Nabiel abdel-Hakeem

1
Guidelines for the Early Management of Patients
With Acute Ischemic StrokeThe American Heart
Association/American Stroke Association

• By
• Nabiel abdel-Hakeem
• A . Professor and Head of Neuro-Psychiatry dep.
• Al Azhar University Faculty of Medicine -Assiut

2
The goal is to provide updated recommendations
used by primary care physicians, emergency
medicine physicians, neurologists, and other
physicians who provide acute stroke care from
admission through 1st 24 to 48 hs of
hospitalization by addressing the diagnosis and
emergent ttt of CVS, and management of its acute
and subacute neurological and medical
complications.

• Therapies to prevent recurrent stroke, also a
  component of acute management, are similar to
  prophylactic medical or surgical therapies used
  for pts with TIAs and other high-risk pts.

3
Level of evidenceLevel I Data
from randomized trials with low false-positive
and low false-negative errorsLevel II
Data from randomized trials with high
false-positive or high false-negative
errorsLevel III Data from non-randomized
concurrent cohort studiesLevel IV Data
from non-randomized cohort studies using
historical controlsLevel V Data from
anecdotal case series

• Strength of recommendation
• Grade A Supported by level I evidence
• Grade B Supported by level II evidence
• Grade C Supported by level III, IV, or V
  evidence

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Immediate Diagnosis and EvaluationIs to -
Confirm that the pts impairments are due to
ischemic stroke. - Determine advisability for
acute ttt with thrombolytic agents.
- Screen for acute medical or neurological
complications of stroke. -
Provides data about the vascular distribution of
the stroke and its likely
pathophysiology and etiology, and are essential
for prevention of recurrent stroke.

• History and Physical Examination
• Rapidly provide the urgent evaluation, and is
  supplemented with selected diagnostic tests.
• The physician must 1st determine
  the reason for pts neurological impairments.
• Stroke pts usually present with a
  history of sudden or rapid onset of focal
  neurological sms. Some pts may have a
  stepwise or gradual worsening or waxing and
  waning of sms.
• Most pts are alert, although pts
  with major hemispheric infarctions, basilar
  artery occlusion, or cerebellar strokes with
  edema causing brain stem compression can have a
  decreased level of consciousness.
• Headaches occur in about 25 of
  cases. Nausea and vomiting can occur with strokes
  in the brain stem or cerebellum.
• In general, the diagnosis of stroke
  is straightforward.
• In one series of 821 consecutive pts
  initially diagnosed with stroke, 13 were later
  determined to have other conditions.

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• Conditions mimic stroke
• including unrecognized sz,
  confusional states, syncope, toxic or metabolic
  disorders, including hypoglycemia, brain tumors,
  and subdural hematoma.
• These stroke mimics are commonly, but not
  always, associated with global rather than focal
  neurological sms and are usually readily detected
  with standard lab tests.

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• Immediate Diagnostic Studies
• Evaluation of a Pt with Suspected
  Acute Ischemic Strok
• All patients
• - Brain CT (brain MRI could be considered
  at qualified centers)
• - ECG - Bl glucose -
  Serum electrolytes
• - Renal function tests -CBC,
  including platelet count
• - Prothrombin time / INR - Activated
  partial thromboplastin time
• Selected patients
• Hepatic function tests Toxicology
  screen
• Bl alcohol determination
  Pregnancy test
• Oxygen saturation or arterial bl gas tests (if
  hypoxia is suspected)
• Chest radiography (if lung disease is
  suspected)
• Lumbar puncture (if SA hge is suspected and CT
  is negative for bl)
• EEG (if sz are suspected)

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History and physical ex. can be helpful in
Differentiation of ischemic from hgic stroke. For
example, the chance of hge was more than doubled
with the presence of at least one of the
following coma on arrival, vomiting, severe
headache, current warfarin therapy, systolic bl
pr gt220 mm Hg, or glucose level gt170 mg/dL in a
nondiabetic pt.  The absence of these
features decreases the odds of hge by
approximately one third. Because
clinical findings overlap, a brain imaging study
is mandatory to distinguish ischemic stroke from
hge or other structural brain lesions.
The time of onset is most critical (ttt), the
onset is assumed as the time that the pt was last
known to be symptom-free.
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• Because ischemic stroke is often
  painless, most pts are not awakened by its
  occurrence. If a pt had mild impairments but then
  had worsening over the subsequent hours, the time
  1st sm began is assumed to be the time of onset.
• In contrast, if a pt has sms that
  completely resolved (TIA) and then has a second
  event, the time of onset of the new sms is used.
• Other important information includes
  any recent medical or neurological events,
  including trauma, hge, surgery, MI, or previous
  stroke.

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Pts should be queried about their
use of medications, especially oral
anticoagulants and antiplatelet agents. If the pt
is confused, aphasic, or unconscious, information
might be available from family, friends, or
emergency medical service personnel. A coworker,
shop owner, apartment manager, or other observer
might be reached by phone. They might be able to
provide information about the time of onset of
stroke. Attention should be paid
to the pts vital sns, (breathing, arrhythmias,
hypertension, or fever). The vital signs also
provide clues about the cause of stroke and
prognosis. An irregularly
irregular heart rhythm might suggest AF.
Severe elevations of bl pr might
point to hypertensive encephalopathy or increase
the likelihood of a primary IC hge.
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Fever can suggesting an infectious
cause of stroke or it may be secondary to an
acute complication. In addition, the
general ex includes an assessment for sns of
trauma and a cardiovascular evaluation and
clinical evidence of active bleeding.

•   Approximately 60 to 70 of pts with
  an acute ischemic stroke and a baseline NIHSS
  score lt10 will have a favorable outcome after 1
  year as compared with only 4 to 16 of those
  with a score gt20.   The NIHSS score can
  also help identify those pts at greatest risk for
  IC hge associated with thrombolytic ttt.

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Brain Imaging Playing important role
in initial evaluation, including the size,
location, and vascular distribution of the
infarction, and the presence of bleeding, affect
both acute and long-term ttt decisions.
In addition, information about the
possible degree of reversibility of ischemic
injury, the status of intracranial vessels, and
cerebral hemodynamic status can be obtained from
modern imaging studies. At
present, the usual brain imaging test is CT.
Newer neuroimaging procedures must be weighed
against the time cost, the availability and
financial costs.
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CT Scan of the Brain Is
currently the most commonly employed initial
neuroimaging study. CT accurately identifies most
cases of IC hge and helps discriminate
nonvascular causes of neurological sms, eg, brain
tumor (grade B). It is relatively insensitive in
detecting acute and small cortical or subcortical
infarctions, especially in the posterior fossa.
Contrast infusion does not
provide additional information and is not
necessary unless it is required for CT
angiography (and more recently CT perfusion) or
there is a concern about a brain tumor or
infectious process. Early infarct sns or
arterial occlusion include the hyperdense MCA
sign that is indicative of a thrombus or embolus
in 1st portion of MCA. In addition, the loss of
the gray-white differentiation in the cortical
ribbon (particularly at the lateral margins of
the insula) or the lentiform nucleus, and sulcal
effacement appear to be important. These sns may
be detected within 6 hs of onset of sms in up to
82 of pts with ischemia in the territory of MCA
(class C). The presence of these sns is
associated with poor outcomes (class A).
The presence of widespread sns of early
infarction is correlated with a higher risk of
hgic transformation following thrombolytic
therapy (level I).
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 Because of early changes of
decreased water diffusion within ischemic brain
tissue, diffusion-weighted imaging (DWI) allows
visualization of ischemic regions within minutes
of onset of sms.  PWI, usually
performed with the rapid administration of IV
contrast agent, provides relative measures of
cerebral hemodynamic status. It allows
early identification of the lesion size, site,
and age. It can detect relatively small cortical
or subcortical lesions, including those in the
brain stem or cerebellum. 

• Multimodal MRI Standard MRI
  sequences (T1-WI, T2-WI, and proton density) are
  relatively insensitive to the changes of acute
  ischemia within 1st hs after onset. These
  sequences will show abnormalities in lt 50 of
  pts (class A).

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The initial volumes of the lesions
seen on DWI and PWI correlate well with the final
size of the stroke found on follow-up brain
imaging.  In addition, these lesion
volumes correlate well with both severity of
stroke as rated by clinical scales and outcomes
(class C).

• The ischemic penumbra has been characterized on
  MRI as regions of perfusion change without a
  corresponding diffusion abnormality
  (diffusion-perfusion mismatch).
• An important limitation of MRI is
  the potential difficulty in identifying acute IC
  hge, cost, limited availability, and pt
  contraindications such as claustrophobia, cardiac
  pacemakers, or metal implants.

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Other Brain Perfusion Techniques
Oxygen-15 PET can quantify regional brain
perfusion and oxygen consumption. PET provided
the first evidence of a penumbra in stroke
patients by identifying regions of decreased
cerebral blood flow (CBF) and increased oxygen
extraction fraction (OEF) with relatively
preserved oxygen metabolism. However, logistical
and pragmatic considerations limit the
application of PET in the setting of acute
stroke. Xenon-enhanced CT provides a
quantitative measurement of CBF by employing
inhaled xenon. Perfusion CT measures CBF by
mapping the appearance of a bolus of iodinated
contrast. Both can be used to screen for
thresholds of reversible or irreversible ischemia
among patients with acute stroke. These
techniques have the advantages of acquiring data
relatively rapidly and can be performed with
conventional CT equipment.

• CT perfusion is more readily
  quantitative as compared with MR and can be
  completed within 3 to 5 minutes following the
  standard non-contrast CT scan.
• SPECT is minimally invasive and
  measures relative CBF. SPECT might be able to
  identify thresholds for reversible ischemia and
  could be helpful in predicting outcomes or
  monitoring responses to ttt. Limitations include
  lack of availability, expense, and the difficulty
  associated with tracer preparation.

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• Cardiac Tests
• A clinical CV ex and ECG
  should be performed in all stroke pts.
• Cardiac abnormalities are prevalent
  among pts with stroke and may mandates urgent
  ttt. For example, acute MI can lead to stroke,
  and acute stroke can lead to MI. 
• Arrhythmias can occur among
  pts with acute ischemic stroke. AF, an important
  potential cause of stroke, can be detected in the
  acute setting. 
• Cardiac monitoring often can be
  conducted after stroke to screen for serious
  cardiac arrhythmias.

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Blood Tests Identify systemic
conditions that may mimic or cause stroke, or
that may influence choices for acute ttt.
These include blood glucose, electrolytes,
CBC with platelet count, prothrombin time,
activated partial thromboplastin time, and renal
and hepatic function studies. Because
time is critical, therapy involving rtPA should
not be delayed while waiting for the results of
the prothrombin time or activated partial
thromboplastin time unless there is clinical
suspicion of a bleeding abnormality or unless pt
has been taking warfarin and heparin or their use
is uncertain.

• Hypoglycemia may mimic stroke, and
  hyperglycemia is associated with unfavorable
  outcomes.
• Platelet count and, the prothrombin
  time/INR are required prior thrombolytic therapy.

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A toxicology screen, blood alcohol
level, and pregnancy test should be obtained if
the physician is uncertain about the patients
history and/or suggested by findings on
examination. Arterial blood gas levels
should be obtained if hypoxia is suspected.
Chest radiography was previously recommended for
the evaluation of all pts with acute ischemic
stroke.

• Examination of CSF is
  indicated if pt has sms suggestive of SA hge and
  a CT does not demonstrate blood. Fortunately, the
  clinical features of SA hge differ from ischemic
  stroke. EEG may be helpful for
  evaluating pts in whom sz are suspected as the
  cause of the neurological deficits or in whom sz
  could have been a complication of the stroke. Sz
  is a relative contraindication for rtPA in acute
  ischemic stroke.

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Vascular Imaging A wide variety of
imaging techniques have been used to assess the
status of the large cervicocephalic vessels.
Choices depend on availability, individual pt
characteristics, and the type of information
being sought. TCD, MRA, CT
angiography, and catheter angiography have been
used to detect IC or extracranial arterial
occlusions.

• TCD and angiography are used to
  monitor the effects of thrombolytic therapy over
  time and can help determine prognosis.
• Because time is of the essence in
  acute stroke care, institutions should have these
  diagnostic studies available on a 24-h/day and
  7-d/week basis. If the tests are not readily
  available, and if time and the patients
  condition permit, the patients transfer to
  another medical facility equipped to do so should
  be considered.

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General Supportive Care and Treatment of Acute
Complications

• Airway, Ventilatory Support, and Supplemental
  Oxygen
• Maintaining adequate tissue
  oxygenation is of great importance during periods
  of acute cerebral ischemia in order to prevent
  hypoxia and potential worsening of the
  neurological injury.
• The most common causes are partial
  airway obstruction, hypoventilation, aspiration
  pneumonia, or atelectasis.
• Pts with a decreased level of
  consciousness or brain stem stroke have an
  increased risk of airway compromise due to
  impaired oropharyngeal mobility and loss of
  protective reflexes. 
• The prognosis of pts who need
  endotracheal intubation is very poor (about 50
  die within 30 days).
• Elective intubation might help
  in the management of pts with severely increased
  ICP or who have severe brain edema. Although no
  clinical trial has tested the utility of
  endotracheal intubation in this situation, there
  is general agreement that an endotracheal tube
  should be placed if the airway is threatened
  (level V).

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 Following stroke, some pts develop
Cheyne-Stokes respiration with decreases in
oxygen saturation that can be readily reversed
with oxygen supplementation.  The
results of a recent controlled trial do not
support the use of supplemental oxygen therapy at
3 L/min for most pts with acute ischemic stroke
(level V). However, pts with acute stroke should
be monitored with pulse oximetry with a target
oxygen saturation level of 95 (level V).

• Supplemental oxygen should be
  administered if there is evidence of hypoxia by
  bl gas determination, desaturation detected by
  pulse oximetry, or there are other specific
  reasons.
• Hyperbaric oxygen therapy might be
  useful for ttt of selected pts with ischemic
  neurological sms secondary to air embolism (level
  V).  Data are lacking to support its general use
  in pts with acute ischemic stroke (levels III and
  IV).

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Fever

• Increased body temp in the setting of
  acute ischemic stroke has been associated with
  poor neurological outcome (increase in morbidity
  and mortality (level I), possibly due to
  increased metabolic demands, enhanced release of
  neurotransmitters, and increased free radical
  production..  
• The source of any fever should be
  ascertained, and the fever should be tted with
  antipyretic agents.
• Lowering an acutely elevated body
  temp might improve the prognosis of pts with
  severe events.
• Measures can include antipyretic
  medications and cooling devices.
• Hypothermia has been shown to be
  neuroprotective after experimental global and
  focal hypoxic brain injury (levels II to V)
  however, the efficacy of this approach has been
  established (levels III and IV).

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Cardiac Rhythm

• MI and arrhythmias are potential
  complications of acute ischemic stroke. 
• Pts with infarctions in Rt
  hemisphere may have a high risk of arrhythmias,
  due to disturbances in autonomic nervous system
  function (level V).  
• ECG changes secondary to stroke
  include ST segment depression, QT interval
  prolongation, inverted T waves, and prominent U
  waves.  
• Acute or subacute MI is a
  potential complication due to a release of
  catecholamines. The most common arrhythmia is AF.
  Life-threatening arrhythmias are relatively
  uncommon, sudden death can occur.

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Arterial Hypertension

• Can result from the stress of the
  stroke, a full bladder, pain, preexisting
  hypertension, a physiological response to
  hypoxia, or increased ICP.
• Theoretical reasons to lower bl pr
  include reducing the formation of brain edema,
  lessening the risk of hgic transformation, and
  preventing further vascular damage, and early
  recurrent stroke.
• However, aggressive ttt of elevated bl pr
  could expand the size of the infarction.
• In a majority of pts, bl pr often
  falls spontaneously when the pt is moved to a
  quiet room, the bladder is emptied, pain is
  controlled, and the pt is allowed to rest. In
  addition, ttt of increased ICP can result in a
  decline in arterial bl pr.
• In most circumstances, the bl pr
  should generally not be lowered. Situations that
  might require urgent antihypertensive therapy
  include hypertensive encephalopathy, aortic
  dissection, acute renal failure, acute pulmonary
  edema, or acute MI.

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Although severe hypertension might be
considered as an indication for ttt, there are no
data to define the levels of arterial
hypertension that mandate emergent
management. Antihypertensive agents should be
withheld unless the diastolic bl pr is gt120 mm Hg
or unless the systolic bl pr is gt220 mm Hg (level
V).

• Approach to Elevated Blood Pressure in
  Acute Ischemic Stroke
• When ttt is indicated, lowering the bl
  pr should be done cautiously. Parenteral agents
  such as labetalol that are easily titrated and
  that have minimal vasodilatory effects on
  cerebral blood vessels are preferred.
• In some cases, IV infusion of sodium
  nitroprusside may be necessary for adequate bl pr
  control. Pts also can be tted with oral agents,
  such as captopril or nicardipine.
• Sublingual use of a calcium antagonist,
  such as nifedipine, should be avoided because of
  rapid absorption and a secondary precipitous
  decline in bl pr (level V).
• Among pts who are candidates for ttt
  with thrombolytic agents, careful management of
  bl pr is critical before and during the
  administration of rtPA and during the ensuing 24
  hs because excessively high bl pr is associated
  with parenchymal hge.

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Arterial Hypotension

• Persistent arterial hypotension is
  rare.
• Causes include aortic dissection, volume
  depletion, and decreased cardiac output secondary
  to myocardial ischemia or cardiac arrhythmias.
• Correction of hypovolemia and
  optimization of cardiac output are important
  priorities during 1st hs after stroke.
• Ttt includes volume replacement
  with normal saline and correction of
  arrhythmiassuch as slowing ventricular response
  to rapid AF. If these measures are ineffective,
  vasopressor agents such as dopamine may be used.

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Hypoglycemia

• Because hypoglycemia can cause
  focal neurological sns that mimic stroke and
  because severe hypoglycemia can itself lead to
  brain injury, prompt measurement of the serum
  glucose and rapid correction of a low serum
  glucose is important. A finger stick can be done
  to rapidly measure glucose levels.
• Diabetes mellitus is an important
  risk factor for ischemic vascular disease. The
  severity of strokes may be increased among
  diabetic pts.
• In addition, several clinical
  studies have associated hyperglycemia with poor
  outcomes.
• However, hyperglycemia can be a
  consequence of a severe stroke and thus, the
  elevated bl sugar can be a marker of a serious
  vascular event.
•   The detrimental effects of
  hyperglycemia are not clearly understood but can
  include increasing tissue acidosis secondary to
  anaerobic glycolysis and increased BBB
  permeability.
• Still, there is uncertainty
  whether hyperglycemia worsens stroke
  outcomes. For example, outcome after stroke is
  not worse among pts with elevated levels of
  glycosylated hemoglobin as compared with persons
  with normal levels. 

28
There are no data evaluating the impact
on outcomes of maintaining euglycemia during the
period of acute stroke. A small randomized trial
showed that glucose and an insulin infusion could
be safely given to pts with mild to moderate
hyperglycemia.  However, the efficacy of this
approach is not established (level II).

• There is general agreement to
  recommend control of hypoglycemia or
  hyperglycemia following stroke. A reasonable goal
  would be to lower markedly elevated glucose
  levels to lt300 mg/dL (lt16.63 mmol/L) (grade C).
   Management of an elevated bl glucose level
  following stroke should be similar to that given
  to ttt of other acutely ill pts who have
  hyperglycemia. Blood glucose should be monitored.
  IV glucose-containing solutions should be
  avoided. However, fluids and insulin should be
  administered if the blood glucose is markedly
  elevated. Overly aggressive therapy should be
  avoided because it can result in fluid shifts,
  electrolyte abnormalities, and hypoglycemia, all
  of which can be detrimental to the brain.

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Treatment of the Acute Ischemic Stroke

• Measures to Restore or Improve Perfusion
• Restoration or improvement of
  perfusion to the ischemic area is a key
  therapeutic strategy. The concept of an ischemic
  penumbra is fundamental to the current approach
  to ttt .
• Intravenous Thrombolysis With rtPA
• Approval of this ttt by the FDA was based
  on the results of the National Institute of
  Neurological Disorders and Stroke (NINDS) rt-PA
  Stroke Study.
• Two large trials, the European
  Cooperative Acute Stroke Study (ECASS) and
  ECASS-II. A favorable responses to ttt with rtPA
  were highest among pts with a NIHSS score lt10 and
  a normal baseline CT scan.
• Pts with CT evidence of edema and/or
  ischemia involving more than 1/3 of the territory
  of MCA were less likely to have a good outcome
  after ttt with rtPA than did those who received
  placebo.

30
Tow American trial .   Besides a
risk of IC hge, other potential adverse
experiences include systemic bleeding, myocardial
rupture if the agent is given within a few days
of acuteMI, and allergic reactions including
anaphylaxis. 

• Violations of the FDA-approved
  protocol may increasing complications (level
  V). The investigators concluded that the earlier
  ttt is initiated, the better the prognosis.

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Characteristics of Patients With Ischemic Stroke
Who Could Be Treated With rtPA

• Diagnosis of ischemic stroke causing measurable
  neurological deficit
• The neurological signs should not be clearing
  spontaneously
• The neurological signs should not be minor and
  isolated
• Caution should be exercised in treating a patient
  with major deficits
• The symptoms of stroke should not be suggestive
  of subarachnoid hge
• Onset of symptoms lt3 hours before beginning
  treatment
• No head trauma or prior stroke in previous 3
  months
• No myocardial infarction in the previous 3 months
• No gastrointestinal or urinary tract hemorrhage
  in previous 21 days
• No major surgery in the previous 14 days

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No arterial puncture at a
noncompressible site in the previous 7 days

• No history of previous intracranial hemorrhage
• Bl pr not elevated (systolic lt185 mm Hg and
  diastolic lt110 mm Hg)
• No evidence of active bleeding or acute trauma
  (fracture) on examination
• Not taking an oral anticoagulant or if
  anticoagulant being taken, INR 1.5
• If receiving heparin in previous 48 hours, aPTT
  must be in normal range
• Platelet count 100 000 mm3
• Blood glucose concentration 50 mg/dL (2.7
  mmol/L)
• No seizure with postictal residual neurological
  impairments
• CT does not show a multilobar infarction
  (hypodensity gt? cerebral hemisphere)
• The patient or family understand the potential
  risks and benefits from ttt

33
Regimen for Treatment With Intravenous rtPA

• Infuse 0.9 mg/kg (maximum of 90 mg) over 60 min
  with 10 of the dose given as a bolus dose over 1
  min.
• Admit the pt to an ICU or a stroke unit for
  monitoring.
• Perform neurological assessments every 15 min
  during the infusion of rtPA and every 30 min for
  the next 6 hs and then every hour until 24 hs
  from ttt.
• Increase the frequency of bl pr measurements if
  a systolic bl pr 180 mm Hg or diastolic bl pr of
  105 mm Hg is recorded.
• Administer antihypertensive medications to
  maintain bl pr at or below these levels.

34
If diastolic blood pressure 105120 mm Hg or
systolic blood pressure 180230 mm Hg,
intravenously administer 10 mg labetalol over 12
minutes.

• If diastolic blood pressure 105120 mm Hg or
  systolic blood pressure 180230 mm Hg,
  intravenously administer 10 mg labetalol over 12
  minutes.
• May repeat or double the dosage or labetalol
  every 10 to 20 minutes to a maximum dose of 300
  mg.
• As an alternative, can start with the
  initial bolus dose of labetalol and then follow
  with a continuous labetalol infusion given at a
  rate of 28 mg/min.
• If diastolic blood pressure 121140 mm Hg or
  systolic blood pressure gt230 mm Hg, intravenously
  administer 10 mg labetalol over 12 minutes. May
  repeat or double labetalol every 10 minutes to a
  maximum dose of 300 mg. As an alternative, can
  start with the initial bolus dose of labetalol
  and then follow with a continuous labetalol
  infusion given at a rate of 28 mg/min. If the
  blood pressure is not controlled, consider
  starting an infusion of sodium nitroprusside.
• If diastolic blood pressure gt140 mm Hg, start
  infusion of sodium nitroprusside at a rate of 0.5
  mg/kg/min.
• Delay placement of nasogastric tubes,
  indwelling bladder catheters, or intra-arterial
  pressure catheters.

35
Intravenous Administration of Streptokinase

• Trials were halted prematurely because
  of an excess of poor outcomes or deaths (level
  I). The dose of streptokinase was 1.5 million
  units, the same given to pts with MI, and may
  have been too high for ttt of pts with stroke.
• No evidence that IV streptokinase
  is of benefit in pts with acute ischemic stroke.
• Other Thrombolytic Agents (IV)
• Including reteplase,
  urokinase, anistreplase, and staphylokinase .
  None of these agents have been tested
  extensively.
• Defibrinating Enzymes Ancrod,
• An enzyme derived from snake venom
  that degrades fibrinogen.
• A preliminary trial found that ancrod
  ttt improved outcomes in pts with blood
  fibrinogen levels lt100 mg/dL having the best
  responses (level I). A subsequent study found a
  favorable benefit-risk (level I).

36
Conclusions

• IV rtPA is currently the only
  FDA-approved therapy for ttt of pts with acute
  ischemic stroke. Its use is associated with
  improved outcomes for a broad spectrum of
  carefully selected pts who can be tted within 3
  hs of onset (level I).
• Earlier ttt (lt90 min) may be more
  likely to result in a favorable outcome (level
  II). Later ttt, at 90 to 180 minutes, is also
  beneficial (level I).
• Ttt with rtPA is associated with
  symptomatic IC hge, which can be fatal (level I),
  its management is problematic. The best methods
  for preventing bleeding complications are careful
  selection of pts and scrupulous ancillary care.
• Close observation and monitoring of
  the pt and early management of arterial
  hypertension are critical.
• The use of anticoagulants and
  antiplatelet agents should be delayed for 24 hs
  after ttt.

37
Recommendations

• IV rtPA is strongly recommended for
  carefully selected pts who can be tted within 3
  hs of onset (grade A).
• The decision for ttt with rtPA is
  based on several features. The physician should
  review each of the criteria to determine the pts
  eligibility.
• The safety and efficacy of rtPA for
  ttt of pediatric pts are not established.
• Pts with major strokes (NIHSS score
  gt22) have a very poor prognosis whether or not
  they are tted with rtPA.  the risk of hge is
  considerable among this population,
• Currently available data do not
  support the clinical use of either streptokinase
  or ancrod (grade A).

38
A pt whose bl pr can be lowered without
an IV infusion of sodium nitroprusside might be
eligible for ttt, and the physician needs to
assess the stability of the bl pr prior to
starting ttt.

• Because time is limited, most pts
  with markedly elevated bl pr cannot be managed
  adequately and still meet the lt3-h requirement.
• A pt with a sz at onset of stroke
  might be eligible for ttt as long as the
  clinician is convinced that the residual
  impairments are due to stroke and not the sz.
• Although a written consent is not
  necessary, pts and their families should be
  informed about the potential risks and benefits.
• No other thrombolytic agent has
  been established as a safe and effective
  alternative to rtPA.

39
Intra-arterial Thrombolysis

• Although recanalization rates for
  pts with occlusion of MCAs presumably would be
  superior with intra-arterial thrombolysis, there
  are no studies directly comparing IV and
  intra-arterial thrombolytic agents.
• A prospective, randomized,
  placebo-controlled phase II study evaluated the
  utility of intra-arterial administration of
  recombinant prourokinase (r-proUK) in combination
  with heparin and demonstrated that the
  combination was successful in achieving
  recanalization more frequently, but increased the
  risk of IC bleeding (level I).
• The feasibility of combining
  early IV rtPA in a lower dose followed by
  arterial administration was examined in the
  Emergency Management of Stroke (EMS) Bridging
  Trial (level III), could achieve recanalization
  and might be associated with a reasonable degree
  of safety.

40
Conclusions

• Intra-arterial administration of at
  least one specific thrombolytic agent appears to
  be of some benefit in ttt of carefully selected
  pts with acute ischemic stroke secondary to
  occlusion of MCA (level I).
• The resources (equipment and
  physician expertise) required to administer
  intra-arterial thrombolytic agents are not widely
  available.
• The time to transfer a pt to an
  institution that has these resources or to
  mobilize these services means that lags in ttt
  are likely to occur.
• Diagnostic tests, such as diffusion
  and perfusion MRI, to select the pts might
  engender additional delays and affect outcomes.
  These delays may lessen the utility of
  intra-arterial thrombolysis in treating acute
  ischemic stroke.

41
Recommendations

• Intra-arterial thrombolysis is an
  option for ttt of selected pts with major stroke
  of lt6 hs due to large vessel occlusions of MCA
  (grade B).
•   It should be recognized that
  intra-arterial thrombolysis is not FDA approved.
• Further, recombinant prourokinase
  tested is not available for clinical use.
• Case series data suggest this
  approach may also be of benefit in pts with
  basilar artery occlusion treated at longer
  intervals. Ttt requires the pt to be at an
  experienced stroke center with immediate access
  to cerebral angiography and interventional
  neuroradiology. Importantly, the availability of
  intra-arterial thrombolysis should generally not
  preclude IV rtPA in otherwise eligible pts.

42

• Anticoagulants
• The usefulness of emergent
  anticoagulation for acute stroke care has been
  the subject of debate.
• There have been disagreements
  about the best agent to use, the level of
  anticoagulation required, the route of
  administration, the duration of treatment, and
  the use of a bolus dose to start therapy.
• The primary safety issue is that
  urgent anticoagulation might lead to symptomatic
  IC bleeding.
• Low-Molecular-Weight Heparins
• A small trial from Hong Kong.
  Another trial of nadroparin did not find any
  improvement in the rates of favorable outcomes.
• A Norwegian trial compared the
  utility of dalteparin or aspirin in prevention of
  early recurrent stroke or improvement among pts
  with presumed cardioembolic stroke. Although no
  significant differences in outcomes or the rates
  of recurrent stroke were noted, the pts receiving
  aspirin had fewer second strokes (level I).
• A German trial compared four
  different doses of certoparin (level I). The
  highest dose of certoparin was associated with
  the highest rate of bleeding with no differences
  in the rates of favorable outcomes noted among
  the four groups.

43

• Heparinoid
• A randomized, double blind,
  placebo-controlled trial tested the usefulness of
  danaparoid (ORG 10172).
• The trial halted ttt of pts with
  moderate-to-severe stroke (NIHSS scores of 15 or
  greater) because of an increased rate of
  symptomatic hgic transformation (level I).
• The only subgroup that showed benefit
  were those pts with stroke attributed to large
  artery atherosclerosis (level II).

44

• Anticoagulants as an Adjunctive Therapy
• Anticoagulants and platelet
  antiaggregants is currently contraindicated
  during 1st 24 hs following IV rtPA.
• In the first study, recanalization
  and the risk of hemorrhagic transformation were
  greater among the patients who received the
  higher of two doses of heparin than among the
  patients receiving the lower dose (level II). 
• Two small studies examined the use
  of intravenously administered heparin immediately
  following treatment with rtPA (level V). 
• The rates of favorable outcomes
  were satisfactory and the rates of major bleeding
  complications were not higher than expected with
  rtPA alone.

45

• Conclusions
• Parenteral anticoagulants
  (heparin, LMW heparins, or heparinoid) are
  associated with an increased risk of serious
  bleeding complications (level I), especially
  among pts with severe strokes, and increase the
  risk of serious bleeding in other parts of the
  body.
• Bleeding can complicate either SC
  or IV anticoagulants. Monitoring of the level of
  anticoagulation and adjustment of the dosage/ttt
  regimen increase the safety of ttt with these
  agents.
• Present data indicate that the early
  administration of the tested rapidly acting
  anticoagulants does not lower the risk of early
  recurrent stroke, including among pts with
  cardioembolic stroke (level I).
• Early administration of anticoagulants
  does not lessen the risk of neurological
  worsening (level I). There are no adequate data
  to demonstrate efficacy of anticoagulants in
  potentially high-risk groups such as those pts
  with intracardiac or intra-arterial thrombi.

46

• The efficacy of urgent
  anticoagulation is not established for ttt of pts
  with vertebrobasilar artery disease or arterial
  dissection.
• Urgent anticoagulants does not
  increase the likelihood of a favorable outcome
  following acute ischemic stroke (level I).
• A subgroup analysis from one trial
  found that an anticoagulant might improve the
  chances of favorable outcomes among pts with
  stroke secondary to large artery atherosclerosis
  (level II).
• Additional information about the
  utility of urgent anticoagulant ttt is needed
  before the therapy can be considered as effective
  in this setting.
• Additional research is needed to
  define the role of adjunctive anticoagulation in
  addition to mechanical or pharmacological
  thrombolysis for ttt of acute ischemic stroke
  (levels II to V).

47

• Recommendations
• Urgent routine anticoagulation
  with the goal of improving neurological outcomes
  or preventing early recurrent stroke is not
  recommended for the ttt of pts with acute
  ischemic stroke (grade A). More studies are
  required to determine if certain subgroups
  (large-vessel atherothrombosis or pts perceived
  to be at high risk of recurrent embolism) may
  benefit from urgent anticoagulation.
• Urgent anticoagulation is not
  recommended for ttt of pts with
  moderate-to-severe stroke because of a high risk
  of serious IC bleeding complications (grade A).
• Initiation of anticoagulant
  therapy within 24 hs of ttt with IV rtPA is not
  recommended (grade A).
• Parenteral anticoagulants should
  not be prescribed until a brain imaging study has
  excluded the possibility of a primary IC hge. The
  level of anticoagulation should be closely
  monitored if a pt is receiving one of these
  medications. Adjustment in the dosage of
  medication should be done if the level of
  anticoagulation is outside the desired range.

48

• Antiplatelet Agents
• Antiplatelet therapy is used for
  both the management of acute ischemic stroke and
  for the prevention of stroke.
• Antiplatelet therapy reduces the
  incidence of stroke in pts at high risk for
  atherosclerosis and in those with known
  symptomatic cerebrovascular disease.
• ASPIRIN
• The most commonly used antiplatelet
  agent, inhibits the enzyme cyclooxygenase,
  reducing production of thromboxane A2, a
  stimulator of platelet aggregation. This
  interferes with the formation of thrombi, thereby
  reducing the risk of stroke.
• The effectiveness of aspirin for
  preventing ischemic stroke and cardiovascular
  events is supported by a meta-analysis from the
  Antithrombotic Trials Collaboration (ATC). The
  ATC analyzed 195 randomized controlled trials
  comparing antiplatelet therapy, primarily
  aspirin, with placebo in the prevention of
  stroke, MI, and vascular death among high-risk
  pts with some vascular disease or other condition
  implying an increased risk of occlusive vascular
  disease. Pts treated with an antiplatelet agent
  (primarily aspirin) had a 25 relative risk
  reduction in nonfatal stroke compared with
  placebo.

49

• Stopping antiplatelet therapy in
  high-risk pts may itself increase the risk of
  stroke.
• Furthermore, there is considerable
  evidence that long-term aspirin use reduces the
  risk of death from certain cancers.
• Dose of aspirin
• A review of 195 trials showed that
  doses of 75 to150 mg/day produced the same risk
  reduction, compared with placebo, as doses of 150
  to 325 mg/day. In the ATC analysis of trials
  directly comparing aspirin lt75 mg/day to aspirin
  75 mg/day, there was no significant difference
  in effectiveness between the two regimens.
• The Dutch TIA Trial found similar
  efficacy for stroke prevention with 30 mg
  compared with 283 mg/day. In the European Stroke
  Prevention Study-2 (ESPS-2), 50 mg of aspirin
  daily reduced stroke risk by 18 percent compared
  with placebo. This benefit seen with very
  low-dose aspirin is consistent with laboratory
  observations that 30 mg of aspirin per day
  results in complete suppression of thromboxane A2
  production.
• We recommend a dose of 50 to
  100 mg/day for the secondary prevention of
  ischemic stroke.

50

• Toxicity and risk of bleeding
• Lower doses of aspirin appear
  to be associated with less gastrointestinal
  toxicity. The overall rate of bleeding
  complications with aspirin lt100 mg/day was
  associated with a lower risk compared with the
  100 to 200 mg/day and gt200 mg/day groups.

51

• CLOPIDOGREL
• Is a thienopyridine that
  inhibits ADP-dependent platelet aggregation.
• The CAPRIE trial randomly
  assigned 19,185 pts with recent stroke, MI, or
  symptomatic peripheral artery disease to ttt
  with aspirin (325 mg) or clopidogrel (75 mg). The
  primary end point, a composite outcome of stroke,
  MI, or vascular death, was significantly reduced
  with clopidogrel compared with aspirin.
• Side effects of clopidogrel
• The side effect profile
  of clopidogrel is favorable compared
  with aspirin, with a slightly higher frequency of
  rash and diarrhea, but a slightly lower frequency
  of gastric upset or gastrointestinal bleeding.
  Unlike its close relative ticlopidine, severe
  neutropenia is not seen more frequently with
  clopidogrel than with aspirin.

52

• Aspirin plus clopidogrel
• For most pts, the combined
  long-term use of aspirin and clopidogrel does not
  offer greater benefit for stroke prevention than
  either agent alone but increase the risk of
  bleeding.
• The combination of aspirin and clopid
  ogrel has been shown to have benefit over aspirin
  alone in pts with acute coronary syndromes.

53

• Stroke subtype
• In a randomized trial (SPS3)
  evaluating over 3000 pts with subcortical (ie,
  lacunar) stroke confirmed by MRI, the arm testing
  the combination of aspirin plus clopidogrel
  versus aspirin alone was terminated before
  completion because of a higher frequency of
  bleeding events (mostly systemic) and a higher
  mortality rate in pts assigned to dual
  antiplatelet therapy.
• In the final analysis, subjects
  treated with aspirin plus clopidogrel compared
  with aspirin alone had a significantly increased
  annual rate of both major hge and all-cause
  mortality. These results, together with those of
  the MATCH trial, suggest that dual antiplatelet
  therapy with aspirin and clopidogrel is harmful
  for long-term use in pts with lacunar stroke.
  Furthermore, ttt with aspirin and clopidogrel
  compared with aspirin alone in the SPS3 trial did
  not reduce the risk of recurrent stroke.

54

• Two small trials (CARESS and
  CLAIR) of pts with recently symptomatic large
  artery stenosis found that, compared
  with aspirin alone, early ttt with aspirin plus
  clopidogrel reduced the number of microembolic
  signals detected on transcranial Doppler
  ultrasound. However, whether this surrogate
  measure would translate into clinical benefit for
  pts with symptomatic large artery stenosis
  remains uncertain.
• In the SAMMPRIS trial, which
  evaluated angioplasty and stenting plus intensive
  medical management versus intensive medical
  management alone for pts with recently
  symptomatic IC large artery stenosis, all
  subjects received combined aspirin and clopidogrel
   for the first 90 days after enrollment. The
  results were notable for a reduced rate of
  recurrent stroke and death in the medical
  management arm compared with historical controls,
  suggesting that short-term dual antiplatelet
  therapy is beneficial in this scenario.
  Therefore, we suggest dual antiplatelet therapy
  with aspirin plus clopidogrel for 90 days,
  followed by antiplatelet monotherapy, for pts
  with recently symptomatic intracranial large
  artery disease.

55

• DIPYRIDAMOLE 
• Impairs platelet function by
  inhibiting the activity of adenosine deaminase
  and phosphodiesterase, which causes an
  accumulation of adenosine, adenine nucleotides,
  and cyclic AMP. Dipyridamole may also cause
  vasodilation.
• Dipyridamole is currently available in two forms
• An immediate-release form, usually given as
  50 to 100 mg three times per day
• A formulation containing
  both aspirin (25 mg) plus extended-release dipyrid
  amole (200 mg), given two times per day.
• The effectiveness
  of dipyridamole monotherapy for secondary stroke
  prevention was established The ESPS-2 trial
  randomly assigned 6602 pts with a recent TIA or
  ischemic stroke to one of four groups
• - 200 mg extended-release dipyridamole alone
  given twice daily
• - 25 mg aspirin alone given twice daily
• - a combination of 25 mg aspirin plus 200 mg
  extended-release dipyridamole given twice daily
• - and placebo.

56

• A significant risk reduction was
  observed for both extended-release dipyridamole
  monotherapy and aspirin monotherapy compared with
  placebo. The benefit of combination aspirin-extend
  ed-release dipyridamole was significantly greater
  still than the two components alone and
  significantly greater than placebo.
• Side effects of dipyridamole
• Headache most frequent adverse
  event, more significant in women. Mostly
  self-limited, declined markedly over seven days
  to less than 20 percent.
• Gastric upset and/or diarrhea
  requiring drug cessation was also more common
  with dipyridamole compared with aspirin or
  placebo.
• The frequency of bleeding
  complications with dipyridamole was comparable to
  placebo.

57

• Cardiac effects
•   Concern that dipyridamole use
  might lead to increased rates of myocardial
  ischemia has been largely laid to rest by data
  from two large clinical trials and a
  meta-analysis. This concern is related to the
  potential for coronary VD (steal phenomenon), and
  it first arose with the use of IV dipyridamole in
  cardiac stress testing. Because of this issue,
  the 2002 American College of Cardiology/AHA
  guideline for the management of pts with chronic
  stable angina recommend avoidance of dipyridamole
  in pts with stable angina.
• However, extended-release dipyridam
  ole use for stroke prevention is NOT associated
  with an increased risk of myocardial ischemia or
  infarction.

58

• Aspirin plus dipyridamole
• The combination of aspirin-extended-
  release dipyridamole is significantly more
  effective than aspirin alone for stroke
  prevention.
• The combination of aspirin and
  immediate-release dipyridamole was
  non-significantly better than aspirin alone for
  secondary prevention of stroke.
  Aspirin-extended-release dipyridamole was
  associated with a significant reduction in stroke
  risk compared with aspirin alone.

59

• Aspirin plus extended-release dipyridamole versus
  clopidogrel
• The PRoFESS trial showed
  that clopidogrel monotherapy and aspirin-extended-
  release dipyridamole have similar risks and
  benefits for secondary stroke prevention. The
  trial enrolled 20,332 pts with noncardioembolic
  ischemic stroke and randomly assigned them to ttt
  with either aspirin-extended-release dipyridamole 
  (25/200 mg twice daily) or clopidogrel (75 mg
  once daily).
• At an average follow-up of 2.5 years, the
  following observations were noted
• There was no difference
  between ttt with aspirin-extended-release
  dipyridamole or clopidogrel for the primary
  outcome of recurrent stroke and the composite
  secondary outcome of stroke, MI, or vascular
  death.
• The rate of recurrent ischemic
  stroke was slightly lower in those assigned
  to aspirin-extended-release dipyridamole compared
  with clopidogrel, but hgic strokes were slightly
  increased. The benefit-risk ratio, expressed as
  the combination of recurrent stroke plus major
  hge, was not significantly different.
• New or worsening heart failure
  was slightly less frequent, but
  discontinuation due to headache was significantly
  more frequent in pts assigned to aspirin-extended-
  release dipyridamole.

60

• OTHER AGENTS
• Ticlopidine
• Ticlopidine is a thienopyridine with a chemical
  structure and mechanism of action similar
  to clopidogrel. Its role in stroke prevention has
  been evaluated in three major trials. -The CATS,
  TASS and AAASPS trials.
• Despite the evidence of benefit
  in the CATS and TASS trials, ticlopidine is
  generally not considered a first-line
  antiplatelet agent for stroke prevention because
  of side effects and relatively high cost.
• Side effects of ticlopidine
• The most serious complication is
  severe neutropenia, in approximately 1 percent of
  pts. Thus, for the 1st 3 ms of ttt, pts must
  undergo biweekly CBC. Rash and diarrhea occur
  more frequently than aspirin.

61

• Cilostazol
• The antiplatelet agent cilostazol is
  a phosphodiesterase 3 inhibitor that is used
  mainly for intermittent claudication in pts with
  peripheral artery disease. Several controlled
  trials have found that cilostazol is effective
  for preventing cerebral infarction (CSPS, CASISP
  and CSPS II trials, Annual rates of hgic events
  were lower with cilostazol than with aspirin.
  However, headache, diarrhea, palpitation,
  dizziness, and tachycardia were more frequent
  with cilostazol, and more pts discontinued
  cilostazol than aspirin (20 versus 12 ).
• These data support the safety
  and efficacy of cilostazol for secondary stroke
  prevention in Asian populations. However, there
  are as yet no high-quality data regarding the use
  of cilostazol for secondary stroke prevention in
  non-Asian ethnic groups. Also, the lower
  tolerability and higher cost of cilostazol
  compared with aspirin may limit its more
  widespread use for stroke prevention.

62

• Triflusal
• Triflusal is an antiplatelet
  agent that is structurally related to aspirin. It
  is available as a licensed pharmaceutical in some
  European and Latin American countries, but is
  considered investigational in USA.
• In a randomized trial, the
  effectiveness of triflusal was similar
  to aspirin at preventing vascular events after
  stroke, but it did have a lower rate of hgic
  complications.
• Similar findings were noted in a
  smaller randomized trial and a meta-analysis of
  four trials. It is not clear whether triflusal
  would have had a lower rate of hgic complications
  than lower-dose aspirin.

63

• CHOOSING INITIAL THERAPY
•  Aspirin is effective for
  secondary stroke prevention in pts with
  noncardioembolic TIA and ischemic stroke.
  However, clopidogrel ttt was better than aspirin
  as measured by a composite outcome of stroke, MI,
  or vascular death in the CAPRIE study, and the
  combination of aspirin-extended-release
  dipyridamole had greater benefit for secondary
  stroke risk reduction than aspirin alone in two
  clinical trials (ESPS-2 and ESPRIT).
• Current guidelines from
  AHA/ASA and the American College of Chest
  Physicians (ACCP) recommend that pts with a
  noncardioembolic (ie, atherothrombotic, lacunar,
  or cryptogenic) stroke or TIA and no
  contraindication receive an antiplatelet agent to
  reduce the risk of recurrent stroke. These
  guidelines note that aspirin, clopidogrel, and
  the combination of aspirin-extended-release
  dipyridamole are all acceptable options for
  preventing recurrent noncardioembolic ischemic
  stroke or TIA. The 2012 ACCP guidelines
  include cilostazol in this group of recommended
  antiplatelet agents, and further suggest the use
  of the combination of aspirin-extended-release dip
  yridamole or clopidogrel over aspirin or
  cilostazol.

64

• Given the available data, we
  suggest ttt with either clopidogrel 75 mg daily
  as monotherapy, or aspirin-extended-release
  dipyridamole 25 mg/200 mg twice a day, rather
  than aspirin alone. Some experts still prefer
  aspirin as the first-line agent, noting that the
  alternative antiplatelet regimens (clopidogrel or
  aspirin-extended-release dipyridamole) have an
  apparent modest advantage in benefit that is
  potentially offset by a disadvantage in cost.
• Immediate-release dipyridamole ca
  nnot be routinely recommended for secondary
  prevention of ischemic stroke, given the limited
  evidence supporting its effectiveness and the
  significant pharmacokinetic differences between
  it and extended-release dipyridamole.
•   Ticlopidine is rarely used
  because of its side-effect profile and lack of
  clear superiority over the other available
  agents.
• Aspirin and clopidogrel should not be used in
  combination for stroke prevention, given the lack
  of greater efficacy compared with either agent
  alone, and given the substantially increased risk
  of bleeding complications.

65

• SUMMARY AND RECOMMENDATIONS
• Aspirin, clopidogrel, and the combination
  of aspirin-extended-release dipyridamole are all
  acceptable options for preventing recurrent
  noncardioembolic ischemic stroke.
• For pts with a history of
  noncardioembolic stroke or TIA of
  atherothrombotic, lacunar (small vessel occlusive
  type), or cryptogenic type, we recommend ttt with
  an antiplatelet agent (Grade 1A). We suggest
  initial antiplatelet therapy using
  either clopidogrel (75 mg daily) as monotherapy,
  or the combination of aspirin-extended-release
  dipyridamole (25 mg/200 mg twice a day), rather
  than aspirin (Grade 2A). The choice between
  clopidogrel and aspirin-extended-release dipyridam
  ole is dependent mainly on pt tolerance and
  contraindications. These recommendations apply as
  long as the choice will not impose a substantial
  financial burden. Initial therapy with aspirin is
  appropriate for pts who cannot afford or cannot
  obtain the more effective antiplatelet agents
  (clopidogrel or aspirin-extended-release
  dipyridamole).

66

• Although the optimal dose
  of aspirin is uncertain, there is no compelling
  evidence that any specific dose is more effective
  than another, and fewer gastrointestinal side
  effects and bleeding occur with lower doses (325
  mg a day). We recommend a dose of 50 to 100 mg
  daily when using aspirin for the secondary
  prevention of ischemic stroke (Grade 1B).
• For pts having carotid
  endarterectomy, we recommend aspirin (81 to 325
  mg daily) started before surgery and continued
  indefinitely in the absence of a contraindication
  (Grade 1A).
• Aggrenox (aspirin-extended-release
  dipyridamole) should not be used in pts who
  cannot tolerate aspirin. Clopidogrel (75 mg/day) i
  s an obvious alternative for pts who cannot
  tolerate aspirin. Ticlopidine should be reserved
  for pts intolerant of aspirin and clopidogrel.
• For most pts with a
  noncardioembolic stroke or TIA, we
  recommend not using aspirin and clopidogrel in
  combination for long-term stroke prevention,
  given the lack of greater efficacy compared with
  clopidogrel alone and the substantially increased
  risk of bleeding complications (Grade 1A).

67

• However, selected pts with a
  recent acute MI, other acute coronary syndrome,
  or arterial stent placement are treated
  with clopidogrel plus aspirin.
• For pts with recently symptomatic
  intracranial large artery disease, we suggest
  dual antiplatelet therapy with aspirin plus clopid
  ogrel for 90 days, followed by antiplatelet
  monotherapy (Grade 2C).
• Well-documented and modifiable risk factors
• include hypertension
  , exposure to cigarette smoke, diabetes, AF, dysl
  ipidaemia, carotid artery stenosis, sickle cell
  disease, postmenopausal hormone therapy, poor
  diet, physical inactivity, and obesity -
  especially truncal obesity.
• Less well-documented or potentially modifiable
  risk factors include