STROKE
Ischemic
Stroke
Hemorrhagic
Stroke
Ischemic Stroke
Caused either by local thrombus formation or by
embolic phenomena, resulting in occlusion of a
cerebral artery.
Atherosclerosis, particularly of the cerebral
vasculature, is a causative factor in most cases of
ischemic stroke, although 30% are cryptogenic.
Emboli can arise from either intracranial or extracranial
arteries or, as is the case in 20% of all ischemic
strokes, the heart.
Cardiogenic embolism is presumed to have occurred if
the patient has concomitant atrial fibrillation, valvular
heart disease, or any other condition of the heart that
can lead to clot formation.
Hemorrhagic Stroke
Less common but significantly more lethal than
ischemic stroke
1. Subarachnoid Hemorrhage (SAH)
Occurs when blood enters the subarachnoid
space (where cerebrospinal fluid is housed)
owing to trauma, rupture of an intracranial
aneurysm, or rupture of an arteriovenous
malformation (AVM)
Hemorrhagic Stroke
2. Intracerebral Hemorrhage (ICH)
Occurs when a blood vessel ruptures within
the brain parenchyma itself, resulting in the
formation of a hematoma
Often are associated with uncontrolled high
blood pressure and sometimes
antithrombotic or thrombolytic therapy
3. Subdural Hematomas
Collections of blood below the dura (covering
of the brain), and are often caused by trauma
RISK FACTORS
Potentially
Modifiable, well
Nonmodifiable modifiable, less
documented
well documented
Age Cigarette smoking Migraine with aura
Sex Hypertension Metabolic syndrome
Drug and alcohol
Low birth weight Diabetes
abuse
Race Atrial fibrillation
Oral Contraceptive
Family History
use
Obesity
PATHOPHYSIOLOGY
Ischemic Stroke
Normal cerebral
blood flow is
maintained over Arterial Infarction
a wide range of occlusion
blood pressures (obstruction
by a process Atheroscleros (severe of the blood
called cerebral is, Chronic reduction supply to an
autoregulation. HTN, Stroke in cerebral organ causing
Cerebral blood local death of
vessels dilate blood the tissue)
and constrict in flow)
response to
changes in BP.
Hemorrhagic Stroke
The presence of blood in the brain parenchyma
causes damage to the surrounding tissue through
the mechanical effect it produces (mass effect) and
the neurotoxicity of the blood components and their
degradation products.
Approx. 30% of Intracerebral Hemorrhage (ICH)
continues to enlarge over the first 24 hrs, most
within 4 hrs, and clot volume is the most important
predictor of outcome, regardless of location.
Much of the early mortality of hemorrhagic stroke
(up to 50% at 30 days) is caused by the abrupt
increase in intracranial pressure that can lead to
herniation and death.
Clinical Presentation
GENERAL
The patient may not be able to
reliably report the history owing to
cognitive or language deficits.
A reliable history may have to
come from a family member or
another witness.
Clinical Presentation
SYMPTOMS
Weakness on one side of the body
Inability to speak
Loss of vision
Vertigo
Falling
Ischemic stroke: not usually painful, but patients
may complain of headache
Hemorrhagic stroke: symptoms can be very severe
Clinical Presentation
SIGNS
Multiple signs of neurologic dysfunction, and
the specific deficits are determined by the area
of the brain involved
Hemiparesis (weakness of one entire side of the
body) or monoparesis, hemisensory deficit
Px with vertigo and double vision are likely to
have posterior circulation involvement
Clinical Presentation
Aphasia (impairment of language) is
common in px with anterior circulation
strokes
Dysarthria (motor speech disorder),
visual field defects, and altered levels of
consciousness
Clinical Presentation
LABORATORY
TESTS
Laboratory Tests
Tests for hypercoagulable states (protein C
deficiency, antiphospholipid antibody)
should be done only when the cause of the
stroke cannot be determined based on the
presence of well-known risk factors for
stroke.
Protein C, protein S, and antithrombin III
are best measured in the “steady state,”
not in the acute stage
Laboratory Tests
Antiphospholipid antibodies
(anticardiolipin antibodies, B2-
glycoprotein I, and lupus anticoagulant)
screen are of higher yield than protein C,
protein S, and antithrombin III but
should be reserved for px who are <50
yrs. old, have had multiple venous/
arterial thrombotic events, or have
livedo reticularis (a skin rash).
Other Diagnostic Tests
CT Scan of the head
reveal an area of hyperintensity (white)
in the area of hemorrhage; normal or
hypointense (dark) in the area of
infarction; may take 24 hrs to reveal the
area of infarction
MRI of the head
reveal areas of ischemia with higher
resolution; earlier than the CT Scan;
Diffusion-weighted imaging (DWI) will
reveal an evolving infarct within minutes
Other Diagnostic Tests
Carotid Doppler (CD)
Determines whether the px has a high degree of
stenosis in the carotid arteries supplying blood
to the brain (extracranial disease)
Electrocardiogram (ECG)
Determines whether the patient has atrial
fibrillation
Transthoracic echocardiography (TTE)
Determines whether valve abnormalities or wall-
motion abnormalities are sources of emboli to
the brain
Other Diagnostic Tests
Transesophageal echocardiography (TEE)
A more sensitive test for thrombus in the left
atrium
Effective at examining the aortic arch for
atheroma, a potential source of emboli
Transcranial Doppler (TCD)
Determines whether the px is likely to have
intracranial stenosis
TREATMENT
DESIRED OUTCOMES
Reduce the ongoing neurologic injury
and decrease mortality and long-term
disability
Prevent complications secondary to
immobility and neurologic dysfunction
Prevent stroke recurrence
TREATMENT
GENERAL APPROACH TO TREATMENT
Ensure that the px is supported from a
respiratory and cardiac standpoint and to
quickly determine whether the lesion is
ischemic or hemorrhagic, based on a CT
scan.
Ischemic stroke px: if presenting within
hours of the onset of their symptoms, they
should be evaluated for reperfusion therapy
TREATMENT
GENERAL APPROACH TO TREATMENT
Px with elevated BP should remain
untreated unless their BP exceeds 220/120
mmHG, or they have evidence of aortic
dissection, acute myocardial infarction,
pulmonary edema, or hypertensive
encephalopathy. If BP is treated, short-
acting parenteral agents (labetalol,
nicardipine, nitropusside) are favored.
TREATMENT
GENERAL APPROACH TO TREATMENT
Subarachnoid Hemorrhage: if an aneurysm
is found by angiography, endovascular
coiling or clipping via a craniotomy should
be performed to reduce the risk of
rebleeding.
Intracerebral Hemorrhage: px may require
external ventricular drainage if there is
intraventricular blood and evolving
hydrocephalus.
TREATMENT
GENERAL APPROACH TO TREATMENT
Once the px is out of the
hyperacute phase, attention is
place on preventing worsening,
minimizing complications, and
instituting appropriate secondary
prevention strategies.
TREATMENT
NONPHARMACOLOGIC
THERAPY
Nonpharmacologic
Therapy
ISCHEMIC STROKE
With a large infarction in the middle
cerebral artery territory: decompressive
surgery to reduce intracranial pressure;
the surgery must be performed within 48
hrs of stroke onset to significantly improve
functional outcome.
If significant swelling associated with a
cerebellar infarction: surgical
decompression.
Nonpharmacologic
Therapy
In secondary prevention:
Carotid endarterectomy of an ulcerated
and/or stenotic carotid artery is a very
effective way to reduce stroke incidence and
recurrence
Carotid stenting is a less invasive alternative
and can be effective in reducing recurrent
stroke risk in patients <70 yrs. old.
Aggressive medical management > stenting
in reducing recurrent stroke in px with
intracranial stenosis.
Nonpharmacologic
Therapy
HEMORRHAGIC STROKE
Subarachnoid Hemorrhage: surgical
intervention to either clip or ablate the
offending vascular abnormality
Intracerebral Hemorrhage: surgical
evacuation is beneficial if undertaken
within 8 hrs, of onset and in px with
intermediate hemorrhage volumes (20-
50mL).
Nonpharmacologic
Therapy
HEMORRHAGIC STROKE
Insertion of an external ventricular
drain for hydrocephalus and
subsequent monitoring of
intracranial pressure are done
commonly; the least invasive of the
procedures done in these px.
TREATMENT
PHARMACOLOGIC
THERAPY
Pharmacologic
Therapy RECOMMENDATION
Acute Treatment tPA 0.9 mg/Kg IV (max 90mg) over 1 hr in selected px
within 3 hrs of onset
tPA 0.9 mg/Kg IV (max 90mg) over 1 hr between 3 and
4.5 hrs of onset
ASA 160 -325mg daily; started within 48 hrs of onset
*tPA (tissue plasminogen activator)
Secondary
Prevention Antiplatelet therapy
Noncardioembolic Aspirin 50-325mg daily
Clopidogrel 75mg daily
Aspirin 25mg + extended release dipyridamole 200mg
twice daily
Cardioembolic Vit. K Antagonist
(esp Atrial Dabigatran 150mg twice daily
fibrillation)
Atherosclerosis Intense Statin Therapy
50% reduction in LDL or ≤70mg/dL (≤1.81 mmol/L)
GENERAL
INFORMATION
REGARDING
SAFETY AND EFFICACY
ASA
In the International Stroke Trial (IST),
aspirin 300mg/day significantly reduced
stroke recurrence within the first 2 wks
without effect on early mortality, resulting
in a significant decrease in decrease in
death and dependency at 6 mos.
In the Chinese Acute Stroke Trial (CAST),
aspirin 160mg/day reduced the risk of
recurrence and death in the first 28 days,
but long-term death and disability were not
different than with placebo.
ASA
In both trials, a small but significant
increase in hemorrhagic
transformation of the infarction was
demonstrated.
Overall, the beneficial effects of the
early aspirin have been embraced
and adopted into clinical guidelines.
Antiplatelet Agents
All patients who have had an acute
ischemic stroke or transient ischemic
attack (TIA) should receive long-term
antithrombotic therapy for secondary
prevention.
In px with noncardioembolic stroke, this
will be some form of antiplatelet
therapy.
Antiplatelet Agents
Clopidogrel:
Slightly more effective than ASA but
both have similar incidence of adverse
effects (accdng to Clopidogrel vs Aspirin
in Px at Risk of Ischemic Events [CAPRIE]
trial)
Used widely in px with atherosclerosis
Antiplatelet Agents
The combination of Dipyridamole
(83% extended release) + ASA (30-
325mg daily) is more effective than
ASA alone in reducing recurrent
stroke. (Accdng to
European/Australasian Stroke
Prevention in Reversible Ischemia
Trial [ESPRIT]).
Antiplatelet Agents
Cilostazol:
Mostly used in the tx of intermittent
claudication
Significantly reduces the risk of
recurrent vascular events and
hemorrhagic stroke compared to ASA
Causes less bleeding events than ASA
but more overall minor adverse events
including headache and GI disturbance
Oral Anticoagulants
Tx of choice in the prevention of stroke in px with
atrial fibrillation
Newer oral anticoagulants including dabigatran
(direct thrombin inh), rivaroxaban, and apixaban
(direct factor Xa inh) have significant advantages
over warfarin in terms of ease of dosing and less
food and drug interactions.
All three agents are as effective as, in some
cases, superior to, warfarin in reducing
recurrent events and intracranial hemorrhage
Oral Anticoagulants
Dabigatran 150mg twice daily is
recommended as either a first line agent or
one of several first-line oral anticoagulants
ASA therapy was as effective as and safer
than warfarin in px with intracranial
stenosis (accdng to Warfarin-Aspirin in
Intracranial Disease [WASID])
BP Lowering
American Heart Association and ASA
guidelines recommend reduction of BP in
px with stroke or transient ischemic
attack.
Early BP lowering can worsen symptoms,
however; therefore, recommendations
are limited to px outside of the acute
stroke period (first 7 days)
Statins
Statins have been shown to reduce the
risk of stroke by approx. 30% in px with
coronary artery disease and elevated
plasma lipids.
Atorvastatin 80mg daily reduced the risk
of recurrent stoke by 16% and coronary
events by 42% in px with no cardiac
history (accdng to Stroke Prevention by
Aggressive Reduction in Cholesterol
Heparin for Prophylaxis
of Deep Vein Thrombosis
(DVT
Use of low-molecular-weight heparins
or low-dose subcutaneous
unfractionated heparin (5,000 units
three times daily) can be
recommended for the prevention of
DVT in hospitalized patients with
decreased mobility owing to their
stroke and should be used in all but
the most minor strokes.
ALTERNATIVE DRUG
TREATMENTS
ASA + Clopidogrel
The risk of life-threatening bleeding
increased from 1.3% to 2.6% (accdng to
Management of ATherothrombosis with
Clopidogrel in High-risk Patients
[MATCH]).
This combination should only be used in
selected patients with a recent MI
history or intracranial stenosis and only
with ultra-low-dose ASA to minimize
bleeding risk.
Heparins
The use of full-dose unfractionated heparin
in the acute stroke period has never been
proven to positively affect stroke outcome,
and it significantly increases the risk of
Intracerebral Hemorrhage (ICH)
Other potential but unproven uses for
treatment doses of either unfractionated or
LMWH include bridge therapy in px being
initiated on warfarin, carotid dissection, or
continuous worsening of ischemia despite
adequate antiplatelet therapy.
DRUG CLASS
INFORMATION
ASA
ASA exerts its antiplatelet effect by
irreversibly inhibiting cyclooxygenase,
which, in platelets, prevents conversion of
arachidonic acid to thromboxane A2 (TXA2),
which is a powerful vasoconstrictor and
stimulator of platelet aggregation.
ASA also inhibits prostacyclin (PGI2) activity
in the smooth muscle of vascular walls.
PGI2 inhibits platelet aggregation, and the
vascular endothelium can synthesize PGI2
such that the platelet aggregating effect is
maintained.
ASA
Upper GI discomfort and bleeding are
the most common A/E and have been
shown to be dose related
The onset if the antiplatelet effect of ASA
is <60 mins.; However, other px either
have or develop “aspirin resistance” and
require higher doses to achieve the
desired antiplatelet effect.
ASA
Administration of Ibuprofen prior to the
administration of a daily aspirin doses
inhibits the ASA from binding irreversibly
to the cyclooxygenase and can decrease
its antiplatelet effect.
Recommendations are to administer ASA
at least 2 hrs before ibuprofen or to wait
at least 4 hrs after an ibuprofen dose.
Clopidogrel
Clopidogrel has a unique platelet
antiaggregatory effect in that it is an
inhibitor of the adenosine diphosphate
(ADP) pathway of platelet aggregation and
inhibits known stimuli to platelet
aggregation.
This effect causes an alteration of the
platelet membrane and interference with
the membrane-fibrinogenic interaction
leading to a blocking of the platelet
glycoprotein IIb/IIIa receptor.
Clopidogrel
A time lag of 3-7 days before the antiplatelet
effect is maximal should be expected.
The tolerability of clopidogrel 75mg/day is at
least as good as medium-dose (325mg/day)
ASA; there is lesser GI bleeding
Clopidogrel is assoc. with an increased risk
of diarrhea and rash, but discontinuation
rates owing to adverse effects are similar to
those with ASA 325mg/day.
Extended-Release
Dipyridamole + ASA
DIPYRIDAMOLE
In high doses, inhibits platelet aggregation by
inhibiting phosphodiesterase, leading to
accumulation of cyclic adenosine
monophosphate (cAMP) and cyclic guanosine
monophosphate (cGMP) intracellularly, which
prevent platelet activation.
Dipyridamole also enhances the
antithrombotic potential of the vascular wall.
Extended-Release
Dipyridamole + ASA
DIPYRIDAMOLE
The extended-release formulation is
important in that it allows twice-daily
administration and higher doses to be
tolerated in patients.
A/E: headache
EVALUATION OF
THERAPEUTIC
OUTCOMES
Monitoring of the
Pharmaceutical Care
Plan
Patients with acute stroke should be monitored
intensely for the development of:
Neurologic worsening (recurrence or
extension)
Complications (thromboembolism or
infection)
A/E from pharmacologic and
Monitoring of the
Pharmaceutical Care
Plan
The most common reasons for deterioration in
a stroke patient are:
Extension of the original lesion –ischemic
or hemorrhagic—in the brain
Development of cerebral edema and
raised intracranial pressure
Hypertensive emergency
Monitoring of the
Pharmaceutical Care
Plan
The most common reasons for deterioration in
a stroke patient are:
Infection (urinary and respiratory are
most common)
Venous thromboembolism (DVT and
pulmonary embolism)
Electrolyte abnormalities and cardiac
rhythm disturbances (can be associated
with brain injury)
Recurrent stroke
Monitoring Stroke
Therapy
Monitoring
Drug Adverse Effect
Parameters
tissue plasminogen
Bleeding Neurologic exam
activator
ASA Bleeding
Clopidogrel Bleeding
ERDP-ASA Headache, Bleeding
Warfarin Bleeding INR, Hb/Hct
Dabigatran Bleeding
