2021 Secondary Stroke Prevention

Diagnostic Evaluation for Secondary Stroke Prevention

Routine workup for all patients

• Workup should be completed or underway within 48h of onset of stroke/TIA
• CT or MRI brain
• EKG
• CBC, PT, PTT, glucose, HbA1c, creatinine and lipid profile
• Vascular Imaging: Either carotid duplex or CTA/MRA head and neck. CTA/MRA can identify intracranial atherosclerotic disease, Moya Moya, dissection or other vasculopathies.

Workup for ESUS

• TEE, Cardiac CT or Cardiac MRI

Patients with PFO

• TCD with embolus detection may be reasonable to screen for Rt-Lt shunt

Workup for Cryptogenic stroke

• TTE with or without contrast
• Outpatient cardiac telemetry or implantable loop recorder
• Hypercoagulable panel
• Systemic inflammatory markers
• Screen for infections that can cause CNS vasculitis (HIV, syphilis)
• Drug screen (meth or cocaine)

Vascular Risk Factor Management

Nutrition

• Reasonable to advise patients to follow Mediterranean diet:
  • Mono-unsaturated fat (use olive oil for cooking, consumption of tree nuts)
  • Increase plant-based foods (fruit, vegetables, legumes, whole grains, cereals)
  • Increase fish consumption
  • Lower meat consumption, avoid red and processed meat
  • Moderate milk and dietary consumption
  • Avoid soda, pastries, sweets, bakery products
• Salt restriction to 2.5g/day in patients with HTN

Physical activity

• 10 minutes, 4 times weekly of moderate Intensity aerobic exercise or 20 minutes, twice weekly vigorous exercise

Alcohol use

• Counsel patients who drink >2 drinks/day for men or >1 drink/day for women to reduce or eliminate alcohol consumption.

Hypertension

• BP goal of < 130/80 is recommended
• Thiazides, ACE or ARBs are useful for lowering BP and reducing stroke risk.

Hyperlipidemia

LDL

• Start statins (atorvastatin 80) for stroke patients with LDL > 100 mg/dl if there is no other vascular risk factors, or LDL > 70 if known to have atherosclerotic disease (CAD, carotid disease, intracranial atherosclerosis).
• Add Ezetimibe if needed to get LDL < 70 mg/dl
• Add PCSK9 inhibitor (Repatha or Praluent) for very high risk patients with LDL > 70 mg/dl despite statins and ezetimibe.
  • High risk patients are:
    • Stroke + (recent ACS, Hx of MI, sPAD) or
    • Multiple risk factors: Age > 65, HTN, DM, CKD, smokers, hx of CABG or prior cardiac stents
• Repeat fasting lipid profile after 4-12 weeks of therapy then every 3-12 months.

Triglycerides

• Moderate hypertriglyceridemia (135-499) with LDL 40-100, HbA1c < 10 and no history of pancreatitis, AF or HF → treatment with IPE (icosapent ethyl, Vascepa) 2g bid is reasonable
• Severe hypertriglyceridemia (> 500), fibrates can be used if necessary

Diabetes

• It is reasonable to screen for prediabetes/diabetes in ischemic stroke patients using HbA1c
• HbA1c target < 7 is recommended for most patients
• Prediabetic patients with BMI > 35 or those < 60 years of age or gestational diabetes, metformin may be beneficial to prevent progression to diabetes

Antithrombotic Therapy

Patients with stroke/TIA not attributable to other etiology with specific antithrombotic recommendations:

• Aspirin, clopidogrel or aspirin 25 mg plus dipyridamole 200 mg bid is indicated for secondary prevention in non-cardioembolic stroke
• DAPT (aspirin and clopidogrel) should be initiated early (within 24h, maximum within 7 days) in patients with minor stroke (NIHSS =<3) or high risk TIA for 21 to 90 days followed by SAPT. POINT trial
• DAPT (aspirin and ticagrelor) for 30 days may be considered in patients with minor-moderate stroke (NIHSS =<5) or high-risk TIA or symptomatic intra or extracranial stenosis >30%, although it may increase risk of serious bleeding. THALES trial
• For patients already on aspirin at time of non-cardioembolic stroke or TIA, effectiveness of increasing dose of aspirin or changing to clopidogrel is not well established.
• Continuous use of DAPT > 90 days or the use of triple therapy in patients with non-cardioembolic stroke is associated with excess risk of hemorrhage.
• Aspirin dosing may be guided by weight: aspirin 75-100 in patients <70kg and higher dose in patients >70kg

Management by Etiology

Intracranial Atherosclerosis

Antiplatelets

• Stroke/TIA caused by intracranial stenosis 50-99% → aspirin 325 mg daily is recommended
• Stroke/TIA caused by intracranial stenosis 70-99% → Adding clopidogrel to aspirin for 90 days is reasonable. (SAMMPRIS)
• Minor Stroke/TIA caused by intracranial stenosis > 30%, adding ticagrelor 90 mg bid to aspirin for 30 days can be considered
• Stroke/TIA caused by intracranial stenosis 50-99%, adding cilostazol 200mg/day to aspirin can be considered
• Avoid: clopidogrel, cilostazol or ticagrelor alone. Avoid aspirin + dipyridamole.

Other measures: maintain SBP < 140, high intensity statins and regular exercise

Angioplasty/Stenting

• Avoid angioplasty/stenting prior to maximizing medical therapy first.
• Patients with recurrent symptoms despite the above, usefulness of angioplasty/stenting is unknown.

Extracranial-intracranial bypass: is not recommended

Extracranial Carotid Stenosis

Revascularization indication

• Stroke/TIA with ipsilateral Carotid artery stenosis 70-99% → CEA is recommended
• Stroke/TIA with ipsilateral Carotid artery stenosis 50-69% → CEA is recommended

CEA vs CAS vs TCAR

• Patients > 70 years, it is reasonable to select CEA over CAS to reduce periprocedural stroke rate
• If revascularization is planned within 1 week of index stroke, it is reasonable to select CEA over CAS to reduce periprocedural stroke rate
• Patients with severe stenosis with increased risk for surgery (medical risk, anatomic risk, radiation-induced stenosis), it is reasonable to select CAS over CEA.
• Patients with stenosis > 70% (non-invasive imaging) with low risk of periprocedural stroke, CAS can be considered as alternative to CEA.
• TCAR usefulness is uncertain

Timing

• In patients with non-disabling stroke or TIA, it is reasonable to perform the procedure within 2 weeks of index event rather than delayed.

Symptomatic Extracranial Vertebral Artery Stenosis

• Main therapy is intensive medical management: antiplatelets, lipid lowering, BP control.
• Usefulness of stenting is not well established VAST, VIST trials
• Usefulness of open surgical procedures (endarterectomy, transposition) is not well established

Aortic Arch Atherosclerosis

• Target LDL < 60 mg/dl is recommended
• Antiplatelet therapy is recommended

Moya Moya Disease

• Surgical revascularization with direct (STA-MCA) or indirect (encephaloduroarteriosynangiosis) bypass can be beneficial JAM trial
• Aspirin monotherapy may be reasonable

Small Vessel Disease

• Antiplatelets (aspirin, clopidogrel) along with modifying risk factors
• Cilostazol usefulness in prevention of SVD stroke is still uncertain

Atrial Fibrillation

• Anticoagulation is recommended for stroke/TIA patients with nonvalvular AF (regardless if paroxysmal or persistent) or atrial flutter.
• DOACs (apixaban, rivaroxaban, dabigatran or edoxaban) are recommended in preference to warfarin in patients with no mechanical valve and no severe mitral stenosis.
• Patients with ESRD or on dialysis, use warfarin or apixaban,
• Stroke with low risk of hemorrhagic conversion: it is reasonable to initiate anticoagulation 2-14 days after onset.
• Stroke with high risk of hemorrhagic conversion (NIHSS > 9 or complete arterial territory): it is reasonable to delay initiation of anticoagulation beyond 14 days.
• If there is contraindication for lifelong anticoagulation but can tolerate at least 45 days, Watchman device closure of atrial appendage is reasonable.

Valvular Heart Disease

AF with moderate or severe mitral stenosis or mechanical valve

• Warfarin is recommended in patients with valvular AF.
• Aspirin in addition to warfarin is recommended to patients with mechanical mitral valve and a history of prior stroke/TIA before valve replacement.
• Avoid dabigatran in patients with stroke and mechanical heart valve.

Mechanical aortic valve

• Warfarin with target INR of 2.5 is recommended for bileaflet or tilting disc valves.
• Higher intensity warfarin (2.5-3.5 GELIA trial) can be beneficial in patients with mechanical aortic valve with prior

IE patients with recurrent stroke and persistent vegetations despite antibiotics

• Early surgery (before completion of AB course) is reasonable if there is no evidence of hemorrhagic conversion or extensive neurologic damage.
• Early surgery may be considered in patients with mobile vegetations > 10mm if there is no evidence of hemorrhagic conversion or extensive neurologic damage
• Delaying surgery for 4 weeks may be considered in patients with major ischemic stroke or intracranial hemorrhage.

LV Thrombus

• Stroke/TIA with LV thrombus, warfarin for at least 3 months is recommended. Safety of DOACs is still uncertain.
• Stroke/TIA with acute MI, contrast TTE or cardiac MRI are reasonable to look for thrombus.
• Stroke/TIA with acute MI with reduced EF (< 50%), empirical anticoagulation for at least 3 months may be considered.

Cardiomyopathy

• LV noncompaction patients with stroke/TIA → warfarin can be beneficial
• Mechanical assist device (LVAD) patients with stroke/TIA → warfarin and aspirin can be beneficial. Dabigatran should be avoided, causes harm. So far, DOACs should be avoided in patients with LVAD.
• Cardiomyopathy with reduced EF but no AF and no LV thrombus → effectiveness of anticoagulation vs antiplatelets is uncertain, treatment should be individualized.

PFO

• PFO closure is reasonable in patients 18-60 year-old with ESUS and PFO WITH high risk anatomic features
• PFO closure benefits are not well established in patients 18-60 year-old with ESUS and PFO WITHOUT high risk anatomic features
• PFO closure should only rarely be performed in older patients (>60) and only in very unusual clinical circumstances.

Dissection

• Extracranial carotid or vertebral dissection, treatment with antithrombotic (aspirin or anticoagulation) for 3 months is indicated.
• Patients with recurrent stroke in setting of dissection despite antithrombotic, endovascular therapy may be considered.

Hypercoagulable state

• PT20210 mutation, activated protein C resistance, elevated factor VIII, deficiency of protein C or S or antithrombin III:
  • Antiplatelet therapy is reasonable
  • Testing for protein C, S or antithrombin III should be done or repeated at least 4-6 weeks after acute stroke.
• Antiphospholipid syndrome:
  • Isolated antiphospholipid Abs but doesn’t fulfill the criteria → antiplatelets (WARSS subgroup analysis)
  • Fulfill the criteria for antiphospholipid → warfarin
  • Fulfill the criteria with triple positive Ab, rivaroxaban is NOT recommended

Hyperhomocysteinemia

• Vitamin B6, B12 and folate supplementation is not effective in preventing stroke in patients with stroke and Hyperhomocysteinemia VITATOPS trial
• There is one study showed evidence of benefit of folic acid addition to enalapril in patients with Hyperhomocysteinemia and MTHFR mutation.

Sickle Cell Disease

• Chronic blood transfusion to keep HbS < 30% is recommended in patients with prior stroke/TIA and sickle cell disease STOP trial
• In patients for whom transfusion is not available, treatment with hydroxyurea is reasonable SWiTCH, TWiTCH trials

Vasculitis

Giant Cell Vasculitis

• Immediate initiation of steroids is recommended in patients stroke/TIA attributed to GCA
• Methotrexate or tocilizumab therapy adjunctive to steroids is reasonable in these patients
• Infliximab shouldn’t be used in stroke/TIA and GCA, it was associated with markers of disease activity and ocular symptoms.

Takayasu

• Steroids plus methotrexate, azathioprine or leflunomide.

Primary CNS angiitis

• High dose steroids followed by steroid sparing agents (azathioprine, cyclophosphamide, mycophenolate, methotrexate or rituximab.

Infectious vasculitis

• VZV cerebral vasculitis, neurosyphilis or bacterial meningitis → treat infectious etiology
• HIV vasculopathy → aspirin in addition to HIV therapy

Neoplastic vasculitis (invasion of BVs by tumor cells)

• Angiotropic lymphoma is the most common neoplastic vasculitis, treat underlying lymphoma

Other Genetic Disorders

Cystathionine B-synthase deficiency

• Low methionine, cysteine-enhanced diet with supplementation with pyridoxine, B12 and folate is recommended to reduce plasma homocysteine level

Anderson Fabry disease

• Agalsidase alpha and beta are of uncertain value in preventing stroke.

Carotid Web

• Antiplatelets are recommended as first line in patients with carotid web in the distribution of stroke/TIA
• Carotid stenting/CEA may be considered in patients with ischemic stroke refractory to medical therapy

Fibromuscular dysplasia

• Antiplatelets, BP control are recommended for secondary stroke prevention
• Antiplatelets are recommended in patients with FMD and dissection with stroke/TIA
• Carotid angioplasty or stenting may be reasonable in patients with FMD with recurrent stroke.

Dolichoectasia

• Antiplatelet therapy or anticoagulation is reasonable in patients with stroke and dolichoectasia

ESUS

• Oral anticoagulants are not recommended for secondary stroke prevention
• Ticagrelor is not recommended for secondary stroke prevention

Compiled by Ahmed Koriesh, MD · summarized from the 2021 AHA/ASA secondary-prevention guideline.