Secondary Prevention of. Stroke: What a GP needs to know

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1 Secondary Prevention of P. O Mahony Consultant Stroke Physician St Helier Hospital, Surrey S. Howie V. Jones Stroke: What a GP needs to know Correspondence: P. O Mahony Stroke Department, St Helier Hospital, Carshalton, Surrey paul.omahony@esth. nhs.uk Abstract Secondary prevention of stroke can make a significant difference to a patient s outcome. Identifying the aetiology of the stroke and treating the modifiable risk factors must be a priority. Education must continue to reiterate that stroke is a medical emergency. Keywords Secondary Prevention, Stroke, TIA. Introduction In recent years, stroke care has been transformed. The National Stroke Strategy 2007 recognized the growing body of evidence supporting rapid assessment, diagnosis and treatment of transient ischaemic attack (TIA) and stroke, and has forced a change in attitudes amongst the medical profession. Many of the interventions have been involved with improving early diagnosis and outcome after the initial event. However, we know that the risk of a recurrent stroke within 5 years of the first event can be up to 42%. 1 For this reason, stroke medicine must also focus on identifying and treating the underlying aetiology to reduce this risk. This article aims to highlight the important modifiable risk factors for stroke which can reduce the likelihood of further events and disability in the future. Stroke Aetiology With improvements in imaging, it is becoming apparent that the underlying aetiology of the stroke may be different depending on the area of brain affected. A high proportion of recurrent strokes are of similar subtypes to the initial event, supporting the theory that different disease processes are involved. 2 Many research trials now utilise the Trial of ORG in Acute Stroke Treatment (TOAST) criteria to subdivide ischaemic stroke and this is useful when identifying and modifying risk factors likely to have caused the stroke (Figure 1). Secondary Prevention The main drive of secondary prevention must focus on the individual patient and efforts must be made to identify the underlying aetiology of the index event. Inevitably some risk factors are not modifiable and others have been linked to stroke but with no treatment proven to change that risk. It is important to be aware of these but treating the modifiable risk factors is the priority (Figure 2). Notably, risk factors for stroke Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

2 Ischaemic Stroke Large artery stroke: occlusion or stenosis (>50%) in large extracranial or intracranial artery (carotid, vertebral, basilar, anterior cerebral, middle cerebral, posterior cerebral), with ischaemia in that arterial territory. Probable aetiology: atherosclerosis Cardioembolic stroke: one or more of the following conditions: mechanical prosthetic valve, atrial fibrillation, myocardial infarction within last 2 months, dilated cardiomyopathy/congestive heart failure at stroke onset, endocarditis, sick sinus syndrome, atrial myxoma, left ventricular thrombus. Probable aetiology: embolism Lacunar stroke (Small vessel thrombosis): lacunar syndrome (pure motor stroke, pure sensory stroke, ataxic hemiparesis, clumsy hand dysarthria) with either no lesion on brain imaging or a deep infarct ( 1.5cm diameter) in a location consistent with the clinical syndrome. Probable aetiology: atherosclerosis Other determined aetiology: includes the rarer causes of stroke e.g. nonatherosclerotic vasculopathies, hypercoagulable states, haematological disorders Undetermined aetiology Multiple possible aetiologies Haemorrhagic Stroke Primary intracerebral haemorrhage Primary subarachnoid haemorrhage Possible aetiologies: hypertension, structural intracerebral abnormalities, anticoagulants, haematological disorders Figure 1: Pathophysiological classification of stroke based on but modified from TOAST and Stroke Data Bank Criteria Non-modifiable Age: >55 yrs, incidence of stroke doubles with every decade Sex: M > F Ethnic origin: increased in Afro-Carribeans and Chinese, greater mortality rates in Asians Social class: increased in lower socioeconomic groups Raised homocysteine levels: no evidence so far to support treatment Genetic factors e.g Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), Fabry s disease Previous TIA/stroke Other atheromatous disease e.g ischaemic heart disease, peripheral vascular disease, renovascular disease Modifiable Hypertension Smoking Diabetes Mellitus Hypercholesterolaemia Alcohol Atrial Fibrillation Physical inactivity Obesity Medication e.g. oral contraceptive pill, hormone replacement therapy Thrombophilic disorders Recreational drugs Sickle Cell disease?obstructive sleep apnoea?migraine Figure 2: Non-modifiable and modifiable risk factors for stroke. and ischaemic heart disease are similar, but their relative risks are slightly different (Figure 3). Ischaemic Stroke Initially, the main intervention for all patients who have had a TIA or ischaemic stroke (Figure 4), is to treat those risk factors contributing to the patient s atherosclerotic burden. This principally benefits those patients with strokes attributable to small and large vessel thrombosis, but patients with other causes of ischaemic stroke, e.g. cardioembolic, will also benefit from these measures. Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

3 Antiplatelet drugs Recent changes have been made to the National Institute for Health and Clinical Excellence (NICE) recommendations. In the acute phase, it is still advised to start 300mg aspirin once haemorrhage has been excluded by brain imaging. Currently guidelines suggest this should continue for two weeks before long-term antiplatelets are started. Patients who have had an ischaemic stroke should then be started on monotherapy of clopidogrel. The ongoing Triple Antiplatelets for Reducing Dependency in Ischaemic Stroke (TARDIS) trial may help clarify the optimum regimen in the first month after an ischaemic stroke, as in practice, long-term antiplatelets are often started earlier. As clopidogrel is not licensed for use in TIA, NICE have continued to recommend a combination of aspirin and modified-release dipyridamole for secondary prevention in these circumstances. In practice, clopidogrel is often used as an alternative in TIA, especially as imaging often reveals an area of infarct. NICE did acknowledge that clopidogrel is often better tolerated than dipyridamole and there are obvious benefits in reducing polypharmacy. Consideration should be given to impending endoscopic or surgical procedures with clopidogrel in particular, as it will often have to be stopped 7 days before high-risk procedures. Other comorbidities may also determine which regimen to follow. Proton pump inhibitors should be considered for gastroprotection in cases where there is a clinical indication. There are ongoing uncertainties as to the effectiveness of clopidogrel in particular, in combination with some of these drugs, when histamine receptor antagonists may be more appropriate. Risk Factor Relative Risk of Stroke Age (75 vs years) 5 Blood pressure (160/90 vs.120/80mmhg) 7 Smoking (current status) 2 Diabetes Mellitus 2 Figure 4: CT scan showing a right hemispheric ischaemic stroke. United Kingdom social class (V vs. I) 1.6 Ischaemic Heart Disease 3 Heart Failure 5 Atrial Fibrillation 5 Past TIA 5 Physical Inactivity (little or none vs. some) Oral Contraceptives Figure 3: Relative risk associated with risk factors for stroke. 3 Antihypertensives Hypertension is a major risk factor for both ischaemic and haemorrhagic stroke. In addition to evidence supporting treatment for primary prevention of stroke, it has been demonstrated that treating hypertension results in significant reduction of recurrent stroke. 4 The Royal College of Physicians guidelines define it in this population as sustained measurements above 130/90 mmhg and recent NICE guidelines have recommended the use of ambulatory blood pressure monitoring to aid diagnosis. Target blood pressure should be <130/80mmHg unless there is evidence of severe carotid artery stenosis when a systolic of 150mmHg may be more appropriate. Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

4 Lifestyle intervention is imperative and should include salt restriction, exercise, and moderation of alcohol intake. All anti-hypertensives have been shown to have a protective effect against stroke and NICE suggest an algorithm to follow depending on the age and ethnicity of the patient. In practice, treatment should be tailored to the individual patient. Treatment of hypertension is initiated immediately if the patient has been diagnosed with a TIA. If the patient has had a stroke, new treatment is frequently delayed for 2 weeks. This protects any retrievable areas (the ischaemic penumbra) in the brain from hypoperfusion and further neurological damage. However, most patients who are already on treatment continue with this immediately poststroke. As with antiplatelet treatment, it is unclear as to the benefit of very early intervention of blood pressure Reduction in stroke. Clarification of such issues is the subject of ongoing research trials (e.g. Efficacy of Nitric Oxide in Stroke (ENOS) trial) Cholesterol-lowering drugs Although a causal link between increased cholesterol and stroke has not been proved so far, there is evidence to suggest that treating hypercholesterolaemia reduces stroke risk. 5 Treatment should be started if the total cholesterol > 3.5mmol/L or LDL>2.5mmol/L, aiming for either, a 25% reduction in total cholesterol and a 30% reduction in LDL or, total cholesterol <4mmol/L and LDL<2mmol/L, whichever results in the lower value. A period of at least 48 hours should be given before treatment is started after an acute stroke, although if a patient is already on it, it should be continued. Statins are not recommended in haemorrhagic stroke, although in patients with co-existent vascular disease such as previous myocardial infarction or indeed previous ischaemic stroke, they may be considered appropriate. Smoking Cessation It is well known that smoking is a risk factor for ischaemic stroke in particular. Patients should be encouraged and supported to stop. Patients should be made aware that studies have demonstrated a substantial reduction in cardiovascular mortality soon after stopping, even after many years of heavy smoking. Glucose Control Diabetes has been identified as not only a risk factor for stroke but also specifically for carotid disease. Guidelines recommend using insulin or oral hypoglycaemics to achieve an HbA1c of <53mmol/mol (7%). Recreational drugs A clear link has been demonstrated between the use of recreational drugs and both ischaemic and haemorrhagic strokes. Implicated drugs include cocaine, crack-cocaine, heroin, amphetamines, phencyclidine (PCP) and lysergic acid diethylamide (LSD). The principal mechanisms are thought to be due to hypertension and embolic phenomena with injected drugs. There is little stroke-specific research examining the role of diet, exercise and alcohol in terms of secondary prevention. However, data from primary prevention studies would suggest that there is a benefit in modifying these risk factors also. Alcohol moderation Public awareness has increased regarding the protective effect of alcohol and indeed there does appear to be a benefit in terms of ischaemic stroke risk reduction with moderate consumption. However, there is a link between heavy alcohol intake and haemorrhagic stroke in particular. Advice should be to follow the Department of Health guidelines of no more than 3-4 units per day for men and 2-3 units per day for women, with at least 2 alcohol-free days per week. Physical Exercise Lack of exercise has been shown to be a risk factor for stroke. This may in part be due to the higher incidence of hypertension and obesity that results, both of which are independent risk factors for stroke. It is also well documented that stroke patients have a low level of physical fitness and muscle strength and their ability to function after their stroke is often related to this. Benefits of exercise post-stroke have been demonstrated to improve functional outcome. New community-based Exercise After Stroke services are emerging and patients should be encouraged to make use of them. Diet/ Weight loss Recommendations should be the same as those given to patients with cardiovascular disease: 5 or more portions of fruit and vegetables per day 2 portions of fish per week, one of which should be oily Replace saturated fats with polyunsaturated or monounsaturated fats Low salt diet In addition to addressing the above factors, other modifiable risk factors should be identified, in particular in those patients who have had large artery or cardioembolic strokes. Carotid Disease It has been shown that the risk of recurrence after stroke if the initial event is caused by large artery disease, is the highest of all aetiologies at 19% (cf. 3% with lacunar infarcts). 6 Carotid endarterectomy has been shown to be highly effective at reducing this risk. The identification of carotid disease is time dependent because intervention is most beneficial within two weeks of the original event (Figure 5) Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

5 Current guidelines suggest that all patients who have had an anterior circulation non-disabling stroke or TIA should have a carotid Doppler scan within one week. High risk TIA patients (i.e. those with ABCD2 score 4, those with 2 or more events in one week, those on warfarin), however, should be scanned within 24 hours. There is no definite evidence that surgery in asymptomatic disease is beneficial and optimal medical treatment as described above is advised. The benefit of intervention for vertebral artery stenosis remains uncertain and is the subject of ongoing Research. Cardioembolic disease Although there are multiple possible sources of embolism (Figure 6), stroke caused by cardioembolic disease often has certain characteristics clinically and on imaging. Large vessel occlusions or multiple territory infarcts may suggest an embolic source, most commonly atrial fibrillation (AF). If the resting ECG shows sinus rhythm, ambulatory monitoring may be arranged to look for paroxysmal atrial fibrillation, which carries the same stroke risk as permanent or persistent atrial fibrillation and should be treated in the same way. The relative risk of stroke in patients with AF increases dramatically with age, from 1.5% in year olds to 23.5% in patients between 80 and 89 years old. 8 For this reason, increasingly more elderly patients are being anticoagulated with oral vitamin K antagonists (usually warfarin). A meta-analysis 9 has demonstrated that treatment with anticoagulation can reduce the risk of stroke by 64% and yet in spite of this, only approximately 50% patients who are eligible for anticoagulation are treated. 10 The Accelerating Stroke Improvement (ASI) Programme has focused upon this and has set a target for 60% of stroke patients with AF to be anticoagulated (or have a plan to be) within a month of discharge from hospital after a stroke. As with primary prevention, a risk/benefit analysis should be carefully performed. However, it is important to note that in secondary prevention, all ischaemic stroke patients with atrial fibrillation would benefit from anticoagulation. In view of this, there must be a clear contraindication for treatment not to be started. It is important to be aware that using aspirin as an alternative is not as effective (RR reduction of 22% vs. 64% with warfarin). 9 In addition, risk of haemorrhage is not significantly lower with aspirin and gastro-intestinal side effects are more prevalent. In patients diagnosed with a TIA, warfarin should begin immediately. In the event of a stroke, especially those of a significant size, antiplatelet medication should be initiated and the transition to anticoagulation is recommended at least two weeks after the event. This is intended to reduce the risk of haemorrhagic transformation. However, there is no evidence to suggest when warfarin should be initiated and the decision should be made in conjunction with the local stroke specialist. Figure 5: Absolute reduction with surgery in the 5-year cumulative risk of ipsilateral carotid ischaemic stroke and any stroke or death within 30 days after trial surgery in patients with 50-69% stenosis and 70% stenosis without nearocclusion stratified by the time from last symptomatic event to randomisation. Numbers above bars indicate actual risk reduction. Vertical bars are 95% CIs 7 If a patient is intolerant of vitamin K antagonists, new oral anticoagulant drugs are becoming available, for example dabigatran, a direct thrombin inhibitor or rivaroxaban, a factor Xa inhibitor. NICE has recently issued guidance on presecibing these and most localities are drawing up local guidelines. Alternatively, certain tertiary centres are inserting mechanical devices percutaneously to close the left atrial appendage, preventing clot formation in patients unable to maintain long-term oral anticoagulation. Left ventricular thrombus is another potential source of embolism. This may be identified using a transthoracic echocardiogram. It is associated with prothrombotic states, acute myocardial infarction, ischaemic heart Figure 6: Sources of embolic stroke. Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

6 disease, left ventricular akinesis or aneurysm and other cardiomyopathies. The treatment is anticoagulation. Carotid dissection There is no consensus yet on the optimum treatment of carotid artery dissection. The Cervical Artery Dissection in Stroke Study (CADISS) is an on-going randomized controlled trial involving large artery dissections, comparing antiplatelet medication and anticoagulation. Patent Foramen Ovale There is a high prevalence of patent foramen ovale (PFO) in the normal population and the challenge is to determine how significant a PFO may have been in the aetiology of a stroke. Echocardiogram with colour flow Doppler and bubble studies are helpful in evaluating the structural deficit and right to left shunts and evidence of venous thrombosis may also be useful. Treatment will depend on how relevant the PFO is felt to have been in contributing to the initial stroke. Options include antiplatelet medication, anticoagulation and percutaneous or open closure of the defect. The evidence is not clear on the best form of treatment. Other factors to consider in ischaemic stroke Oral Contraceptive Pill /Hormone Replacement Therapy Neither the oral contraceptive pill nor hormone replacement therapy should be routinely prescribed following a stroke. Migraine Migraine may be an independent risk factor for stroke. The risk appears to be particularly high in young women who smoke and take the oral contraceptive pill. Further research is needed. conditions will be guided by haematology specialists but may include venesection and/or use of drugs such as hydroxyurea. Sickle Cell Disease Patients with homozygous sickle cell disease are at an increased risk of stroke at a rate of 1% per year, with the highest rates in early childhood. Adults who are at high risk of stroke are often treated with hydroxyurea. Haemorrhagic stroke Haemorrhagic strokes account for approximately % of all strokes (Figure 7). As with ischaemic strokes, the focus must be to identify the most likely aetiology of the initial event and modify the related risk factors as much as possible. Intracerebral haemorrhages most commonly result from hypertensive damage to the cerebral blood vessels, with at least two thirds of patients having pre-existing or a new diagnosis of hypertension on presentation. They can, however, also occur due to underlying structural abnormalities, the treatment of which may be neurosurgical (Table 1). It is important to be aware that underlying abnormalities may not be identified at the time of the acute episode and follow up imaging, usually with MRI +/- angiography should be performed at 12 weeks after the stroke, in particular in cases where no clear cause has been found. Treatment of hypertension and any underlying causes for the haemorrhage are the mainstay of secondary (2) Obstructive Sleep Apnoea Emerging evidence suggests that obstructive sleep apnoea may be an independent risk factor for vascular disease. For this reason potential patients should be referred for specialist evaluation and treatment. Thrombophilic disorders Because of the high risk of recurrence, cerebral infarction due to antiphospholipid syndrome should be treated with long-term oral anticoagulation therapy with a target INR 2.5. Cerebral venous thrombosis is a cause of stroke which tends to occur (although not exclusively) in those with a prothrombotic tendency. These strokes (including those with secondary cerebral haemorrhage) should be fully anticoagulated. Polycythaemia and thrombocythaemia may also predispose to cerebral infarction. Treatment of these (1) Figure 7: Intraparenchymal bleed (1) with surrounding oedema (2). 168 Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

7 Subarachnoid haemorrhage Primary Intracranial Haemorrhage Malformations or changes in cerebral vessels Hypertension Haematological factors Drugs Other causes Table 1: Aetiological Classification of Cerebral Haemorrhage. 3 Saccular aneurysm Normal Angiogram Rare causes Lipohyalinosis/microaneurysms in perforating arteries Amyloid angiopathy Cerebral arteriovenous malformations Moya-moya syndrome Cavernoma Mycotic aneurysms Vasculitis Treatment-related: anticoagulation, thrombolysis, antiplatelet agents Haemophilia Leukaemia Thrombocytopenia Alcohol Amphetamines Cocaine Cerebral tumours prevention in haemorrhagic stroke but it is still important to identify and modify any other risk factors such as diabetes, smoking, obesity and alcohol intake. Particular note should be made of the following. Hypertension Immediate treatment is not advised (except in patients with particularly high blood pressure (>200mmHg systolic) or when a subarachnoid haemorrhage is suspected), to preserve any ischaemic penumbra which could be salvaged with a higher mean arterial pressure. Two weeks after the initial event, anti-hypertensive medication should be initiated as for ischaemic strokes. Cholesterol-lowering drugs Some data have emerged to suggest that there may be an association between the use of statins and intracerebral haemorrhage. Until further evaluation is undertaken, the advice is to withhold the use of statins in patients who have had a haemorrhagic stroke, unless there are other reasons for their use. Recognition of Recurrent Events Patients who have already had a stroke should be identified as being at higher risk of further events in the future. It is imperative that patient education continues on an individual basis and symptoms of a stroke are considered a medical emergency. The Face, Arm, Speech, Time (FAST) screen is a useful way to for patients to recognize the symptoms of a stroke (Figure 8). If the patient s neurology has fully resolved on presentation to suggest a TIA rather than a stroke, risk of further events should be calculated using the ABCD2 score (Figure 9). High risk patients are identified as those scoring 4, those with 2 or more events in one week, and those who are on warfarin. These patients should be seen, investigated and treated in a specialist service within 24 hours. Aspirin 300mg should be started immediately (except for those on warfarin), whilst waiting for specialist review. Patients scoring lower should be started on high dose aspirin and should be seen within 1 week. Other secondary prevention measures as detailed in this article should also be implemented. Patients should be informed of the DVLA guidelines preventing them from driving for at least one month following a stroke or TIA. Summary Patients who have survived a stroke or who have had a TIA, present the opportunity to modify multiple risk Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

8 factors. The measures that have been described should continue for the rest of the patient s life and the importance of them continually reiterated. Primary care physicians are best-placed to ensure that this unique chance to significantly alter a patient s outcome is exploited to the full. Red Flags/ When to refer History and examination consistent with TIA (i.e. symptoms <24 hours + no residual neurology on examination): ABCD2 score 4 2 or more events within one week 1. Refer immediately to TIA service to be seen within 24 hours 2. Start 300mg aspirin once daily immediately 3. Start blood-pressure and cholesterol-lowering medication if indicated 4. Advise not to drive for one month Figure 8: The screen for recognising stroek. ABCD2 score < 4 (It is likely there will be local arrangements for urgent assessment of patients on warfarin so they can have immediate brain scanning). 1. Refer to TIA service to be seen within one week Features of ABCD2 score Points Age 60 1 BP 140/90 mmhg on initial presentation 1 Clinical features of TIA: Unilateral weakness 2 Speech disturbance without weakness 1 Duration of symptoms: minutes 1 60 minutes 2 Diabetes Mellitus 1 Figure 9: ABCD2 score. 2,3,4 as above History and examination consistent with acute stroke: Dial 999 for transfer to acute stroke unit Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):

9 References 1. Sacco, et al. Survival and recurrence following stroke: The Framingham Study Stroke 1982; 13: Hankey, et al. Long-term risk of first recurrent stroke in the Perth Community Stroke Study Stroke 1998; 29: Madden K, et al. Accuracy of initial stroke subtype diagnosis in the TOAST trial. Neurology 1994; 44(suppl 2): A Rashid, et al. Blood pressure reduction and secondary prevention of stroke and other vascular events Stroke 2003; 34: Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in highrisk individuals: a randomised placebo-controlled trial Lancet 2002; 360: Lovett, et al. Early risk of recurrence by subtype of ischaemic stroke in population-based studies Neurology 2004; 64 (4): Rothwell et al. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery Lancet 2004; 363(9413): Wolf, et al. Atrial fibrillation as an independent risk factor for stroke: The Framingham study Stroke 1991; 22: Hart, et al. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation Annals of Internal Medicine 2007; 146(12): Go, et al. Warfarin Use among Ambulatory Patients with Nonvalvular Atrial Fibrillation: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study Annals of Internal Medicine 1999; 131: Further Reading 1. The National Stroke Strategy PublicationsPolicyAndGuidance/DH_ NICE guidelines Stroke NICE guidelines Hypertension 4. Royal College of Physicians. National Clinical Guidelines for Stroke 5. European Society of Cardiology Guidelines Atrial Fibrillation The Stroke Association 8. Accelerated Stroke Improvement Programme Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3):