antiagregantes lecturamanagement of transient ischemic attack.pdf

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http://www.medscape.com/viewarticle/736922

www.medscape.com

Contemporary Management of Transient Ischemic AttackRole of the Pharmacist

Denise H. Rhoney, Pharm.D., FCCP, FCCM

Feb 16, 2011

Pharmacotherapy. 2011;31(2):193-213. 2011 Pharmacotherapy Publications

Abstract and Introduction

Abstract

Transient ischemic attacks (TIAs) have been redefined recently. The new tissue-based definition of TIA

abandons the 24-hour restriction on symptom duration previously used to differentiate TIA from acute

ischemic stroke and requires neuroimaging studies to identify the cause of the ischemia and to determine

the presence and extent of brain injury. This new definition brings to light the need for urgent diagnostictesting and timely initiation of treatment, as well as secondary prevention measures to reduce the

increased risk of stroke, cardiovascular complications, and death in the days and weeks after a TIA.

Pharmacists play a key role in identifying patients at risk for a first or recurrent TIA or stroke, educating

high-risk patients on the signs and symptoms of TIA or stroke and the need for urgent evaluation and

treatment, overcoming barriers to timely diagnosis and treatment, and ensuring that appropriate primary

or secondary prevention strategies are in place. Furthermore, studies have shown that pharmacist-led

interventions can lead to significant improvements in modifiable risk factors, such as blood pressure and

cholesterol levels, as well as drug adherence, and may reduce the occurrence of strokes. These

interventions may also help maintain patients' health-related quality of life and improve patients'

satisfaction with care.

Introduction

Transient ischemic attack (TIA) has traditionally been defined as a sudden, focal neurologic deficit that

lasts for less than 24 hours, is presumed to be of vascular origin, and is confined to an area of the brain

or eye perfused by a specific artery.[1] This definition blurs the lines between TIAwhich is presumably

associated with complete resolution of ischemia and no permanent brain injuryand ischemic stroke

which is known to be associated with permanent brain injury. Consequently, TIA and ischemic stroke

have been differentiated strictly by the duration of symptoms. It is clear that most TIA symptoms last less

than 1 hour and typically less than 30 minutes,[2,3] and that patients who have symptoms lasting longer

than 1 hour have a greater chance of developing permanent deficits.[4] Thus, the assignment of a 24-hour

cutoff to the traditional definition of TIA is arbitrary, and practitioners who follow this guideline may be

placing their patients in harm's way. The arbitrary 24-hour cutoff leads many clinicians to postponetreatment to see if the symptoms resolve spontaneously and, in effect, diminishes the severity and

urgency of TIA and fosters use of the terms ministroke, transient stroke, and warning stroke. [1]

In the late 1990s, data demonstrating the presence of permanent ischemic brain injury in patients with a

diagnosis of TIA began to emerge.[1] In effect, in these patients, TIA was misdiagnosed based on duration

of symptoms, and the diagnosis should have been stroke based on the presence of cerebral infarct and

injury. It has been estimated that as many as one third of patients receive a misdiagnosis of TIA based
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on 24-hour symptom duration when tissue infarction is in fact present. [5] Although some experts proposed

a change as early as 2002 in the definition of TIA that would abandon the 24-hour time constraint and

elevate the severity and urgency of TIA, [1] it was not until 2009 that the American Heart Association

(AHA) and the American Stroke Association (ASA) adopted a new nontime-specific definition of TIA.[5]

The new definition of TIA is a transient episode of neurologic dysfunction caused by focal brain, spinal

cord, or retinal ischemia, without acute infarction.[5] This new tissue-based definition of TIA uses

neuroimaging studies to identify the cause of the ischemia and to determine the presence and extent of

brain injury, and, like tissue-based definitions used to differentiate angina from myocardial infarction, can

be used to differentiate TIA from acute ischemic stroke. [5] Although data on the percentage of TIAs due to

noncardioembolic and cardioembolic causes are lacking, it is estimated that 20% of ischemic strokes are

cardioembolic, with most cardioembolic strokes caused by atrial fibrillation, 30% are cryptogenic

(unknown cause), and the remaining 50% are noncardioembolic (i.e., atherosclerotic, lacunar). [6]

Cryptogenic strokes are generally classified as noncardioembolic strokes; thus, noncardioembolic

strokes account for approximately 80% of ischemic strokes.[6]

The new definition of TIA means that diagnostic evaluation will need to be performed in a more timely

and more stringent manner. Consequently, treatment and secondary preventive measures will be startedmore rapidly than under the old definition of TIA. Because most TIAs are presumably noncardioembolic

in nature, this article focuses primarily on non-cardioembolic TIAs or TIAs in general. Although less

emphasis is placed on cardioembolic TIAs, information specific to cardioembolic TIAs is included where

appropriate. Pharmacists can play a major role in diagnosing, preventing, and treating TIA by identifying

patients at risk for a first or recurrent TIA or stroke, educating high-risk patients on the signs and

symptoms of TIA or stroke and the need for urgent evaluation and treatment, overcoming barriers to

timely diagnosis and treatment, and ensuring that appropriate treatment and prevention strategies are in

place.

Overview of Transient Ischemic Attack

According to results from a population-based study, an estimated 240,000 Americans experienced a TIA

in 2002 (according to the traditional definition of TIA). [7] The frequency of TIA increases with age and is

higher among men than women and among African-Americans than Caucasians. [7] The new definition of

TIA is likely to cause a shift in the rate of reported TIAs and strokes as clinicians incorporate

neuroimaging studies into routine diagnostic procedures.[5] The accuracy with which neuroimaging

studies are able to detect cerebral infarction is likely to cause a decrease in the frequency of TIAs and a

corresponding increase in the frequency of strokes. As a result, direct comparison of TIA and stroke

incidence rates after routine implementation of neuroimaging studies with incidence rates from previous

studies will be impossible.[5]

Transient ischemic attack increases the risk of subsequent stroke. It is estimated that 795,000 Americans

experience a new or recurrent stroke each year, of which 185,000 (~23%) are recurrent strokes. [8] It isalso estimated that 15% of strokes are preceded by a TIA.[8] The remaining lifetime risk of stroke is 1 in 6

among 40-year-old men and 1 in 5 among 40-year-old women.[8] at 90 days after TIA Results from a

pooled analysis, based on a random-effects model and from a systematic review and meta-analysis of 11

observational studies, revealed that the risk of stroke was 3.5% at 2 days, 8.0% at 30 days, and 9.2% at

90 days after TIA.[9] When a meta-analysis was conducted on three studies that included an active

ascertainment of outcome (face-to-face encounter with medical or nursing staff), the risks increased to

9.9%, 13.4%, and 17.3% at each time point, respectively.[9] One study of 1707 patients that was designed


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to determine the short-term risk of stroke after emergency department diagnosis of TIA found that the

presence of select risk factors was independently associated with 90-day risk of stroke. In this study, age

older than 60 years, diabetes mellitus, symptom duration longer than 10 minutes, weakness, and speech

impairment were all independently associated with risk of stroke within 90 days. [10] Furthermore, presence

of multiple risk factors increased the risk in a step-wise fashion (Figure 1).[10]

Figure 1.

Ninety-day stroke risk by number of risk factors (age > 60 yrs, diabetes mellitus, symptom duration > 10

min, weakness, and speech impairment) in 1707 patients who came to an emergency department with a

transient ischemic attack (TIA).10

Three scoring systems have been validated in patients with TIA: the California score, the ABCD (age,

blood pressure, clinical features, duration) score, and the ABCD2 (ABCD plus diabetes) score, which is a

hybrid of the ABCD and California scores and is described in more detail later.[5] These stratification

systems are helpful in identifying patients at increased risk for stroke (regardless of etiology) after a TIA

but have not been validated to identify patients who need emergent treatment. These scoring systems

should be used only to supplement clinical assessment and judgment, keeping in mind that

neuroimaging studies might also assist in identifying patients at increased risk for stroke irrespective of

these scoring systems. The ABCD2 assigns points based on the following criteria:

Age > 60 years: 1 point

Blood pressure > 140/90 mm Hg: 1 point


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Clinical features:

Unilateral weakness: 2 points

Speech impairment without weakness: 1 point

Duration:

> 60 minutes: 2 points

1059 minutes: 1 point

Diabetes: 1 point

The risk of stroke within 2 days of a TIA is high (8.1%) in patients with a total ABCD2 score of 6 or 7,

moderate (4.1%) in patients with a total score of 4 or 5, low (1.3%) in patients with a total score of 2 or 3,

and zero in patients with a total score of 0 or 1. [5] The estimated risk of stroke at 2, 7, 30, and 90 days

after experiencing a TIA according to total ABCD2 score is presented in Figure 2.[11]

Figure 2.

The short-term risk of stroke at 2, 7, 30, and 90 days after experiencing a transient ischemic attack as

measured by total ABCD2 (age, blood pressure, clinical features, duration, diabetes) score. The higher

the ABCD2 score, the higher the risk of stroke. (Reprinted with permission from reference 11.)


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Ischemic stroke and TIA increase subsequent risk of myocardial infarction and vascular death. According

to results from a systematic review and meta-analysis of 39 studies that included a total of 65,996

patients and had a mean follow-up of 3.5 years, the annual risk of myocardial infarction is 2.2% and the

annual risk of nonstroke vascular death is 2.1% in patients who have had a TIA or ischemic stroke.[12]

According to the results from another study, the risk of all-cause mortality is 8.3% within 6 months of a

TIA.[7]

Role of the Pharmacist

Clinical pharmacists are key members of the multidisciplinary team responsible for the management of

patients who have had a TIA or stroke, as well as those at risk for a first TIA or stroke. Pharmacists can

assist in the following areas:

Identifying patients at risk for a first TIA or stroke.

Educating high-risk patients and families of high-risk patients on the signs and symptoms of TIA

and stroke (including the mnemonic FAST for face, arms, speech, and time, which is described

in the Diagnosis section) and the need for urgent evaluation and treatment, specifically the needto call 911 in the event of suspected TIA or stroke.

Initiating appropriate primary and secondary prevention strategies targeting modifiable risk

factors (as outlined in the Primary and Secondary Prevention sections). Specifically,

pharmacists are in an ideal position to ensure that blood pressure, hemoglobin A1c, fasting

plasma glucose concentration, postprandial glucose concentration, and lipid goals are being

met, and that necessary pharmacologic interventions are being prescribed and dosed

appropriately. Pharmacists can also ensure appropriate utilization of the guidelines.

Results from a small trial of 160 outpatients with ischemic stroke showed that those who were allocated

to receive routine practice plus a 1-hour pharmacist-intervention education program once/month for 6

months had significant improvements in mean blood pressure, total cholesterol level, and low-densitylipoprotein cholesterol (LDL) level from baseline (p


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In patients admitted to the hospital for a first or recurrent TIA or stroke, pharmacists can help to ensure

timely initiation of early pharmacologic therapy in eligible patients, as well as ensure that patients are

discharged with appropriate drug therapy for secondary stroke prevention, including antiplatelet or

anticoagulation therapy. Given the high risk of stroke in the days and weeks after a TIA, [5, 911] it is

imperative that patients with a diagnosis of TIA be treated with the same urgency as though they have

had an acute ischemic stroke.[17] Pharmacist-led interventions, such as drug therapy review, counseling

on the mechanisms of action of drugs, adverse effects, and drug interactions, as well as risk factor

modification, in the year after an ischemic stroke may help maintain patients' health-related quality of life

and improve their satisfaction with care.[18]

Pharmacists can also provide patient counseling on nonpharmacologic and pharmacologic approaches

to risk factor modification; the efficacy and safety of therapeutic interventions; the importance of drug

adherence; and the risk of potential diet, herbal, and drug interactions with agents commonly used in

prevention regimens, which may interfere with achievement of optimal therapeutic goals. Potential drug-

drug interactions to be aware of in patients treated with antiplatelet therapy for primary or secondary

stroke prevention are listed in . [19, 20] For information on potential drug-drug interactions with warfarin,

readers are encouraged to consult a previously published article.[21]

Table 1. Potential Drug-Drug Interactions with Antiplatelet Drugs Used in Primary and

Secondary Stroke Prevention19, 20

AntiplateletDrug

Drugs with Potentialfor Interaction

Anticipated Response Clinical Consideration

Aspirin Acetazolamide acetazolamide serumconcentration

May need to acetazolamide dosage

ACE inhibitors hypotensive effect of ACEinhibitor

May need to ACE inhibitordosage

Anticoagulant therapya bleeding riskMay need to anticoagulant dosage

-Blockers hypotensive effect of -blocker

May need to -blockerdosage

Diuretics hypotensive effect of diureticMay need to diureticdosage

Methotrexate renal clearance ofmethotrexate

May need to methotrexatedosage

NSAIDs bleeding risk, renal function Coadminister with caution

Oral hypoglycemics effectiveness of oralhypoglycemic

May need to oralhypoglycemic Dosage

Phenytoin total concentration of

phenytoin

May need to phenytoin

dosage

Uricosuric agentsb uricosuric actionMay need to uricosuricdosage

Valproic acid valproic acid serumconcentration

May need to valproic aciddosage

Dipyridamole Adenosine plasma levels of adenosineMay need to adenosinedosage


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Cholinesteraseinhibitors

anticholinesterase effect ofcholinesterase inhibitor

May need to cholinesterase inhibitordosage

Clopidogrel Antiretrovirals platelet inhibition Avoid concomitant use

Azole antifungals platelet inhibition Avoid concomitant use

Cimetidine platelet inhibition Avoid concomitant use

Felbamate platelet inhibition Avoid concomitant use

NSAIDs bleeding risk Coadminister with caution

Phenytoin Altered phenytoin metabolism Coadminister with caution

Proton pump inhibitors platelet inhibition Avoid concomitant use

SSRIs platelet inhibition Avoid concomitant use

Statins Altered statin metabolism Coadminister with caution

Tamoxifen Altered tamoxifen metabolism Coadminister with caution

Ticlopidine platelet inhibition Avoid concomitant use

Tolbutamide Altered tolbutamide metabolism Coadminister with caution

Torsemide Altered torsemide metabolism Coadminister with caution

Warfarin bleeding risk Coadminister with caution

ACE = angiotensin-converting enzyme; NSAIDs = nonsteroidal antiinflammatory drugs; SSRIs =

selective serotonin reuptake inhibitors.aHeparin and warfarin.bProbenecid and sulfinpyrazone.

Pharmacists should also provide diligent monitoring for prevention of drug-related errors in these

potentially complex drug regimens. Other services include therapeutic monitoring and health care

provider education, if found to be lacking. Pharmacist-managed anticoagulation services have been

found to be significantly more effective than routine physician care at maintaining the international

normalized ratio (INR) within the target range in patients treated with warfarin. [15] Finally, pharmacists

should monitor compliance with the "Get With the GuidelinesStroke" quality-of-care measures

established by the AHA and ASA,[22] especially those that are applicable to TIA and pertain to drug

therapies.

Primary Prevention

Specific preventive strategies for TIA have not been established; however, because TIA and ischemic

stroke have similar pathophysiology, preventive strategies established for ischemic stroke are the same

as those for TIA.[23]

Primary prevention of TIA involves management of modifiable risk factors accordingto national treatment guidelines, where available. Although a thorough overview of risk factor

modification and primary prevention strategies is beyond the scope of this review, specific

recommendations pertinent to pharmacists will be highlighted. For additional information on this topic,

readers are encouraged to consult two other publications.[24,25]

Risk Factor Modification


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Nonpharmacologic and pharmacologic interventions should be used as necessary to achieve the

therapeutic targets listed in .[2630] Data from the Justification for the Use of Statins in Prevention: An

Intervention Trial Evaluating Rosuvastatin (JUPITER) study suggest that use of a statin in apparently

healthy patients (i.e., no history of cardiovascular disease, LDL level < 130 mg/dl, triglyceride level < 500

mg/dl) with elevated high-sensitivity C-reactive protein ( 2.0 mg/L) may be a prudent primary prevention

strategy.[31] Significant reduction in the frequency of the composite end point of nonfatal myocardial

infarction, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or death from

cardiovascular causes was reported in patients treated with a statin compared with those treated with

placebo. Risk reductions were similar across various subgroups, including patients traditionally

considered to be at low risk for cardiovascular events. In addition, use of a statin in this patient

population was associated with significant reductions in the individual end points of myocardial infarction

(nonfatal and any), stroke (nonfatal and any), arterial revascularization, and all-cause mortality. In fact,

stroke rates were reduced by nearly one half in patients treated with a statin (8901 patients) compared

with those treated with placebo (8901 patients). Nonfatal stroke occurred in 30 patients treated with a

statin (event rate 0.16/100 patient-yrs) and 58 patients treated with placebo (event rate 0.31/100 patient-

yrs, hazard ratio [HR] 0.52, p=0.003), whereas any stroke occurred in 33 patients treated with a statin

(event rate 0.18/100 patient-yrs) and 64 patients treated with placebo (event rate 0.34/100 patient-yrs,

HR 0.52, p=0.002).

Table 2. Therapeutic Targets for Risk Factor Modification: Primary and Secondary

Prevention of Transient Ischemic Attack and Ischemic Stroke2630

Risk Factor Therapeutic Target

Blood pressure Primary prevention: < 140/90 mm Hga

Secondary preventionb

Hemoglobin A1c 6.5% (AACE) or < 7.0% (ADA)

Fasting plasma glucoseconcentration

< 110 mg/dl (AACE) or 70130 mg/dl (ADA)

2-hr postprandial glucoseconcentration

< 140 mg/dl (AACE) or < 180 mg/dl (ADA)

LDL level < 160 mg/dl if 01 risk factor for CHD

< 130 mg/dl if 2 risk factors for CHD and 10-yr risk 20%

< 100 mg/dl if CHD or CHD risk equivalentcor 2 risk factors for CHDand 10-yr risk > 20%

< 70 mg/dl (optional goal) in very high-risk patientsd

Non-HDL levele 30 mg/dl > LDL goal

HDL level > 40 mg/dl

Triglyceride level < 150 mg/dl

AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association; LDL

= low-density lipoprotein cholesterol; CHD = coronary heart disease; HDL = high-density lipoprotein

cholesterol.aBlood pressure target < 130/80 mm Hg in patients with diabetes mellitus or chronic kidney disease.bBlood pressure target < 120/80 mm Hg or individualized; benefit has been associated with an average

reduction of ~10/5 mm Hg.


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cCHD risk equivalent = a condition that increases the absolute risk for developing new CHD in a patient

without CHD to the same level of risk as having a recurrent CHD event in a patient with CHD.dVery high-risk patients = established cardiovascular disease plus any of the following: multiple major risk

factors, severe and poorly controlled risk factors, multiple risk factors of the metabolic syndrome, or

acute coronary syndrome.eNon-HDL = total cholesterol minus HDL.

Other studies have shown that use of a statin before ischemic stroke onset is associated with smaller

infarct size on diffusion-weighted magnetic resonance (MR) images,[32,33] reduced mortality at 1 month

and after a mean follow-up of 2.4 years, [34] and improved functional outcome as measured by the

modified Rankin Scale score at 10 days[35] and by the Barthel Index at 3 months.[36]

Antithrombotic Therapy

Prevention of Noncardioembolic Stroke Aspirin is not recommended for the primary prevention of

stroke in men; however, low-dose aspirin is recommended for primary prevention of stroke in women in

whom the potential benefit outweighs the potential risks (hemorrhagic stroke, gastrointestinal

hemorrhage).[37] According to the United States Preventive Services Task Force, the use of aspirin for the

primary prevention of ischemic stroke should be limited to women aged 5579 years.[37] Aspirin is

recommended for primary prevention of stroke in patients with asymptomatic carotid artery stenosis,

unless contraindicated.[37]

Prevention of Cardioembolic Stroke Aspirin or warfarin (as appropriate) is recommended for primary

prevention of cardioembolic stroke in patients with atrial fibrillation.[37] Since publication of the guidelines,

dabigatran has been approved by the United States Food and Drug Administration for reducing the risk

of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (see discussion below).

One factor to consider when evaluating the appropriateness of aspirin or warfarin for primary stroke

prevention in patients with atrial fibrillation is the patient's CHADS2 (cardiac failure, hypertension, age,

diabetes, stroke or TIA) score. The CHADS2 is a stroke risk index that may be used to identify patients

with atrial fibrillation who are at increased risk for cardioembolic stroke. The CHADS2 score assignspoints based on the following criteria:[25]

Cardiac failure: 1 point

Hypertension: 1 point

Age 75 years: 1 point

Diabetes: 1 point

Stroke or TIA: 2 points

The risk for cardioembolic stroke in patients with atrial fibrillation increases as the CHADS2 score

increases (Figure 3).[25] It is recommended that patients with no risk factors for TIA or stroke other than

atrial fibrillation (CHADS2 score = 0) receive aspirin therapy and that patients with any high-risk factor or

more than one moderate-risk factor (CHADS2score 2) receive warfarin therapy targeting an INR of 2.5

(range 2.03.0; ).[25] Although patients with one moderate-risk factor (CHADS2 score 1) may be treated

with either aspirin or warfarin therapy, warfarin is the preferred antithrombotic because it is significantly

more effective at reducing the risk of stroke than is aspirin in patients with atrial fibrillation.[25,38] In these

patients at moderate risk for stroke, antiplatelet therapy should be used only if a contraindication to


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warfarin exists. Given the potential for food and drug interactions, the need for routine monitoring of INR,

and data suggesting that only one half of eligible patients actually receive warfarin therapy, safe and

effective alternatives to warfarin that do not require routine therapeutic monitoring and frequent dosing

adjustments are needed.[39]

Table 3. Recommended Antithrombotic Therapy for Patients with Atrial Fibrillation25

No. of Risk FactorsCHADS2Scorea

Recommended Therapy

None 0 Aspirin 81325 mg/day

One moderate-risk factorb 1Aspirin 81325 mg/day or warfarin (target INR 2.5,range 2.03.0)c

Any high-risk factord or > 1moderate-risk factorb

2 Warfarin (target INR 2.5, range 2.03.0)e

INR = international normalized ratio; CHADS2 = cardiac failure, hypertension, age, diabetes, stroke or

transient ischemic stroke.a

Higher scores indicate higher risk for cardioembolic stroke or transient ischemic attack.bModerate-risk factors are age 75 yrs, hypertension, heart failure, left ventricular ejection fraction

35%, and diabetes mellitus.cWarfarin preferred, as it is significantly more effective at reducing risk of stroke in these patients; aspirin

should be used only if a contraindication to warfarin exists. Dabigatran was recently approved by the

U.S. Food and Drug Administration for stroke prevention in patients with atrial fibrillation.dHigh-risk factors are previous stroke, transient ischemic attack, or embolism; mitral stenosis, and

prosthetic heart valve.eIf the patient has a mechanical prosthetic heart valve, target INR is 3.0 (range 2.53.5).


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Figure 3.

The risk of stroke as measured by CHADS2 score in patients with atrial fibrillation not treated with aspirin

or warfarin. CHADS2 = cardiac failure, hypertension, age, diabetes, stroke or transient ischemic attack.

(Reprinted with permission fromreference 25.)

The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) clinicaltrial program included three trials: ACTIVE W, ACTIVE A, and ACTIVE I. The ACTIVE W trial was

designed to evaluate the efficacy and safety of combination antiplatelet therapy consisting of aspirin plus

clopidogrel versus warfarin therapy in patients with atrial fibrillation; ACTIVE A was designed to evaluate

the efficacy and safety of clopidogrel versus combination antiplatelet therapy (aspirin plus clopidogrel) in

patients unwilling or unable to take warfarin; and ACTIVE I was designed to evaluate the role of blood

pressure lowering with an angiotensin II receptor blocker ([ARB] irbesartan) in patients enrolled in

ACTIVE W or ACTIVE A.[39] Preliminary data from ACTIVE I suggest that irbesartan does not provide

additional benefit in patients with atrial fibrillation who are well controlled with current therapy.[40]

In ACTIVE W, the combination of aspirin 75100 mg/day plus clopidogrel 75 mg/day was associated with

a significantly greater risk of the composite end point of stroke, noncentral nervous system (CNS)

systemic embolus, myocardial infarction, or vascular death than warfarin targeting an INR of 2.03.0

after a median follow-up of 1.28 years (relative risk [RR] 1.44, p=0.0003).[39] This finding was primarily

attributed to differences in the risks of systemic embolism (RR 4.66, p=0.005) and stroke (RR 1.72,

p=0.001) in this study of 6706 patients with atrial fibrillation who had one or more stroke risk factors.

Patients who entered the trial while receiving warfarin therapy were more compliant, had better INR

control, and realized a greater benefit with warfarin therapy (RR with aspirin plus clopidogrel 1.50,

p=0.0005) than those not receiving warfarin before enrollment (RR with aspirin plus clopidogrel 1.27,


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prevention in the future. For additional information on these investigational drugs, readers are

encouraged to consult two previously published articles.[42,43]

Screening

Although it is recommended that all patients undergo an assessment of TIA and/or stroke risk, a single,

comprehensive, validated risk-assessment tool that can accurately account for the large number of riskfactors and the complexity of the relationships between risk factors has not yet been developed.[24] Until

such a tool is developed, the Framingham Stroke Risk Profile or other similar risk-assessment tools may

be used. A Modified Framingham Stroke Risk Profile, which calculates the cumulative 10-year risk of

stroke based on independent stroke predictors, including sex, age, systolic blood pressure, use of

antihypertensive drugs, history of diabetes, cardiovascular disease, atrial fibrillation, left ventricular

hypertrophy, and smoking status, is available in the AHA-ASA primary stroke prevention guidelines.[24]

The U.S. Preventive Services Task Force guidelines cite an online stroke risk estimation tool (available

fromwww.westernstroke.org/PersonalStrokeRisk1.xls), also based on Framingham data, that calculates

a person's cumulative 10-year risk of stroke by using the same stroke predictors as the AHA-ASA's

Modified Framingham Stroke Risk Profile.[37] Although stroke risk assessment tools based on the

Framingham study are widely used, their validity is limited to patients fitting the patient profile of the

Framingham cohort.[24]

Diagnosis

Although pharmacists play a very limited role, if any, in diagnosing a TIA, it is important to be familiar with

the clinical manifestation and diagnostic studies used and how these relate to determining the etiology of

the TIA, which ultimately determines the appropriate pharmacologic intervention.

A thorough physical examination is essential to exclude the presence of subtle persistent neurologic

deficits. The stroke examination commonly used is the National Institutes of Health Stroke Scale

([NIHSS] available fromhttp://www.ninds.nih.gov/doctors/NlH_Stroke_Scale.pdf). Physical examination

identifies the signs and symptoms of TIA, which are the same as those of a stroke and other strokemimics, and include sudden onset of numbness or weakness of the face, arm, or leg that may be one- or

two-sided; confusion; trouble speaking or understanding; visual disturbances (e.g., vision loss, double or

blurry vision) in one or both eyes; gait disturbances, such as trouble walking, dizziness, or loss of

balance or coordination; and severe headache of unknown etiology[46] Other possible signs and

symptoms include difficulty swallowing; tingling or pain in the face, arm, leg, or trunk; drooling; and falling

to one side with standing or walking. [47] Psychiatric symptoms may include apathy or inappropriate

behavior, excessive somnolence, and agitation or psychosis.[47]

A mnemonic used to identify the more apparent symptoms of a stroke or TIA is FAST:[48]

Face: one side may droop when the patient smiles

Arms: patient may not be able to raise both arms evenly

Speech: patient may slur his or her words and may not be able to repeat a simple sentence

correctly

Time: if the patient displays any of these symptoms, call 911 immediately
http://www.westernstroke.org/PersonalStrokeRisk1.xlshttp://www.westernstroke.org/PersonalStrokeRisk1.xlshttp://www.westernstroke.org/PersonalStrokeRisk1.xlshttp://www.ninds.nih.gov/doctors/NlH_Stroke_Scale.pdfhttp://www.ninds.nih.gov/doctors/NlH_Stroke_Scale.pdfhttp://www.ninds.nih.gov/doctors/NlH_Stroke_Scale.pdfhttp://www.ninds.nih.gov/doctors/NlH_Stroke_Scale.pdfhttp://www.westernstroke.org/PersonalStrokeRisk1.xls


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Some patients experiencing a TIA or stroke may present with multiple signs and symptoms, whereas

others may have symptoms that go unnoticed. Results from one study found that as many as 18% of the

general population who have no known history of a stroke or TIA have in fact had at least one symptom

of a stroke.[49] The authors of the study hypothesized that these patients may have experienced mild

strokes that went undiagnosed.

The new tissue-based definition of TIA places less emphasis on the length of time that the ischemic

event lasted, a central component of the traditional time-based definition of TIA, and places more

emphasis on the cause of the ischemia and the presence and extent of brain injury due to infarction.

Thus, the new definition of TIA requires neurodiagnostic testing to differentiate TIA from stroke. [5]

Diagnostic testing should include a neuro-imaging evaluation within 24 hours of symptom onset.

Diffusion-weighted MR imaging is the preferred diagnostic test because it is highly sensitive for

identifying acute infarcts and distinguishing acute lesions from chronic lesions. It is further useful in

identifying patients at high risk for a subsequent vascular event and those with a high-risk mechanism for

TIA (high-grade carotid stenosis, atrial fibrillation).[5052] However, diffusion-weighted MR imaging is more

expensive and not as widely available as computed tomography (CT). [5]

Other diagnostic tests include angiography (MR angiography, CT angiography), which remains the gold

standard in diagnostic testing,[5] and carotid ultrasonography or transcranial Doppler ultrasonography, a

noninvasive means of imaging the extracranial and intracranial vessels. [5] If findings of two noninvasive

tests are conclusive, invasive angiography may be unnecessary. [5] Cardiac evaluation of patients with

suspected TIA may include electrocardiography, echocardiography (transthoracic echocardio-graphy,

transesophageal echocardiography), and cardiac monitoring (inpatient telemetry, Holter monitor).[5]

Routine blood tests that should be ordered include complete blood cell count, chemistry panel, basic

coagulation studies (prothrombin time, activated partial thrombo-plastin time), glucose concentration, and

fasting lipid profile.[5]

Emergency Treatment

Guidelines specific to the emergency treatment of TIA are not available. Nevertheless, a vital part of

emergency treatment of TIA is timely diagnostic evaluation and faster initiation of risk reduction

strategies. To achieve timely diagnostic evaluation and faster initiation of risk reduction strategies, one

must have an understanding of potential barriers to these processes.

Barriers to Initiation of Therapy

Delayed initiation of emergency therapy can be traced to the following: poor patient knowledge of risk

factors for and symptoms of TIA or stroke, the need for urgent care, and available treatment options;

incorrect or lack of advice given to patients by health care professionals on the need for immediate

diagnostic evaluation; and delayed initiation of diagnostic testing. Although pharmacists have little to no

control over how quickly diagnostic testing is performed, they are in an ideal position to help overcome

the other barriers to initiation of therapy.

A recent survey of 558 patients who had experienced a TIA or stroke found that awareness of risk factors

at the time of stroke or TIA was lowest for atrial fibrillation (69%) and hyperlipidemia (73%), and highest

for hypertension (83%) and diabetes (87%). [53] Pharmacologic treatment of these risk factors before

hospitalization for stroke or TIA in patients aware of their risk factor(s) was equally suboptimal, ranging

from 37% among patients with hyperlipidemia to 80% among patients with hypertension (Figure 4). In the


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subset of 383 patients who were aware of their risk factor(s) before hospitalization and had completed a

1-year follow-up survey, pharmacologic treatment of these risk factors increased in all risk factor groups,

with the greatest increases observed among patients with atrial fibrillation and hyperlipidemia. Further

analysis revealed that patients who had a TIA were significantly more likely to discontinue antithrombotic

therapy within the year after the episode compared with patients who had a stroke (27% vs 16%,

p=0.029). Of the 80% of patients who continued their antithrombotic therapy for 1 year (regardless of

stroke or TIA), 18% were treated with an anticoagulant and 62% were treated with an antiplatelet agent.

Figure 4.

Percentages of 558 patients who were aware of their stroke risk factor(s) and were receiving

pharmacologic treatment of these risk factors before hospitalization for stroke or transient ischemic

attack (TIA). In the subset of 383 of these patients who completed the follow-up survey, the percentages

of patients who received pharmacologic treatment of these risk factors at 1-year follow-up increased in all

risk factor groups.53

Pharmacists should emphasize the importance of drug adherence as a risk reduction strategy for primary

and secondary prevention of a TIA or stroke. The frequency with which pharmacists encounter patients

taking drugs for chronic conditions, such as atrial fibrillation, dyslipidemia, hypertension, and diabetes,

which are all known to increase the risk of TIA and stroke, provides regular intervals at which to monitor

drug adherence and counsel patients. As part of their patient counseling, pharmacists should educate

patients on the signs and symptoms of TIA and stroke and the need for urgent evaluation and treatment.


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In 1999, the National Stroke Association (NSA) conducted a telephone survey of 10,112 adults in the

United States to determine the prevalence and knowledge of TIA among the general population. [54]

Approximately 2% of participants reported receiving a diagnosis of TIA and another 2% reported

receiving a diagnosis of stroke. Of participants reporting a TIA, only 64% reported seeking medical

attention within 24 hours of the event and 16% were seen by a health care provider more than 1 week

after symptom onset. An additional 3% of study participants reported experiencing symptoms of a TIA

but did not seek medical attention. Fewer than 9% of participants could correctly define TIA or identify a

typical symptom of TIA.

More recently, a prospective survey of 400 patients who came to an emergency department with a

probable diagnosis of acute ischemic stroke or TIA between July 2005 and September 2006 found that

only 42% of patients thought their symptoms were consistent with those of a stroke, 52% were aware of

the importance of timely evaluation and treatment, and 21% had heard of thrombolytic therapy. [55] Median

time to presentation at the emergency department was 3.4 hours after symptom onset. The results of this

study are surprising given the fact that 40% of patients surveyed had experienced a prior TIA or stroke.

Compounding the problem of poor patient knowledge of symptoms and management of TIA is inaccurate

advice from health care professionals on the need for immediate diagnostic evaluation. In a scriptedtelephone survey of health hotlines at 46 U.S. hospitals with neurology residencies, 78% of operators

advised the caller (a relative of a person complaining of stroke symptoms) to call 911 (the correct

response); the remaining 22% advised the caller to contact the patient's primary care provider.[56] Of the

19 hospitals with Joint Commissioncertified primary stroke centers, 32% of operators advised calling the

patient's primary care physician. A total of 24% of the operators could not name one sign or symptom of

a stroke. In a similar survey of 42 U.S. primary care physicians' offices, 71% of respondents

recommended calling 911, whereas the remaining 29% recommended scheduling an office appointment

for later in the day if the patient's symptoms did not resolve; 95% of the respondents were able to identify

at least one sign of a stroke. [57] Similar results were found in a telephone survey of 71 community

pharmacies, in which only 20% of respondents (pharmacists, technicians, assistants, or students)

advised the caller to call 911; 69% recommended taking the patient to the emergency department and

11% recommended contacting the patient's primary care physician.[58] Pharmacists who encounter similar

scenarios should direct patients to call 911.

As demonstrated in one retrospective medical record review of 27 primary care practices between

August 1, 1992, and July 31, 1994, outpatient management of TIA or stroke by a primary care physician

may lead to delays in diagnostic evaluation and treatment initiation.[59] In this study, 79% of 95 patients

experiencing their first TIA were evaluated by their primary care physician within 1 day of symptom

onset, 2% were admitted to a hospital for evaluation and treatment on the same day as their outpatient

visit, and 3% were admitted to the hospital during the 30 days after the initial visit; 31% of patients were

not hospitalized and had no evaluations performed during the 30 days after initial evaluation by their

primary care physician. Furthermore, CT or MR imaging, carotid ultrasonography, electrocardiography,

echocardiography, and angiography were ordered on the day of the initial outpatient visit in 23%, 40%,18%, 19%, and 3% of patients with TIA, respectively. Less than one half of patients with TIA began

taking antiplatelet therapy, had their dosage of antiplatelet altered, or started a new antiplatelet on the

day of their initial outpatient visit, and less than one half of patients with a history of atrial fibrillation were

being treated with an anticoagulant at the time of their initial evaluation by the primary care physician.

Delayed initiation of diagnostic testing during hospital admission also contributes to the delay in initiation

of therapy. In a study of 15,117 patients enrolled in the North Carolina Collaborative Stroke Registry


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between January 2005 and April 2008, the mean time to initial CT from arrival at the hospital was 1.7

hours.[60] Among patients who arrived by means of emergency medical services, the mean time was 1.4

hours, whereas in those who arrived by an alternate mode of transportation, the mean time was 2.1

hoursa significant difference of 42 minutes (p


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well as initiation or intensification of secondary stroke prevention measures, such as antihypertensives,

lipid-lowering therapies, and antiplatelets or anticoagulants, before discharge.

Early Management

As with stroke, the goal of initial management in patients with TIA is to optimize cerebral blood flow.[17]

Because there are limited data specific to acute TIA, some recommendations are based on dataextrapolated from acute ischemic stroke studies, specifically the International Stroke Trial (IST) and the

Chinese Acute Stroke Trial (CAST). The 1ST[67] and CAST[68] studies were the first large-scale clinical

trials to show a benefit (reduced risk of death, recurrent stroke, or the combined end point) with aspirin

therapy in the early inpatient setting (within 48 hrs of symptom onset) in patients who had experienced

an acute ischemic stroke. The IST also included an unfractionated heparin group, which showed no

benefit immediately or at 6 months. These studies largely form the basis for the American College of

Chest Physicians guidelines, which recommend the use of early (within 48 hrs) aspirin therapy (loading

dose of 150325 mg, followed by maintenance dose of 50100 mg/day) in patients with acute ischemic

stroke who are not receiving t-PA. [6] Although not included in the American College of Chest Physicians

guidelines, data from a small pilot study of 40 patients suggest that patients treated with single doses of

clopidogrel 375 mg plus aspirin 325 mg within 36 hours of an acute ischemic stroke or TIA were

significantly less likely than matched control patients to experience neurologic deterioration (assessed by

the NIHSS) within 7 days (odds ratio [OR] 17.2, p


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were started or modified at time of discharge from the clinic. Patients with atrial fibrillation began taking

an anticoagulant (if not receiving an anticoagulant on admission), and those with symptomatic high-grade

stenosis underwent carotid revascu-larization. In this study, the 90-day stroke rate was 1.24% compared

with a rate of 5.96% predicted by the ABCD2 score. When only those patients who were seen in the clinic

within 24 hours of symptom onset were included, the 90-day stroke rate was 1.63% compared with a

predicted rate of 6.49%. The risks of stroke and the combined end point of stroke, myocardial infarction,

and vascular death at 1 year were 1.95% and 2.54%, respectively.

The FASTER trial was a small trial that included only 392 patients who had experienced a TIA or minor

ischemic stroke, defined by a NIHSS score of 3 or less, within the previous 24 hours. [73] The trial was

stopped early due to a failure to recruit patients at the prespecified minimum enrollment rate because of

the high rate of statin use at time of screening among otherwise-eligible patients. All patients were

treated with aspirin 81 mg/day (aspirin-naive patients were given a loading dose of 162 mg), clopidogrel

300-mg loading dose followed by 75 mg/day or placebo, and simvastatin 40 mg/day or placebo. Imaging

studies were conducted within 4 hours, and treatment was assigned within 89 hours. The 90-day stroke

risk was reduced by approximately 30% (from 10.8% to 7.1%) with clopidogrel plus aspirin compared

with aspirin alone (both with or without simvastatin), whereas the risk was increased by approximately

30% (from 7.3% to 10.6%) in those treated with simvastatin plus aspirin versus aspirin alone (both withor without clopidogrel). Similar results were observed for the 90-day risk of stroke, myocardial infarction,

or vascular death, in which the risk decreased with clopidogrel plus aspirin (from 11.9% to 8.6%, both

with or without simvastatin) but increased with simvastatin plus aspirin (from 8.8% to 11.6%, both with or

without clopidogrel). However, none of these results reached statistical significance.

Greater benefit with clopidogrel plus aspirin was observed in the subset of patients not treated with

simvastatin, such that the 90-day stroke risk was reduced from 9.5% to 5.1% and the 90-day risk of

stroke, myocardial infarction, or vascular death was reduced from 11.6% to 6.1%. Two patients in the

clopidogrel-plus-aspirin group had intracranial hemorrhage compared with zero patients not treated with

clopidogrel (absolute risk increase 1.0%, 95% Cl 0.42.4%, p=0.5); therefore, the hemorrhagic risk

associated with the combination of aspirin plus clopidogrel did not offset the potential benefit of

secondary stroke prevention.

The EARLY trial was a prospective, randomized, open-label, blindedend-point trial that evaluated the

efficacy and safety of aspirin plus extended-release dipyridamole versus aspirin monotherapy when

administered within 24 hours of symptom onset in 543 patients who had a TIA or ischemic stroke and

had an NIHSS score of 20 or less.[74] Patients were randomly assigned to receive 7 days of aspirin 25

mgdipyridamole 200 mg twice/day or aspirin monotherapy 100 mg once/day; thereafter, all patients

were treated with aspirin plus dipyridamole for up to 90 days. No significant between-group differences

were noted in the change in NIHSS score at day 8 or day 90. Furthermore, no significant between-group

differences were noted in the percentage of patients experiencing no or mild disability (56% vs 52%)

assessed by the modified Rankin scale score by telephone interview, or in the percentage of patients

experiencing the composite end point of nonfatal stroke, TIA, nonfatal myocardial infarction, majorbleeding complications, or mortality (HR 0.73, 95% CI 0.441.19, p=0.20) at 90 days. The only significant

between-group differences noted in the study were in the percentages of patients experiencing any

adverse event (55% vs 35%, p


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in the study suggest that there may be benefits to starting treatment early, which will need to be further

investigated in a larger study.

Although these studies collectively demonstrate the benefit of early treatment of TIA, they do not provide

clear evidence of the best course of therapy for patients experiencing an acute TIA. Further research is

needed to identify the most effective therapies for use in the 2448 hours immediately after a TIA. Until

more definitive data and nationally recognized treat-ment guidelines specific to the early management of

TIA are available, clinicians must base treat-ment decisions on recommendations extrapo-lated from

acute ischemic stroke and the limited clinical trial data available in patients with TIA. One approach to the

early management of TIA is outlined in Figure 5. [17]


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Figure 5.

Algorithm for the early management of patients with transient ischemic attack. TIA = transient ischemic

attack; CT = computed tomography; UFH = unfractionated heparin; LMWH = low-molecular-weight

heparin; INR = international normalized ratio; ICA = internal carotid artery; ER = extended-release.

(Adapted with permission from reference 17.)

Secondary Prevention

As previously stated, TIAs increase the risk of stroke, especially in the days and weeks immediately after

the initial event.[9] Therefore, it is important to implement secondary prevention strategies in all patients

who experience a TIA. As with primary prevention of TIA, the AHA and ASA advocate management of

modifiable risk factors according to national treatment guidelines, where available. [23] Unless otherwise

stated, the treatment targets outlined in for blood pressure, glucose concentration, and lipid levels are

reasonable targets for secondary prevention.

Table 2. Therapeutic Targets for Risk Factor Modification: Primary and Secondary

Prevention of Transient Ischemic Attack and Ischemic Stroke2630

Risk Factor Therapeutic Target

Blood pressure Primary prevention: < 140/90 mm Hga

Secondary preventionb

Hemoglobin A1c 6.5% (AACE) or < 7.0% (ADA)

Fasting plasma glucoseconcentration

< 110 mg/dl (AACE) or 70130 mg/dl (ADA)

2-hr postprandial glucoseconcentration

< 140 mg/dl (AACE) or < 180 mg/dl (ADA)

LDL level < 160 mg/dl if 01 risk factor for CHD

< 130 mg/dl if 2 risk factors for CHD and 10-yr risk 20%

< 100 mg/dl if CHD or CHD risk equivalentcor 2 risk factors for CHDand 10-yr risk > 20%

< 70 mg/dl (optional goal) in very high-risk patientsd

Non-HDL levele 30 mg/dl > LDL goal

HDL level > 40 mg/dl

Triglyceride level < 150 mg/dl

AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association; LDL

= low-density lipoprotein cholesterol; CHD = coronary heart disease; HDL = high-density lipoprotein

cholesterol.aBlood pressure target < 130/80 mm Hg in patients with diabetes mellitus or chronic kidney disease.bBlood pressure target < 120/80 mm Hg or individualized; benefit has been associated with an average

reduction of ~10/5 mm Hg.cCHD risk equivalent = a condition that increases the absolute risk for developing new CHD in a patient

without CHD to the same level of risk as having a recurrent CHD event in a patient with CHD.dVery high-risk patients = established cardiovascular disease plus any of the following: multiple major risk

factors, severe and poorly controlled risk factors, multiple risk factors of the metabolic syndrome, or


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acute coronary syndrome.eNon-HDL = total cholesterol minus HDL.

Risk Factor Modification

The AHA and ASA recommend antihypertensive drug therapy in patients who experienced a TIA and

who have or do not have a history of hypertension. Although a specific blood pressure target has not yetbeen identified, a reduction of approximately 10/5 mm Hg or maintenance of normal blood pressure (

antiagregantes lecturamanagement of transient ischemic attack.pdf

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