Prevention of Ischemic Stroke

Aka: Prevention of Ischemic Stroke, Cerebrovascular Risk Factor Modification, Risk Factor Modification Following Transient Ischemic Attack, Anticoagulation in Ischemic Stroke, Cerebrovascular Accident Prevention, Carotid Stenosis Medical Management, CVA Prevention, Prevention of Recurrent Cerebrovascular Accident, Antiplatelet Therapy in CVA and TIA, Dual Antiplatelet Therapy After Non-Embolic Ischemic CVA, DAPT after CVA and TIA

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II. Indications

  1. Post-stroke antithrombotic therapy
  2. Atrial Fibrillation
    1. See Atrial Fibrillation Anticoagulation

III. Management: Short term Prevention after EMBOLIC Ischemic Stroke and Transient Ischemic Attack

  1. Indicated in Atrial Fibrillation (or Atrial Flutter) related CVA
  2. Moderate Mitral Stenosis, Mechanical Heart Valve or cardiac source thrombus (left ventricle, atrium, atrial appendage)
    1. Warfarin
  3. Non-Valvular Atrial Fibrillation
    1. Direct Oral Anticoagulant (e.g. Rivaroxaban, Apixaban)
    2. Oral Direct Thrombin Inhibitor (Dabigatran)
  4. Efficacy
    1. Anticoagulation reduces future stroke risk by two thirds

IV. Management: Initial Antiplatelet Agents in NON-embolic Ischemic Stroke and Transient Ischemic Attack

  1. Aspirin monotherapy (first choice, unless dual therapy initially indicated as below)
    1. Dose 81 to 325 mg orally daily indefinately
    2. CVA reduction of 1% with Aspirin by IST trial
    3. Effective in acute CVA therapy as well as prevention
    4. If recurrent stroke on Aspirin
      1. Consider initial combined Clopidogrel and Aspirin for 3 weeks, then Clopidogrel (see below)
      2. No evidence that raising Aspirin dose (e.g. 325 mg) decreases recurrent CVA risk over 81 mg
  2. Clopidogrel monotherapy
    1. Dose 75 mg orally daily
    2. Consider in patients with allergy to Aspirin
    3. In prevention of recurrent CVA or TIA (for CVA not due to intracranial stenosis)
      1. Similar efficacy to Aspirin monotherapy and Aggrenox
    4. Ticagrelor (Brilanta) may be considered an alternative to Clopidogrel
  3. Aspirin and Clopidogrel (DAPT for first 3 weeks after minor CVA, high risk TIA)
    1. Indications: Non-cardio-embolic ischemic cerebrovascular event
      1. Immediately following mild ischemic Cerebrovascular Accident (CVA) with NIH Stroke Scale <=3 (up to 5)
      2. Immediately after high risk Transient Ischemic Attack (TIA) with ABCD2 Score >=4
      3. CVA related to large intracranial artery stenosis >70%
    2. Not recommended for longterm use
    3. Protocol
      1. Best started within 12 to 24 hours of onset
        1. Benefits even if started as late as 72 hours after event
      2. DAPT Course is typically 21 days
        1. May consider early discontinuation at 10 days in those at the highest risk of bleeding
        2. May consider extending for 90 days for large vessel stenosis
      3. Combination protocol for 21 days
        1. Aspirin 81 mg daily (after initial single loading dose of 324 mg) AND
        2. Clopidogrel 75 mg daily (after initial single loading dose of 300 mg)
          1. May substitute Ticagrelor (Brilinta) 180 mg load, then 90 mg twice daily
          2. However, Ticagrelor is associated with a higher risk of Intracranial Hemorrhage
          3. Lun (2022) JAMA Neurol 79(2): 141-8 [PubMed]
          4. Wang (2021) JAMA Neurol 78(9): 1091-8 [PubMed]
      4. After 3 weeks (or up to 90 days for large intracranial vessel stenosis >70%)
        1. Discontinue one of the antiplatelet agents (typically stopping Clopidogrel)
        2. Continue Aspirin indefinately as above
    4. Efficacy
      1. Decreases risk of recurrent TIA or CVA in short term (NNT 29 compared with Aspirin alone)
      2. Not effective long-term (and should not be used for this due to increased bleeding risk) - see below
    5. Adverse effects
      1. Major bleeding occurs in 1 in 200 patients (but does not increase Intracranial Bleeding risk)
    6. References
      1. Bhatia (2021) Stroke 52(6): e17-23 [PubMed]
      2. Pan (2019) JAMA Neurol 76(12): 1466-73 [PubMed]
      3. Prasad (2018) BMJ 363:k5130 +PMID:30563885 [PubMed]
      4. Wang (2015) Circulation 132(1): 40-6 [PubMed]
      5. Wang (2013) N Engl J Med 369(1):11-9 [PubMed]
  4. Aspirin and Dipyridamole (Aggrenox)
    1. Similar efficacy to Aspirin monotherapy, but less well tolerated and twice daily dosing

V. Management: Short term Prevention after NON-embolic Ischemic Stroke and Transient Ischemic Attack

  1. Antihypertensives
    1. See below regarding precautions (do not lower BP on first day) and management strategies
    2. See CVA Blood Pressure Control for acute control
    3. Longterm Blood Pressure goal (after acute CVA stabilization): <130/80 mmHg
    4. ACE Inhibitor with a Diuretic (e.g. Lisinopril/hctz)
      1. Start immediately after hyperacute period
      2. Significantly reduces recurrent CVA risk
        1. (2001) Lancet 358:1033-41 [PubMed]
  2. Low dose non-bolus Heparin (NOT recommended in most cases, see harmful interventions below)
    1. Efficacy
      1. No evidence of benefit in CVA evolution
      2. Less Hemorrhage than ASA by IST trial
      3. CVA reduction 1-2%
      4. Not indicated in most cases (risk without benefit)
        1. Stead (2004) Ann Emerg Med 44:540-2 [PubMed]
    2. Dosing: Goal is PTT approximately twice normal
      1. Dose: 12 mcg/kg/h (NO bolus, by actual weight)
    3. Indications
      1. Cardioembolic CVA
      2. Aortic arch atheroma
    4. Contraindications
      1. Hemorrhagic CVA
      2. Endocarditis on native valve thromboembolic CVA
  3. Avoid potentially harmful interventions
    1. Heparin drip (Regular dose): Do Not Use
      1. No significant benefit by IST trial
      2. Risk of Hemorrhage (especially with bolus)
    2. Low Molecular Weight Heparin
      1. Dose dependent CVA reduction by Hong Kong Study
      2. No benefit and high Hemorrhage risk by TOAST study
    3. Warfarin (Coumadin)
      1. Not recommended in the prevention of Ischemic CVA
      2. Increased bleeding risk, and not more effective than Antiplatelet Therapy
      3. Halkes (2007) Lancet Neurol 6(2): 115-24 [PubMed]
    4. Emergent Anticoagulation not indicated
      1. Recurrent stroke in first 14 days is only 0.06%
      2. Can start in first 48 hours after CVA
      3. Bolus therapy is not indicated
    5. Do not lower Blood Pressure aggressively on first day
      1. See CVA Blood Pressure Control
    6. Ibuprofen
      1. Inactivates Aspirin positive effect
      2. Unclear if other NSAIDs also reduce Aspirin benefit

VI. Management: Evaluate for reversible and modifiable disease

  1. See Transient Ischemic Attack
  2. Large artery atherosclerosis
    1. Carotid Stenosis (e.g. Carotid Endarterectomy)
      1. Indications for Carotid Endarterectomy
        1. See Carotid Stenosis
        2. Carotid endarterectomy is recommended for Carotid Stenosis >70% (and possibly >50%)
        3. Indications depend on patient perioperative risk, comorbidity, age and symptoms
      2. Timing of Carotid Endarterectomy
        1. Optimally performed within 2 weeks of CVA
      3. Efficacy of Carotid Endarterectomy
        1. Carotid Endarterectomy has an NNT 7 to prevent recurrent CVA in 5 years
    2. Intracranial atherosclerosis
      1. Dual antiplatelets for 90 days, then Aspirin 325 mg daily
      2. Cardiovascular Risk Reduction
      3. Target Blood Pressure <140/90 mmHg (higher target due to stenosis CVA risk)
    3. Vertebral Artery stenosis
      1. Cardiovascular Risk Reduction
  3. Small Artery Occlusion (Lacunar Stroke)
    1. Antiplatelet monotherapy (may consider initial, short-term Dual Antiplatelet Therapy)
      1. Xie (2023) Stroke 54(9): 2241-50 [PubMed]
    2. Hypertension Management (target BP <130/80 mmHg)
      1. Benavente (2013) Lancet 382(9891):507-15 +PMID: 23726159 [PubMed]
  4. Cardioembolic Disease (esp. Atrial Fibrillation)
    1. Causes
      1. Atrial Fibrillation is responsible for 1 in 7 strokes
      2. Other cardioembolic conditions include PFO and valvular heart disease
    2. Evaluation
      1. Consider Event Monitor or implantable loop recorder in cryptogenic stroke
      2. Echocardiogram
        1. Obtain in all stroke patients
        2. Evaluate for intracardiac thrombus, PFO, reduced EF, valvular disease
    3. Management
      1. Cardiovascular Risk Reduction
      2. Left Atrial Appendage Closure Device (and shorterm Anticoagulation) OR
      3. Longterm Anticoagulation
        1. Direct Oral Anticoagulant (DOAC) OR
        2. Warfarin (INR target 2.5 to 3.5) Indications
          1. Mechanical Heart Valve
          2. Moderate to severe Mitral Stenosis
  5. Cryptogenic CVA
    1. Evaluate for Cardioembolic Disease (esp. Atrial Fibrillation)
    2. Consider 30 day Event Monitor (or implantable loop recorder)
  6. Silent CVA
    1. Incidental, prior Ischemic CVA on MRI Brain imaging is common in older patients
    2. Often associated with Small Artery Occlusion CVA (Lacunar Stroke)
    3. Recurrent CVA risk approaches 2-3 fold
    4. Employ Cardiovascular Risk Reduction (see below)
  7. Specific Conditions related to stroke requiring Anticoagulation, Antiplatelet Therapy or correction
    1. Antiphospholipid Antibody Syndrome
      1. Warfarin (INR 2 to 3) if syndrome is confirmed
      2. Antiplatelet Therapy if Antibody positive only
    2. Cardiomyopathy
      1. Warfarin (INR 2 to 3) for 3 months after Ischemic Stroke
    3. Carotid Artery Dissection or Vertebral Artery Dissection
      1. Anticoagulation for 3 months following stroke, then Antiplatelet Therapy
    4. Fibromuscular Dysplasia
      1. Urgent risk reduction (see below)
      2. Antiplatelet Therapy if dissection
    5. Temporal Arteritis (Giant Cell Arteritis)
      1. See Temporal Arteritis
      2. High dose Corticosteroids
    6. Hypercoagulable State
      1. Antiplatelet Therapy
    7. Left Ventricular Thrombus
      1. Myocardial Infarction complication
      2. Warfarin (INR 2 to 3) for 3 months after Ischemic Stroke
    8. Sickle Cell Disease
      1. See CVA in Sickle Cell Disease
      2. Blood Transfusion to reduce Hemoglobin S to less than 30% of total Hemoglobin
  8. Surgery Indications following Cerebrovascular Accident
    1. See Carotid Endarterectomy as above
    2. Cardiac Tumor
    3. Infective Endocarditis
    4. Moyamoya Disease (Occlusive disease of Circle of Willis)
    5. Patent Foramen Ovale (PFO)
      1. Indications for PFO Closure
        1. Age <60 years (esp. large shunts or atrioseptal aneurysm)
        2. PFO Closure NNT 29 to prevent recurrent CVA in 5 years
      2. Alternatives to PFO closure
        1. Anticoagulation (DOAC, Warfarin)
      3. References
        1. Messe (2020) Neurology 94(20): 876-85 [PubMed]

VII. Management: Longterm Prevention (Primary and Secondary Prevention)

  1. Key measures that reduce Ischemic Stroke recurrence (>80%)
    1. Antihypertensives
    2. Statin Therapy
    3. Diet modifications (DASH Diet, Mediterranean Diet)
    4. Exercise
    5. Aspirin
    6. Blood Glucose management
    7. Tobacco Abuse
    8. Obstructive Sleep Apnea management
    9. Hackam (2007) Stroke 38(6): 1881-5 [PubMed]
    10. Wu (2023) Stroke 54(9): 2369-79 [PubMed]
  2. Antiplatelet agents after Non-Embolic CVA or TIA
    1. Antiplatelet agents are key in non-embolic CVA
      1. Contrast to Anticoagulation for embolic CVA (e.g. Atrial Fibrillation, valvular disease, PFO)
      2. See Anticoagulation in Atrial Fibrillation
    2. First-Line options (after first 21 days)
      1. See above for acute antiplatelet management (for immediate, first 21 days)
      2. Background: Agent comparison
        1. Aspirin alone offers 18-22% Relative Risk Reduction of subsequent stroke or TIA
        2. Aggrenox or Plavix each offer a 37% Relative Risk Reduction of subsequent stroke or TIA
      3. Aspirin 81 to 325 mg daily
        1. Use concurrently with PPI if history of GI Bleeding on Aspirin
      4. Clopidogrel (Plavix) 75 mg daily
        1. Indicated if Aspirin intolerant or high risk
        2. Equivalent to Aggrenox in cerebrovascular event risk reduction
        3. Slightly lower risk of GI Bleeding than with Aggrenox
      5. Aspirin 50 mg with Dipyridamole 400 mg (Aggrenox)
        1. Consider over Aspirin in highest risk patients (TIA or CVA on Aspirin)
        2. Better efficacy over Aspirin alone (and similar to reduction with Plavix)
        3. Minimal increased risk of bleeding
        4. Poorly tolerated (stopped due to Headache in 25%) and twice daily
        5. Expensive! ($320 versus Aspirin $1 or Clopidogrel $10 per month)
        6. References
          1. Diener (1996) J Neurol Sci 143:1-13 [PubMed]
          2. Halkes (2006) Lancet 367:1665-73 [PubMed]
    3. Avoid Warfarin (Coumadin) after nonembolic stroke
      1. No advantage over Aspirin to prevent recurrent CVA
      2. Warfarin is indicated in thromboembolic stroke (esp. Atrial Fibrillation)
      3. Mohr (2001) N Engl J Med 345:1444-51 [PubMed]
    4. Avoid combination of Aspirin and Clopidogrel longterm (aside from 3 week acute course)
      1. Bleeding risk outweighed small vascular benefit
        1. Diener (2004) Lancet 364:331-7 [PubMed]
      2. However consider for first 3 weeks following mild CVA or TIA
        1. See above (under short-term)
  3. Other measures
    1. Treat Coronary Artery Disease
    2. Optimize Diabetes Mellitus control
      1. Screen for Diabetes Mellitus (Fasting Glucose, Hemoglobin A1C, OGTT) in undiagnosed patients
      2. Maintain Blood Pressure <130/80 (most important)
      3. Maintain Fasting Glucose <126 mg/dl (Hemoglobin A1C <7%)
      4. Weight loss
      5. First-Line Agents
        1. Metformin
        2. GLP-1 Agonist
        3. Pioglitazone
      6. Other agents that may lower overall cardiovascular events
        1. SGLT2 Inhibitors (Flozins)
      7. Avoid agents that are associated with increased risk of cardiovascular events (including Ischemic CVA)
        1. Sulfonylurea
        2. Rosiglitazone
    3. Control Hyperlipidemia
      1. Goal LDL Cholesterol <70-100 mg/dl
        1. LDL Cholesterol <70 mg/dl compared with 95 mg/dl decreases risk of CV event in 3.5 years (NNT 42)
        2. Amarenco (2019) N Engl J Med 382:9-19 [PubMed]
      2. High Intensity Statin Drugs are preferred
        1. Atorvastatin (Lipitor) 40 to 80 mg daily
        2. Rosuvastatin (Crestor) 20 mg daily
    4. Control Hypertension to Blood Pressure target (after initial 24-48 hours)
      1. Avoid Blood Pressure lowering in first 24 hours of acute CVA (except Hemorrhagic CVA, Thrombolytics)
      2. Longterm target Blood Pressure <130/80 following CVA, as well as for Diabetes Mellitus and CKD
      3. Systolic Blood Pressure as a predictor of subsequent stroke (Hazard Ratios)
        1. Maximum systolic Blood Pressure: Hazard Ratio 15
        2. High variability in systolic Blood Pressure: Hazard Ratio 6
        3. Rothwell (2010) Lancet 375(9718): 895-905 [PubMed]
      4. First-Line Interventions
        1. See DASH Diet
        2. Thiazide Diuretics
        3. Angiotensin Receptor Blockers (or ACE Inhibitor)
      5. Additional agents if needed
        1. Calcium Channel Blockers
          1. May lower Blood Pressure lability
          2. However, unknown efficacy in CVA Prevention
        2. No evidence for Beta Blockers in CVA Prevention
          1. De Lima (2014) Cochrane Database Syst Rev 2014(10):CD007890 +PMID: 25317988 [PubMed]
    5. Manage Major Depression (up to 20% of patients after stroke)
      1. Screen for and treat comorbid Major Depression
      2. Reduces mortality after Ischemic Stroke
      3. Consider Selective Serotonin Reuptake Inhibitor (SSRI
      4. Jorge (2003) Am J Psychiatry 160:1823-9 [PubMed]
    6. Tobacco Cessation
      1. Tobacco Cessation is the single most effective measure in CVA Prevention (NNT 14.5 for 1 CVA death)
      2. Risk of CVA is 50% higher in smokers
      3. Shinton (1999) BMJ 298:789-94 [PubMed]
    7. Alcohol only in moderation
      1. Alcohol in moderation (1-2 drinks per day in men) may reduce the risk of recurrent CVA
      2. Heavy Alcohol use (>4/day in men, >3/day in women) increases the risk of recurrent CVA
        1. Mostofsky (2010) Stroke 41(9): 1845-9 [PubMed]
    8. Drug Abuse Cessation
      1. Cocaine and Methamphetamine increase risk of cardiovascular events
      2. Intravenous drug use increases risk of Infective Endocarditis
    9. Physical Activity
      1. AHA/ASA recommends Exercise to lower CVA recurrence risk
        1. Perform Exercise 10 min four times weekly or 20 min two times weekly
      2. Target regular Exercise >30 minutes, >3 days/week (120 to 150 min/week)
      3. Break up sedentary time with 3 min light activity every 30 min (improves Blood Pressure)
      4. High intensity Exercise is associated with a 64% CVA Relative Risk Reduction
      5. Lee (2003) Stroke 34(10): 2475-81 [PubMed]
    10. Nutrition
      1. Limit Dietary Fat, processed meat, fried food and sugar sweetened beverages
        1. Judd (2013) Stroke 44(12): 3305-11 [PubMed]
      2. Fish intake (1-4 servings per month)
        1. Lowered Ischemic Stroke risk by 40%
        2. He (2002) JAMA 288:3130-6 [PubMed]
      3. Mediterranean Diet
        1. Fung (2009) Circulation 119(8): 1093-1100 [PubMed]
      4. DASH Diet
        1. Chiavaroli (2019) Nutrients 1(2):338 +PMID: 30764511 [PubMed]
    11. Weight loss (in Obesity)
      1. Increased waist to hip ratio (Apple Obesity) is associated with an increased CVA risk (OR 1.65)
      2. Weight loss also improves Hypertension, dyslipidemia and Type 2 Diabetes MellitusGlucose control
    12. Obstructive Sleep Apnea (OSA
      1. Present in 50-70% of patients with prior stroke or TIA
      2. Screen for OSA (e.g. STOP-Bang Questionnaire)
      3. Treat moderate to severe OSA
  4. Ineffective measures
    1. Homocysteine modification with Vitamins not effective
      1. Toole (2004) JAMA 291:565-75 [PubMed]

VIII. References

  1. (2015) Presc Lett 22(9): 53
  2. Lyden (2001) CMEA Medicine Lecture, San Diego
  3. Lyden (1998) CMEA Medicine Lecture, San Diego
  4. Adams (2007) Stroke 38(5): 1655-711 [PubMed]
  5. Beauchamp (1999) Radiology 212(2):307-24 [PubMed]
  6. Dickerson (2007) Am Fam Physician 76(3):382-8 [PubMed]
  7. Ford (2026) Am Fam Physician 113(1): 57-69 [PubMed]
  8. Kernan (2014) Stroke 45(7): 2160-236 [PubMed]
  9. Kleindorfer (2021) Stroke 52(7):e364-7 +PMID: 34024117 [PubMed]
  10. Ingall (2000) Postgrad Med 107(6):34-50 [PubMed]
  11. Larson (2023) Am Fam Physician 108(1): 70-7 [PubMed]
  12. Loza (2017) Am Fam Physician 96(7): 436-40 [PubMed]
  13. Sacco (2000) Arch Intern Med 160(11):1579-82 [PubMed]
  14. Simmons (2012) Am Fam Physician 86(6): 527-32 [PubMed]
  15. Solenski (2004) Am Fam Physician 69:1691-8 [PubMed]

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