Secondary stroke prevention

1. Secondary stroke prevention Clin/A/Prof Darshan Ghia MBBS(Hons) MD DNB FRACP Clinical Senior lecturer, School of Medicine and Pharmacology, UWA Consultant Neurologist and Head of stoke unit, Fiona Stanley hospital Darshan.Ghia@health.wa.gov.au

2. Introduction • The world is facing a stroke epidemic: • between 1990 and 2010, the number of stroke-related deaths increased by 26% • disability-adjusted life-years by 19% • stroke the second leading cause of death • third leading contributor to disability-adjusted life-years in the world.

3. Importance of secondary stroke prevention • Survivors of stroke and transient ischaemic attacks are at risk of a recurrent stroke, which is often more severe, disabling even fatal and costlier than the index event. • Recurrent strokes continue to account for 25–30% of all strokes and represent unsuccessful secondary prevention • Immediate and sustained implementation of effective and appropriate secondary prevention strategies in patients with first-ever stroke or transient ischaemic attack has the potential to reduce the burden of stroke by up to a quarter

4. Early recurrent strokePrognosis • The risk of a recurrent stroke after an ischaemic stroke or TIA • 1% at 6 h • 2% at 12 h • 3% at 2 days • 5% at 7 days • 10% at 14 days • Therefore, ischaemic stroke or TIA is a medical emergency that demands immediate diagnosis and treatment.

5. Early recurrent strokeAcute specialty units • Patients with suspected TIAshould be assessed and managed urgently in an acute specialty unit, such as a dedicated TIA clinic • Patients with acute stroke should be ideally managed in a stroke unit environment • Investigations usually comprise • immediate imaging of the brain, arteries to the brain, and heart; • electrocardiograph; • measurement of fasting blood glucose and lipids • Holter and echocardiogram

6. Early recurrent strokeAntiplatelet therapy • All patients with acute TIA and ischaemic stroke should be given at least 160 mg of aspirin or acetylsalicylic acid immediately as a single loading dose • In dysphagic patients, aspirin can be given by enteral tube or by rectal suppository • In patients given recombinant tissue plasminogen activator,aspirin should be delayed until after the 24 h post-thrombolysis scan has excluded intracranial haemorrhage • Aspirin (50–150 mg daily) should then be continued indefinitely or until an alternative antithrombotic regimen is started

7. Early recurrent strokeAntiplatelet therapy • For patients taking aspirin before ischaemic stroke or TIA, clopidogrel can be considered as an alternative • If rapid action is required, use a loading dose of 300 mg or 600 mg of clopidogrel, followed by a maintenance dose of 75 mg once daily • Chinese patients with acute (<24 h) TIA or minor ischaemic stroke should be given a bolus loading dose of at least 160 mg of aspirin and 300 mg of clopidogrel immediately, followed by clopidogrel 75 mg plus aspirin 75 mg for 21 days, and single antiplatelet agent long term.

8. Early recurrent strokeAnticoagulation therapy • Existing evidence does not support the routine or selective immediate use of any anticoagulants in acute ischaemic stroke of presumed arterial or cardiac origin • The optimum timing of oral anticoagulation after acute cardioembolic ischaemic stroke is unclear; it is common practice to wait 2–14 days and repeat brain imaging (CT or MRI) to rule out asymptomatic intracranial haemorrhage before starting oral anticoagulation • Patients with atrial fibrillation and acute transient ischaemic attack can begin oral anticoagulation (warfarin, dabigatran, rivaroxaban, or apixaban) immediately because the risk of intracranial haemorrhage is probably low (ie, there is no fresh brain infarction to become haemorrhagic).

10. Early recurrent strokeStatins • Observational studies suggest that statin treatment at the onset of TIA in patients with symptomatic carotid stenosis is associated with reduced risk of early recurrent stroke. MerwickA, Albers GW, Arsava EM, et al. Reduction in early stroke risk in carotid stenosis with transient ischemic attack associated with statin treatment. Stroke 2013; 44: 2814–20. • However, the few small randomised controlled trials of statins in acute TIA and ischaemic stroke have not shown, nor had the statistical power to show, that early initiation of high-dose statins safely and effectively reduces the risk of early recurrent stroke Beer C, Blacker D, Bynevelt M, Hankey GJ, Puddey IB. A randomized placebo controlled trial of early treatment of acute ischemic stroke with atorvastatin and irbesartan. Int J Stroke 2012;7: 104–11.

11. Early recurrent strokeCarotid revascularisation • Patients with TIA or non-disabling ischaemic stroke and ipsilateral 50–99% internal carotid artery stenosis should be offered carotid endarterectomy : • measured by two concordant non-invasive imaging modalities • as soon as possible, ideally within the first few days and up to 1 week after the ischaemic event • patients are fit and willing for surgery • done by a surgeon with an audited perioperative morbidity and mortality of less than 5% • Carotid stenting might be as safe as endarterectomy in patients less than 70 years of age and for patients who are not candidates for carotid endarterectomy because of technical, anatomical, or medical reasons

12. Long-term recurrent strokePrognosis • The risk of recurrent stroke in survivors of acute stroke is about • 11·1% at 1 year • 26·4% at 5 years • 39·2% at 10 years • Predictors of a raised risk of recurrent stroke in the long term include • prevalent vascular risk factors (older age, hypertension, diabetes, or smoking) • Previous symptomatic vascular disease (stroke, myocardial infarction, or peripheral arterial disease) • Unstable vascular disease (several recurrent recent ischaemic events of the brain, including the capsular warning syndrome) • embolic sources and causes (atrial fibrillation or ischaemic stroke caused by embolism from the heart or large arteries) • and possibly cerebral microbleeds

13. Long-term recurrent strokeAntiplatelet therapy • Aspirin 50–325 mg daily, clopidogrel 75 mg daily, or the combination of aspirin (25 mg) and extended-release dipyridamole (200 mg) twice daily, are all appropriate options • Long-term use (for >3 months) of aspirin and clopidogrel combined is not recommended because of the cumulative risks of bleeding

15. Long-term recurrent strokeAnticoagulation • Patients with AF should be treated with anticoagulation, not antiplatelet therapy • For some patients, the individual’s preferences, level of disability, prognosis, and overall clinical status might preclude oral anticoagulation • Warfarin, dabigatran, apixaban and rivaroxaban are all indicated in non-valvular atrial fibrillation. • The selection of an anticoagulant agent should be individualised on the basis of renal and hepatic function, potential for drug interactions, patient preference, tolerability, and other clinical characteristics, including time in international normalised ratio therapeutic range if the patient has been taking warfarin

16. Long-term recurrent strokeAnticoagulation • Apixaban 2.5 mg twice daily should be considered as an alternative to aspirin in stroke patients with non-valvular atrial fibrillation who are judged unsuitable for vitamin K antagonist therapy if their creatinine clearance is >25 mL per min • For patients with atrial fibrillation who have had a stroke but in whom oral anticoagulation is contra indicated, the left atrial appendage can be occluded by the WATCHMAN device (a self-expanding cage placed in the left atrial appendage via a transeptal approach with femoral access)

17. Long-term recurrent strokeBlood pressure • Gradual, sustained lowering of blood pressure is recommended in all stroke patients, but care is needed, particularly in patients with carotid or vertebrobasilar occlusive disease • The ideal time to start lowering of blood pressure after stroke is uncertain, but it should be started before discharge from hospital • The optimum blood pressure-lowering drugs depend on patient comorbidities • The target systolic blood pressure is lower than 130 mm Hg in patients with lacunar stroke • Sustained lowering of blood pressure by 5·1 mm Hg systolic and 2·5 mm Hg diastolic reduces recurrent stroke by about a fifth • Larger reductions in blood pressure—by 10 mm Hg systolic and 5 mm Hg diastolic—are associated with larger reductions in recurrent stroke of about a third

19. Long-term recurrent strokeStatins • LDL cholesterol concentration should be reduced by atherosclerosis by means of diet and lifestyle modification and statin therapy • The target LDL concentration is lower than 2 mmol/L, TG less than 1.8, total cholesterol less than 4 mmol/L and HDL more than 1 mmol/L. • For patients with stroke who do not achieve a low enough LDL cholesterol concentration, the addition of ezetimibe 10 mg, a cholesterol absorption inhibitor, to statin therapy could produce greater reductions in LDL • Lowering of low-density lipoprotein (LDL) cholesterol concentration by about 1 mmol/L with statins reduces the risk of recurrent stroke by about 12%

20. Long-term recurrent strokeLifestyle behaviours • Smoking • Patients should stop smoking • A combination of pharmacological (nicotine replacement therapy, bupropion, cytisine, or varenicline) and behavioural therapy should be considered • Alcohol consumption • Alcohol consumption should be limited to less than two standard drinks per day; • less than 14 drinks per week for men • less than nine drinks per week for women

21. Long-term recurrent strokeLifestyle behaviours • Physical activity • Routine activities of daily living should be supplemented by moderate physical exercise—walking (ideally briskly), jogging, cycling, swimming, or other dynamic exercise • For 30–60 min on 4–7 days per week • High-risk patients (eg, those with cardiac disease) should participate in medically supervised exercise programmes • Bodyweight • The BMI should be maintained at 18.5–24.9 kg/m2 • waist circumference less than 80 cm for women and • less than 94 cm for men

22. Long-term recurrent strokeLifestyle behaviours • Sodium • The recommended adequate daily sodium intake for people aged 9–50 years is 1500 mg, decreasing to 1300 mg for individuals 50–70 years of age and to 1200 mg for those older than 70 years. • A daily upper consumption limit of 2300 mg should not be exceeded by any age group • Healthy balanced diet • Eat a diet low in saturated fat, cholesterol, and sodium; and high in fresh fruits, vegetables, low-fat dairy products, dietary and soluble fibre, whole grains, and protein from plant sources

23. Long-term recurrent strokeIschaemic stroke from paradoxical embolism • Patients with cryptogenic ischaemic stroke or TIA and a patent foramen ovale have a similar rate of recurrent ischaemic stroke (1·6% per year) as patients without a patent foramen ovale (1.1%) • However, an additional atrial septal aneurysm increases the risk of recurrent stroke (Hazard ratio 4.2) • Possible strategies to reduce recurrent stroke from paradoxical embolism include antiplatelet drugs, anticoagulation, and percutaneous closure of the patent foramen ovale with a device.

24. Conclusions • The combination of five of these strategies—aspirin, an antihypertensive drug, a statin, exercise, and dietary modification—could reduce recurrent stroke by 80% • We should initiate and document appropriate secondary prevention medications according to guidelines while patients are still in hospital • Complementary multifaceted strategies involving the patient, caregiver, doctors and pharmacists in the hospital and primary care setting are needed • We should address reasons for non-compliance, which include inadequate clinican–patient interaction, inadequate instructions about correct intake, complex drug regimes, adverse effects, and patient medication-taking behaviour (not filling the prescription, and not taking the medication as prescribed); • It is important to raise awareness in patients and their doctors of the need for lifelong preventive treatment

25. Thank You