVD) in general, and once the diagnosis
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Cerebrovasc Dis 2003;15(suppl 2):25–30
of CVD has been established, diabetics are at even greater risk of cardiac events. Therefore patients with diabetes belong to the same risk category as patients with known CVD and normal glucose tolerance [5]. Diabetic stroke patients are at double risk of recurrence compared to nondiabetic stroke patients [6]. References 1 Folsom AR, Rasmussen ML, Chambless LE, Howard G, Cooper LS, Schmidt MI, Heiss G: Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Diabetes Care 1999;22: 1077–1083. 2 American Diabetes Association: Facts and Figures 2002. http://www.diabetes.org/ada/facts.asp. 3 Kannel WB, Wolf PA, Garrison RJ (eds): The Framingham Study. An Epidemiological Investigation of Cardiovascular Disease. Bethesda, National Heart, Lung, and Blood Institute, 1987. NIH Publication No. 87-2703. 4 Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, Arky RA, Speizer FE, Hennekens CH: A prospective study of maturityonset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 1991;151:1141–1147. 5 Grundy SM, Howard B, Smith S Jr, Eckel R, Redberg R, Bonow RO: Prevention Conference VI: Diabetes and Cardiovascular Disease. Executive summary: Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2002; 105:2231–2239. 6 Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill PW, Anderson CS, Stewart-Wynne EG: Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke 1998;29:2491–2500.
Question 2
Is Stroke More Severe in Diabetic Patients?
In the Multiple Risk Factor Intervention Trial (MRFIT) 1973–1975, the risk of mortality from stroke in diabetics was increased 2.8 fold (95% CI 2.0–3.7) after adjusting for age, race, income, and cardiovascular risk factors. Other studies showed an increased total and stroke-related mortality as well [1]. In addition, several studies showed that patients with diabetes who develop stroke have a less favourable outcome than non-diabetics [2]. In the NINDS rt-PA Stroke Trial, higher admission glucose levels were associated with less favourable outcome and higher odds for symptomatic intracerebral haemorrhage, regardless of rt-PA treatment [3]. In addi-
Nedeltchev/Mattle
tion, when stroke is treated with intra-arterial thrombolysis, diabetics have less favourable outcomes than patients without diabetes [4]. Moreover, diabetes increases the risk of stroke-related dementia more than 3-fold [5]. Greater pre-existing comorbidity of diabetic patients could account for higher morbidity and mortality, but this could also be due to greater neuronal damage of ischaemic tissue in hyperglycaemia. References 1 Tuomilehto J, Rastenyte D, Jousilahti P, Sarti C, Vartiainen E: Diabetes mellitus as a risk factor for death from stroke. Prospective study of the middle-aged Finnish population. Stroke 1996;27:210–215. 2 Weimar C, Ziegler A, Konig IR, Diener HC: Predicting functional outcome and survival after acute ischemic stroke. J Neurol 2002;249:888–895. 3 Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, Lyden PD, Broderick JP, Kwiatkowski TG, Fineberg SE: Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002;59: 669–674. 4 Arnold M, Schroth G, Nedeltchev K, Loher T, Remonda L, Stepper F, Sturzenegger M, Mattle HP: Intra-arterial thrombolysis in 100 patients with acute stroke due to middle cerebral artery occlusion. Stroke 2002;33: 1828–1833. 5 Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R: Diabetes mellitus and risk of Alzheimer’s disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 2001;154:635–641.
Question 3
Does Diabetes Lead to an Early Occurrence of Stroke?
This question cannot be answered directly from population studies. Since diabetes promotes and accelerates atherosclerosis, it is likely that diabetes will lead to strokes at a younger age compared to the age of first-ever stroke in non-diabetics [1]. Below the age of 55 years, diabetes increases stroke risk more than 10-fold (odds ratio 11.6; 95% CI 1.2–115.2) [2]. The Baltimore-Washington Cooperative Young Stroke Study examined 296 ischaemic strokes among black and white patients aged 18–44 years [3]. The presence of diabetes markedly increased the odds ratio for stroke, ranging from 3.3 for black women to as high as 23.1 for white men. References 1 Jorgensen H, Nakayama H, Raaschou HO, Olsen TS: Stroke in patients with diabetes. The Copenhagen Stroke Study. Stroke 1994;25:1977–1984. 2 You RX, McNeil JJ, O’Malley HM, Davis SM, Thrift AG, Donnan GA: Risk factors for stroke due to cerebral infarction in young adults. Stroke 1997;28:1913–1918. 3 Rohr J, Kittner S, Feeser B, Hebel JR, Whyte MG, Weinstein A, Kanarak N, Buchholz D, Earley C, Johnson C, Macko R, Price T, Sloan M, Stern B, Wityk R, Wozniak M, Sherwin R: Traditional risk factors and ischemic stroke in young adults: The Baltimore-Washington Cooperative Young Stroke Study. Arch Neurol 1996;53:603–607.
Diabetes and Stroke
Question 4
Are There Any Differences in the Frequency and Severity of Stroke in Type I and Type II Diabetic Patients?
Few data are available to answer this question. Type II diabetics seem to be at higher risk of fatal and non-fatal stroke than type I insulin-dependent diabetics. This may be related to the higher prevalence of other risk factors such as overweight, hypertension, hyperlipidaemia and lack of exercise in type II diabetics.
Question 5
Is Hyperglycaemia Itself a Risk Factor for Stroke?
The relationship between blood glucose levels and risk of stroke is less certain than the clearly established relationship between diabetes and stroke. In the Honolulu Heart Program the risk of stroke was elevated for nondiabetic persons with blood glucose in the 80th versus the 20th percentile, and stroke risk was minimal in individuals in the lowest quartile of blood glucose 1 h after a 50gram glucose load [1]. Moreover, results from the Framingham and MRFIT studies suggest that blood glucose level is an independent risk factor for stroke and predictor of stroke mortality [2, 3]. Most likely, increasing glucose levels, both in non-diabetics and diabetics, are continuously increasing the vascular risk. Diabetes has even been considered to be a prothrombotic state. Hyperglycaemia is associated with endothelial dysfunction, increased platelet aggregation and adhesiveness and decreased fibrinolytic activity enhancing thrombogenesis even before atherosclerosis is present. Inflammation in atherosclerosis is probably also increased with hyperglycaemia. References 1 Abbott RD, Donahue RP, MacMahon SW, Reed DM, Yano K: Diabetes and the risk of stroke. The Honolulu Heart Program. JAMA 1987;257: 949–952. 2 Kannel WB, Wolf PA, Garrison RJ (eds): The Framingham Study. An Epidemiological Investigation of Cardiovascular Disease. Bethesda, National Heart, Lung, and Blood Institute, 1987. NIH Publication No. 87-2703. 3 Neaton JD, Wentworth DN, Cutler J, Stamler J, Kuller L: Risk factors for death from different types of stroke. Multiple Risk Factor Intervention Trial Research Group. Ann Epidemiol 1993;3:493–499.
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Question 6
Question 7
What Is the Role of Coexisting Risk Factors for Stroke Frequently Found in Diabetics?
Can Good Metabolic Control Lead to a Decrease in the Risk of Stroke?
Patients with type I and even more patients with type II diabetes frequently have multiple risk factors for ischaemic heart disease and stroke, e.g. hypertension, hyperlipidaemia, obesity, and physical inactivity. High blood pressure is particularly common in patients with type II diabetes, with a prevalence of up to 60% [1]. In addition, many diabetics are smokers, have cardiac disease, atrial fibrillation, or asymptomatic carotid stenosis that greatly increase the risk of stroke and other vascular events. Controlling the modifiable risk factors will significantly reduce the onset of myocardial infarction and stroke in diabetic patients. Therefore major attention must be given to all modifiable risk factors in diabetes, even more than in non-diabetic persons. Reference 1 Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB, Hademenos G, Hill M, Howard G, Howard VJ, Jacobs B, Levine SR, Mosca L, Sacco RL, Sherman DG, Wolf PA, del Zoppo GJ: Primary prevention of ischemic stroke: A statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001;103:163–182.
Intensive treatment of hyperglycaemia reduces the risk of microvascular complications such as nephropathy and retinopathy, as shown by the United Kingdom Prospective Diabetes Study (UKPDS) [1]. In UKPDS, improving insulin resistance with metformin decreased macrovascular events as well. Although UKPDS data support a distinct pathogenesis of microvascular and macrovascular sequelae in diabetes, they emphasise the importance of good metabolic control as an important part of primary and secondary prevention of stroke. Continued improvements in therapy will permit even more effective glycaemic control and enable retesting the hypothesis that intense control of glycaemia reduces atherosclerotic macrovascular complications. Insulin resistance, a cardinal feature of type II diabetes, correlates directly to increasing rates of stroke (fig. 1) [2, 3]. Improving the risk factors that are associated with insulin resistance will decrease hyperglycaemia and other intermediate risk factors related to atherosclerosis and will eventually cause stroke.
Clinical event
Fig. 1. Likely pathways between insulin re-
sistance and stroke. Reprinted with permission from Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Horwitz RI: Insulin resistance and risk for stroke. Neurology 2002;59:809–815. Copyright 2002 by AAN Enterprises, Inc.
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Nedeltchev/Mattle
Increasing evidence indicates that controlling CVD risk factors in diabetics will reduce onset of CVD and its complications. Attention must be given both to major risk
factors such as cigarette smoking, hypertension, elevated LDL cholesterol, diabetic dyslipidaemia and hyperglycaemia as well as to underlying risk factors such as overweight and obesity, physical inactivity and adverse nutrition. When a smoking patient is also diabetic, his risk for CVD is doubled in comparison to a non-diabetic smoker. Therefore he/she should quit smoking. The prevalence of hypertension, often associated with obesity, insulin resistance, hyperinsulinaemia, renal disease and microalbuminuria, is increased in diabetics. Hypertension is an important risk factor in diabetes and deserves aggressive blood pressure control. A goal of 130/ 80 mm Hg is recommended by the American Diabetes Association. Lifestyle changes including increased physical activity and ameliorated eating habits to reduce body weight, lower salt intake, increased fruit and vegetable consumption and higher potassium intake will reduce blood pressure. However, antihypertensive drugs will usually be required to achieve the goal of normal blood pressure. Diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium channel blockers are effective and can be used. Combinations of more than one drug are frequently necessary to control blood pressure and may be more effective than monotherapy [1, 2]. The addition of the ACE inhibitor ramipiril to the medical regimen of diabetics will reduce stroke by an additional 33% [3]. ACE inhibitors and angiotensin II receptor inhibitors will slow progression of nephropathy and are indicated in the presence of microalbuminuria [4]. The angiotensin II receptor inhibitor losartan was more effective than atenolol in preventing cardiovascular morbidity and mortality [5, 6]. Elevated LDL cholesterol or the diabetic dyslipidaemic triad of elevated triglycerides, elevated small LDL particles and low levels of HDL cholesterol are frequent in diabetes and especially common in type II diabetes. Both dietary and drug therapy should be used to achieve an LDL cholesterol level !100 g/dl (2.59 mmol/l). Mostly statins are used, rarely fibrates, and combinations of statins and fibrates only cautiously. Simvastatin and pravastatin improve the lipid profile in diabetes and reduce clinical endpoints such as myocardial infarction, stroke, revascularization procedures and vascular death in diabetics and non-diabetic vascular risk patients [7, 8]. Diabetes harbours a prothrombotic state, especially when associated with insulin resistance. Platelet inhibitors such as aspirin or clopidogrel counteract thrombosis formation both at the platelet and endothelial level. It is probably prudent to give antiplatelet agents to diabetics
Diabetes and Stroke
Cerebrovasc Dis 2003;15(suppl 2):25–30
For prevention of stroke and microvascular disease, control of hyperglycaemia is mandatory. Both type I and type II diabetics will benefit from good glycaemic control to prevent vascular complications such as diabetic nephropathy, neuropathy, retinopathy and myocardial infarction and stroke. The primary goal for glycaemic therapy is to achieve a near-normal fasting glucose level and a haemoglobin A1c level !7%. Glycaemic therapy for type II diabetes usually begins with oral hypoglycaemic agents such as metformin, sulfonureas, or glitazones. After several years of therapy with oral agents, insulin therapy usually will be required to achieve the goals of glycaemic control. References 1 UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853. 2 Folsom AR, Rasmussen ML, Chambless LE, Howard G, Cooper LS, Schmidt MI, Heiss G: Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Diabetes Care 1999;22: 1077–1083. 3 Adachi H, Hirai Y, Tsuruta M, Fujiura Y, Imaizuml T: Is insulin resistance or diabetes mellitus associated with stroke? An 18-year follow-up study. Diabetes Res Clin Pract 2001;51:215–223.
Question 8
How Can We Identify Diabetic Patients at Risk of Stroke?
The presence of vascular risk factors in addition to type I or type II diabetes will increase the risk of vascular events, including stroke, substantially. Diabetes itself is considered an equivalent of a vascular risk, and diabetics should be regarded as having the same risk as non-diabetics who have suffered a myocardial infarction, stroke or any other vascular event. All diabetics should be treated with risk modification as good as possible.
Question 9
What Can Decrease the Risk of Stroke in Diabetic Patients?
29
even when there is no overt vascular disease. However, there is no conclusive evidence from randomised trials to support this [9]. When diabetics have manifest vascular disease, antiplatelet agents are clearly indicated. Because such patients are at especially high risk, clopidogrel should be considered [10]. Weight management is of paramount importance in patients with type II diabetes, especially in those with insulin resistance. Weight reduction can be achieved both by increase in physical activity and change in dietary habits. Such a combination, and even more so when diet and exercise are combined with systematic intensive counselling, can prevent or delay the onset of type II diabetes [11]. Physical activity enhances insulin sensitivity, improves the metabolic syndrome and ameliorates cardiovascular fitness and function. As a minimum, 30 min of moderateintensity exercise is recommended. If more intense exercise can be tolerated, it will provide greater benefit. The goal of dieting is to maintain normal or minimally elevated plasma glucose and lipid levels. Total calorie intake should prevent weight gain and must allow weight reduction in overweight diabetics. Saturated fats should not exceed 7% of total calories. Fruit and vegetable consumption should be proportionately high. References 1 Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755–1762. 2 PROGRESS Collaborative Group: Randomised trial of a perindoprilbased blood pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischemic attack. Lancet 2001;358:1033–1041. 3 Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipiril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253–259. 4 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: 861–869.
5 Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H, The LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): A randomised trial against atenolol. Lancet 2002;359:995–1003. 6 Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S, The LIFE Study Group: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): A randomised trial against atenolol. Lancet 2002;359:1004–1010. 7 Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J: Reduction of stroke events with pravastatin: The Prospective Pravastatin Pooling (PPP) Project. Circulation 2001;103:387–392. 9 Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:23–33. 10 Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. 11 Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ: Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002;90:625–628. 12 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.
Question 10
Does the Correction of Hyperglycaemia Decrease Stroke Severity?
Hyperglycaemia in acute stroke is related to an adverse outcome. Insulin treatment of hyperglycaemic animals was found to exert a beneficial effect in focal and global brain ischaemia. Clinical trials in humans, such as the Glucose Insulin in Stroke Trial, have yet to be performed to answer this question [1]. Until such data are available it is wise to administer glucose- and dextrose-free solutions to stroke patients and cautiously use insulin to lower glucose levels when elevated. Reference 1 Kagansky N, Levy S, Knobler H: The role of hyperglycemia in acute stroke. Arch Neurol 2001;58:1209–1212.
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Nedeltchev/Mattle
Chapter 5 Cerebrovasc Dis 2003;15(suppl 2):31–36 DOI: 10.1159/000069678
High Cholesterol and Its Management Tom Skyhøj Olsen
Question 1
32 Is Hypercholesterolaemia a Risk Factor for Stroke? Question 2
32 Are Low Cholesterol Levels Associated with a Risk of
Haemorrhagic Stroke? Question 3
33 Is Glycoprotein(a) Related to or a Risk Factor for Stroke? Question 4
33 Are Triglycerides Associated with Stroke? Question 5
34 Does Lipid-Lowering Therapy Decrease the Risk of Stroke? Question 6
34 Do Statins Influence Carotid Artery Atherosclerosis? Question 7
34 Should All Patients with Stroke or TIA Have a Lipid Analysis? Question 8
35 What Are the Benefits of Treating Stroke Patients with Statins? Question 9
35 Do Elderly Patients also Benefit from Lipid-Lowering Therapy? Question 10
36 At Which Cholesterol Concentrations Should
Cholesterol-Lowering Therapy Be Initiated?
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Question 1
Is Hypercholesterolaemia a Risk Factor for Stroke?
Although this question has long been considered a controversy, evidence favouring a ‘yes’ to the question is emerging [1, 2]. In the Framingham Study and the Honolulu Heart Study [3, 4], no association between stroke and cholesterol levels could be established. A meta-analysis of 45 prospective cohorts including 450,000 subjects and 13,000 stroke cases also showed no association between stroke and cholesterol. These studies, however, were primarily designed to study coronary heart disease and included middle-aged subjects with a relatively low stroke risk. Furthermore, no differentiation between ischaemic and haemorrhagic stroke was undertaken. In the Multiple Risk Factor Intervention Trial study of 350,000 middle-aged men [5], the risk of fatal non-haemorrhagic stroke was directly related to increasing cholesterol levels. A similar trend was found in the Eastern Stroke and Coronary Heart Disease Collaboration Research Group study of 70,000 subjects [6]. In the Israeli Ischemic Heart study and three case-control studies [7– 10], a relation between cholesterol subfractions and ischaemic stroke was found, and a 15-year follow-up of the Honolulu Heart Study showed a direct relation between stroke and cholesterol [11]. In several large studies of patients with coronary heart disease, cholesterol-lowering statins resulted in a 30% relative reduction of stroke risk [1, 2], and the results of trials with two other non-statin cholesterol-lowering agents niacin and gemfibrozil were almost identical [12, 13]. In conclusion, although direct proof of a stroke-cholesterol relation has still not firmly been established, indirect evidence points to the existence of such a relation. References 1 Sarti C, Kaarisalo M, Tuomilehto J: The relationship between cholesterol and stroke. Implications for antihyperlipidaemic therapy in older patients. Drugs Aging 2000;17:33–51. 2 Demchuck AM, Hess DC, Brass LM, Yatsu F: Is cholesterol a risk factor for stroke? Yes. Arch Neurol 1999;56:1518–1520.
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3 Wolf PA, Kannel WB, Verter J: Current status of risk factors for stroke. Neurol Clin 1983;1:317–343. 4 Kagan A, Popper JS, Rhoads GG: Factors related to stroke incidence in Hawaiian Japanese men. The Honolulu Heart Study. Stroke 1980;11:14– 21. 5 Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD, for the MRF Research Group: Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904–910. 6 Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia. Lancet 1998;352:1801–1807. 7 Tanne D, Yaari S, Goldbourt U: High-density lipoprotein cholesterol and risk of ischemic stroke mortality. A 21 year follow-up of 8586 men from the Israeli Ischemic Heart Disease Study. Stroke 1997;28:83–87. 8 Amarenco P, Elbaz A, on behalf of the GENIC investigators: Hypercholesterolemia as a risk factor for brain infarction. Case control study from GENIC. Cerebrovasc Dis 1998;8(suppl 4):2. 9 Albucher JF, Ferries J, Ruidavets JB, Guiraud-Chaumeil B, Perret BP, Chollet F: Serum lipids in young patients with ischaemic stroke: a casecontrol study. J Neurol Neurosurg Psychiatry 2000;69:29–33. 10 Hachinski V, Graffanino C, Beaudry M, Bernier G, Buck C, Donner A, Spence D, Doig G, Wolfe BMJ: Lipids and stroke. A paradox resolved. Arch Neurol 1996;53:303–308. 11 Benfante R, Yano K, Hwang LJ, Curb D, Kagan A, Ross W: Elevated serum cholesterol is a risk factor for both coronary heart disease and thromboembolic stroke in Hawaiian Japanese men. Implications of shared risk. Stroke 1994;25:814–820. 12 Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410–418. 13 The Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360–381.
Question 2
Are Low Cholesterol Levels Associated with a Risk of Haemorrhagic Stroke?
Low serum cholesterol levels have been associated with haemorrhagic stroke in several prospective studies [1]. In three large American studies the risk of death from intracranial bleeding in men was 2–3 times higher in patients with cholesterol levels below 4.6–4.9 mmol/l [2– 4]. A similar trend was observed in a large Asian study [5]. However, in a very large prospective Korean study based on 115,000 men, low total cholesterol was not identified
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as a risk factor for haemorrhagic stroke [6]. Moreover, cholesterol-lowering treatment with statins, gemfibrozil and niacin did not increase the risk of haemorrhagic stroke. In conclusion, the relation between low cholesterol and risk of intracranial bleeding is not yet clarified. Treatment with cholesterol-lowering agents does not increase the risk of intracranial bleeding. References 1 Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen J, for the MRFIT Research Group: Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904–910. 2 Irribarren C, Jacobs DR, Sadler M, Claxton AJ, Sidney S: Low total serum cholesterol and intracerebral hemorrhagic stroke: Is the association confined to elderly men? The Kaiser Permanente Medical care program. Stroke 1996;27:1993–1998. 3 Neaton JD, Blackburn H, Jacobs D, Kuller L, Lee DJ, Sherwin R, Shih J, Steamler J, Wentworth D: Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Arch Intern Med 1992;152:1490–1500. 4 Gordon T, Kannel WB, Castelli WP, Dawber TR: Lipoproteins, cardiovascular disease, and death: the Framingham Study. Arch Intern Med 1981; 141:1128–1131. 5 Eastern Stroke and Coronary Heart Disease Collaborative Research Group: Blood pressure, cholesterol, and stroke in eastern Asia. Lancet 1998;352:1801–1807. 6 Suh I, Jee SH, Kim HC, Nam CM, Kim IS, LJ Appel: Low serum cholesterol and hemorrhagic stroke in men: Korea Medical Insurance Corporation Study. Lancet 2001;357:922–925.
ies taking care of relevant confounders, no association between lipoprotein(a) and stroke has been demonstrated [1, 2]. In conclusion, although lipoprotein(a) is increased in stroke (a phase reactant?) there is no indication of a causal relationship. References 1 Pantoni L, Sarti C, Pracucci G, Di Carlo A, Vanni P, Inzitari D, for the Italian Longitudinal Study of Aging (ILSA): Lipoprotein(a) serum levels and vascular diseases in an older Caucasian population cohort. J Am Geriatr Soc 2001;49:117–125. 2 Van Kooten F, van Krimpen J, Dippel DWJ, Hoogerbrugge N, Koudstaal PJ: Lipoprotein(a) in patients with acute cerebral ischemia. Stroke 1996; 27:1231–1235.
Question 4
Are Triglycerides Associated with Stroke?
Lipoprotein(a) resembles LDL in structure. It consists of an LDL particle linked to a glycoprotein called apo(a). The physiological functions of lipoprotein(a) are unknown. Lipoprotein(a) is thought to promote atherogenesis by transporting the LDL molecule and influencing smooth muscle proliferation. Lipoprotein(a) may also influence fibrinolysis and platelet function. Lipoprotein(a) concentrations in serum are primarily genetically determined and remain stable during life, they are only minimally influenced by environmental factors such as diet and lipid-lowering agents. Its glycoprotein parts show close structural similarity to plasminogen, with which it competes for binding sites. Elevated concentrations of lipoprotein(a) have been found in the acute as well as in the chronic phase of stroke in one third of the studies. However, in multivariate stud-
Elevated triglyceride levels are associated with increased risk of coronary heart disease and peripheral arterial disease. Factors contributing to elevation of triglycerides are obesity, physical inactivity, smoking, excessive alcohol intake, type II diabetes, chronic renal failure, nephrotic syndrome, genetic disorders such as familial hypertriglyceridaemia, and drugs like corticosteroids, estrogens, and beta-blockers. Elevated triglycerides are most often seen in persons with ‘the metabolic syndrome’ that includes central obesity, insulin resistance, low levels of HDL cholesterol and hypertension [1]. Although high serum triglycerides are commonly found in persons with a high risk of stroke, the association to risk of stroke is still a controversial issue [2]. Several case-control studies have found an association between high triglycerides and ischaemic stroke, but the results of available large prospective observational studies are inconsistent. The Finmark Study found only an association between non-fasting triglycerides and stroke in women, and the Copenhagen City Heart Study found an association for triglyceride levels 18 mmol/l [3, 4]. The British Regional Heart Study, the Australian Dubbo Study and the Framingham Study found no association [5–7]. In conclusion, triglycerides play an important role in atherogenesis and are an important risk factor for coronary heart disease. High triglycerides are commonly found in persons with a high risk of stroke (‘the metabolic syndrome’) but its independent association with stroke remains to be proven.
High Cholesterol and Its Management
Cerebrovasc Dis 2003;15(suppl 2):31–36
Question 3
Is Glycoprotein(a) Related to or a Risk Factor for Stroke?
33
References 1 Rizos E, Mikhailidis DP: Are high density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention? Cardiovasc Res 2001;52:199– 207. 2 Albucher JF, Ferrieres J, Ruidavets JB, Guiraud-Chaumeil B, Perret BP, Chollet F: Serum lipids in young patients with ischaemic stroke: A casecontrol study. J Neurol Neurosurg Psychiatry 2000;69:29–33. 3 Njolstad I, Arnesen E, Lund-Larsen PG: Body height, cardiovascular risk factors, and risk of stroke in middle-aged men and women: a 14-year follow-up of the Finmark Study. Circulation 1996;94:2877–2882. 4 Lindenstrøm E, Boysen G, Nyboe J: Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on the risk of cerebrovascular disease: The Copenhagen City Heart Study. BMJ 1994;309:11–15. 5 Wannamethee SG, Sharper G, Ebrahim S: HDL-cholesterol, total cholesterol, and the risk of stroke in middle-aged British men. Stroke 2000;31: 1882–1888. 6 Simons LA, McCallum J, Friedlander Y, Simons J: Risk factors for ischemic stroke. Dubby Study of the elderly. Stroke 1998;29:1341–1346. 7 Gordon T, Kannel WB, Castelli WP, Dawber TR: Lipoproteins, cardiovascular disease, and death. The Framingham study. Arch Int Med 1981;141: 1128–1131.
Question 5
Does Lipid-Lowering Therapy Decrease the Risk of Stroke?
Meta-analyses of large secondary prevention studies of statins in patients with coronary heart diseases have shown a significant, 30% reduction in the risk of ischaemic stroke (as with ASA) [1]. The same result has now emerged from the very large Heart Protection Study of more than 20,000 patients [2]. In this study, more than 1,800 patients with stroke but without coronary heart disease were included; statin treatment, even in stroke patients without coronary heart diseases, was found to reduce the risk of stroke and other major vascular events by 30%. The effect of treatment was independent of the initial cholesterol concentration. Results like those in the statin trials were also obtained with the non-statin lipid-lowering agents gemfibrozil and niacin. With regard to patients with stroke, the absolute benefit calculated on the basis of the Heart Protection Study was that 100 treatment years with statins are needed to prevent one major vascular event [2]. In a Scottish primary prevention study on middle-aged men, pravastatin reduced coronary events but not the risk of stroke [3]. Several studies designed for the study of the effect of statins on stroke populations are underway. In conclusion, lipid-lowering drugs, in particular statins, significantly reduce the risk of recurrent stroke in patients with stroke and TIA. Stroke and TIA patients, even those without coronary heart disease, should be
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offered lipid-lowering treatment independent of cholesterol concentrations. References 1 Herbert PR, Gaziano JM, Chan S, Hennekens CH: Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomised trials. JAMA 1997;278:313–321. 2 Heart Protection Study Collaboration Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. 3 Shepherd J, Cobbe SM, Ford I, for the West of Scotland Coronary Prevention Study Group: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301– 1307.
Question 6
Do Statins Influence Carotid Artery Atherosclerosis?
Several angiographic studies on atherosclerotic processes in coronary and carotid arteries show retardation of the atherosclerotic process as well as plain plaque regression during treatment with statins [1, 2]. With pravastatin progression of carotid artery thickness was stopped within 6 months in asymptomatic patients with moderate hypercholesterolaemia [3]. In the LIPID Atherosclerotic Study [4], carotid wall thickness declined by 0.0014 mm in the actively treated group compared with a 0.048-mm increase in the placebo group. With lovastatin carotid intima thickness regressed by 0.0095 mm in 4 years compared to an increase of 0.046 mm with placebo. In a Finnish primary prevention study [5], pravastatin treatment reduced progression of carotid artery intima thickness by 45%. In conclusion, statins induce beyond doubt regression of atherosclerotic processes in the carotid arteries. References 1 Demchuck AM, Hess DC, Brass LM, Yatsu F: Is cholesterol a risk factor for stroke? Yes. Arch Neurol 1999;56:1518–1520. 2 Sarti C, Kaarisalo M, Tuomilehto J: The relationship between cholesterol and stroke. Implixcations for antihyperlipidaemic therpy in older patients. Drugs Aging 2000;17:33–51. 3 Mercuri M, Bond MG, Sirtori CR, Veglia F, Crepaldi G, Feruglio FS, Descovich G, Ricci G, Rubba P, Manchini M, Gallus G, Bianchi G, D’Alo G, Ventura A: Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranian population: the Carotid Atherosclerosis Italian Ultrasound Study. Am J Med 1996;101: 627–634. 4 MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H: Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy: LIPID Trial Research Group. Circulation 1998;97:1784–1790. 5 Salonen R, Nyssonen K, Porkkala-Sarataho E, Salonen JT: The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression. Am J Cardiol 1995;76:34C–39C.
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Question 7
Should All Patients with Stroke or TIA Have a Lipid Analysis?
In patients with stroke or TIA (with or without coronary heart disease) treatment with lipid-lowering agents reduces the risk of major vascular events, including stroke, by 30%. Patients with stroke or TIA have a risk 130% of developing manifest ischaemic heart disease within the next 10 years. For these reasons patients with stroke or TIA should always have a complete lipid analysis including total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides. It should be emphasised, however, that the effect of statins according to the Heart Protection Study is independent of the patients’ initial cholesterol concentration, and treatment with statins should be initiated irrespective of this [1, 2]. In conclusion, patients with stroke or TIA should always have a complete lipid analysis, including total cholesterol, LDL, HDL and triglycerides. References 1 Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486–2497. 2 Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB, Hademenos G, Hill M, Howord G, Howard VJ, Jacobs B, Levine SR, Mosca L, Sacco RL, Sherman DG, Wolf PA, del Zoppo GJ: Primary prevention of ischemic stroke. A statement for healthcare professional from the Stroke Council of the American Heart Association. Circulation 2001;103:163–182.
risk reduction) [1, 2]. In absolute terms, the stroke rate in the Heart Protection study decreased by 1.4% from 5.7% in the placebo group to 4.3% in the treatment group. The Heart Protection Study [2] included more than 1,800 patients with stroke who had had no prior coronary heart disease. Treatment with simvastatin prevented 50 major vascular events in 1,000 patients treated for 5 years, i.e. 100 treatment years are needed to prevent 1 major vascular event. The study included more than 7,000 patients who only had coronary heart disease. In this group, treatment with 40 mg of simvastatin prevented 57 major vascular events in 1,000 patients treated for 5 years, i.e. 89 treatment years are needed to prevent 1 major vascular event. When correcting for non-compliance in the study it was concluded from the Heart Protection Study that among all types of high-risk patients included in the study treatment with simvastatin, 5 years of treatment prevent 70–100 major vascular events in 1,000 patients, i.e. 50– 71 treatment years to prevent one major vascular event. In conclusion, statins prevent recurrent strokes and other major vascular events in patients with stroke. References 1 Crouse III JR, Byington RP, Hoen H, Furberg CD: Reductase inhibitory monotherapy and stroke prevention. Arch Intern Med 1997;157:1305– 1310. 2 Heart Protection Study Collaboration Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7–22.
Question 9
Question 8
Do Elderly Patients also Benefit from Lipid-Lowering Therapy?
Stroke prevention with statins has only been studied to a limited degree, therefore our knowledge in this field is still relatively sparse. Statin trials are usually designed for patients with coronary heart disease, a much younger population than the stroke population and comprising more males. Hence, in the Heart Protection Study only 28% of the patients were older than 70 years and only 25% were women. In an unselected stroke population, approximately 70% are older than 70 years and half of the patients are women. The relative effects of statin treatment are comparable for cardiac and cerebrovascular outcomes (30% relative
Most studies on the efficacy of statins have enrolled patients in the late fifties. Limited data on patients from 65 to 70 years of age, however, indicate that older persons with coronary heart disease benefit of statin treatment as much as younger persons [1, 2]. This indication is further supported by results of the Heart Protection Study [3]. In this study of more than 20,000 patients, nearly 6,000 patients were at least 70 years old. Older patients achieved the same risk reduction as the younger. The Cardiovascular Health Study recently also found benefits of statin treatment in persons older than 74 years [4]. Several studies addressing the issue of lipid-lowering therapy in older persons are ongoing. In conclusion, lipid-lowering therapy in patients with stroke is effective regardless of age.
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Cerebrovasc Dis 2003;15(suppl 2):31–36
What Are the Benefits of Treating Stroke Patients with Statins?
35
References 1 Grundy SM: Statin therapy in older persons. Arch Intern Med 2002;162: 1329–1331. 2 Hess DC, Demchuck AM, Brass LM, Yatsu F: HMG-CoA reductase inhibitors (statins). A promising approach to stroke prevention. Neurology 2000; 54:790–796. 3 Heart Protection Study Collaboration Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7–22. 4 Lemaitre R, Psaty BM, Heckbert SR, Kronmal RA, Newman AB, Burke GL: Therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults. Evidence from the Cardiovascular Health Study. Arch Intern Med 2002;162:1395–1400.
Question 10
At Which Cholesterol Concentrations Should Cholesterol-Lowering Therapy Be Initiated?
Results from the Heart Protection Study [1] showed that cholesterol-lowering therapy with simvastatin reduces the relative risk of major cardiovascular events by
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30% in patients with coronary heart disease, diabetes, or other occlusive arterial disease, including stroke, irrespective of their initial cholesterol concentrations. Thus it was concluded that the benefit of lipid-lowering treatment depends on the patients overall risk of major vascular events rather than on their blood lipid concentrations alone. In the Heart Protection Study, an effect of treatment was also seen with LDL cholesterol and total cholesterol concentrations below 3 and 5 mmol/l, respectively. Consequently, initiation of statin treatment is expected to be of benefit in all patients with stroke irrespective of cholesterol concentrations. In conclusion, cholesterol-lowering treatment in patients with stroke should be initiated without regard to initial cholesterol concentration. Reference 1 Heart Protection Study Collaboration Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7–22.
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Chapter 6 Cerebrovasc Dis 2003;15(suppl 2):37–41 DOI: 10.1159/000069679
Other Risk Factors Tom Skyhøj Olsen
Question 1
38 Does Physical Activity Prevent Stroke? Question 2
38 Are Overweight and Obesity Associated with Stroke? Question 3
38 Is Alcohol a Risk Factor for Stroke? Question 4
39 Is Smoking a Risk Factor for Stroke? Question 5
39 Do Oral Contraceptives Increase the Risk of Stroke? Question 6
40 Does Postmenopausal Hormone Replacement Therapy
Influence Stroke Risk? Question 7
40 Are Patients with Migraine at Increased Risk of Stroke? Question 8
41 Is the Finding of Antiphospholipid Antibodies an Indication for
Stroke Preventive Treatment? Question 9
41 Is Homocysteine a Risk Factor for Stroke? Question 10
41 Can Stress Provoke Stroke?
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Question 1
Question 2
Does Physical Activity Prevent Stroke?
Are Overweight and Obesity Associated with Stroke?
The relation between physical activity and the risk of coronary heart disease has been investigated in a great number of studies. Taken together, these studies leave no doubt that physical activity and the risk of coronary heart disease is inversely related. This relation appears to be a dose response with a successively higher risk at the highest physical activity levels. The relation between physical activity and the risk of stroke has been less intensively studied [1]. Some studies have shown a relation, others have not. Taken together, these studies do not clearly suggest a relation between physical activity and risk of stroke. More studies are needed to prove the relation already established in the case of coronary heart disease. In the meantime, most authorities in the field recommend regular moderate exercise (e.g. brisk walking) for at least 30 min on most (preferably all) days of the week. The protective effect of such efforts may be mediated by its role in controlling risk factors such as hypertension, diabetes and obesity [2]. In conclusion, physical activity such as a brisk walk for at least 30 min a day is recommended for stroke prevention. References 1 Kohl HW 3rd: Physical activity and cardiovascular disease: Evidence for a dose response. Med Sci Sports Exerc 2001;33(suppl 6):S472–S483; discussion S493–S494. 2 Gorelick PB, Sacco RL, Smith DB, Albers M, Mustone-Alexander L, Rader D, Ross JL, Raps E, Ozer MN, Brass LM, Malone ME, Goldberg S, Booss J, Hanley DF, Toole JF, Greengold NL, Rhew DC: Prevention of a first stroke. A review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA 1999;281:1112–1120.
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Obesity as well as overweight are risk factors for stroke and double the risk. Obesity is also associated with increased levels of blood glucose, blood pressure and cholesterol, all independent risk factors for stroke. Abdominal obesity rather than general obesity is associated with risk of stroke [1, 2]. Reduction of weight in overweight and obese persons is considered to decrease risk of stroke. References 1 Walker SP, Rimm EB, Ascherio A, Kawachi I, Stempfer MJ, Willett WC: Body size and fat distribution as predictors of stroke among US men. Am J Epidemiol 1996;144:1143–1150. 2 Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, Rimm E, Colditz GA: Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 2001;161:1581– 1586.
Question 3
Is Alcohol a Risk Factor for Stroke?
There is clear evidence that light to moderate intake of alcohol (1–2 drinks per day) is associated with reduced a risk of coronary heart disease. Currently the relation between alcohol and stroke is less clear [1]. There is evidence (and consensus) that long-term heavy alcohol intake as well as binge-drinking are risk factors for haemorrhagic and ischaemic stroke. Heavy alcohol intake in this context means approximately 5 drinks or more a day. As to light or moderate alcohol intake, there is no clear evidence of a protecting effect against stroke [1, 2]. Some studies have shown a U-shaped relation, others have not. Wine was associated with a lower risk of stroke compared to beer and liquor, but this finding is also inconsistent [1, 2]. Wine is usually consumed in a more regular pattern than beer and liquor, which are more likely to be consumed irregularly or during binges.
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Hence, heavy drinking as well as binge-drinking should be discouraged, while there is no need for light to mild consumers of alcohol to change drinking habits. Likewise there is no need for abstainers to change their drinking habits. In conclusion, the current recommendation of the American Heart Association is that ‘alcohol use should be an item of discussion between physician and patient’ [3]. Heavy drinking and binge-drinking are risk factors of haemorrhagic as well as ischaemic stroke. No drinking as well as light to moderate drinking does not seem to influence stroke risk and persons with that drinking habit should not be encouraged to change drinking habits. There is not evidence to support that wine, liquor or beer differ in regard to stroke risk.
The risk of stroke decreases rapidly and drastically after quitting smoking. It is reduced by 50% after 1 year, the risk level of non-smokers is reached after 5 years. Smoking cessation may have enormous consequences for public health. Every time 43 smokers quit smoking 1 stroke is prevented. In conclusion, as much as one quarter of all strokes is attributable to smoking. Smoking cessation should be strongly encouraged. References 1 Hankey GJ: Smoking and risk of stroke. J Cardiovasc Risk 1999;6:207– 211. 2 Shinton R, Beevers G: Meta-analysis of relation between cigarette smoking and stroke. BMJ 1989;298:789–794.
References 1 Mazzaglia G, Britton AR, Altmann DR, Chenet L: Exploring the relationship between alcohol consumption and non-fatal or fatal stroke: A systematic review. Addiction 2001;96:1743–1756. 2 Goldberg IJ, Mosca L, Piano MR, Fisher EA: AHA Science Advisory. Wine and your heart: A science advisory for healthcare professionals from the Nutrition Committee, Council on Epidemiology and Prevention, and Council on Cardiovascular Nursing of the American Heart Association. Stroke 2001;103:591–594. 3 Goldberg IJ, Mosca L, Piano MR, Fisher EA: Wine and your heart. A science advisory for healthcare professionals from the Nutrition Committee, Council on Epidemiology and Prevention, and Council on Cardiovascular Nursing of the American Heart Association. Circulation 2001;103: 472–475.
Question 5
Do Oral Contraceptives Increase the Risk of Stroke?
Up to one quarter of all strokes are attributable to smoking. The mechanisms by which smoking causes stroke are uncertain but most probably the effects of smoking are multifactorial: increase in vascular tone and arterial wall stiffness, increase of fibrinogen levels, blood viscosity, platelet aggregation and influence on lipid metabolism [1]. Smoking nearly doubles the risk of ischaemic stroke. There is a dose response between numbers of cigarettes smoked and the relative risk. The estimated increase in relative risk in smokers is 1.5 for each 10 cigarettes smoked per day. The risk is similar in men and women. Pipe and cigar smoking appear to carry the same risk as cigarette smoking [2]. Even passive exposure to cigarette smoking appears to be atherogenic and increases the risk of cardiovascular disease.
Oral contraceptive use carries an increased risk of stroke of all subtypes. The risk is greatly influenced by the content of oestrogen. In contraceptives with high oestrogen content (650 Ìg) the relative risk may be increased by approximately 3, while in oral contraceptives with low oestrogen content (!50 Ìg) the risk is not or only slightly increased. There is no firm evidence that different progestins in first-, second- or third-generation pills carry any difference in the risk of stroke [1]. The risk of stroke is further enhanced in oral contraceptive users with additional risk factors, in particular hypertension, smoking and migraine. In most studies these risk factors seem to have more than additive effect on the stroke risk. Hypertension is rare in the population using oral contraceptives and can be controlled for. Smoking is the major stroke risk factor in this population and smoking should be strongly discouraged in women taking oral contraceptives. Whether migraine represents a contraindication for use of contraceptives is debatable. One should realise that in cases of migraine with aura the risk is doubled compared to migraine without aura and that smoking confers a more than additive risk of stroke to the patient. The decision should be taken case by case, considering all risks and benefits on an individual basis. If the decision to use oral contraceptives is taken, progestogenonly pills might be a choice, although there are no data on the risk of stroke in this type of oral contraceptives.
Other Risk Factors
Cerebrovasc Dis 2003;15(suppl 2):37–41
Question 4
Is Smoking a Risk Factor for Stroke?
39
It should be emphasised, however, that the absolute excess risk of stroke in oral contraceptive users is very low: approximately 4.1 per 100,000 normotensive, non-smoking low-oestrogen oral contraceptive users or 1 additional stroke per year in 24,000 such women. Hence the potential slight increase in stroke risk by low-dose oral contraceptives easily outweighs the health benefits of improved birth control if other stroke risk factors (hypertension, smoking and migraine) are absent or controlled [1, 2]. In conclusion, oral contraceptives with a low oestrogen content carry a very low (if any) risk of stroke when other stroke risk factors are absent or controlled for. In women taking oral contraceptives smoking is strongly discouraged. References 1 Bousser M-G, Kittner SJ: Oral contraceptives and stroke. Cephalagia 2000; 20:183–189. 2 Gillum LA, Mamidipudi SK, Johnston SC: Ischemic stroke risk with oral contraceptives. A metaanalysis. JAMA 2000;284:72–78.
ready have had a stroke; benefits should be carefully weighted against risks. In conclusion, hormone replacement therapy should not be prescribed to women who have already suffered a stroke. Hormone replacement therapy has no place in primary stroke prevention. References 1 Wilson PWF, Garrison RJ, Castelli WP: Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50: the Framingham Study. N Engl J Med 1985;313:1038–1043. 2 Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243–1249. 3 Simon JA, Hsia J, Cauley JA, Richards C, Harris F, Fong J, Barrett-Connor E, Hulley SB: Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS). Stroke 2001; 103:638–642. 4 Writing group for the Women’s Health Initiative Investigators: Risk and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–333.
Question 7 Question 6
Does Postmenopausal Hormone Replacement Therapy Influence Stroke Risk?
The effect of postmenopausal hormone replacement therapy has long been considered neutral. Except for the Framingham study, which showed a 2.6-fold increase in the risk of stroke [1], studies from the eighties and nineties showed either no effect or a slight reduction in the risk of stroke. The Women’s Oestrogen for Stroke Trial, published in 2001 [2], concluded that oestradiol replacement therapy does not reduce or alter risk of recurrent stroke in postmenopausal women with ischaemic stroke. However, in the secondary stroke prevention study, risk of fatal stroke and non-fatal stroke severity was higher in the oestrogen group. The HERS study [3] showed that hormone replacement therapy in healthy postmenopausal women did not influence the risk of stroke. The Women’s Health Initiative [4] concluded that hormone replacement with oestrogen plus progestin increases the risk of stroke and coronary heart diseases in apparently healthy women; an excess rate of 8 more strokes and 7 more coronary heart diseases per 10,000 person years was observed. Hence, there may be a slight increase of the risk of stroke and the severity of strokes in women on postmenopausal hormone replacement therapy. Thus it is not advisable to prescribe such therapy to patients who al-
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Are Patients with Migraine at Increased Risk of Stroke?
Although definite proof has still not been established, several case-control and prospective studies point to a causal relation between stroke and migraine [1]. The association is strongest in young females and declines with age. Most convincing is the relation between migraine with aura and stroke, where odds ratios between 4 and 9 are reported compared to odds ratios of about 2 for migraine without aura [1]. As the patients at risk are usually young the absolute risk of stroke is low. The absolute risk of stroke in young women is approximately 10 per 100,000 woman years, while in young women with migraine it is estimated to be 19 per 100,000 woman years. Such a low risk does not call for preventive measures [1, 2]. On the other hand, patients with migraine (especially those with migraine with aura) should be strongly advised to abstain from smoking and choose their contraceptive method carefully, especially when other stroke risk factors are present. In conclusion, migraine with aura and maybe also migraine without aura carries an increased risk of stroke that is, in absolute terms, very low. Preventive considerations are only relevant when discussing contraception with women who have other risk factors of stroke, such as smoking and hypertension.
Olsen
References 1 Tzourio C, Kittner SJ, Bousser M-G, Alpérovitch A: Migraine and stroke in young women. Cephalagia 2000;20:190–199. 2 Merikangas KR, Fenton BT, Cheng SH, Stolar MJ, Risch N: Association between migraine and stroke in a large epidemiological study of the Unites States. Arch Neurol 1997;54:362–368.
Question 8
Is the Finding of Antiphospholipid Antibodies an Indication for Stroke Preventive Treatment?
The most commonly detected antiphospholipid antibodies are lupus anticoagulant, anticardiolipin antibodies and anti-ß2-glycoprotein I antibodies. These antibodies are found in 1–5% of young healthy volunteers. In patients with systemic lupus erythematosus, the prevalence of lupus anticoagulant and anticardiolipin antibodies is much higher. The diagnostic criteria of an antiphospholipoid syndrome are met when these antibodies are seen in patients with vascular thrombosis or in certain complications of pregnancy. Although an association between antiphospholipid antibodies and subsequent thrombotic events has been demonstrated, there are, however, no sufficient data to reliably predict those who will eventually have a thrombotic event. In patients with stroke or TIA who have antiphospholipid antibodies, long-term anticoagulation with warfarin is advocated. Aspirin does not seem to offer protection in these patients. There is no evidence to support antithrombotic preventive measures in patients having antiphospholipid antibodies but showing no clinical manifestations. In conclusion, the finding of antiphospholipid antibodies indicates antithrombotic treatment with warfarin only in the presence of clinical manifestations. Reference 1 Levine JS, Branch DW, Rauch J: The antiphospholipid syndrome. N Engl J Med 2002;346:752–763.
Question 9
Is Homocysteine a Risk Factor for Stroke?
Homocysteine is an aminoacid produced from methionine. Increased levels of homocysteine are seen in 20– 40% of stroke patients. Numerous case-control studies
Other Risk Factors
have demonstrated a relation between elevated homocysteine and risk of ischaemic stroke. Effects on vascular smooth muscle and on vascular endothelium have been proposed as the cause of this relation. However, as the epidemiological evidence from large prospective cohort studies is inconsistent, it remains still to be proven that the relation between elevated homocysteine and ischaemic stroke is causal [1]. Normalisation of an elevated homocysteine level can be achieved with a daily intake of folic acid (200 Ìg) and vitamin B12 (1 mg). However, it remains to be proven whether this intervention reduces the risk of stroke [2]. In conclusion, there is an association between elevated homocysteine levels and risk stroke. Whether this association is causal remains to be proven. It is not known whether reduction of the homocysteine level by administration of folic acid and B12 reduces risk of stroke. References 1 Hankey GJ, Eikelboom JW: Homocysteine and stroke. Curr Opin Neurol 2001;14:95–102. 2 Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG: A quantitative assessment of plasma homocystein as a risk factor for vascular disease: Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049– 1057.
Question 10
Can Stress Provoke Stroke?
Many stroke victims suspect stress as the cause of the stroke they suffered. Knowledge in this field is, however, sparse. Exposure to psychological distress has increasingly been recognised as a risk factor for coronary heart disease [1], but the association between psychological distress and stroke is only sparsely explored; results are inconsistent and allow no firm conclusions. A very recent study was not able to demonstrate a role of stress in the precipitation of stroke. However, distressed people had a higher risk of fatal stroke outcome [2]. In conclusion, there is no evidence to support that stress provokes strokes. References 1 Stansfeld SA, Fuhrer R, Shipley MJ, Marmot MG: Psychological distress as a risk factor for coronary heart disease in the Whilehall II Study. Int J Epidemiol 2002;31:248–255. 2 May M, McCarron P, Stansfeld S, Ben-Schlomo Y, Gallacher J, Yarnell J, Smith GD, Elwood P, Ebrahim S: Does psychological distress predict the risk of ischemic stroke or transient ischemic attack? The Caerphilly Study. Stroke 2002;33:7–12.
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Chapter 7 Cerebrovasc Dis 2003;15(suppl 2):43–48 DOI: 10.1159/000069680
Antiplatelet Therapy in Stroke Prevention Peter A. Ringleb Werner Hacke
Question 1
44 Which Role Do Antiplatelet Agents Play in the Primary
Prevention of Stroke? Question 2
44 What Are the Benefits of ADP Receptor Antagonists Compared
to Aspirin? Question 3
45 Is the Combination of ADP Receptor Antagonist and Aspirin
Wise? Question 4
46 What Are the Benefits of the Combination of Dipyridamole and
ASS? Question 5
46 Can Results with Antiplatelet Therapy in Coronary Artery
Disease Patients Be Extrapolated to Stroke Patients? Question 6
47 Which Patients Are Candidates for a Combination Therapy with
Clopidogrel and Aspirin in the Meantime? Question 7
47 Which Role Do Glycoprotein IIb/IIIa Inhibitors Play? Question 8
47 Which Combination Is the Best Antiplatelet Therapy? Question 9
47 Are There Any New Developments of Antiplatelet Agents?
ABC
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Question 1
Which Role Do Antiplatelet Agents Play in the Primary Prevention of Stroke?
In contrast to its efficacy in preventing myocardial infarction, aspirin failed to prove effective in the primary prevention of ischaemic stroke. Even in patients with asymptomatic stenosis of the carotid bifurcation, aspirin did not show any benefit in reducing myocardial infarction or stroke compared to placebo [1]. However, only few patients participated in this trial. Other antiplatelet agents have not been tested in the primary prophylaxis of stroke. In conclusion, if looking at stroke prophylaxis, there is no proven primary prophylaxis with an antiplatelet agent. However, when looking at the individual patient’s risk of myocardial infarction, antiplatelet agents are useful. Reference 1 Côté R, Battista R, Abrahamowicz M, Langlois Y, Bourque F, Mackey A: Lack of effect of aspirin in asymptomatic patients with carotid bruit and substantial carotid narrowing. Ann Intern Med 1995;123:649–655.
Question 2
What Are the Benefits of ADP Receptor Antagonists Compared to Aspirin?
In 2000, the Cochrane Stroke Group published a systematic review of all unconfounded, randomized comparisons of an ADP-receptor antagonist versus aspirin [1]. This meta-analysis included four trials that had enrolled over 22,000 high-risk patients with a history of vascular disease, including 9,840 with cerebrovascular disease. Overall, the meta-analysis showed that ADP-receptor antagonist therapy was superior to aspirin, reducing the odds of a serious vascular event (all-cause stroke, myocardial infarction or vascular death) by 9% (2p = 0.01). Compared with aspirin, ADP-receptor antagonist treatment had a consistent, beneficial effect on a range of secondary outcomes, with a significant reduction in all-cause stroke (odds ratio [OR] = 0.88, 95% CI 0.79–0.98), and a trend towards significant reduction in ischaemic stroke/stroke
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Cerebrovasc Dis 2003;15(suppl 2):43–48
of unknown aetiology (OR = 0.90, 95% CI 0.81–1.01), MI (OR = 0.88, 95% CI 0.76–1.01), vascular death/death of unknown cause (OR = 0.93, 95% CI 0.82–1.06), and allcause mortality (OR = 0.95, 95% CI 0.85–1.05) [1]. More recently, the Antithrombotic Trialists’ Collaboration have also given an overview of data with ADP-receptor antagonists versus aspirin, reporting an odds reduction of 10% (B4%) in favour of clopidogrel for the composite of allcause stroke, MI or vascular death (p = 0.03) [2]. This is consistent with the odds reduction of 12% (B7%) for the same endpoint obtained from pooled data of four trials of ticlopidine versus aspirin in patient populations with different manifestations of atherothrombosis [2]. In the CAPRIE trial, the ADP receptor antagonist clopidogrel showed a slight but significant superiority over aspirin in the prevention of ischaemic stroke, myocardial infarction and vascular death in patients with symptomatic atherosclerosis [3]. Further analysis showed that clopidogrel also reduces the number of rehospitalisations due to ischaemic or bleeding events. The annual event rates for hospitalisation for ischaemia or bleeding were 8.85% with aspirin and 8.03% with clopidogrel (relative risk reduction 9.1%; p = 0.018) [4]. Other analyses showed further evidence that the benefit of clopidogrel is amplified in patients with additional risk factors for atherothrombotic events. CAPRIE patients with diabetes, hypercholesterolaemia, previous acute events (like ischaemic stroke or myocardial infarction) or previous cardiac bypass surgery had higher recurrence rates than patients without these risk factors. In this high-risk patient group, clopidogrel showed a better effect compared to aspirin than in the overall CAPRIE population [5–8]. Another potentially positive feature of clopidogrel is the lack of interaction between ADP receptor antagonists and ACE inhibitors. Concomitant prescription of antiplatelet agents and ACE inhibitors is common in postmyocardial infarction patients. Recent post-hoc analyses have suggested that the beneficial effect of ACE inhibitors is diminished by concomitant use of aspirin in these patients [9]. The mechanism for the interaction between these two drugs is attributed to the inhibitory effect aspirin exerts on the prostaglandin synthesis, which is not the case with ADP receptor antagonists. Consequently the subgroup of CAPRIE patients treated with aspirin in
Ringleb/Hacke
combination with an ACE inhibitor was more likely to have hypertension as an adverse event than the patients treated with clopidogrel and an ACE inhibitor. By contrast, no such difference existed for aspirin versus clopidogrel in patients not taking ACE inhibitors [10]. References 1 Hankey GJ, Sudlow CLM, Dunbabin DW: Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials. Stroke 2000;31:1779–1784. 2 Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. 3 CAPRIE Steering Committee: A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339. 4 Bhatt DL, Hirsch AT, Ringleb PA, Hacke W, Topol EJ: Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Am Heart J 2000; 140:67–73. 5 Hacke W, Hirsch AT, Topol EJ: The benefit of clopidogrel over aspirin is amplified in high-risk subgroups with a prior history of ischaemic events (abstract). Eur Heart J 1999;20(suppl):666. 6 Bhatt DL, Hirsch AT, Chew DP, Ringleb P, Hacke W, Topol EJ: Marked superiority of clopidogrel versus aspirin in patients with a history of previous cardiac surgery. J Am Coll Cardiol 2000;35(suppl A):383. 7 Bhatt DL, Foody JM, Hirsch AT, Ringleb P, Hacke W, Topol EJ: Complementary, additive benefit of clopidogrel and lipid-lowering therapy in patients with atherosclerosis. J Am Coll Cardiol 2000;35(suppl A):326. 8 Bhatt DL, Marso SP, Hirsch AT, Ringleb P, Hacke W, Topol EJ: Superiority of clopidogrel versus aspirin in patients with a history of diabetes mellitus. J Am Coll Cardiol 2000;35(suppl A):409. 9 Nguyen K, Aursnes I, Kjekshus J: Interaction between enalapril and aspirin on mortality after acute myocardial infarction: Subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSU II). Am J Cardiol 1997;79:115–119. 10 Havranek E, Weinberger J: Concomitant use of ACE Inhibitors and antiplatelet therapies: Clopidogrel versus aspirin; in Anonymous. A Collection of Scientific Abstracts and Posters Presented at International Scientific Congresses in 1999. Sanofi-Synthelabo and Bristol-Myers Squibb, 1999, pp 22–23.
Question 3
Is the Combination of ADP Receptor Antagonist and Aspirin Wise?
Since aspirin and ADP receptor antagonists affect platelet function by different mechanisms that block separate pathways (see fig. 1), using a combination to increase antiplatelet efficacy appears logical, provided that bleeding complications are not diminishing this presumed positive effect. When given to patients undergoing coronary stenting for several weeks, the combination of ticlopidine and aspirin is superior to heparin, warfarin and aspirin alone in preventing vascular events [1]. Several randomized trials demonstrated a more favourable safety profile with the concomitant use of clopidogrel and aspirin compared with the combination of ticlopidine and aspirin [2–4]. Two randomized, placebo-controlled trials (CURE and CREDO) have recently demonstrated that clopidogrel, when initiated with a 300-mg loading dose and continued long-term in addition to aspirin, provided significant, incremental early and sustained benefits in patients with acute coronary syndrome (with non-ST-elevation) and in patients after percutaneous coronary intervention [5, 6]. The rapid emergence of the benefit of clopidogrel observed in CURE and CREDO correlates with ex vivo human model data, which showed a significant antithrombotic effect of a clopidogrel loading-dose within a few hours of administration [7]. In 2004, the ongoing MATCH trial will provide evidence on whether the use of clopidogrel and aspirin is also beneficial in cerebrovascular patients. MATCH has re-
Fig. 1. Synergistic effect of aspirin and clopidogrel [modified from Schafer A: Antiplatelet therapy. Am J Med 1996;101:199–209].
Antiplatelet Therapy in Stroke Prevention
Cerebrovasc Dis 2003;15(suppl 2):43–48
45
cruited 7,601 patients with recent ischaemic stroke or TIA who are at higher risk of further ischaemic events, and who are being treated and followed for 18 months [8]. The ongoing CHARISMA trial will provide further evidence on the use of clopidogrel plus aspirin versus aspirin monotherapy in about 15,000 high-risk atherothrombotic patients, including patients with a history of cerebrovascular events [8].
for patients at high risk of stroke. Because of the vasodilatory effect of dipyridamole, headache is the most common side-effect: 7–8% of patients taking dipyridamole ceased their study medication due to headache (compared to 2% of the patients taking aspirin). Fortunately, it appears that a tolerance towards this particular side-effect develops quickly [3]. Concerning risks, the combination of dipyridamole and aspirin doubles the bleeding risk compared to placebo (8.7 vs. 4.5%, p ! 0.001).
References 1 Schöming A, Neumann F-J, Kastrati A, Schulen H, Blasini R, Hadamitzky M, Walter H, Zitzmann-Roth E, Richardt G, Alt E, Schmitt C, Ulm K: A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–1089. 2 Betrand M, Rupprecht H-J, Urban P, Gerschlick A, et al: Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624–629. 3 Müller C, Büttner HJ, Petersen J, Roskamm H: A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000;101:590–593. 4 Taniuchi M, Kurz HI, Lasala JM: Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. Circulation 2001;104:539–543. 5 The Clopidogrel in Unstable angina to prevent Recurrent Events trial investigators: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 6 Steinhubl SR, Berger PB, Mann JT III, Fry ETA, DeLago A, Wilmer C, Topol EJ, for the CREDO Investigators: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA 2002;288:2411–2420. 7 Cadroy Y, Bossavy J-P, Thalamas C, Sagnard L, Sakariassen K, Boneu B: Early potent antithrombotic effect of combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000;101:2823–2828. 8 Bhatt DL, Topol EJ: Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003;2:15–28.
Question 4
What Are the Benefits of the Combination of Dipyridamole and ASS?
According to the Antiplatelet Trialists’ overview, the addition of dipyridamole to aspirin in around 5,000 highrisk patients did not seem to reduce risk of further ischaemic events. The data from the large-scale European Stroke Prevention study [1] show that the combination of dipyridamole and aspirin is associated with a non-significant reduction of 10% (95% CI 0–20%) in the odds of a vascular event [2]. Most of this effect is attributable to a 23% reduction in non-fatal strokes, suggesting that the addition of this substance to aspirin may be appropriate
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References 1 Ferguson JJ: Second European Stroke Prevention Study. Circulation 1996; 93:399. 2 Wilterdink J, Easton J: Dipyridamole plus aspirin in cerebrovascular disease. Arch Neurol 1999;56:1087–1092. 3 Theis JG, Deichsel G, Marshall S: Rapid development of tolerance to dipyridamole-associated headaches. Br J Clin Pharmacol 1999;48:750–755.
Question 5
Can Results with Antiplatelet Therapy in Coronary Artery Disease Patients Be Extrapolated to Stroke Patients?
Cardiovascular and cerebrovascular patients are both at risk of further ischaemic events in different vascular territories, but these patient types differ in some important aspects. Numerous studies have demonstrated that patients who suffer a stroke or TIA are more likely to have a subsequent cerebral ischaemic event than a cardiovascular event in the short term [1]. Bleeding complications of antithrombotic therapy may also differ between cerebrovascular patients and patients in whom other vascular territories are involved. Potential explanations for higher bleeding rates observed in stroke patients might be their older age, comorbidities, and underlying ischaemic brain damage. Hence it is difficult to extrapolate the bleeding risk from cardiac to cerebrovascular patients. Given these differences, results with antiplatelet therapy in coronary artery disease patients can not be extrapolated to stroke patients, or only with great caution. Reference 1
Hankey GJ: Long-term outcome after ischaemic stroke/transient ischaemic attack. Cerebrovasc Dis 2003;16(suppl 1):14–19.
Ringleb/Hacke
Question 6
Which Patients Are Candidates for a Combination Therapy with Clopidogrel and Aspirin in the Meantime?
This combination may be useful for cerebrovascular patients who have a history of recent cardiac ischaemia and appear to be at low risk for haemorrhagic complications. Patients who suffer recurrent stroke while on another antiplatelet therapy may be appropriate candidates. In addition, patients with complex aortic arch atherosclerosis may be candidates because of their high risk of both cardiac and cerebral vascular events despite conventional therapy.
Question 7
Which Role Do Glycoprotein IIb/IIIa Inhibitors Play?
Glycoprotein IIb/IIIa inhibitors block the final pathway for platelet aggregation. The intravenous application of GPIIb/IIIa inhibitors has been shown to reduce mortality and morbidity in acute coronary syndromes and during percutaneous coronary interventions. In the Abciximab in Ischemic Stroke trial [1], the safety of abciximab administered up to 24 h after ischaemic stroke was demonstrated. A large-scaled phase III study with this agent will be finished in the near future. The results of the large-scale trials for the use of oral GP IIb/IIIa inhibitors in cardiac patients demonstrated an increased bleeding risk compared to aspirin. A pooled analysis of these trials showed that the three agents assessed produced a significant 37% increase in mortality in treated patients [2]. The BRAVO trial, evaluating the oral GP IIb/IIIa antagonist lotrafiban in combination with aspirin versus aspirin in patients with TIA, stroke, myocardial infarction, unstable angina, or peripheral vascular disease was stopped because of an increased bleeding risk [3]. In conclusion, intravenous GP IIb/IIIa inhibitors have their role in the per-acute phase of ischaemic stroke, but neither the intravenous nor the oral preparation should be used for secondary prevention. References 1 Abciximab in Ischemic Stroke Investigators: Abciximab in acute ischemic stroke: A randomized, double-blind, placebo controlled, dose-escalation study. Stroke 2000;31:601–609.
Antiplatelet Therapy in Stroke Prevention
2 Chew D, Bhatt D, Topol E: Increased mortality with oral glycoprotein IIb/ IIIa antagonists: A pooled analysis of the large scale oral glycoprotein IIb/ IIIa trials. J Am Coll Cardiol 2000;35(suppl A):393. 3 Topol E, Easton J, Amarenco P, Califf R, Harrington R, Graffagnino C, Davis S, Diener H, Ferguson J, Fitzgerald D, Shuaib A, Koudstaal P, Theroux P, Van de Werf F, Willerson J, Chan R, Samuels R, Ilson B, Granett J: Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. Am Heart J 2000;139:927–933.
Question 8
Which Combination Is the Best Antiplatelet Therapy?
At the present time aspirin, dipyridamole, ticlopidine and clopidogrel are available in several countries. If single antiplatelet therapy fails or a high risk for stroke recurrence is presumed, combination of aspirin with one of the other agents may be appropriate (see question 5). The combination of aspirin and ticlopidine should not be started any more because of a higher risk for haematological complications due to ticlopidine. No trial has been performed to compare the efficacy of dipyridamole versus clopidogrel in combination with aspirin. Thus no clear recommendation for one of these combinations can be given. In cases where a combination of two antiplatelet drugs seems to be superior compared with monotherapy, the decision could be influenced by licensing approvals or economic aspects.
Question 9
Are There Any New Developments of Antiplatelet Agents?
ADP is an important agonist for haemostatis and thrombosis, as mentioned above. Its effects are mediated via three types of ADP receptor, P2X1, P2Y1 and P2Y12 (previously known as P2AAC, P2cyc, or P2TAC). Clopidogrel is an antagonist of the P2Y12 rather than the P2Y1 receptor. Specific nucleotide-analogue inhibitors have entered clinical development as antiplatelet agents. ARC69931MX is an intravenously administered, potent inhibitor of ADP-mediated platelet aggregation. This compound has been shown to abolish thrombus-related cyclic flow variations in a dog model of platelet-dependant arterial thrombosis, without prolonging bleeding time, and to inhibit ADP-induced platelet aggregation in pa-
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47
tients with acute coronary syndrome [1]. However, the clinical development of this compound has recently been halted [2]. AZD6140 is an oral P2Y12 receptor antagonist that is currently at an early stage of clinical development [2].
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References 1 Strony J, Beaudoin A, Brands D, Adelman B: Analysis of shear stress and hemodynamic factors in a model of coronary artery stenosis and thrombosis. Am J Physiol 1993;265:H1787–1796. 2 Collins B, Hollidge C: Antithrombotic drug market. Nat Rev Drug Discov 2003;2:11–12.
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Chapter 8 Cerebrovasc Dis 2003;15(suppl 2):49–55 DOI: 10.1159/000069681
Anticoagulant Therapy Angel Chamorro Victor Obach
Question 1
50 What Is the Rationale behind the Use of Anticoagulants in
Primary or Secondary Stroke Prevention? Question 2
50 Which Main Properties of Oral Anticoagulants Are Used in
Clinical Practice? Question 3
51 What Are the Main Interactions of Oral Anticoagulants? Question 4
51 How Should Oral Anticoagulation Be Started and Monitored? Question 5
52 What Is the Therapeutic Range of Oral Anticoagulants? Question 6
53 What Are the Main Risks of Oral Anticoagulants? Question 7
53 How Well Are Physicians Complying with Anticoagulation? Question 8
54 Are There Special Concerns about Anticoagulating Elderly
Patients? Question 9
54 Can Patients with Leukoaraiosis Be Safely Anticoagulated? Question 10
55 How Strong Is the Indication for Anticoagulation in Patients
with Intracranial Atherosclerosis?
ABC
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Question 1
What Is the Rationale behind the Use of Anticoagulants in Primary or Secondary Stroke Prevention?
parenchymal lesions sustain, independently of the cause of stroke, a transient prothrombotic state triggered by the release of cerebral tissue factor [2]. References
Thrombosis reflects an imbalance of the haemostatic system, which is composed of a highly regulated series of procoagulant and anticoagulant zymogens and cofactors. The haemostatic imbalance can develop in arterial or venous circulation as the result of any of the three abnormalities first described by Virchow: stasis, hypercoagulability, and vascular injury. These prothrombotic events can be prevented and treated with a rapidly enlarging number of anticoagulant drugs. Thrombi are composed of assorted proportions of fibrin and blood cells depending on whether they are formed in the arterial or venous circulation. Whereas activation of blood coagulation and platelets is important in the pathogenesis of arterial thrombosis, only the former mechanism is critical in the pathogenesis of venous thrombosis. The lesser role of platelets in the venous circulation could in part explain the clinical superiority shown by anticoagulants over antiplatelet agents in treating or preventing venous thrombosis. By contrast, the more relevant role of platelet activation for the growth and progression of arterial thrombi could explain the more balanced results obtained in clinical trials that compared anticoagulants and antiplatelet drugs randomly allocated to patients with arterial thrombosis [1]. In patients with stroke, coagulation can be initiated by exposure of blood to tissue factor located in the necrotic core of ruptured atherosclerotic plaques, in the subendothelium of injured vessels, in inflamed or damaged cardiac valves, on endocardium adjacent to a region of myocardial infarction, in dilated dyskinetic cardiac chambers, on prosthetic valves, or on the surface of activated leucocytes attracted to damaged vessels. During the acute phase of ischaemic stroke, exposure of flowing blood to the ischaemic brain parenchyma also activates tissue factor, which behaves as a haemostatic envelope around the CNS and is diffusely expressed in astrocytes and arachnoid meningeal cells. As a result, stroke patients with
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1 Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Kistler JP, Albers GW, Pettigrew LC, Adams HP, et al. for the Warfarin-Aspirin Recurrent Stroke Study Group: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444–1451. 2 Chamorro A: Immediate anticoagulation in acute focal brain ischemia revisited: gathering the evidence. Stroke 2001;32:577–578.
Question 2
Which Main Properties of Oral Anticoagulants Are Used in Clinical Practice?
Oral anticoagulants exert their effect in vivo by inhibiting vitamin K epoxide reductase and possibly vitamin K reductase. Both enzymes are required to maintain the cyclic interconversion of vitamin K and its 2,3 epoxide. Vitamin K, in its reduced form, is an essential cofactor for the post-translational gamma-carboxylation of glutamic acid residues in the coagulation factors II, VII, IX and X and proteins C, S and Z during synthesis in the liver. The resultant vitamin K-dependent proteins are undercarboxylated, cannot bind calcium and, therefore, do not participate normally in the assembly of tenase and prothrombinase complexes. Thrombin generation is thus impaired [1]. Oral anticoagulants are rapidly absorbed by the gastrointestinal tract and eliminated almost entirely by the liver. Oral anticoagulants are bound to plasma proteins in 697%, explaining their frequent interactions with other drugs. Oral anticoagulants or vitamin K antagonists currently used are monocoumarols. Among them, warfarin is used in Anglo-American countries and Asia, whereas phenprocoumon is preferred in Germany, Switzerland and the Netherlands. Acenocoumarol is particularly used in Italy and Spain. The different half-lives of anticoagulants have various consequences for clinical practice. Acenocoumarol has a
Chamorro/Obach
short half-life of 9 h, it is administered once daily although it remains controversial whether it should be given twice daily. Warfarin and phenprocoumon have half-lives of 30–40 h and 90–140 h, respectively, and require long periods until stable levels are reached and still have an effect for a long time after termination of treatment [2]. Interindividual variation in dose response is determined by race and genetic factors such as the hepatic cytochrome P-450 polymorphism. Intra-individual variation occurs as a result of changes in diet, intercurrent illness and concurrent drug therapy. References 1 Hirsh J: Oral anticoagulant drugs. N Engl J Med 1991;324:1865–1875. 2 Harder S, Thurmann P: Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet 1996;30:416–444.
Question 3
What Are the Main Interactions of Oral Anticoagulants?
Nutritional factors, many pharmacological compounds and herbal products (table 1) may modify the pharmacokinetics and pharmacodynamics of oral anticoagulants. Interactions include reduction of the intestinal resorption, displacement from plasma protein binding sites, interference with metabolic degradation, inhibition of the synthesis of vitamin K-dependent coagulation factors and interference with other haemostatic pathways, respectively [1]. A useful recommendation is that patients should get their international normalised ratio (INR) checked 1 week after administration of a new drug or termination of any medication with a known interaction with the oral anticoagulant regime. Intake of foods with high vitamin K content, such as green vegetables, should be kept as uniform as possible to avoid fluctations of dietary vitamin K levels. Patients should also mention any dietary changes that have occurred recently. Healthcare professionals should ask their patients about the use of herbal products and consider the possibility of herb-drug interactions [2]. References 1 Harder S, Thurmann P: Anticoagulants: Clinically important drug interactions. Clin Pharmacokinet 1996;30:416–444. 2 Manotti C, Quintavalla R, Pattacini C, Pini M: Seasonal variation of oral anticoagulant effect. Thromb Haemost 1994;71:802–803.
Anticoagulant Therapy
Table 1. Drugs that may decrease or increase the effects of oral anti-
coagulants Decreased anticoagulation (lower INR) Antiacids Antiepileptics: barbiturates, carbamazepine Antihistamines Antithyroid drugs Cholestyramine Garlic Ginseng Griseofulvin Penicillins Rifampicin St John’s wort Vitamin K Increased anticoagulation (higher INR) Alcohol Allopurinol Amiodarone Anabolic steroids Antibiotics: trimethoprim-sulphamethoxazole, amoxicilin plus clavulanic acid, erytromycin, metronidazole, quinolones, isoniazid, cephalosporin, carbenicillin and high dose penicillins Antifungal (imidazolic group): Ketoconazole, fluconazole Analgesic and anti-inflammatory drugs: aspirin, phenybutazone Cimetidine Clofibrate Disulfiram Ginkgo Heparin Nonsteroidal anti-inflammatory Omeprazole Phenytoin Quinine salts Statines (HMG-CoA reductase inhibitors) Sulfinpyrazone Thyroxine
Question 4
How Should Oral Anticoagulation Be Started and Monitored?
Following the administration of warfarin, acenocoumarol and phenprocoumarol, an observable anticoagulant effect, depending on the dose administrated, occurs within 3–7 days, 2–3 days and 7–14 days, respectively. When a rapid effect is required, heparin should be given concurrently with the oral anticoagulant drug for at least 4 days, 2 days and 10 days, respectively. Heparin is usually discontinued when the INR has been within the thera-
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peutic range on two measurements performed at least 24 h apart. The common practice of initiating warfarin therapy with a loading dose is unnecessary in most patients, and starting with a dose of 5 mg/day usually results in an INR of 2.0 in 4 or 5 days. Acenocoumarol is started at 4 mg/day for 2 days and INR is determined the third day to adjust the subsequent doses. Phencoumarol requires a loading dose of 9 mg on day 1 and 6 mg on day 2. At the beginning of oral anticoagulation, the rapid decrease of factor VII (half-life 6 h) causes the fastest alteration in coagulation tests (INR). However, reaching a therapeutic INR does not mean that all other vitamin Kdependent coagulation factors, such as prothrombin (halflife 50 h), have already reached low levels of functional activity. Protein C also has a short half-life (6 h) and can be strongly reduced, whereas other coagulation factors still circulate at high levels. This can lead to a transient procoagulant imbalance, particularly in patients with acquired or inborn deficiency of protein C or protein S. The fear of creating a hypercoagulable state in patients with unrecognised protein C deficiency who are not simultaneously receiving heparin has not been substantiated. However, in patients with known protein C deficiency or other thrombophilic state, it would be prudent to begin the administration of heparin before or at the same time as oral anticoagulants [1]. The response to oral anticoagulants differs from patient to patient, thus anticoagulant activity and dosage must be closely monitored. INR is a recommended method for reporting anticoagulant activity and has replaced the non-standardised prothrombin time and quick tests for the management of anticoagulant activity. The INR is the local observed prothrombin ratio raised to the power of C, where C represents the International Sensitivity Index (ISI) that indicates the relation between the sensitivity of the thromboplastin of the local laboratory and the international reference thromboplastin. The INR allows to anticoagulate patients within a target INR interval independent of the local reagents used. INR monitoring is usually performed daily until the therapeutic range has been reached and maintained for at least 2 consecutive days, then it is monitored 2–3 times weekly for 1–2 weeks. If the INR remains stable, the frequency of testing can be reduced to intervals as long as 4 weeks. In over-anticoagulated patients, oral low-dose vitamin K (1 mg) was shown to rapidly lower raised INR and to reduce bleeding episodes in combination with a temporary withdrawal of anticoagulants. For urgent normalisation
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of coagulation, intravenous administration of coagulation factors II, VII, IX and X (fresh-frozen plasma or prothrombin complex concentrates or PPSB complex) and 0.5–1 mg of vitamin K is required for acenocoumarol and warfarin. Patients treated with phenocoumarol require higher doses of vitamin K (1–5 mg) [2]. Conversely, when an invasive procedure is planned, oral anticoagulants should be switched to full dose of standard unfractionated heparin. The use of low-molecularweight heparin offers a possible alternative of treatment but its efficacy has to be proven. Acenocoumarol, warfarin and phenocoumarol need a wearing-off time of 2, 4 and 10 days, respectively. These intervals can be shortened by the administration of vitamin K 24–48 h prior to the procedure. Caution should be taken to avoid a procoagulant state. References 1 Ansell J, Hirsh J, Dalen J, Bussey H, Anderson D, Poller L, Jacobson A, Deykin D, Matchar D: Managing oral anticoagulant therapy. Chest 2001; 119(suppl 1):S22–S38. 2 Makris M: The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol 2001;114:271–280.
Question 5
What Is the Therapeutic Range of Oral Anticoagulants?
The optimal therapeutic range of oral anticoagulant therapy should balance the risks of thrombus formation and cerebral or systemic bleeding in each individual subject. The large European Stroke Prevention in Reversible Ischemia Trial (SPIRIT) compared oral anticoagulation (target INR 3.0–4.5) to aspirin in patients with non-cardioembolic stroke. SPIRIT found an excessive risk of brain haemorrhage in anticoagulated patients [1]. In the Warfarin-Aspirin Recurrent Stroke Study (WARSS), the target INR of 1.4–2.8 was as safe as with aspirin (325 mg/day), although no benefit of oral anticoagulation was found [2]. The European-Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) is still evaluating the benefit of oral anticoagulation (target INR 2.0–3.0) over aspirin alone or in combination with dypiridamole in patients with non-cardioembolic stroke [3]. Several trials of patients with atrial fibrillation revealed that an INR 61.6 offered substantial protection against ischaemic stroke. The effect became maximal
Chamorro/Obach
when the INR exceeded 2.0, non-acceptable risks of major haemorrhage were found when INR was above 4.0. In clinical practice two different levels of intensity of anticoagulation are empirically recommended: a low INR target of 2.0–3.0 for the majority of patients requiring chronic oral anticoagulation, and a high INR target of 2.5–3.5 for patients with mechanical prosthetic heart valves as well as for stroke recurrence despite adequate compliance with a low INR target [4, 5]. References 1 The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study group: A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857–865. 2 Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Kistler JP, Albers GW, Pettigrew LC, Adams HP, et al, for the Warfarin-Aspirin Recurrent Stroke Study Group: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444–1451. 3 DeSchryver ELLM, on behalf of the European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) Group: Design of ESPRIT: an international randomized trial for secondary prevention after non-disabling cerebral ischaemia of arterial origin. Cerebrovasc Dis 2000; 10:147–150. 4 Albers GW, Amarenco P, Easton JD, Sacco R, Teal P: Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001;119(suppl 1):S300– 320S. 5 Hart R: Oral anticoagulants for secondary prevention of stroke. Cerebrovasc Dis 1997;7(suppl 6):24–29.
Question 6
What Are the Main Risks of Oral Anticoagulants?
Oral anticoagulants cross the placenta and teratogenic effects can be seen, especially during the first trimester of pregnancy. Safe contraception is required during anticoagulation. If pregnancy is planned, therapy should be switched to heparin in good time. Other side effects are hypersensitivity reactions, alopecia, increased transaminases and skin necrosis. Anticoagulant skin necrosis is an uncommon complication with a prevalence of 0.001–0.1% of all treated patients and occurs between the 3rd and 8th day after initiation of therapy. It is caused by extensive thrombosis of the venules and capillaries within the subcutaneous fat. Painful confluent skin haemorrhages rapidly develop, followed by skin necrosis within 1–2 weeks. Associations between anticoagulant-induced skin necrosis and protein C or S deficiencies have been reported but this complication also occurs in patients with no such deficiency. The occurrence of coumarin necrosis has been reported at initiation of oral anticoagulation with high loading doses. Combined treatment with heparin while oral anticoagulant is started may be required for patients with a known deficiency of these proteins. If this complication is suspected therapy should rapidly be switched to heparin. There are reports suggesting that skin necrosis due to warfarin may be the result of heparin-induced thrombocytopenia and thrombosis. References 1 Torn M, Algra A, Rosendall FR: Oral anticoagulation for cerebral ischemia of arterial origin. High bleeding risk. Neurology 2001;57:1993–1999. 2 The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study group: A randomised trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857–865.
Bleeding is the main complication of oral anticoagulant therapy. It occurs more frequently in the first months of treatment and is strongly related to age, hypertension (especially high systolic blood pressure), and intensity of anticoagulation. The annual rate of major bleeding and intracranial haemorrhage is 2–4% and 0.25–0.6%, respectively. Contraindications against oral anticoagulants include diseases with increased bleeding tendency such as active peptic ulcer, alcoholism, coagulopathy, occult bleeding, gait instability and falls, uncontrolled seizures, severe hepatic or renal diseases, severe hypertension and poor patient compliance to treatment and INR monitoring. Procedures such as lumbar puncture, intramuscular injections, operation or arterial catheterism are contraindicated under therapy with oral anticoagulants. Bleeding when INR is !3.0 is frequently associated with an obvious underlying cause or an occult gastrointestinal tumour [1, 2].
Randomised clinical trials have led to evidence-based guidelines for anticoagulation in several clinical conditions that can lead to first stroke (primary prevention) or recurrent stroke (secondary prevention) [1]. However, there is concern that anticoagulation is underused and that these guidelines are not being adequately implemented in clinical practice. Nevertheless, there are some indications that this tendency may be changing. Using data collected from the early to mid-1990s, several observational studies have suggested that warfarin therapy for primary prevention has been substantially
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Question 7
How Well Are Physicians Complying with Anticoagulation?
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underused in eligible atrial fibrillation patients, particularly among the elderly. In some studies, only about 20% of these patients were being anticoagulated. Even physicians with good experience and favourable opinions did not prescribe warfarin to half of their patients for whom warfarin was independently judged appropriate. This pattern of care has been documented among patients residing in the long-term care setting, in teaching and community hospital patients, and among community-dwelling outpatients. Whereas in some studies daily use of aspirin did not increase over time, the use of warfarin increased 4-fold from 13% in 1990 to 50% in 1996 among patients with prevalent atrial fibrillation. Subjects younger than 80 years were 4 times more likely to use warfarin in 1996 than those 80 years and older. In other studies, suboptimal use of anticoagulation was particularly suboptimal in patients 180 years old attended by primary care physicians. Underuse of anticoagulation in older patients is particularly annoying as this age group is at greater risk of first or recurrent stroke [2]. References 1 Perez I, Melbourn A, Kalra L: Appropriateness of antithrombotic measures for stroke prevention in atrial fibrillation. Heart 1999;82:570–574. 2 Smith NL, Psaty BM, Furberg CD, White R, Lima JAC, Newman AB, Manolio TA: Temporal trends in the use of anticoagulants among older adults with atrial fibrillation. Arch Intern Med 1999;159:1574–1578.
Question 8
Are There Special Concerns about Anticoagulating Elderly Patients?
175 years and with a high embolic risk should be targeted to achieve lower INR values (INR 1.6–2.5). However, it is uncertain whether this is of any clinical value [2]. Non-rheumatic atrial fibrillation justifies most instances of oral anticoagulation for primary or secondary stroke prevention in the elderly. However, stroke in these patients can occur for a variety of reasons and is not exclusively due to cardiogenic emboli. Older subjects have a higher prevalence of atrial fibrillation but increasing age has also been associated with a higher prevalence of smallvessel disease. Some studies have shown that a significant proportion of recurrent strokes in anticoagulated patients is due to small vessel disease. Further, anticoagulation not only may fail to prevent stroke recurrence but it may even increase the risk of intracranial haemorrhage in these patients. Therefore individual decisions will establish whether antiaggregants or oral anticoagulants should be used as the first therapeutic option in asymptomatic patients with non-rheumatic atrial fibrillation and neuroimaging studies disclosing signs of small vessel disease. For secondary stroke prevention it should be taken into consideration whether the previous stroke suggested embolism or symptomatic small vessel disease. While in the former case warfarin would be indicated, in the latter an antiplatelet agent would probably be the best option. Influenza vaccination is safe in patients on oral anticoagulants. However, in patients older than 70 years, vaccination may be followed by a reduction of anticoagulation intensity and a prolonged time below the therapeutic range. This can persist for 3 months after vaccination, suggesting the need for more frequent INR monitoring after vaccination in the elderly. References
When administering oral anticoagulants to the elderly, one should take into consideration the special circumstances that may concern this age group, e.g. hypersensitivity to these agents, which translates into the need of lower dosages compared to younger patients. In most studies, the risk of bleeding complications associated with the use of anticoagulant drugs was higher in older individuals (subjects aged 165 years) than in younger patients. In this age group, the absolute rate of intracranial haemorrhage ranged between 0.3 and 1% a year. The mortality of oral anticoagulation-associated intracerebral haemorrhage is approximately 60% (range 46–68%) [1]. Thus, although older age is not an absolute contraindication for anticoagulation, the risk-benefit ratio of this treatment modality should be carefully assessed. It has been suggested that individuals aged
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1 The Stroke Prevention in Atrial Fibrillation Investigators: Bleeding during antithrombotic therapy in patients with nonrheumatic atrial fibrillation. Arch Int Med 1996;156:409–416. 2 Hylek EM, Skates SJ, Sheehan MA, Singer DE: An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540–546.
Question 9
Can Patients with Leukoaraiosis Be Safely Anticoagulated?
Leukoaraiosis is a radiological term that describes the appearances of patchy or diffuse abnormalities in deep white matter, emerging as low-attenuation areas on CT scan or hyperintense signals on T2-weigthed MRI se-
Chamorro/Obach
quences. Leukoaraiosis is more frequent in the elderly and in patients with elevated arterial blood pressure or with a history of hypertension. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) compared the efficacy and safety of 30 mg aspirin daily and oral anticoagulation (INR 3.0–4.5) in patients with stroke associated with arterial disease. The trial was stopped at the first interim analysis because an excess incidence of major bleeding (7% per year) was found in patients treated with oral anticoagulation. In this study, leukoaraiosis (hazard ratio 2.7, 95% CI 1.4–5.3) and age older than 65 years (hazard ratio 1.9, 95% CI 1.0–3.4) were independent predictors of all anticoagulation-related haemorrhages. The incidence of intracranial bleeding was 3.7% per year; this incidence increased by a factor of 1.37 for each 0.5 INR unit [1]. Patients with cerebral ischaemia of presumed arterial origin had a 19 times (95% CI 2.4–150) higher risk of intracranial haemorrhages than those with atrial fibrillation. The effect of leukoaraiosis on the risk of intracranial bleeding remained essentially the same in a multivariate analysis after simultaneous adjustment for age (165 years), history of hypertension, baseline systolic blood pressure 1180 mm Hg, and diastolic blood pressure 1100 mm Hg. The adjusted hazard ratio of patients with leukoaraiosis was 6.0 (95% CI 2.6–14) for intracranial bleeding. Patients with severe leukoaraiosis have an approximately 2.5-fold higher risk for intracranial bleeding complications than those with moderate leukoaraiosis. By contrast, patients with a lacunar infarct on the baseline CT did not have an increased risk for intracranial bleeding complications. Based on these findings some authors believe that patients whose baseline CT shows leukoaraiosis should preferably not be treated with anticoagulants [2]. Ongoing studies will establish the value of gradientecho MRI sequences to select the best candidates for chronic anticoagulation when conventional MRI discloses signs of leukoaraiosis. It is speculated that this highly sensitive technique for the detection of microbleeds
could be used to prescribe chronic anticoagulation only to those patients with leukoaraiosis in whom microbleeds are not discovered.
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References 1 The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) study group: A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857–865. 2 Gorter JW: Major bleeding during anticoagulation after cerebral ischemia patterns and risk factors. Stroke Prevention in Reversible Ischemia Trial (SPIRIT) and European Atrial Fibrillation Trial (EAFT) study groups. Neurology 1999;53:1319–1327.
Question 10
How Strong Is the Indication for Anticoagulation in Patients with Intracranial Atherosclerosis?
Recent series of consecutive patients have identified symptomatic intracranial atherosclerosis as the most likely aetiology of stroke in 8% of consecutive ischaemic stroke patients [1]. Retrospective studies indicate a possible superiority of warfarin over aspirin for prevention of stroke in patients with symptomatic intracranial stenosis, and this assumption is currently being tested in the Warfarin versus Aspirin for Symptomatic Intracranial Disease trial [2]. Meanwhile, the optimal treatment for patients with symptomatic intracranial atherosclerosis is unknown, as no randomised trial has convincingly demonstrated the superiority of any specific antithrombotic agent in preventing recurrent cerebral ischaemic events. References 1 Sacco RL, Kargman DE, Gu Q, Zamanillo MC: Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995;26:14–20. 2 Chimowitz MI, Kokkinos J, Strong J, et al: The Warfarin-Aspirin Symptomatic Intracranial Disease Study. Neurology 1995;45:1488–1493.
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Chapter 9 Cerebrovasc Dis 2003;15(suppl 2):57–61 DOI: 10.1159/000069682
Stroke Prevention in Carotid Stenosis Markku Kaste
Question 1
58 When Is Carotid Endarterectomy Indicated? Question 2
58 Which Type of Preoperative Evaluation Should Be Carried Out? Question 3
58 Which Patients Should Be Evaluated? Question 4
59 When Is Carotid Endarterectomy Justified? Question 5
60 Is Surgery Justified in Asymptomatic Patients with Carotid
Stenosis? Question 6
60 Who Should Perform the Carotid Endarterectomy? Question 7
60 Could Angioplasty and Stenting Replace Carotid
Endarterectomy? Question 8
61 Could Extracranial-Intracranial Bypass Surgery Be an
Alternative for Carotid Endarterectomy?
ABC
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Question 1
Question 2
When Is Carotid Endarterectomy Indicated?
Carotid endarterectomy (CE) for ipsilateral tight carotid stenosis (70% or more) in a symptomatic patient is highly beneficial in the hands of a surgeon with a perioperative mortality and morbidity as low as in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST). The natural course of this disease without surgery, even with the best medical therapy, is bad, and the more risk factors for stroke a patient has the worse the potential outcome without CE. CE should be considered when (1) it is likely that the symptoms of the patient, whether TIA or minor stroke, are caused by embolization from the detected ipsilateral carotid stenosis and not from other sources, e.g. from the heart; (2) the stenosis is severe (670%); (3) the patient is a good candidate for surgery, i.e. can be operated on without major risks and has a reasonable life expectancy, and (4) the surgeon has a low perioperative mortality and morbidity (less than 6%). One should also remember that patients with less severe stenosis have a lower risk of stroke, and their gains from surgery are smaller compared to patients with a more severe stenosis. This is even more important to keep in mind in patients with asymptomatic stenosis. If such patients are operated on, the surgeon has to be able to perform CE with an exceptionally low complication rate. The perioperative mortality and morbidity must be less than 2.3%. In NASCET there was a 17% absolute risk reduction, which means that 6 CEs needed to be performed in order to prevent 1 ipsilateral stroke over the following 2 years. The benefits from surgery were somewhat lower in ECST but the differences between NASCET and ECST may be explained by differences in the trial design. The more severe the symptomatic stenosis is, the more beneficial the CE. During a 2-year follow up after surgery in NASCET, the absolute risk reduction favouring surgery was 26% for patients with 90–99% stenosis, 18% for those with 80–89% stenosis, and 12% for those with 70–79% stenosis.
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Which Type of Preoperative Evaluation Should Be Carried Out?
Standard angiography is the gold standard when one has to decide whether or not surgery is appropriate for a patient. Digital subtraction angiography is the method of choice because it was used for patient selection in two studies that verified the appropriateness of CE in symptomatic patients. The results of these trials can only be applied to clinical practice when the same methodology is used in patient selection. Magnetic resonance angiography (MRA) does not yet have the spatial resolution, selectivity, or dynamic character of conventional angiography. However, the use of Doppler and MRA have replaced conventional angiography in many hospitals even though this may be premature. These non-invasive methods should not lead to the elimination of conventional angiography in any patients other than in those where there is good concordance between Doppler and MRA.
Question 3
Which Patients Should Be Evaluated?
Hemispheric TIAs or Mild Hemispheric Strokes CE is a prophylactic operation. Restoration of the blood flow has not been shown to improve a persistent neurologic deficit. CE is not indicated in patients who have suffered severe, permanent damage in that hemisphere. Patients with persistent severe deficits are not candidates for CE even when the non-invasive evaluation of ipsilateral carotid bifurcation has revealed tight stenosis. For this reason CE is only indicated in patients without substantial neurologic deficits, i.e. in patients with TIA or mild completed stroke and with ipsilateral atherosclerotic moderate- or high-grade stenosis localised close to/at the common carotid bifurcation.
Kaste
Asymptomatic Patients The Asymptomatic Carotid Atherosclerosis Study (ACAS) demonstrated a small benefit of CE in patients with asymptomatic carotid stenosis 160%. The benefit was less than 1% per year for a !80% stenosis but 4.8% per year for a 190% stenosis. Fifty patients needed to be operated to prevent 1 stroke in 5 years, and CE had to be performed with a complication rate as low as in ACAS (!2.3%). This implies that there are only a few hospitals with the necessary expertise, and even then surgery is not economically justified. Accordingly, it is not appropriate to screen for such a pathology but in selected patients, such as those with carotid bruits or planned coronary artery bypass surgery. If a stenosis is detected, the examination can be repeated every 6–12 months to determine whether it progresses. Meanwhile all risk factors should be treated appropriately. If the stenosis becomes severe (190%), CE may be contemplated if the patient prefers surgery after the risks and benefits have been explained to him. Question 4
When Is Carotid Endarterectomy Justified?
Thanks to NASCET and ECST we now know the indications for CE in a large proportion of potential candidates for the procedure. Some of the most important criteria are discussed below. Symptomatic Patients Surgery is highly justified in a patient with tight stenosis (170%). The number of patients needed to be operated in order to prevent 1 stroke or stroke death (NNT) is 6. In moderate stenosis (50–69%), NNT is 15. A 30-day rate of surgical death and disabling stroke should not exceed 2% in patients with moderate stenosis, which means that exceptional surgical competence is obligatory for performing CE in this category. The decision to perform CE must take the risk factors into account. Patients with a high risk of stroke during the next 2–3 years (even if treated medically) can be expected to benefit from CE. Male sex, recent stroke or recent hemispheric TIA support surgery. The risk of perioperative stroke or death is increased in patients with diabetes, elevated blood pressure, contralateral occlusion of the carotid artery or lesions present on computed tomography or magnetic resonance imaging ipsilateral to the stenosed artery for which surgery is contemplated. Patients with a stenosis !50% do not benefit from CE.
Stroke Prevention in Carotid Stenosis
Time Window of 4–6 Months after the Ischaemic Event The longest period from the onset of symptoms to CE were 4 and 6 months in NASCET and ECST, respectively. Accordingly, we do not know whether surgery carried out later is beneficial. Medically treated patients free of TIAs for 12–18 months after randomisation in NASCET and ECST had a relatively low risk of brain infarction, which reduces the indication for CE. Age Criteria The risk of stroke increases with age, but age is not a contraindication for CE in symptomatic patients with an ipsilateral high-grade carotid stenosis. NASCET demonstrated that surgery is not only beneficial in younger patients but also in elderly patients up to 80 years of age. Multiple Risk Factors The likelihood of stroke increases with the number of risk factors. In NASCET, the overall risk of stroke was much greater in patients with multiple risk factors than in those with no or only a few. Based on NASCET results, these patients do need surgery. In NASCET, after successful surgery, there was no difference between the cumulative risk after 2 years of ipsilateral stroke in patients with multiple risk factors and in those with no or a few risk factors. Accordingly, those who most benefited from surgery were those at the highest risk. TIA versus Amaurosis fugax Patients with hemispheric TIAs have a higher risk of ipsilateral stroke than patients with amaurosis fugax. The risk of any ipsilateral stroke at 2 years is 44% for patients with hemispheric TIA, while it is 17% for those with amaurosis fugax. When balancing the risks and benefits of CE in an individual patient the symptom type needs appropriate attention. This holds true particularly for patients with a moderate stenosis (50–69%). Occlusion of the Contralateral Carotid Artery Occlusion or tight stenosis of the contralateral carotid artery is often considered a contraindication for CE of symptomatic ipsilateral tight carotid stenosis, but it also means severe outcome without surgery. Thirty-four percent of such individuals have a stroke or die within 2 years without surgery, whereas surgery was equally beneficial in patients with and without contralateral tight stenosis or occlusion at 2 years in NASCET. The situation in patients with moderate stenosis (50–69%) differs. These individuals experience a much better natural course even without
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surgery than those with tight stenosis, but the surgical risk related to the contralateral occlusion remains. In patients with moderate stenosis and contralateral occlusion, CE doubles the operative risks. Concomitant Intracranial Carotid Artery Stenosis Intracranial atherosclerotic disease is an independent risk factor for subsequent stroke in patients with symptomatic internal carotid stenosis. In NASCET, patients who had evidence of concomitant intracranial carotid artery stenosis rather than normal intracranial arteries benefited substantially from surgery. Accordingly, the presence of mild or moderate intracranial atherosclerotic disease is not a reason to abandon carotid surgery in patients with severe symptomatic carotid stenosis. Silent Brain Infarctions Silent brain infarctions (SBIs) are common in patients with TIA and high-grade stenosis. They may be located ipsilaterally but also in other vascular territories. In NASCET it was found that if SBIs were located ipsilaterally to the carotid stenosis, they seemed to increase the risk of further ipsilateral stroke in medically treated patients compared to patients with SBIs on the contralateral side, which also increases the perioperative risks, but surgery is beneficial for these patients.
Accordingly, CE cannot be routinely recommended for patients with asymptomatic carotid stenosis.
Question 6
Who Should Perform the Carotid Endarterectomy?
Not all surgeons are equal. The beneficial results detected in NASCET, ECST and ACAS only apply to surgeons and institutions with as low a perioperative morbidity and mortality as was characteristic for these trials. The selection of patients also plays a role, but equally important is the selection of the surgeon and the hospital team. Preventive surgery is only indicated when it can be performed with low complication rates. The greatest possible misunderstanding of the message from NASCET, ECST and ACAS is to assume that the beneficial effects of CE apply to all surgeons and hospitals in an equal way. The benefits of CE in moderate and tight symptomatic carotid stenoses as well as in asymptomatic stenosis only apply to institutions and surgeons who have a low perioperative morbidity and mortality rate. This implies that the referring physician and the patient consenting to CE should know the perioperative complication rate of the local surgeon and the institution.
Question 5
Is Surgery Justified in Asymptomatic Patients with Carotid Stenosis?
The Asymptomatic Carotid Artery Study (ACAS), the largest and most recent of the trials studying the benefits of prophylactic CE in asymptomatic patients, showed that surgical treatment of asymptomatic stenosis of carotid artery bifurcation increases the chance of being alive and stroke-free by 5 years. The earlier studies could not verify the benefits of surgery in asymptomatic patients. An absolute risk reduction of 5.9% in 5 years was detected in ACAS. The annual risk of 2% was diminished to 1% in ACAS. The perioperative stroke and death rate was 2.3%, underlining again that exceptional competence is a prerequisite for CE in asymptomatic patients. A meta-analysis showed that CE in patients with asymptomatic carotid stenosis unequivocally reduces the incidence of ipsilateral stroke, although the absolute benefit is relatively small. NNT to prevent 1 stroke was 50 during a 3-year followup, which is not a cost-effective way to prevent strokes.
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Question 7
Could Angioplasty and Stenting Replace Carotid Endarterectomy?
In the future, carotid angioplasty and stenting may be good alternatives for CE but that time has not arrived yet. Angioplasty was compared with CE in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), a randomised clinical trial. In CAVATAS, the 30day death and stroke rate of CE was 9.9 and that of angioplasty 10.0%, i.e. higher than in NASCET, ECST and ACAS. Since the beginning of CAVATAS, improved surgical techniques, such as cerebral protection by an umbrella or an occlusive balloon distal to the site of angioplasty, and combining angioplasty with a stent to decrease the risks of dissection and re-stenosis have become available. For these reasons, new trials (CAVATAS 2 and the Carotid Revascularization Endarterectomy Versus Stenting Trial) are under way. They compare angioplasty combined with stenting to CE in patients with symptomatic
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The Asymptomatic Carotid Atherosclerosis Study Group: Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421–1428. Barnett HJM, Taylor DW, Eliasziw M, et al: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998;339:1415–1425.
Benavente O, Moher D, Pham BA: Carotid endarterectomy for asymptomatic carotid stenosis: A meta-analysis. BMJ 1999;317:1477–1480. Bettman MA, Katzen BT, Whisnant J, et al: Carotid Stenting and Angioplasty. A Statement for Healthcare Professionals from the Councils on Cardiovascular Radiology, Stroke, Cardio-Thoracic and Vascular Surgery, Epidemiology and Prevention, and Clinical Cardiology, American Heart Association. Stroke 1998;29:336–348. Bogousslavsky J, Kaste M, Olsen TS, Hacke W, Orgogozo J-M for the EUSI Executive Committee: Risk factors and stroke prevention. Cerebrovasc Dis 2000;10(suppl 3):12–21. Caplan LR, Wolpert SM: Angiography in patients with occlusive cerebrovascular disease: Views of a stroke neurologist and neuroradiologist. AJNR Am J Neuroradiol 1991;12:593–601. Cavatas Investigators: Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study: A randomized trial. Lancet 2001;357:1729–1737. EC/IC Bypass Study Group: Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med 1985;313:1191–1200. European Carotid Surgery Trialists’ Collaborative Group: Risk of stroke in the distribution of an asymptomatic carotid artery. Lancet 1995;345:209– 212. European Carotid Surgery Trialists’ Collaborative Group: MRC European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991;337:1235– 1243. European Carotid Surgery Trialists’ Collaborative Group: Randomized trial of endarterectomy for recently symptomatic carotid stenosis: Final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379– 1387. Hankey GJ, Warlow CP: Treatment and secondary prevention of stroke: Evidence, costs, and effects on individuals and population. Lancet 1999;354: 1457–1463. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445–453. Samsa GP, Matchar DB, Goldstein L, Bonita A, et al: Utilities for major stroke. Results of a survey of preferences among persons at increased risk for stroke. Am Heart J 1998;136:703–713.
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tight carotid stenosis. With a few exceptions, before the results are available, the use of carotid angioplasty and stenting should be limited to well-designed, well-conducted, randomised studies with a careful, dispassionate overview according to the statement of the American Heart Association Expert Group.
Question 8
Could Extracranial-Intracranial Bypass Surgery Be an Alternative for Carotid Endarterectomy?
The rise and fall of extracranial-intracranial (EC/IC) bypass surgery was a short episode in the history of modern surgery for stroke prevention. One definitive randomised trial, the EC/IC Bypass Study showed that EC/IC bypass has a role in preventing stroke caused by intracranial atherosclerotic disease or proximal carotid artery occlusion. Accordingly, with a few exceptions, it does not have a place in surgery for stroke. Recommended Reading
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Chapter 10 Cerebrovasc Dis Cerebrovasc Dis 2003;15(suppl 2):63–69 DOI: 10.1159/000069683
Stroke Services Michael Brainin
Question 1
64 Are Stroke Units Effective and How Should a Stroke Service Be
Organised? Question 2
64 What Is the Minimal Infrastructure Needed to Run a Stroke Unit? Question 3
66 What Is the Importance of Having a Neurologist Perform
Diagnosis of Stroke Syndromes in the Early Stage of Stroke? Question 4
66 Which Type of Hospital Should Run a Stroke Unit? Question 5
67 What Are the Issues That Make Stroke Unit Treatment Cost
Effective? Question 6
67 What Type of Health Care Professionals Should Take Part in a
Stroke Service or Unit? Question 7
68 Should Access to Stroke Services Be Limited by Age, Clinical
Syndromes or Aetiologic Factors? Question 8
69 Of the Many Investigative Procedures Performed in Advanced
Stroke Units, How Many Are Really Necessary to Reach a Reliable Diagnosis for the Average Stroke Patient?
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Question 1
Are Stroke Units Effective and How Should a Stroke Service Be Organised?
Today, evidence favours treatment of stroke patients within stroke units. These services are organised as spezialised hospital units focusing exclusively on stroke treatment. On such a unit, a rapid diagnosis is made, confirmed by neuroimaging and followed by early treatment centred on saving brain tissue in order to minimise residual disability. Prevention, early recognition as well as treatment of complications arising from the stroke are also an important domain of the stroke units. Still within the acute phase, rehabilitation is initiated and followed by seamless further treatment and neurorehabilitation. There are three organisation types of stroke units: E the acute stroke unit (including the ‘intensive care’ stroke unit) includes emergency treatment of stroke, mean stay: !1 week E the subacute stroke unit (‘comprehensive care’ stroke unit) takes patients that have been treated in the emergency department for the first few days and starts detailed work-up, secondary prevention and rehabilitation. Mean stay: 2–3 weeks E the rehabilitation stroke unit takes the patients from the department or hospital that performs the acute treatment and focuses on rehabilitation and further management. Mean stay: several weeks. Evidence favours all strokes to be treated in stroke units regardless of patient age, stroke severity and subtype. Evidence from randomised trials shows all types of stroke units to be very effective, especially when compared to treatment in general medical wards, geriatric wards or any other kind of hospital department in which no devoted area of beds or specialised staff are exclusively dedicated to stroke care. The Stroke Unit Trialist’s Collaboration [1] has shown that stroke units reduce early fatality (death within 12 weeks) by 28% and death by the end of the follow-up (median 1 year after stroke) by 17% (relative risk reduction). In the Stroke Unit Trialists’ Collaboration, a crude outcome measure beyond case fatality (‘poor outcome’) was
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used, defined as death or institutional care at the end of follow-up (median 1 year after stroke). The proportion of ‘poor outcome’ patients treated in a stroke unit early after stroke was reduced by 23% compared with patients treated in general wards. When expressed as the proportion of patients suffering death or being dependent on others for their primary activities of daily living, management in stroke units means a 25% reduction. Transferring these relative risk reductions into absolute numbers means that for every 100 patients managed in a stroke unit, 3 deaths would be prevented, 3 patients would avoid long-term nursing home care and an extra 6 would return home (almost all independent) compared with conventional care in a general medical ward. In conclusion, stroke unit care reduces mortality, institutionalisation and dependency and is, of course, most effective if organised to treat the patient as soon as possible from the beginning of his admission to early rehabilitation. References 1 The Stroke Unit Trialists’ Collaboration: Organised inpatient (stroke unit) care for stroke (Cochrane Review). Cochrane Database Syst Rev 2002;1: CD000197. 2 Asplund K, Indredavik B: Stroke units and stroke teams: Evidence-based management of stroke; in Castillo J, Davalos A, Toni D (eds): Management of Acute Stroke. Barcelona, Springer, 1997, pp 3–15. 3 Langhorne P, Dennis M: Stroke Units: An Evidence-Based Approach. London, BMJ Books, 1998.
Question 2
What Is the Minimal Infrastructure Needed to Run a Stroke Unit?
In some cases, emergency screening and confirmation of diagnosis has already been performed in the emergency ward, therefore the stroke unit itself does not need investigatory facilities also available in the emergency room. More often, though, the emergency room is bypassed and the acute stroke patient is directly admitted to the acute stroke unit. This, it seems, is the most time-saving and
Brainin
reasonable organisational principle and makes the most sense for the rapid implementation of therapy. It is mandatory to start with a rapid neurological investigation that aims at confirming the diagnosis to rule out other frequent clinical conditions that mimic stroke. For an experienced ‘strokologist’ this does not take more than a few minutes. Sometimes it might become necessary to transfer the patient to another ward if a non-stroke cause turns out to be the underlying disease (e.g. transferring a patient with unrecognised head trauma to the trauma department or a severely hypoglycaemic patient to the endocrinological department). Sometimes it might be necessary to perform different diagnostic tests or perform them in a different order (e.g. serum electrolytes for electrolyte imbalance or cardiac and laboratory monitoring for cardiac insufficiency). It cannot be stated often enough that non-stroke diagnosis has to be considered a part of the emergency work and the neurologist who sees the patient first has to be trained to recognise non-stroke conditions mimicking a stroke. All organisational aspects of stroke care, especially during its acute phase, must consider that time-delays should be avoided. In all stages of acute management, stroke patients must be considered as requiring urgent medical attention. Time delays include admission policies stipulating that patients be placed on general medical wards, lack of access to early brain imaging facilities, evaluation of the stroke as non-urgent by hospital staff, lack of treatment facilities for stroke and unavailability of a neurologist or other physician with special expertise in stroke in the emergency room. It is therefore advisable to set up a protocol for stroke care in every institution. Written protocols for the management of stroke patients play an essential part in minimising these internal delays and are important for the quality management of standardised acute stroke care. Diagnostic tests are needed to further differentiate between the different types of acute stroke, e.g. ischaemic stroke, brain or subarachnoid haemorrhage, in order to rule out other brain diseases, get an impression of the underlying cause of brain ischaemia, provide a basis for physiological monitoring of the stroke patient and to identify comorbidities or complications associated with stroke that may influence prognosis. Non-stroke causes mimicking a stroke syndrome often have to be identified and treated as well. Emergency diagnostic tests include: E CT/MRI E MRA, Diffusion MRI E ECG
E Transcranial Doppler, Duplex E Echocardiography E Laboratory: haematology, electrolytes, hepatic and renal chemistry, infection markers.
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Cranial Computerised Tomography CT reliably distinguishes between haemorrhagic and ischaemic stroke. CT signs of early ischaemia can be detected as early as 2 h after stroke onset, but they may also develop later. Very extensive early infarct signs in the first hours after stroke indicate a very serious ischaemia with a higher risk of secondary haemorrhage or of large oedema formation. While CT usually detects large infratentorial haemorrhages or cerebellar infarcts, smaller infarcts in the brainstem may be missed. CT also rules out many other neurological diseases that may cause strokelike symptoms. Magnetic Resonance Imgaging MRI is more sensitive but has not yet reached the level of a standard procedure in most centres. Modern MRI techniques such as magnetic resonance angiography, diffusion MRI and perfusion MRI require major resources that are slowly becoming more available. Other Emergency Tests An electrocardiogram should be performed in all stroke patients because of the high incidence of heart disease in stroke patients. Hemispheric or brainstem stroke may cause arrhythmias, subendocardial infarction and heart failure. Arrhythmias are frequently the cause of embolic stroke. Ultrasound studies are frequently performed in stroke centres throughout Europe. They include not only cwDoppler or duplex sonography of the extra-cranial cervical arteries but also transcranial Doppler. They are used to identify vessel occlusion, the state of the collaterals, or recanalisation. Other ultrasound studies include transthoracic and transoesophageal echocardiography to screen for cardiogenic emboli. Laboratory tests include haematology and clotting parameters, electrolytes, hepatic and renal chemistry, and basic markers of infection. References 1 Bowen J, Yaste C: Effect of a stroke protocol on hospital costs of stroke patients. Neurology 1994;44:1961–1964. 2 Brainin M, Kaste M, Czlonkovska A, et al: Neurological acute stroke care: The role of European neurology. Eur J Neurol 1997;4:435–441. 3 European Stroke Initiative: Recommendations for Stroke Management. Cerebrovasc Dis 2000;10(suppl 3):1–33.
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Question 3
What Is the Importance of Having a Neurologist Perform Diagnosis of Stroke Syndromes in the Early Stage of Stroke?
The efficacy of a stroke unit does not only depend on the ready availability of high-tech apparatuses to screen brain tissue and visualise brain vessels but also on qualified staff for nursing care and rehabilitation. With regard to medical specialists responsible for stroke care, it is primarily neurologists who have made themselves increasingly available for this task. Neurologists throughout Europe have actively entered this field of care more than any other medical subspecialists. Neurology has incorporated acute and chronic stroke care into its core curricula in all countries. It must be mentioned that this has brought about vast changes of the self-perception of clinical neurology itself. Awareness of the clinical importance of this new field of stroke care has undoubtedly changed clinical neurological practice more than any other development since the advent of rapid imaging diagnosis, such as CT, more than 25 years ago. Neurologists have also contributed mostly to this field through basic and clinical research, textbooks and clinical trials, and are continuing to do so. This is not surprising considering that stroke is, above all, a disease of the brain, therefore it is the neurologist as the specialist for brain diseases that should take the lead in caring for such patients. This perception has also contributed to the further development of neurointensive care as well as neurorehabilitation. Considering that many patients with acute stroke have additional diseases like arterial hypertension and diabetes, or cardiac conditions such as atrial fibrillation, it is clear that interdisciplinary measures have to be taken. For the general care, internists, haematologists, endocrinologists, and many other subspecialties are indispensable. In practice, the clinical signs lead the way to recognising the distribution of the infarct in the brain, this again can be attributed to brain vessel anatomy and this lends support to a reliable pathophysiological cause and thus to a plausible aetiology of the stroke. It is clear that the rapid identification of the underlying aetiology of the stroke has a protective potential for the patient, especially as a basis for protection from further recurrence. In some European countries the predominant role of neurology in stroke care has led to the development of acute stroke services that are exclusively or almost exclusively attached to neurological departments, as is the case in Austria and in most of Germany. Understandably no randomised trials testing neurological versus non-neurological stroke care have been con66
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ducted. This would be a tautological task with trivial and useless conclusions. It is like comparing skiers with swimmers for a nautical task and to expect that both produce similar results. All this should not discourage other professionals to embark on the important task of stroke care. In countries that have insufficient numbers of trained neurologists to take the lead in acute stroke care and rehabilitation, other subspecialties with remarkable expertise have evolved, such as geriatricians and internists that consider themselves ‘strokologists’. The pioneering work and scientific contributions of some of these specialists are considerable. References 1 Brainin M, Kaste M, Czlonkovska A, et al: Neurological acute stroke care: The role of European neurology. Eur J Neurol 1997;4:435–441. 2 Madden KP, Karanjia PN, Adams HP, Clarke WR, and the TOAST investigators: Accuracy of initial stroke subtype diagnosis in the TOAST study. Neurology 1995;45:1975–1979. 3 Mitchell JB, Ballard DJ, Whisnant JP, Ammering CJ, Samsa GP, Matchar DB: What role do neurologists play in determining the costs and outcomes of stroke patients? Stroke 1996;27:1937–1943.
Question 4
Which Type of Hospital Should Run a Stroke Unit?
Any hospital can be activated to establish and efficiently run a stroke unit that possesses the basic requirements for acute stroke care, including day and night availability of experienced staff, ready availability of CT, ECG, and laboratory examinations. This unit must be ready to accept a large number of acute and largely unselected strokes. Acute strokes should come from a defined reservoir that usually comprises a population of 150,000– 300,000 inhabitants. On the basis of most European incidence data, this will result in the admission of 300–600 strokes per year (including about 20% haemorrhagic and recurrent strokes). A further advantage of a defined population is that campaigns to speed up the prehospital phase can be launched more effectively, the efficacy of such campaigns can be measured and measurement can be repeated at regular intervals. In most countries, hospitals that are responsible for such comparatively small populations as mentioned above do not have all the facilities necessary to treat all causes of stroke. Co-operations with larger hospitals, especially tertiary care or teaching hospitals, exist for the treatment of other diseases and these collaborations should be fruitfully expanded to cover all Brainin
aspects of stroke care that cannot be supplied by the primary or secondary type of hospital. This usually concerns neurosurgical procedures for evacuation of intracerebral haematoma, management of strokes that are associated with rare diseases or need for specialised haematological or cardiologic care. This co-operation should probably also cover carotid surgery as it has been extensively proven that carotid surgery should comply with a set of standardised measures that are usually not easily upheld in smaller hospitals. In spite of the variations of stroke care that exist throughout Europe, the acute type of stroke unit which cares for the patient ‘from the first minute’ should also be capable of performing systemic thrombolysis on a routine basis. Considering the fact that no more than 10% of all strokes submitted will ever receive systemic thrombolysis within 180 min following the onset of stroke, it is reasonable to plan for a sufficiently large number of stroke patients to be admitted to a stroke unit that also performs thrombolysis on a routine basis. This should be possible with a thrombolysis rate of at least 60–80 patients per year. References 1 Brainin M, Kaste M, Czlonkovska A, et al: Neurological acute stroke care: The role of European neurology. Eur J Neurol 1997;4:435–441. 2 EUSI: Recommendations for Stroke Management. Cerebrovasc Dis 2000; 10(suppl 3):1–33. 3 Hacke W, Schwab S, de Georgia M: Intensive care of acute ischemic stroke. Cerebrovasc Dis 1994;4:385–392. 4 Kalra L: Organisation of stroke services: The role of stroke units. Cerebrovasc Dis 1996;6:7–12.
Question 5
What Are the Issues That Make Stroke Unit Treatment Cost Effective?
departments have virtual budgets that include all kind of costs not involved in the treatment decisions. The direct costs may be added up against the activities within a stroke unit, but the true cost-effectiveness lies in the saving of indirect costs. For instance, the considerable costs for long-term institutional care can be saved by stroke unit treatment because of its beneficial effect on residual impairment in stroke survivors, but this factor does not account for all the benefits of stroke units. The true and enormous dimensions of these indirect costs have only recently started to emerge. It is known, for instance, that at least 25% of all patients survive their stroke with considerable motor and cognitive impairment and therefore need long-term care, including nursing care. Apart from the medical costs, which include the costs for physicians, nursing, technical aid and transport as well as rehabilitative care, other long-term factors have become evident. It is often the relatives from the younger generation that provide this kind of invisible help that is unaccounted for but does represent a considerable financial burden in terms of loss of family wealth, household income and loss of skilled labour for society and the economy as a whole. This example shows that cost effectiveness needs to be defined not only in terms of conventional direct and indirect costs but also in terms of unpaid social work and assistance given to stroke survivors. Then it is possible to argue that better stroke care results in better health of the survivors, thus reducing indirect costs and improving quality of life. In spite of the high costs for the instalment and the high running costs especially in the beginning, it is foreseeable for the immediate future that stroke units will be a success story. References 1 Bergman L, Van der Meulen JHP, Limburg M, Habbema JDF: Costs of medical care after first-ever stroke in the Netherlands. Stroke 1995;26: 1830–1836. 2 Kaste M, Palomäki H, Sarna S: Where and how should elderly stroke patients be treated? Stroke 1995;26:249–253.
For physicians who are already working with stroke units it is quite clear that the beginning of the treatment is the most cost-intensive part because every lifesaving procedure is more expensive than leaving survival up to chance. It has to be argued firmly towards health care providers that not every single cent that is spent has to be accounted for immediately by a direct cost account. If health care providers and politicians start to take such an attitude, it is hopeless to argue that stroke units would be cost effective. Besides, it is not even an easy task to add up the true direct costs for stroke treatment as most departments do not have cost accounts that truly reflect the absolute costs that are run up for these patients. Most
This depends on the treatment goals of the stroke unit. Basically, all types of health care professionals needed to attain these treatment goals should be involved. These
Stroke Services
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Question 6
What Type of Health Care Professionals Should Take Part in a Stroke Service or Unit?
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goals are based on the specialised organisation of the stroke unit, which permits numerous interventions including rehabilitation as early as possible. In Austria, for example, which is considered to have a rather uniform and advanced system of stroke unit care, it is mandatory to have a physiotherapist, an occupational therapist and a speech therapist assigned to the stroke unit. In addition there is ‘sociotherapy’, which includes additional training for activities of daily living, counselling, and social work. It is also mandatory that these therapies are performed at least 3 h per day and only by trained therapists. In addition, neuropsychologists are necessary for the quantitative assessment of the numerous cognitive and emotional impairments following stroke as well as for determining the goals of neurorehabilitation and developing therapy plans. Further tasks involve psychological counselling of patients and their relatives. Social workers have to be available to organise home care and community help, and to guarantee seamless long-term rehabilitation wherever necessary. In addition, other therapeutic professionals are involved, including a dietician and – wherever possible – an orthoptist. Other professionals are getting increasingly involved as their specialities also become available for stroke unit patients, including music therapy, physical therapy (including sport therapy), hippotherapy and other leisure or health activities. When comparing some of the rehabilitation trials it seems that not only are the total number of therapeutic sessions with physiotherapy, occupational therapy, and speech therapy essential for a favourable outcome but also the context in which they are performed. In most studies, daily or at least weekly staff conferences play a decisive role for the success of a stroke unit, as well as the early integration of relatives or caregivers into the therapeutic process. Additional studies have uniformly shown that staff meetings held at weekly (sometimes even daily) intervals have a tremendous beneficial effect in adjusting a patient’s therapy, setting effective goals and preventing complications. It is advisable for all professionals to attend these meetings as the team effort is based upon the information given and the agreement reached in those meetings. Other factors include staff training and early involvement of the patients’ relatives and spouses in the rehabilitation process. References 1 Davenport RJ, Dennis MS, Wellwood I, Warlow CP: Complications after acute stroke. Stroke 1996;27:415–420. 2 Kalra L, Eade J: Role of stroke rehabilitation units in managing severe disability after stroke. Stroke 1995;26:2031–2034.
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Question 7
Should Access to Stroke Services Be Limited by Age, Clinical Syndromes or Aetiologic Factors?
As has been already stated at the beginning of this chapter, available evidence favours all strokes to be treated within stroke units. There is no scientific evidence in favour of restricting or limiting access to stroke unit care on any grounds, including age, clinical syndrome or stroke aetiology. Although most evidence supporting unlimited access to stroke units is retrospective, it is again the argument of cost rather than medical reasoning which forces us to give recommendations in this direction. We must accept the fact that there are not enough stroke units to provide quality care for all stroke patients. When entering a discussion on reasonable limits of stroke care, two factors have to be stressed, one being that stroke treatment becomes ‘catastrophe medicine’: decisions have to be made which patients should receive treatment and which should not. This compares to mass road or railway accidents or many victims following snow avalanches. When discussing issues of limited access we should always consider that the restrictions recommended are provisional, only valid during a period of shortage and have to be revised after some time. At all times it is necessary to emphasise that treating strokes outside of stroke units does not correspond to the scientific standards. The second point to consider is that limiting access on the grounds of old age is unethical and cannot be recommended as a treatment principle under any circumstances. This is not only true for old patients but also for first-ever versus recurrent strokes, patients with and without comorbidities, severe versus less severe strokes, or strokes distributed in the anterior versus the posterior brain circulation. No single piece of evidence points to the direction of limiting access by such criteria. One solution, which also acknowledges the limited resources available, is to go by pre-existing disability. If an individual has a stroke but was already significantly disabled before (either by a previous disabling stroke or some other incapacitating disease), then there is not much independence to be saved compared to an individual who was completely independent before the acute stroke. Saving brain tissue, already the major functional principle of a stroke unit, can thus be used as a selection criterion. An additional solution that has also been recommended is the set-up of a stroke team wherever stroke units are not feasible. Although there is only very little
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scientific evidence that compares mobile stroke teams to stroke units, it seems reasonable to set up such a mobile team. The major difference is that such a mobile team goes to the ward where the patient has been admitted instead of the patient being transferred to the stroke unit. It has become common experience that wherever the work of a mobile stroke team is performed with enthusiasm and documented with diligence, the health providers and hospital administration will sooner or later favour a stroke unit. References 1 Brainin M, Kaste M, Czlonkovska A, et al: Neurological acute stroke care: The role of European neurology. Eur J Neurol 1997;4:435–441. 2 Jorgensen HS, Nakayama H, Raaschou HO, Larsen K, Hübbe P, Olsen TS: The effect of a stroke unit: Reductions in mortality, discharge rate to nursing home, length of hospital stay, and cost: A community-based study. Stroke 1995;26:1178–1182. 3 Jorgensen HS, Reith J, Nakayama H, Kammersgard LP, Raaschou HO, Olsen TS: What determines good recovery in patients with the most severe strokes? The Copenhagen Stroke Study. Stroke 1999;30:2008–2012. 4 Kaste M, Palomäki H, Sarna S: Where and how should elderly stroke patients be treated? Stroke 1995;26:249–253.
Question 8
Of the Many Investigative Procedures Performed in Advanced Stroke Units, How Many Are Really Necessary to Reach a Reliable Diagnosis for the Average Stroke Patient?
Such a question somehow implies an attitude of particular cost sensitivity towards stroke, as if this were a disease that should cost less than it does now. Such an attitude of particular cost restriction towards stroke has, of course, to be refuted on neurological grounds. There is no reason to assume that any kind of exceptional cost sensi-
Stroke Services
tivity could be warranted for stroke compared to any other disease treated within the general health system. Questions like these are very difficult to answer because they are usually posed by health care providers that do not easily acknowledge the vast possibilities of stroke manifestations and the enormous difference in consequences for the individual stroke victim and his family. A specific trait of this chronic brain disease is that it occurs suddenly, unexpectedly, and has unimagined consequences, which is why it cannot easily be compared to other diseases such as hip fracture or knee joint replacement. These also occur unexpectedly but have more foreseeable and comparable consequences for most individuals. On the other hand, if we assume that the question primarily is medically oriented than it must be stated that the most overused method is probably Duplex sonography (at least in Western Europe). It is, on the other hand, not easy to foresee which patients have symptomatic carotid stenosis and therefore might be candidates for surgery. Experience shows that the percentage of stroke patients undergoing carotid surgery is extremely small, probably no more than 3%. Arterial digital angiography is also almost completely dispensable if advanced imaging (including MRA and CTA) are available. Probably one of the most expensive attitudes in stroke management is to start with the cheapest method and then proceed to the expensive ones. Such a work-up sequence means many patients have a multitude of investigations with overlapping information. In a considerable number of cases it might be recommendable to start with the most informative and not the cheapest investigation. Reference 1 Mohr JP, Biller J, Hilal SK, et al: Magnetic resonance versus computed tomographic imaging in acute stroke. Stroke 1995;26:807–812.
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Subject Index
Alcohol, stroke incidence effects 38, 39 Anticoagulation complications 53 contraindications 53 drug interactions 51 drug types and mechanisms 50 elderly patients 54 initiation 51, 52 leukoaraiosis patients 54, 55 monitoring 52 pharmacology 50, 51 prescription compliance 53, 54 stroke prevention 9, 50 therapeutic range 52, 53 Antiphospholipid antibodies, stroke risks 41 Antiplatelet therapy, see also specific drugs ADP receptor antagonist-aspirin combination therapy 44–47 ADP receptor antagonists vs aspirin 44 drug development 47 glycoprotein IIb/IIIa inhibitors 46 stroke primary prevention 9, 44 Aspirin ADP receptor antagonist-aspirin combination therapy 44–47 stroke prevention 9 Blood pressure, see Hypertension Carotid endarterectomy age criteria 59 angioplasty and stenting comparison trials 60, 61 asymptomatic patients 60 concomitant intracranial carotid artery stenosis 60 contralateral carotid artery occlusion 59, 60 indications 58 multiple risk factors in candidates 59 preoperative evaluation 58, 59 silent brain infarctions 60 statins and atherosclerosis prevention 34 stroke prevention 9, 10 surgeons 60 symptomatic patients 59 TIA vs amaurosis fugax 59 time window after ischemic vent 59 Cholesterol, see Hypercholesterolemia
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Clopidogrel aspirin combination therapy 44–46 benefits vs aspirin 44, 45 stroke prevention 9 Computed tomography angiography 7, 69 stroke diagnosis 6, 7 stroke unit 15, 65 Diabetes diet and exercise 30 epidemiology 26 stroke age of onset 27 coexisting risk factors 28 hyperglycemia as independent risk factor 27 metabolic control in prevention 28, 29 outcomes 26, 27 prevention 29, 30 risks 26 type I vs type II diabetes patients 27 Dipyridamole, aspirin combination therapy 45 Exercise diabetics 30 stroke prevention 38 Extracranial-intracranial bypass surgery, trials 61 Glycoprotein IIb/IIIa inhibitors, stroke prevention 46 Homocysteine, stroke risks 41 Hormone replacement therapy, stroke risks 40 Hypercholesterolemia diabetics 29 screening 34, 35 statin therapy benefits of stroke patient treatment 35 carotid artery atherosclerosis prevention 34 elderly patients 35 initiation 36 stroke prevention 34 stroke risks of high and low cholesterol 32
Hyperglycemia, stroke risk factor 27 Hypertension acute stroke antihypertensive drug management 21, 22 blood pressure course 21 blood pressure variations and neurological deficits 22 diabetics 29 stroke etiology 20 stroke prevention studies 20, 21 treatment recommendations 22, 23 Ischemic stroke, types 2, 3 Leukoaraiosis, anticoagulation safety 54, 55 Lipoprotein(a), levels and stroke 33 Magnetic resonance imaging angiography 7, 58 stroke diagnosis 6, 7 stroke unit 15, 65, 69 Migraine, stroke association 40 Neurologist, stroke diagnosis in stroke unit 14, 66 Obesity, stroke risks 38 Oral contraceptives, stroke risks 39, 40 Percutaneous transluminal angioplasty, stroke prevention 10 Risk factors, see specific risk factors Smoking, stroke risks 39 Statins, see Hypercholesterolemia Stroke acute, management 8 diagnosis 5–7 frequency 3 manifestations 4, 5 prevention primary prevention 9 secondary prevention 9, 10 risk factors 5 types 2, 3 warning symptoms 3
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Stroke unit acute stroke unit 12 clinical efficacy studies 16, 17, 64 comprehensive stroke unit 12 cost-effectiveness issues 15, 16, 67 hospital requirements 14, 15, 66, 67 infrastructure 13, 64, 65 laboratory tests 15, 65, 69 neurologist diagnosis 14, 66 organization 13, 64
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patient selection 16, 68, 69 rehabilitation unit 12 setting 12 team 12, 14, 67, 68 Subarachnoid hemorrhage, secondary prevention 10
Transient ischemic attack definition 2 lipid analysis 34, 35 management 3 presentation 3 Triglycerides, elevation and stroke 33
Thrombolytic therapy, acute stroke management 8
Ultrasound, stroke unit 65
Cerebrovasc Dis Vol. 15, Suppl. 2, 2003
Warfarin, see Anticoagulation
Subject Index
