ISCHEMIC CEREBROVASCULAR DISEASE

ISCHEMIC CEREBROVASCULAR DISEASE

Treatment of ischemic stroke has improved significantly in the past few years, and mortality and disability rates owing to this condition have decreased. The management of patients in stroke units and the demonstration of the efficacy of thrombolysis and thrombectomy have been crucial in this achievement. Control of vascular risk factors has decreased the number and severity of events. Improved management has included high-quality rehabilitation, which is started as soon as possible to improve the recovery (i.e., functional independence) of stroke survivors.

The multidisciplinary management of stroke can be improved with specific educational programs aimed at increasing awareness of stroke in the general population and among professionals. The concept of time is brain has great value in emphasizing that stroke is an emergency. Because the window for the available time-dependent treatments is very narrow, avoiding delay is the major goal in the prehospital phase of acute stroke care. All stroke patients must be transported as soon as possible to the closest hospital with a stroke unit. In rural or remote areas with no stroke unit facilities, telemedicine has proved to be a valid alternative.

Prevention

Lifestyle modification can be a major contributor to reducing the risk of ischemic stroke. Strategies to achieve this protection include avoiding smoking and excessive alcohol consumption, keeping a low– normal body mass index, practicing regular exercise, and having a diet low in salt and saturated fat, high in fruits and vegetables, and rich in fiber. There is no need to add vitamin supplements to the diet because they have not been found to affect stroke prevention.

Regular assessment of vascular risk factors (e.g., hypertension, diabetes, hypercholesterolemia) is important because their control can reduce significantly the incidence of vascular events. Blood pressure should be managed with diet and pharmacologic therapy, aiming at normal levels of 120/80 mm Hg. After an ischemic stroke, blood pressure should be lowered even in patients with normal blood pressure. Diabetes should be managed with lifestyle modification and pharmacologic therapy as required, and blood pressure needs to be more tightly controlled in these patients (< 130/80 mm Hg). The best antihypertensive treatments for diabetics are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists.

Hypercholesterolemia should be managed with lifestyle modification and a statin. After a noncardioembolic ischemic stroke, statins are beneficial in all patients for secondary prevention.

Postmenopausal hormone replacement therapy should be avoided for the primary or secondary prevention of stroke because it can increase the risk of new vascular events. Other strategies to prevent stroke include the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) breathing.

Antithrombotic Therapy

Low-dose aspirin can be used for the primary prevention of stroke in women or of myocardial infarction in men. Nevertheless, its effect is very small, and it cannot be recommended on a population-wide basis. Aspirin is beneficial for the prevention of stroke in patients with asymptomatic carotid stenosis.

In patients with atrial fibrillation, the CHA2DS2-VASc scale (Table 1) is used to decide whether or not to use anticoagulation. If the score is 2 or more, treatment with oral anticoagulants is indicated. With a score of 1, the decision should be made according to the presence of risk factors, risk of bleeding, and patient choice. There is no need to start antithrombotic treatment, either antiplatelets or anticoagulants, if the score is 0. All patients with stroke or transient ischemic attack (TIA) should be anticoagulated, unless strictly Patients with valvular atrial fibrillation require anticoagulation with warfarin, aiming at an international normalized ratio (INR) of 2.0 to 3.1. Patients with prosthetic heart valves should also receive warfarin, and the target INR depends on the prosthesis type. In nonvalvular atrial fibrillation the treatment options include warfarin (INR 0–3.0) or one of the new direct oral anticoagulants (dabigatran [Pradaxa], apixaban [Eliquis], rivaroxaban [Xarelto], edoxaban [Savaysa]). The newer agents are associated with a decreased risk of intracranial hemorrhage. Dabigatran (150 mg bid) and apixaban (5 mg bid) have shown to be superior to warfarin in stroke prevention. The dose of the direct oral anticoagulants needs to be adjusted depending on age, renal function, or weight.

Table 1

Prevention of Stroke in Patients With Atrial Fibrillation

After ischemic stroke, all patients should receive antithrombotic therapy. Antiplatelet agents are the first choice unless anticoagulation is required. The most effective regimen is clopidogrel (Plavix) or aspirin plus dipyridamole (Aggrenox). However, low-dose aspirin is a reasonable alternative. During the first 3 weeks after a minor stroke or TIA, the combination of aspirin plus clopidogrel can be more effective in reducing ischemic events than clopidogrel alone, although the evidence is scarce. However, this dual antiplatelet treatment is not recommended in the long term, except if there is an association with unstable angina or non-Q-wave myocardial infarction or if there has been a recent stenting.

Anticoagulation is usually indicated for secondary prevention if the stroke cause is cardioembolic and in specific situations such as aortic arch atheroma, fusiform aneurysms of the basilar artery, or patent foramen ovale in the presence of proven deep venous thrombosis. However, level 1 evidence is lacking for these approaches.

Management of Carotid Stenosis

In patients with asymptomatic carotid stenosis (≥ 60%), surgery is indicated only if the risk of stroke is high. Endarterectomy is the treatment of choice if the stenosis is symptomatic (i.e., has been associated with an ipsilateral stroke or TIA) and severe (70%–99%). Surgery should be performed in centers with a perioperative complication rate of less than 6% and as soon as possible after the last ischemic event.

Endarterectomy may be indicated for certain patients with moderate stenosis (50%–69%), although it should be performed only in centers with a perioperative complication rate of less than 3% to be effective. In cases of symptomatic carotid lesions, angioplasty plus stenting is a reasonable alternative, mainly in patients younger than 70 years old. If stenting is performed, a combination of clopidogrel and aspirin is required immediately before the procedure and for at least 1 month to prevent stent thrombosis.

In patients with intracranial atheromatosis and stroke recurrences, intensive medical treatment is the preferred option. Angioplasty and stenting are not recommended.

Management of Acute Ischemic Stroke

All stroke patients should be treated in a stroke unit, because this is associated with a reduction of death, dependency, and the need for institutional care. This effect is seen for all types of patients, irrespective of gender, age, stroke subtype, and stroke severity.

Patients with stroke should have a careful clinical assessment, including a neurologic examination. The use of a stroke rating scale, such as the National Institutes of Health Stroke Scale (NIHSS), provides important information about the severity of stroke.

Urgent cranial computed tomography (CT) is mandatory after an ischemic stroke before starting any therapy. Alternatively, magnetic resonance imaging (MRI) or CT perfusion (CTP) can be performed and can provide additional information about the selection of patients for thrombolytic therapy beyond 4.5 hours, or when the time of onset is unknown. However, there is not enough evidence to recommend its routine use in the acute stroke setting.

For the detection and early management of the medical complications of stroke, neurologic status, pulse, blood pressure, temperature, and oxygen saturation should be monitored. Similarly, serum glucose levels need to be monitored and hyperglycemia treated with insulin accordingly. Normal saline is recommended for fluid replacement during the first 24 hours after stroke. If the patient has a fever, treatment with paracetamol (acetaminophen) may be used while sources of infection are being sought. Reducing blood pressure is recommended only in patients with extremely high blood pressure or when indicated by other medical conditions. Blood pressure should be lowered gradually, avoiding abrupt changes.

Thrombolysis

All patients with an ischemic stroke within 4.5 hours of onset should receive thrombolytic treatment with intravenous tissue plasminogen activator (tPA [Activase]) unless contraindicated, because it is effective in improving stroke outcome (Box 1). There is also evidence from phase II trials (e.g., EPITHET) that selecting patients with MRI to assess the penumbra can be an appropriate tool to extend the time window of this treatment, because tPA was associated with increased reperfusion in these patients and a trend toward better outcomes.

Nevertheless, increasing the time window does not mean that treatment can be delayed. As evidenced by pooled analysis, earlier treatment results in a better outcome. There is enough evidence indicating that thrombolysis is still effective in the very elderly, even with significant comorbidities.

Box 1
Treatment of Acute Ischemic Stroke: Intravenous Administration of Tissue Plasminogen Activator
• Infuse 0.9 mg/kg (maximum dose 90 mg) of tissue plasminogen activator (tPA [Activase]) over 60 minutes, with 10% of the dose given as a bolus over 1 minute.

• Admit the patient to a stroke unit for monitoring. Perform neurologic assessment and blood pressure measurement every 15 minutes during the infusion, every 30 minutes thereafter for the next 6 hours, and then hourly until 24 hours after treatment. Administer antihypertensive medications to maintain systolic blood pressure ≤ 180 and diastolic ≤ 105.

• If intracranial hemorrhage is suspected, discontinue the infusion and obtain an emergency computed tomography scan.

• Obtain a follow-up computed tomography scan at 24 hours before starting anticoagulants or antiplatelet agents.

Endovascular Thrombectomy

Mechanical thrombectomy using stent retrievers in addition to thrombolysis is more effective in improving outcome than thrombolysis alone in anterior circulation strokes and a large artery occlusion, with a time window of up to 6 hours. This treatment is also effective when thrombolysis cannot be administered. In a recent meta- analysis of five major trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA), endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (odds ratio 2.49), with a number needed to treat of 2.6. This effect was seen in all subgroups of patients. Therefore health authorities have to implement access to thrombectomy within a reasonable time range in a network including stroke centers.

Antithrombotic Drugs

All patients should receive a low dose of aspirin daily, and this should be started within 48 hours after stroke onset. The use of other antiplatelet agents during the acute phase of stroke cannot be recommended based on available evidence. Similarly, early administration of unfractionated heparin, low-molecular-weight heparin, or heparinoids is not indicated in patients with acute ischemic stroke.

Treatment of Stroke Complications

Brain edema develops between the second and fifth day after stroke onset and is the cause of early deterioration and death. In the case of a malignant infarction of the middle cerebral artery, the mortality rate is 80%. In patients younger than 60 years with this pattern of cerebral infarction, hemicraniectomy has been effective in reducing mortality and severe disability, as shown in the pooled analysis of the DECIMAL, DESTINY, and HAMLET trials. Decompressive hemicraniectomy is also effective in reducing mortality in patients older than 60 years, although the rates of severe disability are very high. Surgery needs to be performed within 48 hours after symptom onset. Surgical decompression is also indicated in the case of large cerebellar infarctions that compress the brainstem.

Stroke-associated infections require appropriate antibiotics, but prophylactic administration is discouraged. Venous thromboembolism is a frequent complication after stroke, but its incidence can be reduced with appropriate hydration and graded compression stockings. If the risk of deep venous thrombosis or pulmonary embolism is high, the use of subcutaneous heparin or low- molecular-weight heparin is beneficial. Early mobilization is an effective way of preventing complications such as aspiration pneumonia or pressure ulcers. Anticonvulsants are administered only to prevent recurrent seizures but are not used prophylactically.

In case of urinary incontinence, specialist assessment and management are recommended. Dysphagia is common after stroke and is associated with a higher incidence of medical complications and increased mortality. Malnutrition also predicts a poor functional outcome and increased mortality, and it is important to assess the swallowing capacity and the nutritional status of the patient.

Rehabilitation should be started after admission to the stroke unit. The optimal timing of first mobilization is unclear, but mobilization within the first few days appears to be well tolerated. However, very early mobilization can be associated with a worse outcome, as shown in the AVERT trial. An early, lower-dose out-of-bed activity regimen is preferable to very early, frequent, higher-dose intervention. It is important to assess cognitive deficits and depression during the patient’s hospital stay, because this may require specific intervention, although evidence about the type is lacking.

References

1.     AVERT Trial Collaboration Group, Bernhardt J., Langhorne P., Lindley R.I., et al. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): A randomised controlled trial. Lancet. 2015;386(9988):46–55.

2.    European Stroke Organisation (ESO), Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis. 2008;25:457–507.

3.     Goyal M., Menon B.K., van Zwam W.H., et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta- analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723–1731.

4.    Hacke W., Kaste M., Bluhmki E., et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329.

5.     Jauch E.C., Saver J.L., Adams Jr. H.P., et al. Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947.

6.      Kent D.M., Thaler D.E. Stroke prevention—Insights from incoherence. N Engl J Med. 2008;359:1287–1289.

7.    Sacco R.L., Diener H.C., Yusuf S., et al. Aspirin and extended- release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238–1251.

8.    Vahedi K., Hofmeijer J., Juettler E., et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: A pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6:215–222.

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