2. Outline
• Epidemiology
• Intracranial Hemorrhage
• Spontaneous
• Risk of anticoagulation
• Treatment
• Ischemic Stroke
• Vascular Disease in the Brain
• Cardioembolic Source
• Treatment Strategies
3. Epidemiology
• Stroke is almost as important as ischemic heart disease
• Here are the numbers
• Acute coronary syndrome - 1.2 million per year in the US
• Transient Ischemic Strokes - 750,000 per year in the US
• Ischemic strokes - 200,000 to 500,000 per year in the US
• Intracerebral hemorrhage - 37,000 to 52,400 per year in the US
• Eighty percent of strokes are caused by focal cerebral ischemia due to
arterial occlusion
• Remaining twenty percent are caused by hemorrhages
• Mortality rates
• For ischemic strokes mortality rates range from 10 to 17 percent at
one year
• Wide variability ranging from 2.5% for lacunar infarcts to 78% in
patients with space-occupying hemispheric infarction
• For hemorrhagic strokes, mortality rates are 62% surviving the first year
Brott T NEJM 2000
4. Intracerebral Hemorrhage
• Classification
• Primary
• Accounts for 78 to 88 percent
• Originates from spontaneous rupture of small vessels damaged by
chronic hypertension or amyloid angiopathy
• Secondary
• Occur from vascular abnormalities (i.e. AV malformations or aneurysm)
• Tumors
• Impaired coagulation
• Incidence
• Worldwide - 10 to 20 cases per 100,000 population
• More common in men than women
• African-Americans and Japanese have high incidence (50 per 100,000
population)
Qureshi NEJM 2001
6. Intracerebral Hemorrhage associated
with oral anticoaguation
• Mortality at one year is much higher in this population close to 67 %
• Patients receiving anticoagulation have a 7 to 10 fold increased in developing ICH
• Underlying cause of spontaneous versus anticoagulation associated ICH are likely the same
• Anticoagulation, however, may act as an exacerbating factor
• Hematoma expansion in patients on anticoagulation occurs for a longer period of time
• Treatment Strategies
• Vitamin K
• Takes at least 2 to 6 hrs to take effect
• Allows for a more sustained reversal of anticoagulation
• IV Vitamin K has a low risk of allergic or anaphylactic reaction in one study 3 per
10,000 doses [4]
• FFP
• Contains all factors in a non concentrated form requiring large volume to have
effective hemostasis
• Ideally, 1mL of FFP/kg body weight is required to bring INR down 1 to 2 IU/dL
• ? Novoseven
1 Steiner, T Stroke 2006
9. Vascular Disease and the Brain
• The incidence of silent strokes
• On serial MRI approximately 6 to 7 % at age 60 which increases to 28% at
age 80
• Presence of silent brain infarct more than doubles the risk of dementia with a
hazard ratio 2.26
• Silent thalamic infarcts in particular were responsible for a decrease
memory performance
• Occur due to obstruction of end vessels which have no collateral supply
• Small vessel disease is likely a global phenomenon affecting the brain, heart,
retina, kidneys and other organs with high blood flow
• Affected the vascular risk factors such age, hypertension, diabetes, and renal
disease
• There may be a possibility that small vessel disease in one organ may
precipitate progression in other organ
Vermeer SE Lancet Neurology 2007
Vermeer SE, NEJM 2003
10. Transient Ischemic Attack - the unstable angina of
the brain
• Defined as a neurologic deficit lasting less than 24 hrs that is attributed to focal cerebral
or retinal occlusion
• There is much controversy over how to define TIAs
• Rapid recovery may be the most important characteristic in defining a distinct clinic
entity
• But this may portend a more unstable pathophysiology
• Diagnosis is difficult because it is usually based on clinical history alone relying on the
memories of patients who were neurlogically impaired.
• Broad differential include migraine, seizure, vasovagal, syncope, arrhythmia,
compressive neuropathy, anxiety, and conversion disorder
• Risk of stroke after a TIA
• Study of 1707 patients given diagnosis of TIA were studied for a 90-day period [5]
• Roughly 1 in 9 patients had a stroke after diagnosis
• Half of all strokes happened within two days of diagnosis
• 2.6 percent of patients had a cardiac event
• 2.6 percent died
• Patients with atrial fibrillation had an 11 percent chance of stroke at 90 days
Johnston, SC NEJM 2002
12. The subtypes of ischemic stroke
• In a study of 5,017 patients with acute ischemic
stroke
• Cardioembolism was the most common 25.6%
• Large artery atherosclerosis 20.9%
• Small vessel 20.5%
• Neurological deficit on admission was most
severe in cardioembolism
• Mortality was highest in cardioembolic stroke
(22.6%) compared to large vessel (9.3%) and
microangiopathy (3.3%)
Grau Stroke 2001
13. Cardioembolic Stroke
• Background
• These strokes are generally severe and prone to early recurrence
• Due to their large size, cardiac emboli have a predilection for the middle cerebral
artery
• What clinical signs make a cardioembolic source more likely?
• Sudden onset
• Hemorrhagic transformation of an ischemic infarct
• Visual field abnormalities
• Neglect
• Neurological defect involving multiple brain areas
• Wernicke aphasia, or global aphasia without hemiparesis are common
• The issue of hemorrhagic transformation
• About 20 to 40% of all patients with stroke
• Increased on cardioembolic stroke - occurs in up to 71% of patients.
• Possible explanation that the hemorrhage is a result of local vascular spasm which
leads to reperfusion injury Ferro, J The Lancet Neurology 2003
14. Cardioembolic stroke - when do you start anticoagulation?
• Purpose - To see if early
anticoagulation (<48 hrs) is 426 Stroke February 2007
beneficial compared to other
treatments (placebo or aspirin)
• Methods - Seven studies were
included in the meta analysis of
these 3792 patients had atrial
fibrillation and 827 had other
cardioembolic sources
• Results
• Anticoagulation was
associated with a non
significant difference in death
or disability (73.5% vs 73.8%,
OR 1.01, p 0.9)
• Anticoagulation was
associated with a significant Figure 2. Death or disability in trials comparing anticoagulants with other treatments (a, anticoagulants versus placebo or aspirin; b,
anticoagulants versus aspirin; c, anticoagulants versus placebo) for the initial treatment of acute cardioembolic stroke.
increase in symptomatic ICH analysis (none in CESG, HAEST, and Camerlingo; 11 in significant (OR 1.18; 95% CI: 0.74 to 1.88, P 0.49, P for
(2.5 vs 0.7%, OR 2.9, P 0.02 TAIST; 25 patients overall in TOAST without specific heterogeneity 0.25). Anticoagulants were associated with a
Paciaroni Stroke 2007
information about the number of patients with cardioem- nonsignificant reduction in recurrent stroke within 7 to 14
bolic stroke; 99.99% completed for 14 days outcome and days (3.0% versus 4.9%, OR 0.68; 95% CI: 0.44 to 1.06,
99.2% completed 6-month outcome in IST). P 0.09, number needed to treat 53) but were associated
15. Cardiac Catheterization and Stroke
• Prevalence of Aortic Atherosclerosis
• In a study of 588 patients enrolled at random (average age 66.9 years) who underwent
TEE,
• Aortic plaque was present 43.7%
• Complex plaque was present in 7.6%
• Ascending aortic plaque was present 8.4%
• Iatrogenic Embolization from Aortic Plaque
• Overall rate is low from 0.2% to 0.4%
• More frequent with DM, HTN, prior stroke, or renal failure
• Procedural Characteristics
• Longer procedure time
• Larger contrast load
• More likely urgent procedure
• More likely to have IABP
Kronzon I Circulation 2007
Hamon M Circulation 2008
16. Cardiac Catheterization thrombolytic bolus of 20 mg of recom- by recent literature is that stroke oc-
the case study described above, binant tissue plasminogen activator. curring during cardiac catheterization
cause the stroke occurred during the As soon as patency of the vertebral is the most treatable of neurological
Periprocedural Stroke in PCI
First aim: clinical confirmation With NIHSS rating
Consider sedation reversal, assess glycemia & O2 saturation
Per-procedure Timing? Post-procedure
Experience in selective
cerebral angiography?
Brain Imaging required:
- MRI (DWI/PWI/MRA/T2*)
YES NO - or Plain CT, CT perfusion/CTA
Proceed with selective No evidence Acute
cerebral angiography of acute haemorrhage haemorrhage
No
Ischemic stroke confirmed
thrombolysis
with arterial occlusion found?
Significant PWI-DWI mismatch No significant mismatch
YES NO or CT perfusion mismatch
Hypoperfusion No Hypoperfusion
Consider endovascular Consider IA or combined IV/IA
Intervention thrombolysis or endovascular No extensive Extensive No
and/or IA thrombolysis Intervention especially DWI lesion DWI lesion thrombolysis
for distal ICA ‘’T’’occlusion
Consider Consider brain
thrombolysis decompression
ure 2. Algorithm for the management of periprocedural stroke in the setting of cardiac catheterization. IA indicates intra-arterial; ICA,
ernal carotid artery; CTA, computed tomography angiography; DWI, diffusion-weighted imaging; IV, intravenous; MRA, magnetic res-
ance angiography; MRI, magnetic resonance imaging; and PWI, perfusion-weighted imaging.
17. Management of Acute Stroke
• Making the diagnosis
• Common things being common atherosclerosis and cardioembolic
sources are leading causes, but
• Ptosis and miosis on the contralateral side of the deficit may
indicate carotid-artery dissection
• Fever and cardiac murmur - endocarditis
• Headache and elevated ESR in pt >50 yo may indicate giant cell
arteritis
• Imaging
• CT and MRI have a sensitivity for acute intracranial bleed, but MRI
has a much high sensitivity for acute ischemic changes esp in the
posterior fossa and early in the evolution of a stroke
• MRI can detect cytotoxic edema within minutes after the onset
of ischemia
Worp HB NEJM 2007
18. Figure 3 gives the results of an intention-to-treat analysis
of data pooled from randomized trials of rtPA for ischemic
Time lost is brain lost
stroke (NINDS, ECASS-I, ECASS-II, and ATLANTIS) that
included 2775 patients treated up to 6 hours after symptom
onset at more than 300 hospitals located in 18 countries.20
The analysis supports the primary finding of the NINDS trial
Goldstein Acute Stroke Treatment
in that treatment within 3 hours (and possibly up to 4.5 hours) 1505
of symptom onset is associated with a greater chance of a
Figure 1. Relationship between cerebral blood flow, time, func- favorable outcome at 3 months. Moreover, as expected on the
tional impairment, and infarction. Even within 3 hours, ischemic basisnous rtPA included the European Cooperative Acute Stroke
of the principles illustrated in Figure 1, the likelihood of
tissue might go on to infarction or be viable if reperfused.
Reproduced from Jones et al3 with permission from the Journal
of Neurosurgery. Copyright 1981, American Association of Neu-
What to consider when administering t-
benefit diminishes as time after used a onset dose of rtPA and
Study (ECASS)-I, which symptomhigher elapses (ie,
the chances of benefit decrease hours after the onset of symp-
randomized patients up to 6 as time to reperfusion
rological Surgeons. toms.
PA
increases).17 In the negative ECASS-II, the dose of tissue plasmin-
A ogen activator was identical to that used in thestroke
second concern was that a baseline imbalance in NINDS trial,
treatment, and because the overall benefit in the NINDS trial
included a 10-fold increase in the proportion of treated
> Onset of symptoms less than 3 h
severity between the rtPA- and placebo-treated groups in the patients
but there was a 6-hour treatment window, with most
NINDS trial after 3explain18 The Alteplase Thrombolysis for Acute
treated might hours. the observed benefit. An indepen-
patients having symptomatic intracerebral hemorrhage (6.4%
versus 0.6%), which could compromise the benefit when used before beginning treatment
dent Noninterventionalthe trial dataIschemic Stroke (ATLANTIS)
group reanalyzed Therapy in and found a clinically
important and statistically significant treatment to the NINDS trial
study used a treatment protocol identical benefit de-
outside a clinical trial setting.
Negative thrombolytic studies differed from the NINDS > No head trauma or previous stroke in
spitebut randomized patients 3 baseline stroke severity.21
subgroup imbalances in to 5 hours after stroke.19
Multiple exploratory analyses failedof an intention-to-treat analysis
Figure 3 gives the results to identify any subgroup
trial in fundamental and important ways (eg, different of ischemic pooled patients who wouldtrialsmore likely to
of data stroke from randomized be of rtPA for ischemic
thrombolytic drugs, different doses of rtPA, and longer
intervals between symptom onset and treatment). Trials of
the previous 3 m
either benefit from treatment or be harmed by it.
stroke (NINDS, ECASS-I, ECASS-II, and ATLANTIS) that
A third concern has been that the benefits of intravenous
another thrombolytic, streptokinase, included patients treated
beyond 3 hours of symptom onset and generally incorporated
> No MI in previous 3 m
included 2775 patients treated up to 6 hours after symptom
rtPA found in the NINDS trial would be not be generalizable
onset at more than 300 hospitals located in 18 countries.20
to nonstudy settings. Several observational studies reinforced
the concomitant use of other antithrombotic drugs, which was
prohibited in the NINDS trial.14 –16 Negative trials of intrave-
> No GI bleed in previous 21 days
this The analysis supportsratesprimary finding of the NINDS trial
fear, because higher the of bleeding complications
occurred more commonly when treatment protocols were hours)
in that treatment within 3 hours (and possibly up to 4.5
favorable outcome at 3 months. Moreover, as expected on the in previous 14 days
> No major surgery
of symptom onset is associated with a greater chance of a
Figure 1. Relationship between cerebral blood flow, time, func-
tional impairment, and infarction. Even within 3 hours, ischemic
benefit diminishes > time afterarterial puncture at a non
as No symptom onset elapses (ie,
basis of the principles illustrated in Figure 1, the likelihood of
tissue might go on to infarction or be viable if reperfused.
Reproduced from Jones et al3 with permission from the Journal
the chances of benefit decrease as time to reperfusion
of Neurosurgery. Copyright 1981, American Association of Neu-
rological Surgeons. increases). compressible site in previous 7 days
A second concern was that a baseline imbalance in stroke
treatment, and because the overall benefit in the NINDS trial severity between the rtPA- and<185/110 in the
> BP placebo-treated groups
included a 10-fold increase in the proportion of treated NINDS trial might explain the observed benefit. An indepen-
patients having symptomatic intracerebral hemorrhage (6.4% dent group reanalyzed No active bleeding or trauma
> the trial data and found a clinically
Figure 2. Algorithm for the management
versus 0.6%), which could compromise the benefit when used of patients with acute ischemic stroke.
important and statistically significant treatment benefit de-
outside a clinical trial setting. > Not taking oral anticoagulant or INR
IV-tPA indicates intravenous tissue plas-
spite subgroup imbalances in baseline stroke severity.
minogen activator; Rx, treatment.
21
Negative thrombolytic studies differed from the NINDS Multiple exploratory analyses failed to identify any subgroup
trial in fundamental and important ways (eg, different of ischemic stroke<1.7 who would be more likely to
patients
thrombolytic drugs, different doses of rtPA, and longer either benefit from treatment or be harmed by it.
intervals between symptom onset and treatment). Trials of A third concern > been that the benefits of intravenous
has PTT in normal range
another thrombolytic, streptokinase, included patients treated rtPA found in the NINDS trial would be not be generalizable
beyond 3 hours of symptom onset and generally incorporated
the concomitant use of other antithrombotic drugs, which was
> Plt greater 110k Goldstein LB Circulation 2007
to nonstudy settings. Several observational studies reinforced
this fear, because higher rates of bleeding complications
prohibited in the NINDS trial.14 –16 Negative trials of intrave- occurred more commonly when treatment protocols were
20. Recombinant Tissue Plasminogen
Activator - the NINDS trial
• Study Design
• Alteplase given to patient with a clear clinical diagnosis
of stroke
• Within 3 hours of onset of symptoms
• Following CT head to confirm no hemorrhage present
• Patients aged 18-80
• Symptoms present for at least 30 minutes
• Large number of other exclusion criteria
21. Results of the NINDS
• Part 1 (291 patients) looked at
clinical improvements at 24 hours
• No sig difference at 24 hours
• Part 2 (333 patients) looked at
functional outcomes at 3 month
New England Journal, 1995
• Alteplase associated with an
NINDS tPA Stroke Trial
increase in intracranial
hemorrhage (6.4% vs. 0.6%)
•
30 Hemorrhage
Alteplase associated with a 30%
30
p < .05
increase in chance of either none 20
20
or minimal disability (mRS of 31
0-1)
9 20
•
20
Alteplase associated with small
10 10
non-significant reduction in
0 0
8
1
mortality (p=0.30) tPA Placebo tPA Placebo
NIHSS Excellent Total Death
NINDS study group NEJM 1995 Recovery (%) Rate (%)
22. ECASS-3
• Prospective, multicenter, randomized study looking at the tPA
treatment (n 418) versus placebo (n 403) in 3 to 4.5 hour
window from the onset of symptoms
• Trial excluded persons older than 80 yo, baseline
NIHSS>25, patients taking anticoagulants or who had
previous history of stroke
• Intracranial hemorrhage was increased in the arm that
received tPA (7.9%) vs placebo (3.5%; OR 2.38 p 0.006)
• Primary efficacy outcome (Rankin Score 0 to 1) was
significantly increased with tPA (52.4%) than with placebo
(45.2% risk ratio 1.16 p 0.04)
• This benefit was smaller than NINDS as ECASS-3 OR for
global favorable outcome 1.28 compared to 1.9 for NINDS
Zoppo GJ Stroke 2009
24. International Stroke Trial 1997
International Stroke Trial
Recurrent Stroke at 14 days
RecurrentN =Stroke Within 14 Days
19,435 patients
Recurrent Stroke Within 14 Days
(N = 19,435)
25. The Acute Hypertensive
Response post-stroke
• Prevalence
• In the International Stroke Trial, mean systolic BP was 160.1 mmHg and 82%
of patients had high BP at enrollment
• Pathophysiology
• Stroke involves transient or permanent damage or areas involved in the
regulation of CV functioning
• These areas are diffusely distributed in the brain
• Increased BP may also be a sign of increased ICP
• In acute stroke, autoregulation is impaired for a given region
• After an stroke the core region has a severe reduction in flow eventually
leading to necrosis, while the penumbra has a moderate reduction
• The penumbra remains viable for hours because of some degree of
blood flow is sustained through collateral flow
26. Algorithm for treating hypertension
178 Circulation July 8, 2008
Clinical diagnosis of acute stroke
Reduce BP if >185/110 mm Hg using short acting IV medication*
Ischemic Emergent computed tomographic scan Intracerebral
stroke hemorrhage
Candidate for Not a candidate for Suspect Do not suspect
thrombolysis thrombolysis high ICP high ICP
Reduce BP if Reduce BP if Reduce BP if Reduce BP if
>185/110 mm Hg >220/120 mm Hg SBP >180 mm Hg SBP >180 mm Hg
using short acting using short acting or MAP >130 mm Hg or MAP >130 mm Hg
IV medication. α IV medication. using short acting using short acting
Avoid and treat IV medication; IV medication.
hypotension ICP monitoring Monitor neurological
(<100/70 mm Hg).α recommended to examination every
maintain 15 minutes. β
CPP >60 mm Hg. β
Treat with
thrombolysis.
Maintain BP
<180/105 mm Hg
using short acting
IV medication or Oral antihypertensive agents may be considered after 24 hours; BP goal ≈160/110 mm Hg.
infusions for 24 h. α Titrate to more aggressive goals after neurological stability is achieved. α
Figure. Algorithm for treatment of acute hypertensive response among patients with stroke and stroke subtypes. IV indicates intrave-
27. In Summary
• Majority of strokes are ischemic (80%) compared to hemorrhagic (20%)
• Though hemorrhagic strokes have much higher mortality rates
• Common sites of spontaneous hemorrhagic strokes are cerebral lobes, basal ganglia,
thalamus, the brain stem, or the cerebellum
• Anticoagulation increases risk and administration of activated Factor VII has not been
shown to have a mortality benefit
• Small vessel disease plays an important role in silent stroke
• These silent strokes are associated to the development of dementia
• TIA portend worse outcomes esp., in patients with atrial fibrillation
• Anticoagulation has not been shown to be superior to antiplatelet therapy
• Cardioembolic stroke has a high rate of mortality and disability
• Early anticoagulation does not lead to better outcomes
• tPA for ischemic stroke is the mainstay of treatment
• The longer you wait the worse the outcome
• Administration > 4.5 hours has not been shown to be beneficial