Stroke Lecture 2017





  1. Ensure medical stability
  2. Quickly reverse any condition contributing to the symptoms
  3. Determine eligibility for thrombolytic therapy
  4. Uncovering pathophysiologic basis of neurologic symptoms


Important concepts:

  1. tPA Improves functional outcome at 3-6 months when given within 4.5 hours of stroke onset
  2. Benefit of thrombolysis decreases over time
    1. Each 15 min reduction in time to tPA associated with
      1. increase odds of walking independently at discharge (4%)
      2. increase odds of being discharged to home vs institution (3%)
  • decrease odds of death before discharge (4%)
  1. decrease odds of symptomatic hemorrhagic transformation of infarction (4%)
  1. THEREFORE: Give ASAP, do not delay until end of “time window”
  1. Early IA treatment with 2nd gen thrombectomy devices is safe and effective for prox anterior circulation large artery occlusion




IST-3 Trial

  1. Effectiveness of tPA from 4.5-6h equivocal
  2. 3035 adults within 6h, tPA vs alteplase
    1. Nonsignificant trend for favorable outcome (alive and independent) (37% vs 35% OR 1.13, 95% CI 0.95-1.35)
    2. Subgroup of 4.5-6h – nonsignificant trend towards favorable outcome (47% vs 43%, adj OR 1.31, 95% CI 0.89-1.93)


*early treatment

*selection of appropriate candidates – neuro exam, neuroimaging, inclusion exclusion


*22% of all AIS present to ED within 3 hours, only 8% meet eligibility criteria


GOAL of tPA: clot lysis à recanalization à restoration of blood flow à rescue of ischemic brain tissue à improvement in clinical outcome


MA of 53 studies (2002):

  • 2066 patients
  • recanalization associated with good functional outcome (3mos) OR 4.43 95% CI 3.32-5.91
  • recanalization associated with reduced mortality (3 most) OR 0.24 95% CI 0.16-0.35
  • symptomatic ICH similar (OR 1.11 95% CI 0.71-1.74)
  • recanalization varies accdg to intervention:
    1. Spontaneous, 24.1%
    2. IV thrombolysis, 46.2%
    3. IA thrombolysis, 63.2%
    4. IV+IA thrombolysis, 67.5 %
    5. Mechanical, 83.6%


Factors affecting recanalization:

  1. Location of occlusion in the arterial tree
    1. More proximal occlusion more resistant to thrombolysis
    2. Clots in cervical ICA promotes adjacent thrombosys, long thrombus unlikely to be lyzed by IV tPA alone
  2. Clot-specific factors: size, composition, source
    1. SIZE: Larger clots more resistant to thrombolysis
    2. SOURCE: In situ thrombosis / atherosclerotic lesions more resistant than fibrin-rich cardiac emboli
    3. COMPOSITION: recanalization related to amount of RBC, inversely to volume of emboli, and fibrin content, and density of clot, tPA unlikely to disrupt calcified plaque / fat1
    4. AGE: tPA more effective for recent thromboemboli; thrombectomy more effective for older thromboemboli; (fibrin / plasminogen content replaced) hyperacute thromboemboli may be platelet rich, less amenable to lysis
  3. Availability of collateral supply
  4. Elevated HCT – reduced reperfusion, larger infarct size *HCT determines whole blood viscosity, inversely related to cerebral blood flow


  • EC ICA occlusion: IV tPA associated with partial or complete recanalization in 63%, often high-grade stenosis persists
  • Carotid T occlusion: occlusion of ICA at bifurcation, IV tPA resulted in complete or partial recanalization in 40-67% within 24-36h
  • MCA occlusion: complete recanalization in 39% by 2 hours, 9 % with tandem stenosis of ICA; prox MCA occlusion opened by IV tPA in ~20%, complete MCA recanalization at 24h in 53-68%

Hyperdense artery sign / dense MCA sign:  hyperdensity of the MCA on noncontrast CT

  • Highly specific, poorly sensitive sign of MCA occlusion
  • Associated with lower rates of favorable outcome at 90d

Hypointense signal on MRI (GRE or T2W sequences)

  • Denotes acute thrombosis / occlusion of MCA – AKA MCA susceptibility sign
  • Often accompanied by ICA occlusion
  • Associated with failed recanaliztion after tPA


Basilar occlusion

  • Limited data regarding recanalization therapy


Should we exclude patients >80?

  1. Patients >=80y/o appear to benefit from tPA despite higher mortality, risk of symptomatic ICH increased, but evidence conflicting
  2. MA: 1711 pts >80, 5174 pts <=80;
    1. tPA within 3 hours, OR for favorable outcome at end of f/u similar (>80 years, OR 1.68, 95% CI 1.20-2.34; ≤80 years, OR 1.51, 95% CI 1.18-1.93)
    2. tPA within 6 hours, reduced benefit, but remained similar (>80 years, OR 1.22, 95% CI 0.98-1.53; ≤80 years, OR 1.16, 95% CI 1.04-1.29).
  3. do not exclude older patients from IV tPA for AIS



  1. initial stroke severity and severe ipsilateral carotid disease associated with increased risk of early MCA reocclusion after tPA therapy
  2. measures to prevent reocclusion?
  3. Small pilot study: reocclusion treated with IV abciximab (G2B3A antagonist) – 4 patients, successful restoration of flow


In a prospective study, 4 patients with reocclusion after tPA clot lysis were treated with abciximab.  a 0.2mg/Kg bolus was given, followed by a maintenance infusion of 0.125 ug/kg/min x 12 hours.


Dose for abciximab in UpToDate (for PCI):


Percutaneous coronary intervention (PCI): IV: 0.25 mg/kg bolus administered 10 to 60 minutes prior to start of PCI followed by an infusion of 0.125 mcg/kg/minute (maximum: 10 mcg/minute) for 12 hours


Recurrent Ischemic Stroke: multiple cerebral vascular territories – likely disintegration and showering of cardiac or aortic thrombi


Thrombectomy recommended regardless of tPA if:

  1. Neuroimaging c/w small infarct core, no hemorrhage
  2. Angio demonstrates proxim LVO in anterior circulation
  3. Performed at a stroke center with appropriate expertise
  4. IS thrombectomy initiated as early as possible within 6h stroke onset


5 multicenter, open-label RCTs



  • Demonstrate superiority to standard treatment with tPA alone
    1. 1287 subjects
    2. Functional independence (90d MRS 0-2) 46% vs 27% OR 2.35, 95% CI 1.85-2.98
    3. Reduced disability / improvement of >=1 on 90d mRS (OR 2.49 95% CI 1.76-3.53)
    4. Beneficial across wide range of patient subgroups
      • Age>=80y
      • High initial stroke severity
      • Not treated with tPA
    5. No difference for rates of symptomatic ICH or 90d mortality


*all 4 trials stopped early after MR CLEAN results announced in late 2014

*4 trials enrolled overlapping but not identical populations, generally had similar results

    1. largest and most inclusive, 500 adults, angio-confirmed prox occlusion in anterior circulation, IA therapy within 6 hours of onset vs usual care, therapy left to discretion of interventionalist, but retrievable stents used in 82%, ~90% in both groups received tPA
    2. RESULTS:
      1. 90d mRS lower OR 1.67 95% CI 1.21-2.30
      2. Higher rate of functional independence (mRS 0-2) at 90d – 32.6% vs 19.1% 95% CI 5.9-21.2; NNT 7.4
  • No difference in symptomatic ICH or death
    1. 316 adults, no upper age limit, disabling stroke with prox large artery occlusion in ant circulation, up to 12h of onset, large infarct core or poor collateral on CTA excluded; 75% treated with tPA
    2. RESULTS:
      1. Functional independence 53% vs 29%, NNT 4.2
      2. Lower MRS scores OR 2.6 95% CI 1.7-3.8
  • Symptomatic ICH 3.6% vs 3.7%
  1. Beneficial for all prespecified subgroups: age>80, men vs women, moderate vs severe strokes, tPA vs no tPA
    1. 196 adults 18-80, confirmed LVO in anterior occlusion, within 6h onset; Solitaire FR device, 100% tPA within 4.5 hours, large infarction on neuroimaging excluded
    2. RESULTS:
      1. Shift to lower mRS at 90d
      2. Higher functional independence 60% vs 35%, NNT 4
  • No difference in mortality at 90d (9% vs 12%) or symptomatic ICH at 27h (0 vs 3%)
    1. 70 patients, AIS receiving tPA, Solitaire FR device, excluded patients without salvageable brain tissue or core infarction >= 70cc,
    2. RESULTS:
      1. Higher functional independence (71% vs 40%) NNT 3.2
      2. No difference in rates of symptomatic ICH or mortality
      1. 206 patients, Solitaire stent retriever, most received tPA, presence of prox anterior circulation occlusion 30m after tPA
      2. Higher rates of functional independence at 90d (44% vs 28%) NNT 6.3
      3. Reduced disability over the range of mrS (adjusted OR for 1 point improvement in mRS 1.7 95% CI 1.05-2.8)
      4. No difference in rates of symptomatic ICH or mortality


SUMMARY: all 5 trials provide compelling evidence that quick, early thrombectomy with second-generation stent retriever devices is safe and effective for reducing disability when used to treat stroke caused by proximal large artery occlusions in the anterior circulation.  NNT ranged from 3-7.5.

MR CLEAN was the largest and with least restrictive eligibility criteria.


Earlier trials:

  2. Reasons for failure
    1. Older-generation devices less likely to achieve recanalization
    2. Did not require confirmation by CT angio of intracranial LVO – nearly ½ did not have imaging confirmation


TICI scores



  1. First generation:
    1. Merci Retriever, Penumbra system devices
    2. Unproven clinical utility
  2. Second generation:
    1. Solitaire Flow Restoration Device, Trevo retriever
    2. Higher recanalization rates, better patient outcomes


Who should undergo mechanical thrombectomy?

  1. Criteria modified from MR CLEAN trial:
    1. Clinical diagnosis of stroke, NIHSS >=2, ASPECTS >=6 on noncontrast CT
    2. CT/MRI evidence rule out ICH
    3. Intracranial occlusion of distal ICA or M1 M2 or A1 A2 arteries demonstrated with CTA / MRA or DSA
    4. Sufficient time to initiate thrombectomy within 6 hours of onset
    5. Informed consent
    6. >=18y
  2. Exclusion
    1. BP >185/110 mm Hg
    2. Glu <2.7 or >22.2
    3. s/p tPA with dose >0.9mg/Kd or 90mg
    4. coagulopathy (Plt <40, INR >3)


goal is to achieve recanalization (TICI 2b or 3 perfusion grade) as early as possible, within 6 hours of stroke onset.


ESCAPE and EXTEND restricted eligibility to patients who were functioning independently prior to stroke onset


Window in ESCAPE up to 12h, but few patients were enrolled beyond 6 hours


ESCAPE required small infarct core defined by ASPECTS 6-10, and evidence of mod to good collateral circulation (filling of >=50% of MCA territory pial circulation on CTA)


EXTEND required evidence of salvageable brain tissue and ischemic core lesion volume <70ml on CT perfusion imaging.



  1. Alberta Stroke Program Early CT Score
  2. Normal CT scan = ASPECTS of 10 points
  3. Diffuse ischemia of MCA territory = ASPECTS of 0 points



  1. Only 10% have prox occlusion in ant circulation who present early enough
  2. Only few centers have expertise


Basilar artery occlusion

  1. Often have progressive or fluctuating symptoms
  2. Longer treatment time limit


CLOTBUST: 126 patients with acute stroke MCA occlusion, continuous 2MHz TCD US and tPA or placebo and tPA.  Rate of sustained complete recanalization at 2 hours 38% vs 13%.  Nonsignificant trend towards increased rate of good clinical outcome at 3 months.


Effectiveness of US still unproven.  Concerns regarding risk of symptomatic hemorrhage.


Advanced Neuroimaging in Stroke:

  1. Identify salvageable ischemic brain tissue and responsible vascular lesion
  2. Presence of viable ischemic brain tissue defined b either diffusion / perfusion MRI or multimodal CT



G2B3A antagonists:

  1. Goal to improve early reperfusion, decrease rate of vessel reocclusion
  2. Tirofiban used in many studies due to short half-life (1.6h) – reduced risk of ICH
  3. IV eptifibatide also used


Risk of ICH

  1. Stroke severity
  2. Early CT changes – brain edema or mass effect on pretreatment CT scan’ ear;u CT cjamges
  3. Not age
  4. Others:
    1. IHD, HF, Afib
    2. Hyperglycemia, high A1C, DM
    3. Renal impairment
    4. HTN first 24h after onset
    5. Antiplatelets / warfarin / low platelet
    6. Leukoaraiosis
    7. Size of acute lesion on DWI
    8. Persistent occlusion at end of tPA infusion


Prior antiplatelet use is not a contraindication, but antiplatelets should not be used within first 24 hours (ARTIS trial).


Informed decision-making

  1. Should be based upon a brief discussion of risk and benefits with patient and family if possible.
  2. Neuro deficits preclude ability of patient to participate in the decision
  3. Time-dependent nature of benefits not conducive to process of informed consent.
  4. Alteplase is approved because of substantial evidence of safety and efficacy.
  5. Consent is not required for tPA as emergent therapy if patient or surrogate consent is not possible.
  6. Need for informed consent outweighed by need for urgent intervention – treated under principle of presumption of consent


“There is a treatment for your stroke called alteplase that must be given within 4.5 hours after the stroke started. It is a ‘clot-buster’ drug. Overall, it is estimated that alteplase treatment is 10 times more likely to help than to harm eligible patients when given within 3 hours of stroke onset. The likelihood of benefit decreases with time, but treatment is still more likely to help than harm up to 4.5 hours after the stroke begins. Thus, the potential benefits of this treatment outweigh the risks. However, this treatment has a major risk, since it can cause severe bleeding in the brain in about 1 of every 15 patients. If bleeding occurs in the brain, it can be fatal. When used to treat large numbers of stroke patients, on average the potential benefits of this treatment outweigh the risks; however, in any individual patient it is a very personal decision.”







Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s

%d bloggers like this: