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A. Considerations in Acute Treatment of Thromboembolic Stroke

  1. Thromboembolic stroke should be considered a medical / neurological emergency
    1. Stroke care units (SCU) are probably the most important advance in last decade
    2. Management in SCU reduces mortality by >20% and improves functional outcomes
  2. Key Early Decisions [16]
    1. Rule out hemorrhagic component
    2. If carotid territory stroke, consider carotid endarterectomy
    3. Give aspirin (ASA) or clopidogrel (Plavix®) if ASA intolerant unless TPA to be given
    4. Consider thrombolysis with tissue plasminogen activator (TPA) if within 3 hours [1,3]
    5. Reduce blood pressure (BP) but maintain above 130/70
    6. Evaluate for atrial fibrillation (AFib) with electrocardiogram (ECG)
    7. Prevent aspiration and deep vein thrombosis (DVT)
  3. Rule out Hemorrhagic Component
    1. MRI (preferred) or computed tomographic (CT) scan as soon as possible [11]
    2. MRI is superior to CT for detection of acute ischemic stroke, similar for hemorrhage [11]
    3. If >7 days after symptom onset, magnetic resonance imaging (MRI) to exclude bleed
  4. Carotid Endarterectomy
    1. If stroke in carotid territory, likely cerebrovascular disease responsible
    2. If good recovery and surgery a possible option, evaluate with carotid duplex ultrasound
    3. Refer for surgery if >70% stenosis on symptomatic side
    4. Endarterectomy efficacy greatest in men > women, age >75 years, and when done within 2 weeks of last ischemic event [41]
    5. Carotid artery stenting with an emboli-protection device is not inferior to carotid endarterectomy [6]
    6. In patients with symptomatic carotid stenosis of >60%, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting [59]
  5. Antiplatelet Therapy
    1. If no hemorrhage, antiplatelet therapy should be given unless TPA is to be given [16]
    2. ASA 160-325mg by mouth (or rectum) should be given immediately
    3. Thereafter, daily maintenance 75-150mg aspirin daily should be given
    4. Clopidogrel 75mg qd prevents second strokes better than aspirin
    5. Dipyridamole with or without aspirin reduces recurrent stroke [52]
    6. ASA may be combined with clopidogrel or dipyridamole if CVA occurs on aspirin
    7. ASA 150mg qd + dipyridamole 200mg bid if CVA on ASA alone
  6. Thrombolysis (see below) [3,4,16]
    1. TPA should be strongly considered within 3 hours of symptom onset [3]
    2. TPA is relatively safe and effective within 3 hours of symptom onset [3,5]
    3. TPA showed no overall benefit when given within 3-5 hours [7]
    4. Streptokinase within 6 hours of stroke onset harmful (increased death) [9]
    5. Streptokinase within 3 hours provided no benefit overall versus placebo [9]
    6. Intra-arterial TPA is effective and complete vessel opening occurs in ~45% [4]
    7. Risk of bleeding is high, so careful evaluation of imaging study is required
    8. Most agents increase risk for intracranial hemorrhage and other bleeding by ~10X
    9. Gradient recalled echo (GRE) MRI is most sensitive for detection of acute hemorrhage []
  7. Anticoagulation
    1. Use of any heparin is controversial except in specific syndromes
    2. Benefit clear for heparin when a cardiac embolic source (such as AFib) is likely
    3. Posterior / Cerebellar Stroke (except Wallenberg Syndrome) - data are weak
    4. Do not use in large embolic strokes (may cause hemorrhage) until 3-5 days post-stroke
    5. LMW Heparin is safer and may be more effective than regular heparin
    6. LMW heparins are not superior to ASA for treatment of acute ischemic stroke [12]
    7. Low dose (5000U sc bid) standard heparin, or LMW heparin, reduce DVT in stroke patients [12]
    8. The LMW heparin enoxaparin (Lovenox®) is more effective than standard heparin for DVT prevention in stroke [10]
    9. Enoxaparin has slightly higher extracranial major bleeding but not overall bleeding [10]
  8. Mechanical Embolus Removal [15]
    1. Mechanical embolectomy - removal of clot in cerebral vasculature
    2. Studies performed 3-8 hours after symptom onset
    3. Also used with <3 hours of symptoms if thrombolysis contraindicated
    4. Canalization with emobolectomy only ~40%; can add intra-arterial TPA (~65% canalization)
    5. Recovery at 1 month in 50% (9/18) of recanalized and 0 of 10 non-recanalized patients
    6. Requires excellent skill but has shown very good results to date
    7. Unclear how mechanical recanalization compares with direct intra-arterial TPA
    8. May be especially useful for occluded circle of Willis vessels
    9. FDA approved Concnetric Merci Retrieval System in 2004
  9. Caridac monitoring should be used for at least 24 hours, since MI and arrhythmias can occur [16]

B. Recommended Acute Therapy [1,2,16]

  1. Acute Noncardioembolic Stroke
    1. Aspirin (ASA) - 160-325 mg po x 1 then 160-325mg/d if no TPA to be used [13,16]
    2. LMW heparin (preferred) or standard heparin prevents DVT [12]
    3. Heparin (IV high dose) - carotid plaque rupture with progression only
    4. Thrombolysis within 3 hours in selected patients [1,3]
    5. Stroke specialist evaluation preferred if thrombolysis is contemplated (see below)
    6. Reduction of BP to SBP <220 and DBP <120 mmHg with intravenous agents
  2. Acute Cardioembolic Stroke
    1. Cardioembolic Sources:
    2. Recent onset AFib
    3. Recent myocardial infarction
    4. Carotid plaques
    5. Other known atherosclerotic lesions
    6. IV heparin or SC LMW Heparin - LMW heparin is more effective and safer than standard
    7. ASA - 325mg/day usually recommended
    8. Warfarin longer term if underlying chronic condition such as atrial fibrillation
    9. Lower BP slowly only if diastolic >120mm or systolic >220mm
  3. Unstable or Progressing Stroke
    1. ASA - as above [13]
    2. LMW or IV Heparin (after MRI or CT Scan to rule out hemorrhage)
    3. Emergent endarterectomy should be considered if significant carotid disease is found
  4. Acute TIA [49]
    1. ASA - prevents recurrence of TIAs or strokes
    2. Clopidogrel - patients with ASA allergies, high risk, Females (less responsive to ASA)
    3. IV Heparin - Vertebrobasilar (posterior) or Crescendo TIA or cardioembolic source
    4. LMW Heparin subcutaneously is as effective and safe as IV heparin; easier to dose
  5. Post-TIA or Post-Stroke
    1. ASA 160-325mg/d strongly recommended as reduces recurrence rates
    2. Clopidogrel 75mg qd should be used in ASA intolerant patients
  6. Carotid Stenosis
    1. ASA ± anticoagulation therapy (particularly with repeat TIAs)
    2. Symptomatic patients with >69% stenosis - endarterectomy is recommended
    3. With symptomatic moderate carotid stenosis (50-69%), 5 year risk of ipsilateral stroke is 15.7% with endarterectomy, 22.2% with medical therapy [17]
    4. Thus, for 50-69% stenosis, 15 patients require endarterectomy for one to benefit
  7. Non-Rheumatic AFib
    1. Warfarin (clearly beneficial over aspirin)
    2. Aspirin if anti-coagulation contraindicated
    3. Subcutaneous, outpatient, LMW heparin is also acceptable
  8. Massive Stroke with Edema [40]
    1. Massive infarction usually due to internal carotid or proximal middle cerebral artery occlusion
    2. Midline shift due to edema can occur leading to risk for herniation
    3. Called "malignant middle cerebral artery" edema syndrome
    4. Neurosurgical intervention is required; condition is 80-90% fatal
  9. Stroke with patent foramen ovale (PFO) treated with warfarin and correction (see below)
  10. Consider mechanical embolectomy if available [15]

C. Thrombolytics [1,2,3]

  1. Overview of Thrombolytics [16]
    1. In general, use after 4 hours of symptom onset shows no overall benefit
    2. Recombinant TPA (rTPA, Alteplase®) provides fastest clot dissolution
    3. TPA approved for up to 3 hours after symptom onset; some benefit up to 6 hours seen
    4. Guidleines for use of TPA must be strictly adhered to
    5. MRI generally preferred over CT for initial evaluation
    6. Early ischemic changes on CT scan predict stroke severity but not benefit from TPA [14]
    7. Older age and reduced consciousness predict poor outcomes with TPA [46]
    8. TPA led to recanalization in ~50% of basilar artery occlusion and is associated with good outcomes and survival rates superior to historical controls [48]
    9. Transcranial Doppler ultrasound enhanced systemic TPA induced arterial recanalization with trends to increased recovery from stroke [50]
  2. Characteristics of Stroke Patients Eligible for Intravenous TPA [4]
    1. Age 18 or older
    2. Ischemic stroek with clinically apparent neurologic deficit
    3. Onset of symptoms within 3 hours before initiating treatment
    4. No stroke or head trauma during preceeding 3 months
    5. No major surgery during preceeding 14 days
    6. No history of intracranial hemorrhage
    7. Blood pressure systolic <220, diastolic <110 mmHg
    8. No rapidly resolving symptoms or only minor symptoms of stroke
    9. No symptoms suggesting subarachnoid hemorrhage (such as severe headache)
    10. No gastrointestinal or urinary tract hemorrhage within past 21 days
    11. No arterial puncture at non-compressible site within last 7 days
    12. No seizure at onset of stroke
    13. Prothrombin time <16 seconds or INR <1.7 wihtout use of anticoagulant drug
    14. Partial thromboplastin time within normal range if heparin was used in past 48 hours
    15. Platelet count >100,000/µL
    16. Blood glucose >50mg/dL (>2.7mmol/L); hypoglycemia can mimic stroke or bleed
    17. No need for aggressive measures to lower blood pressure to within limits above
    18. Advanced age and reduced level of consciousness predict high in-hospital mortality [46]
  3. ECASS II TPA Study [8]
    1. TPA 0.9mg/kg (same to NINDS) given within 6 hours of onset of symptoms
    2. Very careful analysis of initial CT scan led to increased exclusion of patients
    3. No overall benefit for patients receiving TPA versus placebo at 3 months (Rankin Score)
    4. No benefit to early (0-3 hours) versus late (3-6 hours) treatment with TPA
    5. Increase in low level disability (Rankin Score 0-2) with TPA versus placebo
    6. Intracranial hemorrhage in 8.8% with TPA versus 3.4% with placebo
    7. TPA may benefit a small number of patients with acute thromboembolic stroke
  4. NINDS rTPA Stroke Study [5]
    1. Large US Stroke Study with rtPA given within 3 hours of ischemic stroke
    2. Showed benefit in disability level but no difference in mortality
    3. Disability benefit levels were improved with rtPA and maintained over >12 months [17]
    4. Bleeding rates were ~10X higher in rtPA group but neurologic recovery was better
    5. Further studies are needed to define predictors of hemorrhage and response
    6. Negative data with SK and high rate of hemorrhage with TPA are very concerning
  5. Streptokinase (SK) Studies [9,18]
    1. 622 / 310 patients given 1.5MU of SK (1 hour) alone, with aspirin, or placebo only
    2. ASA showed some benefit which was not significant [8]
    3. SK alone or with ASA had higher death rates at 10 days and 6 months versus placebo [8]
    4. SK + ASA was particularly dangerous with increased early and late mortality
    5. SK alone caused increased mortality at 10 days and 6 months [18]
    6. Like all fibrinolytics, SK is contraindicated in hemorrhage stroke
  6. Treatment of Stroke Patients with TPA [4]
    1. Determine eligibility by criteria above (C.2.)
    2. TPA dosed 0.9mg/kg (maximum 90 mg) over 60 minute period
    3. First 10% of TPA dose is given as a bolus over a 1 minute period
    4. Neurologic examinations every 15 minutes during infusion of TPA, every half hour over next 6 hours, and every hour for next 16 hours (intensive care or SCU)
    5. Measure blood pressure every 15 minutes for 2 hours, every 30 min for 6 hours, and every 60 min fornext 16 hours (repeat more often for systolic >180 or diastolic >105)
    6. Maintain blood pressure <180/105 with antihypertensive agents as needed
    7. Lack of improvement within 24 hours of TPA is associated with poor outcome, death [47]

D. Chronic Therapy [1,16,21]

  1. Treatment using existing modalities within 1 day (versus usual 3-20 days) after TIA or minor stroke reduces risk of recurrent stroke at 90 days from 10.3% to 2.1% [61]
  2. Lifestyle Modifications
    1. Stop smoking
    2. Reduce weight
    3. Begin exercise program
  3. Antiplatelet Therapy [19,43,39]
    1. Clopidogrel (Plavix®) is superior to ASA after initial ischemic event [42]
    2. Clopidogrel 75mg qd should be used for secondary prevention after TIA or stroke
    3. Aspirin 75mg qd combined with clopidogrel shows only minor reduction in ischemic events with a significant increase in severe hemorrhage [43]
    4. Clopidogrel 75mg qd should probably be used alone in most patients after TIA or stroke
    5. If ASA is used, it should usually be combined with dipyridamole [16,52,56]
    6. Ticlopidine should not be used due to neutropenia and thrombocytopenia
  4. ASA
    1. Can be given acutely: 160-325mg x 1-2 doses
    2. Adding dipyridamole to ASA reduces recurrent stroke or stroke after TIA [52,56]
    3. Clopidogrel is used in any patients allergic to ASA
    4. In black patients, ticlopidine 500mg/d no more effective than ASA 650mg/d [22]
    5. For chronic, secondary prevention, clopidogrel is superior to ASA [42]
    6. If ASA is used alone, at least 160mg/day should be given [54]
    7. ASA should generally not be used alone in high risk patients
    8. ASA 81mg/d may be added to clopidogrel 75mg po qd but has minimal benefit, increased risk of bleeding [43]
    9. Warfarin showed no benefit but increased complications compared with ASA for secondary stroke prevention [23]
  5. Dipyridamole (Persantine®) [52]
    1. With or without ASA reduces risk of recurrent stroke
    2. Risk reductions are modest, with 24-53 patients treated for every 1 benefit
    3. Should not be used alone due to only modest effects
    4. Dose is 200mg po bid for adults
  6. Long Term Anticoagulation for AFib
    1. Long term for all patients with AFib not in sinus rhythm
    2. Warfarin adjusted dose is highly preferred in AFib
    3. ASA and low dose warfarin are clearly inferior to standard dose warfarin
    4. Combination of adjusted dose warfarin and low dose ASA may be considered
  7. Statin Therapy for All Stroke Patients [44]
    1. Reduce cholesterol with statins regardless of cholesterol levels
    2. Regardless of presence or absence of coronary artery disease (CAD)
    3. Statins provide ~20% relative risk reduction in primary and secondary stroke prevention
    4. Atorvastatin 80mg po qd (high dose) reduced recurrent stroke after TIA or stroke but no known CAD by 16%, and reduced major cardiovascular events 20% within 5 years [57]
  8. Blood Pressure
    1. Initial treatment with diuretic unless comorbid conditions present
    2. ACE inhibitors first line across all patient groups
    3. ACE Inhibitor Perindopril reduced risk of recurrent stroke 28% or any cardiovascular event in patients with previous stroke [24]
    4. Goal chronic BP ~130/80 but not lower (may lead to cerebral hypoperfusion)
  9. Carotid Endarterectomy [25,26]
    1. Clear benefit for symptomatic carotid stenosis >70%
    2. Some benefit for symptomatic carotid stenosis 50-69%
    3. Not used for total carotid occlusion
    4. Percutaneous carotid stenting may be a safer alternative to endarterectomy [27]
  10. Patent Foramen Ovale (PFO) [36,37,53]
    1. PFO diameter is an independent risk factor for all ischemic events, especially strokes
    2. ~55% of patients with cryptogenic embolic stroke have PFO, versus 27% PFO overall
    3. Transcatheter closure of PFO is now safe and very effective
    4. Transcatheter closure of PFO may prevent cryptogenic embolic strokes
    5. Young patients with cryptogenic stroke should have echocardiographic evaluation for PFO
    6. Warfarin for 3-6 months followed by aspirin and repair of PFO recommended [53]
  11. Post-Stroke Depression [20]
    1. Depression is very common (>50%) after stroke: "post-stroke depression"
    2. Assessment for depression after stroke critical for treatment and rehabilitation
    3. After stroke, treatment with escitalopram 10-20mg qd was more effective than problem-solving therapy and placebo in preventing post-stroke depression [20]
  12. Botulinum Toxin A (Botox) [29]
    1. Neuromuscular junction blockade
    2. Botox injection causes muscle paralysis
    3. Improved wrist and finger spacticity after stroke for more than 12 weeks
  13. Levodopa 100mg po qd x 3 weeks with physiotherapy improved hemiplegic recovery [28]
  14. Estrogen replacement therapy (ERT) after stroke or TIA does not reduce recurrence or improve outcomes over ~3 years [30]
  15. Reducing moderately elevated homocysteine with Vit B6 + B12 + folate after initial non- disabling stroke did not reduce recurrent stroke, MI, or death after 2 years [39]
  16. Rehabilitation after Stroke [51]
    1. Increasing expertise in improving condition after stroke
    2. Week 1, acute hospitalization: assess ability to swallow, other activities of daily living (ADL)
    3. Weeks 2-6, inpatient rehabilitation: compensatory techniques, focus on limb training, first simple movements then increasingly complex tasks, reward with feedback
    4. Months 1-6 outpatient rehabilitation: simple, relevant test-retest methods with rewards, progressively intensive practice to maximum level, improve strength, endurance; then task oriented activities relevant to daily needs of patient and family
    5. Beyond 6 months: improvement in skills needed in usual roles and out-of-home activities
    6. Aphasia should be addressed within 1 month of stroke, probably maintained at least 1 year
    7. Constaint-induced movement therapy for 2 weeks performed 3-9 months after stroke led to significant improvements in arm motor function that persisted >1 year [58]
    8. Intensity of speech therapy correlates with good outcomes (5 hours or more weekly)
    9. Long term aerobic and resistance training, exercises to enhance flexibility, balance, coordination

E. Experimental Therapies

  1. Calcium Blocking Agents
    1. Calcium influx into neurons is required in many types of neuronal death
    2. Ischemic neuronal death appears to involve calcium pathways
    3. Blocking calcium influx using various approaches has been studied in great detail
    4. May increase local perfusion to "penumbra" (adjacent) areas of brain tissue
    5. The dihydropyridine nimodipine is indicated in hemorrhagic stroke
    6. When begun within 12 hours of stroke, significant improvement in all strokes observed
    7. Nimodipine may be considered in patients with thromboembolic stroke
  2. NMDA Antagonists
    1. NMDA (N-methyl-D-asparate) binds to a receptor mediated calcium channel
    2. NMDA receptor is related to excitatory glutamate channels
    3. Phase III study of cerestat was halted due to safety concerns
    4. Phase III study of gavestinel, a selective antagonist of glycine site on NMDA receptor, showed no benefit when given within 6 hours of stroke [31,32]
    5. Phase III study of aptiganel, a selective antagonist of ion-channel site of NMDA receptor, was harmful in patients within 6 hours of onset of stroke [33]
    6. NMDA antagonist memantine being investigated in Alzheimer's disease [34]
  3. Glutamate Pathway Inhibition
    1. Inhibiting presynaptic glutamate release also blocks NMDA receptor activation
    2. Blocking sodium conducting channels inhibits glutamate release in neurons
    3. Several anti-seizure agents block sodium conducting channels
    4. Fosphenytoin (antiepileptic) has shown safety in phase II; now in phase III
    5. Lubeluzole has shown untoward effects in Phase III trials
  4. AMPA Antagonists
    1. AMPA is alpha-amino 3-hydroxy 5-methyl 4-isoxazole
    2. AMPA receptor binds glutamate and this regulates a sodium channel
    3. AMPA receptors mediate sodium and some calcium influx in ischemic brain tissue
    4. AMPA antagonists are thusfar toxic
    5. Development of novel agents is underway
  5. Growth Factors
    1. Fibroblast growth factors (FGF) have some activity in animal models of stroke
    2. ß-FGF is safe in phase II stroke trials; phase III underway
    3. Main effects may be on functional recovery (day 28) rather than acute infarct size
    4. Nephrotoxicity has been noted and are of some concern
    5. Other nerve growth factors are being developed and tested
  6. Ancrod [26,60]
    1. Derived from pit viper snake venom
    2. Reduces clot formation by splitting fibrinopeptide A from fibrinogen
    3. Reduction of serum fibrinogen levels also decreases blood viscosity
    4. Improved functional status compared with placebo when used within 3 [26] but not 6 [60] hours of stroke onset
    5. Increased intracranial hemorrhages by ~9% compared with placebo rates
    6. No effect on mortality (about 25% at 90 days)
  7. Reperfusion Injury Blockers
    1. Complement system antagonists
    2. Neutrophil blockers
    3. Anti-oxidants (free radical scavengers)
    4. Proteasome inhibitors
    5. Citicholine - precursor of lipids, anti-oxidant with neural restorative activities
    6. Magnesium - neuroprotective in animal models; no overall benefit in acute stroke [38]
  8. Free-Radical Scavenger NXY-059 [55]
    1. Reduces size of infarct in various animal stroke models and is neuroprotective
    2. Administration within 6 hours in acute stroke reduced disability at 90 days
    3. No effect on NIH Stroke Scale or Barthel index

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