2021 AHA/ASA Secondary Stroke Prevention Guideline Summary

This is a condensed summary of the 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack (Kleindorfer et al.). Recommendations are listed by Class of Recommendation (COR) and Level of Evidence (LOE).

1. Diagnostic Workup

Brain Imaging

• NCCT or MRI to confirm ischemic stroke and exclude hemorrhage (COR 1)
• MRI with DWI recommended, especially for posterior circulation or when CT negative (COR 1)
• Repeat neuroimaging within 1–2 days if initial CT negative but high clinical suspicion

Vascular Imaging

• Noninvasive imaging of cervicocephalic vessels (CTA, MRA, or ultrasound) is recommended (COR 1)
• Both MRA and CTA reliably exclude high-grade intracranial stenosis

Cardiac Evaluation

• ECG is recommended (COR 1)
• Echocardiography is recommended to evaluate for cardiac source — TTE with second harmonic is cost-effective (COR 1)
• TEE changes management in ~1 in 7 patients with ESUS
• Extended cardiac rhythm monitoring for cryptogenic stroke — detects AF in 8.9% vs 1.4% with conventional monitoring at 6 months (COR 1)

Laboratory Testing

• Lipid profile, HbA1c, fasting glucose are recommended (COR 1)
• Hypercoagulable workup: yield is low for patients >50 years; consider in younger patients with cryptogenic stroke
• Toxicology for cocaine/drugs of abuse at presentation (COR 1)

2. Vascular Risk Factor Management

Hypertension

• Thiazide diuretic, ACE inhibitor, or ARB is useful for lowering BP and reducing recurrent stroke (COR 1, LOE A)
• Office BP goal <130/80 mmHg is recommended for most patients (COR 1, LOE B-R)
• Individualize drug regimens based on patient comorbidities and preferences (COR 1, LOE B-NR)
• In patients without prior history of hypertension but BP ≥130/80 after stroke/TIA: antihypertensive treatment can be beneficial (COR 2a, LOE B-R)

Lipid Management

• Ischemic stroke with no known coronary disease, no cardioembolic source, LDL >100 mg/dL: atorvastatin 80 mg daily is recommended (COR 1, LOE A)
• Stroke/TIA with atherosclerotic disease: lipid-lowering to LDL <70 mg/dL with statin ± ezetimibe (COR 1, LOE A)
• Very high-risk patients (stroke + other major ASCVD or + multiple high-risk conditions) on max statin + ezetimibe with LDL still >70: PCSK9 inhibitor is reasonable (COR 2a, LOE B-NR)
• Monitor fasting lipids 4–12 weeks after initiation or dose change, then every 3–12 months (COR 1, LOE A)

Hypertriglyceridemia

• Stroke/TIA with fasting TG 135–499 mg/dL, LDL 41–100 mg/dL on moderate/high-intensity statin, HbA1c <10%: icosapent ethyl (IPE) 2 g twice daily is reasonable (COR 2a, LOE B-R)
• Severe hypertriglyceridemia (TG ≥500 mg/dL): very low-fat diet, avoid refined carbs and alcohol, omega-3 fatty acids, fibrate if needed (COR 2a, LOE B-NR)

Diabetes

• In patients with T2D and stroke/TIA: GLP-1 receptor agonist is recommended to reduce risk of major cardiovascular events (COR 1, LOE A)
• Comprehensive management (diet, exercise, self-management education, medications) for glycemic goals (COR 1)
• Prediabetes: lifestyle optimization (diet, exercise, smoking cessation) is beneficial (COR 2a, LOE B-R)
• Intensive glucose control (HbA1c ≤7%): usefulness beyond acute phase is unknown for stroke prevention (COR 2b)
• Pioglitazone: may be considered ≤6 months after TIA/stroke in patients with insulin resistance, HbA1c <7%, without HF or bladder cancer (COR 2b, LOE B-R)

Lifestyle

• Mediterranean diet is reasonable (COR 2a, LOE B-R)
• Reduce sodium by at least 1 g/d in patients not currently restricting (COR 2a, LOE B-R)
• Aerobic physical activity (moderate intensity, 3–4 sessions/week, 40 min/session) is reasonable (COR 2a, LOE B-R)
• Supervised exercise training is reasonable (COR 2a, LOE B-R)
• Smoking cessation counseling and pharmacotherapy (COR 1, LOE A)
• Heavy alcohol use (>2 drinks/day men, >1 drink/day women): counsel to eliminate or reduce (COR 1, LOE B-R)
• Stimulant use (amphetamines, cocaine, khat): inform of health risks and counsel to stop (COR 1, LOE C-EO)

Obesity

• BMI and waist circumference should be assessed (COR 1, LOE C-EO)
• For overweight/obese patients: weight reduction with diet, exercise, or bariatric surgery may be considered (COR 2b, LOE C-LD)

Sleep Apnea

• CPAP may be considered for patients with stroke/TIA and OSA (COR 2b, LOE B-R)
• Evaluate patients for OSA using polysomnography if clinically warranted (COR 2b, LOE B-NR)

3. Noncardioembolic Stroke — Antiplatelet Therapy

• Antiplatelet therapy is preferred over oral anticoagulation for noncardioembolic stroke/TIA (COR 1, LOE A)
• Acceptable options: aspirin 50–325 mg, clopidogrel 75 mg, or aspirin 25 mg + extended-release dipyridamole 200 mg twice daily (COR 1, LOE A)

Dual Antiplatelet Therapy (DAPT)

• Minor stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4): DAPT (aspirin + clopidogrel) should be started early (ideally within 12–24 hours, at least within 7 days) and continued for 21–90 days, then switch to SAPT (COR 1, LOE A-SR)
• Minor to moderate stroke (NIHSS ≤5), high-risk TIA (ABCD2 ≥6), or symptomatic ≥30% stenosis, within 24 hours: DAPT with ticagrelor + aspirin × 30 days may be considered (COR 2b, LOE B-R-SR)
• DAPT >90 days or triple antiplatelet therapy: associated with excess hemorrhage risk (COR 3: Harm, LOE A-SR)

4. Intracranial Large Artery Atherosclerosis

Antithrombotic Therapy

• 50–99% stenosis of major intracranial artery: aspirin 325 mg/day is recommended over warfarin (COR 1, LOE B-R)
• Recent stroke/TIA (within 30 days) with 70–99% stenosis: adding clopidogrel 75 mg × up to 90 days is reasonable (COR 2a, LOE B-NR)
• Recent (within 24 hours) minor stroke/high-risk TIA with ipsilateral >30% stenosis: adding ticagrelor × 30 days might be considered (COR 2b, LOE B-NR)
• Cilostazol 200 mg/day added to aspirin or clopidogrel might be considered (COR 2b, LOE C-LD)

Risk Factor Management

• 50–99% stenosis: maintain SBP <140 mmHg, high-intensity statin, moderate physical activity (COR 1, LOE B-NR)

Angioplasty & Stenting

• Angioplasty/stenting should NOT be first-line treatment for 70–99% stenosis — even in patients on antithrombotic at time of stroke (COR 3: Harm, LOE A)
• 50–69% stenosis: angioplasty/stenting associated with excess morbidity/mortality vs medical management (COR 3: Harm, LOE B-NR)
• Medical failures with severe stenosis (70–99%) and actively progressing symptoms despite optimal therapy: usefulness of angioplasty/stenting is unknown (COR 2b, LOE C-LD)

EC-IC Bypass

• Extracranial-intracranial bypass is NOT recommended for 50–99% stenosis or occlusion (COR 3: No Benefit, LOE B-R)

5. Extracranial Carotid Stenosis

Revascularization

• 70–99% stenosis with recent nondisabling stroke/TIA: CEA is recommended if perioperative morbidity/mortality <6% (COR 1, LOE A)
• 50–69% stenosis: CEA is recommended depending on patient-specific factors (age, sex, comorbidities) if perioperative risk <6% (COR 1, LOE A)
• Early revascularization (within 2 weeks) is recommended for neurologically stable patients (COR 1, LOE A)
• <50% stenosis: revascularization is NOT recommended (COR 3: No Benefit, LOE A)

CEA vs CAS

• CEA is generally preferred when early revascularization indicated (COR 1, LOE B-R)
• Age >70: CEA preferred over CAS (COR 1, LOE B-R)
• Patients at high surgical risk: CAS may be considered as alternative if perioperative stroke/death <6% (COR 2b, LOE A)
• TCAR: usefulness is uncertain — studied only in registries (COR 2b, LOE B-NR)

Medical Therapy

• Antiplatelet therapy, antihypertensive therapy, and statins are recommended for all patients with symptomatic carotid stenosis (COR 1)

6. Atrial Fibrillation

• Nonvalvular AF with stroke/TIA: oral anticoagulation is recommended (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) (COR 1, LOE A)
• DOACs are preferred over warfarin in patients without moderate-severe mitral stenosis or mechanical valve (COR 1, LOE B-R)
• Anticoagulation is indicated regardless of AF pattern (paroxysmal, persistent, permanent) (COR 1, LOE B-R)
• Atrial flutter: anticoagulation similar to AF (COR 1, LOE B-NR)
• Patients unable to maintain therapeutic INR on warfarin: switch to DOAC (COR 1, LOE C-EO)

Timing of Anticoagulation

• TIA with nonvalvular AF: reasonable to initiate anticoagulation immediately (COR 2a, LOE C-EO)
• Stroke at low risk for hemorrhagic conversion: initiation at 2–14 days may be reasonable (COR 2b, LOE B-NR)
• Stroke at high risk for hemorrhagic conversion: reasonable to delay beyond 14 days (COR 2a, LOE B-NR)

Left Atrial Appendage Closure

• Stroke/TIA with nonvalvular AF, contraindication to lifelong anticoagulation but can tolerate ≥45 days: percutaneous LAA closure with Watchman device may be reasonable (COR 2b, LOE B-R)

Special Populations

• End-stage renal disease or dialysis: warfarin or apixaban (dose-adjusted) may be reasonable (COR 2b, LOE B-NR)

7. Valvular Heart Disease & Endocarditis

• Mechanical heart valve with stroke/TIA: maintain INR based on valve type/location (mitral: 3.0, aortic: 2.5) (COR 1)
• Mechanical valve with history of stroke/TIA: add aspirin 75–100 mg to warfarin OR target higher INR (COR 1)
• DOACs are NOT recommended for mechanical valves — excess thromboembolic and bleeding events (COR 3: Harm, LOE B-R)
• Infective endocarditis with stroke/TIA: treat with appropriate antibiotics (COR 1, LOE B-NR)

8. Patent Foramen Ovale (PFO)

• Age 18–60 years, cryptogenic nonlacunar stroke, no other identified cause, high-risk PFO features: PFO closure is reasonable (COR 2a, LOE B-R)
• PFO closure is superior to antiplatelet therapy alone
• High-risk PFO features: large shunt size (>20 microbubbles), atrial septal aneurysm
• If PFO low-risk anatomically: consider RoPE score to assess likelihood PFO is stroke-related
• Closure vs anticoagulation: effectiveness of closure compared to long-term anticoagulation is unknown (COR 2b, LOE B-R)

9. LV Thrombus

• Stroke/TIA with LV thrombus: anticoagulation with warfarin for at least 3 months is recommended (COR 1, LOE B-NR)
• DOACs may be considered as alternative to warfarin (COR 2b, LOE B-NR)

10. Heart Failure

• Stroke/TIA with reduced EF (<35%) in sinus rhythm: antiplatelet therapy is recommended (COR 1, LOE B-NR)
• Warfarin or rivaroxaban is NOT recommended over antiplatelet in HFrEF without AF or other indication (COR 3: No Benefit)

11. Embolic Stroke of Undetermined Source (ESUS)

• DOACs are NOT recommended — no reduction in secondary stroke risk vs aspirin (COR 3: No Benefit, LOE B-R)
• Ticagrelor is NOT recommended — no benefit demonstrated (COR 3: No Benefit, LOE B-NR)
• Treat with antiplatelet therapy and aggressive risk factor management

12. Antiphospholipid Syndrome

• Ischemic stroke/TIA with persistent positive antiphospholipid antibody only: aspirin is recommended over warfarin (COR 1, LOE B-R)
• Stroke/TIA meeting full antiphospholipid syndrome criteria: warfarin is reasonable, target INR 2–3 (COR 2a, LOE C-LD)
• Triple-positive antiphospholipid syndrome: rivaroxaban is NOT recommended — excess thrombotic events vs warfarin (COR 3: Harm, LOE B-R)

13. Cervical Artery Dissection

• Stroke/TIA from extracranial carotid or vertebral dissection: antithrombotic therapy (antiplatelet or anticoagulation) for at least 3–6 months is reasonable (COR 2a, LOE B-R)
• Antiplatelet vs anticoagulation: no difference in stroke recurrence demonstrated
• Endovascular treatment: may be considered if symptoms recur despite medical therapy (COR 2b, LOE C-LD)

14. Hyperhomocysteinemia

• Folate, vitamin B6, and B12 supplementation is NOT effective for preventing subsequent stroke (COR 3: No Benefit, LOE B-R)

15. Uncommon Causes

Sickle Cell Disease

• Children with sickle cell disease and stroke: chronic transfusion to reduce HbS <30% is recommended (COR 1, LOE B-NR)
• Adults: hydroxyurea and transfusion therapy may be reasonable (COR 2b)

Vasculitis

• Giant cell arteritis: high-dose glucocorticoids are recommended; steroid-sparing agents (methotrexate, tocilizumab) are reasonable (COR 1, LOE B-NR)
• Primary CNS angiitis: high-dose steroids + steroid-sparing agent (cyclophosphamide, azathioprine, mycophenolate, rituximab) is recommended
• VZV vasculitis: acyclovir is recommended (COR 1, LOE B-NR)

Reference

Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021;52:e364–e467. doi: 10.1161/STR.0000000000000375