Ischemic Stroke

These Guidelines are concerned with the diagnosis and treatment decisions of Ischemic Stroke.
(A)  Management of TIA And Minor Stroke

3-    Patients with TIA or minor ischemic stroke should be given antiplatelet therapy provided there is neither a contraindication nor a high risk of bleeding.  The following regimens should be considered as soon as possible:

-   For patients within 24 hours of onset of TIA or minor ischemic stroke and with a low risk of bleeding, the following dual antiplatelet therapy should be given:
Clopidogrel (initial dose 300 mg followed by 75 mg per day) plus aspirin (initial dose 300 mg followed by 75 mg per day for 21 days) followed by monotherapy with clopidogrel 75 mg once daily
OR

-   Ticagrelor (initial dose 180 mg followed by 90 mg twice daily) plus aspirin (300 mg followed by 75 mg daily for 30 days) followed by antiplatelet monotherapy with ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily at the discretion of the prescriber;

-   For patients with TIA or minor ischemic stroke who are not appropriate for dual antiplatelet therapy, clopidogrel 300 mg loading dose followed by 75 mg daily should be given;

-   A proton pump inhibitor should be considered for concurrent use with dual antiplatelet therapy to reduce the risk of gastrointestinal hemorrhage;

-   For patients with recurrent TIA or stroke whilst taking clopidogrel, consideration should be given to clopidogrel resistance.

Strong recommendation

4-    Patients with TIA or ischemic  stroke should receive high-intensity statin therapy (e.g. atorvastatin 20-80 mg daily) started immediately. Strong recommendation

5-    Patients with non-disabling ischemic  stroke or TIA in atrial fibrillation should be anticoagulated, as soon as intracranial bleeding has been excluded, with an anticoagulant that has rapid onset, provided there are no other contraindications. Strong recommendation

6-    Patients with ischemic stroke or TIA who after specialist assessment are considered candidates for carotid intervention should have carotid imaging performed within 24 hours of assessment. This includes carotid duplex ultrasound or either CT angiography or MR angiography. Strong recommendation

7-    Patients with TIA or acute non-disabling ischemic stroke with stable neurological symptoms who have symptomatic severe carotid stenosis of 50–99% should be assessed and referred for carotid revascularization intervention to be performed as soon as possible within 7 days of the onset of symptoms. Strong recommendation

8-    Patients with TIA or acute non-disabling ischemic stroke who have mild or moderate carotid stenosis of less than 50% should not undergo carotid intervention. Strong recommendation

(B)  Management of Acute Ischemic Stroke

-   treatment can be started between 4.5 and 9 hours of known onset, or within 9 hours of the midpoint of sleep when they have woken with symptoms

AND

-   they have evidence from CT/MR perfusion (core-perfusion mismatch) or MRI (DWI-FLAIR mismatch) of the potential to salvage brain tissue.

This should be irrespective of whether they have a large artery occlusion and require mechanical thrombectomy. Conditional recommendation

-   Between 6 and 12 hours: an ASPECTS score of 3 or more, irrespective of the core infarct size;

-   Between 12 and 24 hours: an ASPECTS score of 3 or more and CT or MRI perfusion mismatch of greater than 15 mL, irrespective of the core infarct size.

Conditional recommendation

(C)  LONG-TERM MANAGEMENT AND SECONDARY PREVENTION

1-    Patients with minor ischemic stroke or TIA should receive treatment for secondary prevention as soon as the diagnosis is confirmed. Strong recommendation

3-    People with stroke or TIA should have their risk factors and secondary prevention reviewed and monitored at least once a year in primary care. Strong recommendation

4-    People with stroke or TIA for whom secondary prevention is appropriate should be investigated for risk factors as soon as possible within 1 week of onset. Strong recommendation

5-    Provided they are eligible for any resultant intervention, people with stroke or TIA should be investigated for the following risk factors:

a.  ipsilateral carotid artery stenosis;

b.  atrial fibrillation;

c.  structural cardiac disease.

Strong recommendation

a.  they should have carotid imaging (duplex ultrasound, MR or CT angiography) performed urgently to assess the degree of stenosis;

b.  if the initial test identifies a relevant severe stenosis (greater than or equal to 50%), a second or repeat non-invasive imaging investigation should be performed to confirm the degree of stenosis. This confirmatory test should be carried out urgently to avoid delaying any intervention.

Strong recommendation

7-    People with non-disabling carotid artery territory stroke or TIA should be considered for carotid revascularisation if the symptomatic internal carotid artery has a stenosis of greater than or equal to 50%. Strong recommendation

9-    People with stroke or TIA should have their blood pressure checked, and treatment should be initiated or increased as tolerated to consistently achieve a clinic systolic blood pressure below 130 mmHg, equivalent to a home systolic blood pressure below 125 mmHg. The exception is for people with severe bilateral carotid artery stenosis, for whom a systolic blood pressure target of 140–150 mmHg is appropriate.  Concern about potential adverse effects should not impede the initiation of treatment that prevents stroke, major cardiovascular events or mortality. Strong recommendation

10- For people with stroke or TIA aged 55 or over, antihypertensive treatment should be initiated with a long-acting dihydropyridine calcium-channel blocker or a thiazide-like diuretic.  If target blood pressure is not achieved, an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker should be added. Strong recommendation

11- For people with stroke or TIA younger than 55 years, antihypertensive treatment should be initiated with an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker. Strong recommendation

12- People with stroke or TIA should have their blood pressure-lowering treatment monitored frequently in primary care and increased to achieve target blood pressure as quickly and safely as tolerated.  People whose blood pressure remains above target despite treatment should be checked for medication adherence at each visit before escalation of treatment, and people who do not achieve their target blood pressure despite escalated treatment should be referred for a specialist opinion.  Once blood pressure is controlled to target, people taking antihypertensive treatment should be reviewed at least annually. Strong recommendation

13- People with ischemic stroke or TIA should be offered personalised advice and support on lifestyle factors to reduce cardiovascular risk, including diet, physical activity, weight reduction, alcohol moderation and smoking cessation. Strong recommendation

14- People with ischemic stroke or TIA should be offered treatment with a statin unless contraindicated or investigation of their stroke or TIA confirms no evidence of atherosclerosis.  Treatment should:

a.  begin with a high-intensity statin such as atorvastatin 80 mg daily. A lower dose should be used if there is the potential for medication interactions or a high risk of adverse effects;

b.  be with an alternative statin at the maximum tolerated dose if a high-intensity statin is unsuitable or not tolerated.

Strong recommendation

15- Lipid-lowering treatment for people with ischemic stroke or TIA and evidence of atherosclerosis should aim to reduce fasting LDL-cholesterol to below 1.8 mmol/L (equivalent to a non-HDL-cholesterol of below 2.5 mmol/L in a non-fasting sample).  If this is not achieved at first review at 4-6 weeks, the prescriber should:

a.  discuss adherence and tolerability;

b.  optimise dietary and lifestyle measures through personalised advice and support;

c.   consider increasing to a higher dose of statin if this was not prescribed from the outset;

d.  consider adding ezetimibe 10 mg daily;

e.  consider the use of additional agents such as injectables (inclisiran or monoclonal antibodies to PCSK9) or bempedoic acid (for statin-intolerant people taking ezetimibe monotherapy);

f.   continue to escalate lipid-lowering therapy (in combination if necessary) at regular intervals in order to reduce LDL-cholesterol to below 1.8 mmol/L.

Strong recommendation

16- In people with ischemic  stroke or TIA below 60 years of age with very high cholesterol (below 30 years with total cholesterol above 7.5 mmol/L or 30 years or older with total cholesterol concentration above 9.0 mmol/L) consider a diagnosis of familial hypercholesterolaemia. Strong recommendation

17- For long-term prevention of vascular events in people with ischemic  stroke or TIA without paroxysmal or permanent atrial fibrillation:

a.  clopidogrel 75 mg daily should be the standard antithrombotic treatment;

b.  aspirin 75 mg daily should be used for those who are unable to tolerate clopidogrel;

c.   if a patient has a recurrent cardiovascular event on clopidogrel, clopidogrel resistance may be considered.

d.  The combination of aspirin and clopidogrel is not recommended for long-term prevention of vascular events unless there is another indication e.g. acute coronary syndrome, recent coronary stent.

Strong recommendation

18- People with ischemic stroke with acute haemorrhagic transformation may be treated with long-term antiplatelet or anticoagulant therapy unless the prescriber considers that the risks outweigh the benefits. Conditional recommendation

20- For people with ischemic  stroke or TIA and paroxysmal, persistent or permanent atrial fibrillation (AF: valvular or non-valvular) or atrial flutter, oral anticoagulation should be the standard long-term treatment for stroke prevention.  Anticoagulant treatment:

a.  should not be given if brain imaging has identified significant haemorrhage;

b.  should not be commenced in people with severe hypertension (clinic blood pressure of 180/120 or higher), which should be treated first;

c.   may be considered for patients with moderate-to-severe stroke from 5-14 days after onset. Wherever possible these patients should be offered participation in a trial of the timing of initiation of anticoagulation after stroke.  Aspirin 300 mg daily should be used in the meantime;

d.  should be considered for patients with mild stroke earlier than 5 days if the prescriber considers the benefits to outweigh the risk of early intracranial haemorrhage. Aspirin 300 mg daily should be used in the meantime;

e.  should be initiated within 14 days of onset of stroke in all those considered appropriate for secondary prevention;

f.    should be initiated immediately after a TIA once brain imaging has excluded haemorrhage, using an agent with a rapid onset (e.g. DOAC in non-valvular AF or subcutaneous low molecular weight heparin while initiating a VKA for those with valvular AF);

g.  should include measures to reduce bleeding risk, using a validated tool to identify modifiable risk factors.

Strong recommendation

22- People with ischemic  stroke or TIA due to valvular/rheumatic AF or with mechanical heart valve replacement, and those with contraindications or intolerance to DOAC treatment, should receive anticoagulation with adjusted-dose warfarin (target INR 2.5, range 2.0 to 3.0) with a target time in the therapeutic range of greater than 72%. Strong recommendation

a.  antiplatelet treatment should not be used as an alternative when there are absolute contraindications to anticoagulation (e.g. undiagnosed bleeding);

b.  measures should be taken to reduce bleeding risk, using a validated tool to identify modifiable risk factors. If after intervention for relevant risk factors the bleeding risk is considered too high for anticoagulation, antiplatelet treatment should not be routinely used as an alternative;

c.   a left atrial appendage occlusion device may be considered as an alternative, provided the short-term peri-procedural use of antiplatelet therapy is an acceptable risk.

Strong recommendation

24- People with cardioembolic TIA or stroke for whom treatment with anticoagulation is considered inappropriate for reasons other than the risk of bleeding may be considered for antiplatelet treatment to reduce the risk of recurrent vaso-occlusive disease. Conditional recommendation

25- Patients with ischemic  stroke or TIA not already diagnosed with atrial fibrillation or flutter should undergo an initial period of cardiac monitoring for a minimum of 24 hours if they are appropriate for anticoagulation. Strong recommendation

26- People with ischemic  stroke or TIA and a PFO should receive optimal secondary prevention treatment, including antiplatelet therapy, treatment for high blood pressure, lipid-lowering therapy and lifestyle modification.  Anticoagulation is not recommended unless there is another recognised indication. Strong recommendation

27- Selected people below the age of 60 with ischemic  stroke or TIA of otherwise undetermined aetiology, in association with a PFO and a right-to-left shunt or an atrial septal aneurysm, may be considered for endovascular PFO device closure within six months of the index event to prevent recurrent stroke.  This decision should be made after careful consideration of the benefits and risks by a multidisciplinary team including the patient’s physician and the cardiologist performing the procedure.  The balance of risk and benefit from the procedure, including the risk of atrial fibrillation and other recognised peri-procedural complications should be fully considered and explained to the person with stroke. Strong recommendation

28- People older than 60 years with ischemic  stroke or TIA of otherwise undetermined aetiology and a PFO may be offered closure in the context of a clinical trial or prospective registry. Conditional recommendation

29- People with stroke or TIA should be investigated with transthoracic echocardiography if the detection of a structural cardiac abnormality would prompt a change of management and if they have:

a.     clinical or ECG findings suggestive of structural cardiac disease that would require assessment in its own right, or

b.     unexplained stroke or TIA, especially if other brain imaging features suggestive of cardioembolism are present.

Strong recommendation

30- People with ischemic stroke or TIA due to severe symptomatic intracranial stenosis should be offered dual antiplatelet therapy with aspirin and clopidogrel for the first three months in addition to optimal secondary prevention including blood pressure treatment, lipid-lowering therapy and lifestyle modification.  Endovascular or surgical intervention should only be offered in the context of a clinical trial. Strong recommendation

This guideline covers the management of ischemic stroke and transient ischemic attack (TIA) in adults (i.e., people aged over 16 years).

This edition includes updated evidence with literature searches completed up to September 2022 and with some major publications since that date also included.

The guideline is intended for:

·  those providing care – neurology, intensive care, emergency medicine and internal medicine doctors, nursing staff dealing with stroke patients.

·  those commissioning, providing or sanctioning stroke services;

All Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) by at least two members. The panel decided a cut-off point or rank the guidelines (any guideline scoring above 50% on the rigour dimension was retained). The Guideline Development Group has decided to adapt the current guidelines guided by most recent NICE (2019, reviewed 2022) and AHA/ASA (2019 & 2021) recommendations on ischemic stroke management.

■ GRADE profile software: http://ims.cochrane.org/revman/gradepro

(I) ACUTE CARE OF ISCHEMIC STROKE & TIA

Recommendations

1-    Patients with acute focal neurological symptoms that resolve completely within 24 hours of onset (i.e. suspected TIA) should be given aspirin 300 mg immediately, unless contraindicated by current medical condition of the patient, e.g. active bleeding varices, gastric ulcer or lower GIT bleeding, and assessed urgently within 24 hours by a stroke specialist clinician in a neurovascular clinic or an acute stroke unit. Strong recommendation & High level of evidence (Lavallee et al, 2007; Rothwell et al, 2016)

2-    Patients with suspected TIA that occurred more than a week previously should be assessed by a stroke specialist clinician as soon as possible within 7 days. Strong recommendation & Moderate level of evidence (Giles and Rothwell, 2007)

6 - People with non-disabling carotid artery territory stroke or TIA should be considered for carotid revascularisation, and if they agree with intervention:

8 - Patients with atrial fibrillation and symptomatic internal carotid artery stenosis should be managed for both conditions unless there are contraindications. Strong recommendation & High level of evidence

9- People with stroke or TIA should have their blood pressure checked, and treatment should be initiated or increased as tolerated to consistently achieve a clinic systolic blood pressure below 130 mmHg, equivalent to a home systolic blood pressure below 125 mmHg. The exception is for people with severe bilateral carotid artery stenosis, for whom a systolic blood pressure target of 140–150 mmHg is appropriate.  Concern about potential adverse effects should not impede the initiation of treatment that prevents stroke, major cardiovascular events or mortality. Strong  recommendation & Moderate level of evidence (Rothwell et al, 2003; Ettehad et al, 2016).

Table 1 Eligibility criteria for extending thrombolysis to 4.5-9 hours and wake-up stroke

	Time window	Imaging	Imaging criteria
Wake-up stroke	>4.5 hours from last seen well, no upper limit	MRI DWI-FLAIR mismatch	DWI lesion and no FLAIR lesion
Wake-up stroke or unknown onset time	>4.5 hours from last seen well, and within 9 hours of the midpoint of sleep.  The midpoint of sleep is the time halfway between going to bed and waking up	CT or MRI core-perfusion mismatch	Suggested: mismatch ratio greater than 1.2, a mismatch volume greater than 10 mL, and an ischemic core volume <70 mL
Known onset time	4.5-9 hours	CT or MRI core-perfusion mismatch	Suggested: mismatch ratio greater than 1.2, a mismatch volume greater than 10 mL, and an ischemic core volume <70 mL

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