a stroke of knowledge: cerebrovascular accidents

A Stroke of Knowledge:

Cerebrovascular Accidents/

Transient Ischemic Attack (CVA/TIA)

Shayna Cruz, BS, PharmD Candidate 2019

Heather Powell, PharmD, BCPS

Shayna Cruz and Heather Powell declare no

conflicts of interest, real or apparent, and no

financial interests in any company, product, or

service mentioned in this program, including

grants, employment, gifts, stock holdings and

honoraria.

Disclosures and Conflict of Interest

At the conclusion of the program, the pharmacists will be able to:

1. Describe the risk factors, pathophysiology, and epidemiology of

cerebrovascular accidents (CVA)/transient ischemic attacks

(TIA).

2. Identify pertinent signs and symptoms of a patient who may be

experiencing a CVA/TIA.

3. Describe non-pharmacologic and pharmacologic treatment

regimens for the primary and/or secondary prevention of

CVA/TIA.

4. Compare and contrast antiplatelet therapies for secondary

ischemic stroke prevention.

5. Discuss newly published trials and stroke guidelines

Pharmacist Objectives

At the conclusion of this program, the pharmacy technician will

be able to:

1. Describe the risk factors, pathophysiology, and epidemiology of

cerebrovascular accidents (CVA)/transient ischemic attacks

(TIA).

2. Identify pertinent signs and symptoms of a patient who may be

experiencing a CVA/TIA.

Technician Objectives

Which of the following is/are modifiable risk factors

for CVA/TIA ? Select ALL that apply.

a) Diabetes

b) Hypertension

c) Cigarette smoking

d) Obesity

Pre-Test Question 1

What is the recommended duration of treatment

for dual antiplatelet therapy (aspirin and

clopidogrel) post-ischemic stroke?

a) 21 days

b) 30 days

c) 90 days

d) 365 days

Pre-Test Question 2

A 59 y/o F presents to the ED with unilateral weakness,

confusion, and visual abnormalities. PMH includes DM2,

HTN, and HLD. Current medications include metformin

1000 mg BID, lisinopril 20 mg QD, and atorvastatin 80 mg

QHS. Pt reports an allergy to salicylates (trouble

breathing). She is ultimately diagnosed with a TIA. Which

of the following is the most appropriate secondary

prevention therapy following DAPT?

a) Aspirin 325 mg PO QD

b) Clopidogrel 75 mg PO QD

c) Dipyridamole ER/Aspirin 200/25 mg PO BID

d) Any of the above are options

Pre-Test Question 3

Which of the following are signs/symptoms of

CVA/TIA? Select ALL that apply.

a) One-sided facial droop

b) Ability to keep both arms steady and

level when arms are raised

c) Slurred speech

d) Shooting pains down left arm

Pre-Test Question 4

Cerebrovascular Accidents

Clinical, radiological, or pathological

evidence of ischemia or hemorrhage,

involving a defined cerebral vascular

territory

Comprised of hemorrhagic strokes,

ischemic strokes, and transient ischemic

attacks

Cerebrovascular Accidents (CVA)

REFERENCES: Fagan SC, Hess DC. Chapter 10. Stroke. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic

Approach, 9e New York, NY: McGraw-Hill; 2014.

Leading cause of disability among adults

5th leading cause of death in the US

128,982 deaths in 2011

Annual cost of stroke in the US is ~$33.6

billion

Epidemiology



Currently 6.6 million stroke survivors

Of those with no documented history of

stroke, 20% of people > 45 years old report

experiencing at least one symptom of

stroke

Occurs at higher rates in African Americans

compared to whites

Epidemiology



Risk Factors

Modifiable

Hypertension

Atrial fibrillation

Diabetes

Dyslipidemia

Poor diet/obesity

Smoking

Non-modifiable

Age > 55 years old

Males > females

African Americans

Genetics

Mechanical heart valve



May result from:

o Occlusion of a vessel from an embolus

originating from a distant location

o Major artery stenosis leading to hypoperfusion

o Intracranial vessel thrombosis

Leads to:

o Hypoperfusion

o Ischemia

o Cellular necrosis

Ischemic Stroke



Similar presentation and etiology as

ischemic stroke but the blockage is

temporary

“Mini-stroke”

10-15% risk of stroke in first 3 months

Transient Ischemic Attack (TIA)



Common subtypes:

o Subarachnoid hemorrhage (SAH)

o Intracranial hemorrhage (ICH)

o Subdural hemorrhage (SDH)

May result from:

o Trauma

o Intracranial aneurysm rupture

o Arteriovenous malformation (AVM) rupture

Hemorrhagic Stroke



Leads to:

o Mechanical compression

o Inflammation

o Neurotoxin production

Hemorrhagic Stroke



Sudden onset

Unilateral weakness

Inability to speak or understand

Vision abnormalities

Difficulty walking, dizziness, loss of balance or

coordination

Severe headache with no known cause

Clinical Presentation

REFERENCES: Stroke. 2014; 45: 1-93.

ACT F.A.S.T.

Face → Ask the person to smile. Does one side of the

face droop?

Arms → Ask the person to raise both arms. Does one

arm drift downward?

Speech → Ask the person to repeat a simple phrase. Is

their speech slurred or strange?

Time → If you observe any of these signs, call 911

immediately and note the time of the first symptom

onset.

Clinical Presentation


Stroke: Neurologic deficit lasting > 24

hours

TIA: Neurologic deficit lasting < 24 hours,

but more commonly < 30 minutes

Indistinguishable: Neurologic deficit lasting

< 24 hours but > 1 hour

Clinical Presentation Timeline



Diagnosis

All Patients Select Patients

Brain CT or MRI Hepatic function tests

Blood glucose Toxicology screen

Oxygen saturation Blood alcohol level

Basic Metabolic Panel (BMP) Pregnancy test

Complete Blood Count (CBC) Arterial Blood Gas (ABG)

Markers of cardiac ischemia Chest radiography

Prothrombin time/INR Lumbar Puncture

EKG EEG


Reduce neurologic injury,

mortality, and long-term disability

Prevent secondary complications

Prevent recurrence

Goals of Treatment

REFERENCES: Stroke. 2018;49:e46–e110.

Focus on Ischemic Stroke

Hypertension

o Goal BP <140/90 mmHg

Hyperlipidemia

o High-intensity statin as indicated per ACC/AHA 2013 lipid

guidelines

Diabetes

o Treat per ADA guidelines

Primary Prevention

REFERENCES: Stroke. 2013; 870-947.

Lifestyle changes

o Smoking cessation

o Limit alcohol

o DASH diet

o Exercise

o Screen for sleep apnea

Atrial fibrillation (Afib)

o Non-valvular → Direct-Acting Oral Anticoagulants

(DOACs) preferred

o Valvular → Warfarin

Primary Prevention

REFERENCES: Stroke. 2013; 870-947.

Early rehabilitation

Early revascularization

o Stent placement

o Recanalization via mechanical devices

o Intra-aortic balloon

Ultrasound-enhanced intravenous

thrombolysis

Non-Pharmacologic Treatments

REFERENCES: Frontiers in Neurology. 2011;2:32.

Maintain cerebral perfusion pressure

Maintain normal intracranial pressure

Blood pressure control

Remove/dissolve clot (if possible)

Acute Pharmacologic Treatment


Recombinant Tissue Plasminogen Activator

Recommend treatment within 3 hours of onset of

symptoms

o Expanded to 4.5 hours

Dosing: 0.9 mg/kg IV (90 mg maximum dose) over 60

minutes

o 10% given as bolus over 1 minute

o 90% given as continuous infusion over 60 minutes

Many contraindications/exclusion criteria

Alteplase (tPA) IV


Continue measures discussed in primary

prevention section

If cardioembolic source: initiate

anticoagulation therapy

If non-cardioembolic or TIA: initiate

antiplatelet therapy

Secondary Prevention


Antiplatelet therapy & avoid alcohol


Cholesterol control & Cessation of smoking

DASH diet & Diabetes control

Exercise



Initial therapy

o Aspirin 75-325 mg PO daily (first line)

o Aspirin 25 mg/dipyridamole ER 200mg PO twice daily

o Clopidogrel 75 mg PO daily

Dual Antiplatelet therapy

o Aspirin + Clopidogrel

▪ Recommended for a maximum of 21 days post-

stroke

Antiplatelet Therapy


Clopidogrel in High-Risk Patients with Acute Non-

disabling Cerebrovascular Events (CHANCE)

o Double-blind, placebo controlled RCT in Chinese population

o Primary outcome: recurrent stroke at 90 days (ischemic or

hemorrhagic)

o Treatment Arms (initiated within 24 hours after minor ischemic

stroke or high-risk TIA onset)

▪ Clopidogrel (300 mg initial dose, then 75 mg/day for 90

days) + Aspirin (75 mg/day for first 21 days)

▪ Placebo + Aspirin (75 mg/day for 90 days)

CHANCE Trial Overview

REFERENCES: NEJM. 2013;369:11.

Primary Outcome

o Occurred in 8.2% of patients in ASA + clopidogrel

group compared to 11.7% in ASA +Placebo group

(HR 0.68, 95% CI 0.57-0.81, p<0.001, NNT = 29)

2018 New AHA/ASA Guideline Recommendation

o Class IIa, level B Moderate recommendation

o Recommend DAPT for 21 days post-stroke

CHANCE Trial Outcome

REFERENCES: NEJM. 2013;369:11

Stroke. 2018;49:e46–e110.

Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT)

o Double-blind, placebo controlled RCT in international population

o Primary outcome: time-to-event for composite of major ischemic events (ischemic stroke, MI, or death from ischemic vascular event) at 90 days

o Treatment Arms (initiated within 12 hours after minor ischemic stroke or high-risk TIA onset)

▪ Clopidogrel (600 mg initial dose, then 75 mg/day)+ Aspirin (50 to 325 mg/day) for 90 days

▪ Aspirin (50 to 325 mg/day) for 90 days

POINT Trial Overview

REFERENCES: NEJM. doi: 10.1056/NEJMoa1800410

Primary Outcome

o Occurred in 5.0% of patients in ASA + clopidogrel group compared to 6.5% in ASA +Placebo group (HR 0.75, 95% CI 0.59-0.95, p=0.02, NNT = 67)

Safety Outcome (major hemorrhage)

o Occurred in 0.9% of patients in ASA + clopidogrel group compared to 0.4% in ASA +Placebo group (HR 2.32, 95% CI 1.10-4.87, p=0.02, NNH = 200)

Trial was stopped at 84% enrolled due to increase in hemorrhage in DAPT group

POINT Trial Outcome

REFERENCES: NEJM. doi: 10.1056/NEJMoa1800410

Comparison of Anti-Platelet TherapiesAnti-Platelet

Therapy MOA Contraindications Comments

Aspirin

Irreversibly inhibits COX-1

& COX-2 which decreases

thromboxane &

prostaglandins

NSAID or salicylate allergy

Syndrome of asthma,

rhinitis, nasal polyps

(known hypersensitivity)

Cheapest

Risk of GI hemorrhage

Aspirin +

Dipyridamole

Same as above + inhibits

uptake of adenosine into

platelets which increases

cAMP & indirectly inhibits

platelet aggregation

NSAID or salicylate allergy

Syndrome of asthma,

rhinitis, nasal polyps

(known hypersensitivity)

Keep in original container

Amount of aspirin is not

adequate for cardiac

indications

Clopidogrel

Inhibits P2Y12 mediated

platelet activation &

aggregation

Active bleeding

Discontinue 5 days before

surgery

Do not use in pt with

upcoming CABG

Metabolized by CYP2C19


Aspirin 81 mg vs. 325 mg

Ticagrelor

o SOCRATES trial

o Ticagrelor was not found to be superior to

aspirin (HR = 0.89, 95% CI [0.78-1.01], P=0.07)

in 90 day outcomes of stroke, MI, or death

o Not recommended over aspirin in Acute

Ischemic Stroke/TIA

Prasugrel

o No data/No recommendation

Other antiplatelet therapies

REFERENCES: Stroke. 2018;49:e46–e110, The New England journal of medicine. 2016;375:35-43.





Exercise



Restart home BP medications

Treat aggressively if no tPA was given and

BP > 220/110 mmHg for acute treatment

Initiate anti-hypertensive medication if SBP

> 140/90 mmHg (weak recommendation)

o ACE-I/ARB (first-line), diuretics, CCBs

Blood Pressure Management






Exercise



SPARCL Study

o Recommend high intensity statin regardless of

baseline LDL-C levels in all patients with acute

ischemic stroke

▪ Atorvastatin 80 mg PO daily

o Goal LDL <100 or <70 mg/dL

o Benefits in addition to LDL lowering capabilities

▪ Decrease inflammation

▪ Stabilize plaques

▪ Prevent blood clots

Cholesterol Control

REFERENCES: NEJM. 2006;355:549-559.

Questions??

What is/are modifiable risk factors for

cerebrovascular accidents (CVA)/ Transient Ischemic

Attacks (TIA)? Select ALL that apply.

a) Diabetes

b) Hypertension


d) Obesity

Post-Test Question 1

Which of the following is/are modifiable risk factors

for CVA/TIA ? Select ALL that apply.

a) Diabetes

b) Hypertension


d) Obesity


Explanation: The most common risk factors that can be

modified are hypertension, cigarette smoking, diabetes,

dyslipidemia, and atrial fibrillation. The most common

contributor to CVA/TIA in the United States is hypertension

which affects approximately 1 in 3 adults. Obesity also

increases the risk of developing a TIA in that it predisposes

patients to many relevant comorbidities.

Post Test Question #1 Feedback






a) 21 days

b) 30 days

c) 90 days

d) 365 days





a) 21 days

b) 30 days

c) 90 days

d) 365 days


RESOURCE: NEJM. 2013;369:11.

Explanation: Combination antiplatelet therapy is

only appropriate for a maximum of 21 days after a

CVA/TIA event. After 21 days of DAPT, it is

recommended to use antiplatelet monotherapy.



JB a 59 y/o F presents to the ED with unilateral

weakness, confusion, and visual abnormalities. PMH of

DM2, HTN, and HLD. JB is currently taking metformin

1000 mg BID, Lisinopril 20 mg QD, and simvastatin 20 mg

QHS. JP reports an allergy to salicylates. JB is diagnosed

with a TIA. Which is the most appropriate secondary

prevention therapy after DAPT?

a) Aspirin 325 mg PO QD

b) Clopidogrel 75 mg PO QD

c) Dipyridamole ER/Aspirin 200/25 mg PO BID

d) Any of the above are options


Explanation: Although aspirin is the first line

therapy for secondary prevention of TIA.

Clopidogrel 75 mg monotherapy is a reasonable

option for secondary prevention of stroke in place

of aspirin or combination aspirin/dipyridamole

(Class IIa, Level B). Therefore, in a patient who is

aspirin/salicylate allergic, Clopidogrel is the

preferred option.

Post Test Question #3


Which of the following are signs/symptoms of

CVA/TIA? Select ALL that apply.

a) One-sided facial droop

b) Ability to keep both arms steady and

level when arms are raised

c) Slurred speech

d) Shooting pains down left arm


The acronym “FAST” is used to identify common stroke symptoms?

F: Face → Ask the person to smile. Does one side of the face droop?

A: Arms → Ask the person to raise both arms. Does one arm drift downward?

S: Speech → Ask the person to repeat a simple phrase. Is their speech slurred or strange?

T: Time → If you observe any of these signs, call 911 immediately and note the time of the first symptom onset.


REFERENCES:. Stroke. 2014; 45: 1-93.

Remember to ACT F.A.S.T.

Time is Brain

Early detection & intervention is crucial

Primary prevention aims to reduce modifiable risk

factors of stroke such as hypertension, Afib, &

cigarette smoking

Secondary prevention of ischemic stroke is as easy

as ABCDE

Initiate antiplatelet therapy in all patients, unless

contraindicated

TAKE HOME POINTS

References

1. Fagan SC, Hess DC. Chapter 10. Stroke. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&sectionid=45310472. Accessed March 13, 2018.

2. Smith WS, Johnston S, Hemphill J, III. Cerebrovascular Diseases. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, LoscalzoJ. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1130&sectionid=79755261. Accessed July 17, 2018.

3. Kernan WN, et al; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Counsel on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014; 45: 1-93.

4. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke regarding: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49:e46–e110.

5. Jauch EC, et al; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular Nursing, Counsel on Peripheral Vascular Disease, and Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013; 870-947.

6. Frendl A, Csiba L. Pharmacological and Non-Pharmacological Recanalization Strategies in Acute Ischemic Stroke. Frontiers in Neurology. 2011;2:32. doi:10.3389/fneur.2011.00032.

7. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. NEJM. 2013;369:11.

8. Johnston SC, Easton D, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA [published online ahead of print May 16, 2018]. NEJM. doi: 10.1056/NEJMoa1800410

9. Amarenco P, Bogousslavsky J, Callahan E, Alfred, et al. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. NEJM. 2006;355:549-559.

10. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. The New England journal of medicine. 2016;375:35-43.

Resources & References

Speaker Contact Information

Dr. Heather Powell, PharmD, BCPS,

[email protected]

Shayna Cruz, BS, PharmD Candidate,

[email protected]

a stroke of knowledge: cerebrovascular accidents

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