Secondary Risk Reduction

a f t e r Tr a n s i e n t I s c h e m i c
A t t a c k a n d Mi n o r S t ro k e
a b,
Mohammad J. Ahmad, MD , Nirav R. Bhatt, MD *

KEYWORDS
 TIA  Minor stroke  Secondary stroke prevention  Antithrombotic therapy
 Vascular risk factors

KEY POINTS
 Transient ischemic attack and minor stroke have high risk of recurrence that can lead to
significant morbidity.
 Identifying the stroke subtype and mechanism guides secondary prevention strategies.
 Management of vascular risk factors remains a crucial part in secondary stroke preven-
tion, including lifestyle modifications, blood pressure, lipids, and diabetes control, and
smoking cessation.
 Antithrombotic therapy is recommended for nearly all patients without contraindications.

INTRODUCTION

Transient ischemic attack (TIA) was previously defined as acute focal neurologic deficits
caused by suspected focal cerebral ischemia lasting less than 24 hours. This definition
assumed that the transient symptoms indicated no permanent brain injury had
occurred. However, as advanced imaging modalities became more prevalent in clinical
practice, it became evident that many patients with transient neurologic symptoms
fitting the original TIA definition exhibited signs of infarction on diffusion-weighted
MRI scans. With these observations, the American Heart Association (AHA) redefined
TIA using the tissue-based approach as “a transient episode of neurologic dysfunction
caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”1
More than half of ischemic strokes are considered as minor strokes.2,3 The term
“minor stroke,” also referred to as “mild stroke,” describes patients with mild and/or
nondisabling symptoms. While there is no consensus on a precise definition, minor

a
Cerebrovascular Institute, Cleveland Clinic Foundation, Cerebrovascular Center, 9500 Euclid
Avenue, S80, Cleveland, OH 44195, USA; b University of Pittsburgh School of Medicine, UPMC
Stroke Institute, 200 Lothrop Street, Suite C-400, Pittsburgh, PA 15213, USA
* Corresponding author.
E-mail address: bhattnr@upmc.edu
Twitter: @MoeJAhmad (M.J.A.)

Med Clin N Am 109 (2025) 357–372

https://doi.org/10.1016/j.mcna.2024.09.010 medical.theclinics.com
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 358 Ahmad & Bhatt

strokes are often characterized by a National Institute of Health Stroke Scale (NIHSS)
of 5 or less, though some studies suggest an NIHSS of 3 or less or a score of 1 or less
in any NIHSS category.4
Although the majority of TIA and minor stroke patients present with resolved or non-
disabling symptoms, they are associated with significant long-term disability. This
finding is mainly driven by the high risk of stroke recurrence and modifiable risk fac-
tors5 and warrants expedited comprehensive evaluation to improve outcomes.

EPIDEMIOLOGY

Precise estimates for the incidence of TIAs are difficult due to variations in previous
definitions and underrecognition of TIA symptoms. Within these limitations, the annual
incidence of TIA in the United States has been estimated to range between 200,000
and 500,000.6 The early risk of stroke following a TIA is significant, with 10% to
18% of patients experiencing an ischemic stroke within 90 days, nearly half of these
occurring within the first 48 hours after the initial event.7,8 The risk of cardiovascular
events, including recurrent stroke, after minor strokes and TIAs is estimated to be
12% over a 5 year period.9
Recent cohort studies suggest a reduction in recurrent stroke and TIA rates in recent
years. A meta-analysis found that over the last 2 decades, the 90 day stroke occur-
rence after a TIA has nearly halved compared to data from before 1999.10 When
considering minor strokes and TIAs, the risk of subsequent ischemic stroke within
90 days was 3.7%, with 1.5% occurring within the first 48 hours.11 The reduction in
event rates can be attributed to improvements in the implementation of secondary
stroke prevention strategies.

CLINICAL EVALUATION

An urgent evaluation is critical for patients suspected to have TIA or a minor stroke as
they may be eligible for intravenous thrombolytic (IVT) therapy for disabling symptoms
and there is ongoing research surrounding the benefit of mechanical thrombectomy
among patients with minor stroke who harbor a large vessel occlusion. For patients
with TIA/minor stroke who are deemed ineligible for IVT therapy, since the bulk of
recurrent stroke events has been shown to occur in the early period after the index
TIA/minor stroke, expediting a basic stroke workup as outlined in later discussion is
crucial to optimize secondary prevention.12
History and a detailed neurologic evaluation can help differentiate a TIA/minor
stroke from alternative diagnoses. Recognizing patients with a minor stroke or a
high-risk TIA can guide early antithrombotic therapy. Subsequently, a thorough diag-
nostic workup is necessary to determine the underlying stroke mechanism, which is
crucial for formulating accurate prevention strategies. The Age, Blood Pressure, Clin-
ical Features, Duration, and Diabetes (ABCD2) score is widely used in suspected TIA
cases in clinical practice and in RCTs for risk stratification and early treatment deci-
sion-making.8 It can stratify patients into low-risk, moderate-risk, or high-risk groups
based on their medical history and clinical features (Table 1). The NIHSS is a validated
tool to recognize minor stroke severity and guide secondary prevention strategies.

DIAGNOSTIC EVALUATION
Brain Imaging
Initial assessment with noncontrast head computed tomography (NCCT) can be used
to help establish any subacute ischemia or overt established lesions and rule out

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 Secondary Risk Reduction after TIA and Minor Stroke 359

Table 1
Age, blood pressure, clinical features, duration, and diabetes2 score8

Risk Factor Points 2 d Stroke Risk

Age 60 y 1
Blood pressure
Initial SBP 140 or DBP 90 1
Clinical features of the TIA
Speech disturbance without weakness 1
Unilateral weakness 2
Duration of symptoms
10–59 min 1
60 min 2
History of diabetes 1
Total score 0–7
Risk stratification Score 0–3 1.0%
Score 4–5 4.1%
Score 6–7 8.1%

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

alternative diagnosis such as intracranial hemorrhage and mass lesions. Standard MRI
is more sensitive than computed tomography in identifying ischemic lesions in sus-
pected patients with TIA, as well as in detecting pre-existing lesions. MRI diffusion-
weighted imaging-positive lesions, suggesting acute ischemia, have been reported
in about 30% to 40% of patients presenting with TIA-like symptoms and have been
strongly associated with an increased risk of recurrent strokes.1,13 In some centers
with rapid access to MRI in the emergency department (ED) without delay, NCCT
can be avoided in patients with completely resolved symptoms.12 In addition, the
distribution of infarction (location, laterality, and multitude) can help identify the under-
lying stroke mechanism (eg, scattered emboli in multiple territories suggest cardioem-
bolic mechanism; a single lacune in a deep structure suggests small vessel disease).
Vascular imaging is a critical step in the evaluation of minor stroke/TIA since extra-
cranial or intracranial steno-occlusive lesions are associated with a higher risk of
recurrent stroke. Computed tomography angiography has become the choice of
noninvasive vascular imaging in the United States because of its widespread availabil-
ity and ease of use. Other modalities include carotid Doppler ultrasound and magnetic
resonance angiography.
Other tests including laboratory tests to identify modifiable risk factors including lipid
profile and hemoglobin A1c (HbA1c) should be performed in addition to the basic blood
work. When appropriate, toxicology testing, coagulation profile, and serum troponin
may also be considered to identify and target uncommon risk factors. A standard
cardiac workup involves echocardiography and electrocardiogram (EKG) to rule out
intracardiac pathologies and atrial fibrillation, respectively. Other tests such as trans-
esophageal echocardiography, transcranial Doppler, and long-term heart monitoring
may be considered in special circumstances in conjunction with neurology expertise
to identify patients suspected to harbor a patent foramen ovale (PFO) or occult atrial
fibrillation.

RISK FACTOR MANAGEMENT

Hypertension
Hypertension is one of the most significant risk factors for ischemic stroke, and having
persistently elevated blood pressure increases the risk for stroke or TIA recurrence.14

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 360 Ahmad & Bhatt

Initially after an ischemic stroke, blood pressure can be permissively elevated to main-
tain cerebral perfusion pressure for a short period. Ultimately, long-term management
in the outpatient setting generally targets a blood pressure goal of less than 130/
80 mm Hg to reduce the risk of recurrent stroke and other vascular events.15 Various
blood pressure regimens have been studied, with angiotensin-converting enzyme in-
hibitors, angiotensin II receptor blockers, and diuretics demonstrating benefit in
reducing blood pressure and risk of recurrent stroke.16 The magnitude of blood pres-
sure reduction is important; therefore, individualized antihypertensive regimen is
recommended to achieve target goals. In patients with intracranial atherosclerotic dis-
ease (ICAD), higher long-term blood pressure goals may be appropriate.
Hyperlipidemia
In patients with ischemic stroke or TIA with low-density lipoprotein (LDL) levels above
100 mg/dL, high-intensity statin therapy is recommended to reduce risk of stroke
recurrence. The Treat Stroke to Target trial showed that in patients with recent ischemic
stroke or TIA with evidence of any atherosclerotic disease, an low-density lipoprotein
cholesterol (LDL-C) goal of less than 70 mg/dL is beneficial to reduce the risk of
subsequent cardiovascular events.17 If the LDL target is not achieved with maximal
tolerated statin therapy, adding ezetimibe or Proprotein convertase subtilisin/kexin
type 9 (pcsk-9) inhibitors can further reduce LDL levels.16 In addition to its lipid lowering
effects, statin therapy has been shown to have anti-inflammatory and antithrombo-
genic effects for patients with ischemic stroke due to large vessel atherosclerosis.18
Glucose
Prediabetes and diabetes increase the risk of ischemic stroke occurrence. The Amer-
ican Diabetes Association (ADA) recommends a target HbA1c of less than 7% for most
adult patients with diabetes to lower the risk of cardiovascular events, including
ischemic stroke.19 Metformin and lifestyle modification are first-line therapies recom-
mended by the ADA. In patients with established atherosclerotic cardiovascular dis-
ease (ASCVD), including ischemic stroke, glucagon-like peptide 1 receptor agonists
should be added independent of baseline HbA1c levels. In patients with heart failure
with reduced ejection fraction or chronic kidney disease, sodium-glucose cotrans-
porter 2 inhibitors are recommended.20
Smoking
Cigarette smoking is a significant risk factor for ischemic stroke, and persistent smok-
ing after a stroke roughly doubles the risk of recurrence compared with nonsmokers.21
Smoking cessation after an ischemic stroke or TIA is associated with lower recurrent
vascular events including ischemic strokes.22 All tobacco smokers should be coun-
seled to quit smoking during the initial hospitalization. Effective cessation methods
include behavioral interventions, such as intensive support programs, nicotine
replacement, and combined pharmacology.
Nutrition and Diet
Nutrition plays an important role in cardiovascular health, and dietary interventions
can impact stroke recurrence risk. Although evidence for secondary stroke prevention
is limited, some recommendations are drawn from studies focusing on primary pre-
vention of cardiovascular disease and stroke. The prevención con Dieta Mediterránea
(PREDIMED) trial has shown that implementing a Mediterranean diet supplemented
with olive oil or tree nuts reduces stroke risk in individuals with high cardiovascular
risk compared with a low-fat diet.23 The dietary approaches to stop hypertension

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 Secondary Risk Reduction after TIA and Minor Stroke 361

(DASH) diet, with reduced sodium intake can lower blood pressure and is associated
with decreased stroke risk.24 Diets high in fruits, vegetables, fish, and fiber (key com-
ponents of the Mediterranean and DASH diets) have protective effects against
stroke.16

Obesity
Obesity increases the risk of ischemic stroke by 50% to 100% compared to patients
with normal weight. Weight loss can improve stroke risk factors with as little as losing
5% to 10% of body weight, which can attribute to reducing risk of recurrence and has
been linked with decreased in macrovascular diseases.16 Though there are no specific
data on secondary stroke prevention with weight loss alone, it may be extrapolated
that given weight loss has been shown to reduce stroke risk factors, it should be rec-
ommended for secondary prevention. Weight loss can be initially achieved with
comprehensive lifestyle intervention programs and can be augmented with adjunctive
drugs to reduce appetite and/or bariatric surgery.25

Physical Activity
Regular physical activity reduces stroke risk by improving risk factors such as blood
pressure, cholesterol, and body weight. Exercise-based interventions after an
ischemic stroke or TIA can reduce resting systolic blood pressure, fasting blood
glucose, and increase HDL levels, all of which are beneficial for secondary stroke pre-
vention.26 The AHA recommends low-intensity to moderate-intensity aerobic activity,
muscle-strengthening activity, and reducing sedentary behavior to improve quality of
life and reduce risk of subsequent cardiovascular events in patients with stroke.27

Obstructive Sleep Apnea

Approximately 40% of patients with stroke have OSA. OSA is linked to an increased
risk of hypertension, heart disease, atrial fibrillation (AF), and recurrent cerebrovascu-
lar events and all-cause mortality.28 Although there are limited data on whether OSA
directly increases the risk of recurrence, treatment can be beneficial. Continuous pos-
itive airway pressure (CPAP) is recommended as initial therapy for patients with OSA.
Ongoing clinical trials are being conducted for ischemic stroke or TIA patients with
OSA to investigate if CPAP reduces the risk of recurrent stroke.29

EARLY ANTITHROMBOTIC USE

Antiplatelet therapies have been a key component in the management of noncar-

dioembolic ischemic strokes and TIAs, preferred over oral anticoagulation to reduce
the risk of recurrent ischemic strokes while minimizing the risk of bleeding.16,30 The
optimal choice of antiplatelet therapy to prevent future strokes, while balancing the
risk of bleeding, has been subject of ongoing debate. The etiology of the ischemic
stroke influences the selection of antithrombotic therapy; however, multiple RCTs
have grouped noncardioembolic mild strokes and high-risk TIAs together (Table 2).
High-risk TIA was defined as a TIA with an ABCD2 score of 4 or higher, while the defi-
nition of mild stroke varies between trials but generally includes patients with NIHSS
of 3 or less. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT)
and clopidogrel in high-risk patients with acute nondisabling cerebrovascular events
(CHANCE) trials showed that starting short-term dual antiplatelet therapy (DAPT)
within 24 hours from symptom onset followed by long-term single antiplatelet therapy
reduces the risk of early recurrent stroke in patients with mild stroke and high-risk
TIA.31,32 The intensive statin and antiplatelet therapy for acute high-risk intracranial

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362
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Ahmad & Bhatt

Table 2
Major trials of dual antithrombotic therapy in transient ischemic attack and minor strokes

Trial Name Patient Population Treatment Group Comparison Primary Outcome

CHANCE 201331 5170 patients, ischemic stroke Clopidogrel 300 mg day 1 then Aspirin 75 mg for 90 d Recurrent stroke (ischemic or
with NIHSS 3, TIA with 75 mg for 90 d plus aspirin hemorrhagic) within
ABCD2 4 within 24 h from 75 mg for 21 d 90 d: 8.2% vs 11.7%; P < .001
symptom onset Moderate-to-severe
hemorrhage 0.3% vs 0.3%;
P 5 .73
POINT 201832 4881 patients, ischemic stroke Clopidogrel 600 mg day 1 then Aspirin 50–325 mg for 90 d Major ischemic events
with NIHSS 3, TIA with 75 mg for 90 d plus aspirin (ischemic stroke, myocardial
ABCD2 4 within 12 h from 50–325 mg for 90 d infarction, or death) at
symptom onset 90 d—5% vs 6.5%; P 5 .02
Major hemorrhage 0.9% vs
0.4%; P 5 .02
THALES 202039 11,016 patients, ischemic Ticagrelor 180 mg day 1 then Aspirin 300 mg to 325 mg for Composite stroke or death
stroke with NIHSS 3, TIA 90 mg twice daily plus aspirin 30 d within 30 d—5.5% vs 6.6%;
with ABCD2 6 within 24 h 300–325 mg day 1 followed P 5 .02.
from symptom onset by 75–100 mg daily for 30 d Severe bleeding—0.5% vs
0.1%; P 5 .001
Chance II 202140 6412 patients, CYP2C19 loss-of- Ticagrelor 180 mg day 1 then Clopidogrel 300 mg day 1 then Recurrent stroke (ischemic or
function allele, ischemic 90 mg twice daily plus aspirin 75 mg for 90 d plus aspirin hemorrhagic) within
stroke with NIHSS 3, TIA 75–300 mg day 1 followed by 75–300 mg day 1 followed by 90 d—6.0% vs 7.6%; P 5 .008
with ABCD2 4 within 24 h 75 mg daily for 21 d 75 mg daily for 21 d Moderate-to-severe
from symptom onset hemorrhage 0.3% vs 0.3%;
P 5 .82
INSPIRES 202333 6100 patients, stroke with Clopidogrel 300 mg day 1 and Aspirin 100–300 mg day 1 and Recurrent strokes within
NIHSS 5, TIA with ABCD2 4 75 mg on days 2–90 plus 100 mg daily day 2–90 90 d—7.3% vs 9.2%; P 5 .008
within 72 h from symptom aspirin 100–300 mg day 1 Moderate-to-severe
onset followed by 100 mg day 2–21 hemorrhage 0.9% vs 0.4%;
P 5 .03
 Secondary Risk Reduction after TIA and Minor Stroke 363

or extracranial atherosclerosis (INSPIRES) trial expanded on the inclusion criteria

involving patients with atherosclerotic disease presenting with NIHSS of 5 or less
and loading with DAPT up to 72 hours from symptom onset.33 DAPT therapy is not
recommended for longer than 90 days in most patients due to an increasing risk of
major hemorrhage over time.34,35 Pooled analysis of randomized controlled trial
(RCT) data has demonstrated that the maximal benefit in the reduction of recurrent
ischemic stroke occurred within the first 21 days from the onset of stroke or TIA,
with the risk of moderate to severe bleeding increasing with longer durations. Based
on the findings, clinicians have adopted the use of DAPT with aspirin and clopidogrel
for 21 days, followed by continuation with single antiplatelet therapy.36,37
Clopidogrel is frequently used in combination with aspirin as part of DAPT regimen.
However, clopidogrel is a prodrug that requires conversion into its active metabolite
by the cytochrome p450 system. It has been found to be less effective in individuals
with Cyp2C19 loss-of-function alleles, putting them at a greater risk of stroke and
vascular events compared to noncarriers.38 Carriers of this genetic polymorphism ac-
count for approximately 25% of the white population and 50% to 60% of Asian
population.38
Ticagrelor, in combination with aspirin, has been shown to be superior to aspirin
alone in reducing the risk of recurrent stroke in patients with minor strokes and
high-risk TIAs up to NIHSS 5 when administered within 24 hours of symptom onset
for a duration of 30 days. DAPT combination with ticagrelor was associated with
significantly increased risk of severe bleeding, including a higher incidence of intrace-
rebral hemorrhage.39 The CHANCE-2 clinical trial compared ticagrelor versus clopi-
dogrel in addition to aspirin in a Chinese population who were carriers for CYP2C19
loss-of-function alleles. The study demonstrated a lower rate of stroke recurrence
within 90 days in the ticagrelor group, with similar rates of moderate-to-severe
bleeding between the 2 groups.40 While further studies are needed across broader
populations, these findings highlight that clopidogrel may not be the ideal agent to
use in combination with aspirin in individuals with CYP2C19 genetic mutation, with
ticagrelor as a reasonable alternative for short-term use.

MANAGEMENT BY ETIOLOGY
Large Vessel Disease
Intracranial atherosclerosis
ICAD involves the narrowing of major intracranial arteries, such as the internal carotid
artery, middle cerebral artery, and basilar artery, due to atherosclerosis. Antithrombotic
therapy combined with vascular risk factor control has been shown to effectively
reduce the risk of recurrent stroke or TIA. In the warfarin–aspirin symptomatic intracra-
nial disease (WASID) trial, warfarin was compared to aspirin in patients with ICAD,
which resulted in a higher rate of major hemorrhage with no difference in vascular event
rates.41 Following this, the SAMMPRIS trial showed that DAPT with aspirin and clopi-
dogrel for 90 days, combined with aggressive medical management after an ischemic
stroke or TIA due to severe major intracranial vessel stenosis (70%–99%), was more
effective in reducing recurrence risk than intracranial angioplasty and stenting.
Notably, the stroke recurrence rate with DAPT was lower than that observed in WASID
trial, which used aspirin monotherapy.42
Further supporting evidence for DAPT was provided by the clopidogrel plus aspirin
versus aspirin alone for reducing embolisation in patients with acute symptomatic ce-
rebral or carotid artery stenosis (CLAIR) trial, which found reduction in microemboli
detected on transcranial doppler (TCD) in patients randomized to clopidogrel plus

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 364 Ahmad & Bhatt

aspirin versus aspirin alone within 7 days from symptom onset.43 The (the acute stroke
or transient ischaemic attack treated with ticagrelor and ASA [acetylsalicylic acid] for
prevention of stroke and death [THALES]) and INSPIRES trials included patients with
moderate-to-severe large vessel atherosclerosis (>50% stenosis), predominantly
ICAD in the latter. Both trials showed an overall benefit from DAPT, establishing further
that short-duration DAPT is currently the preferred treatment of minor stroke and TIAs
due to ICAD.33,44 Antiplatelet therapy should be combined with aggressive risk factor
control for optimal secondary stroke prevention. Targets include systolic blood pres-
sure below 140 mm Hg, LDL levels under 70 mg/dL, and moderate physical activity at
least 3 to 5 times per week.16 The ongoing comparison of anti-coagulation and anti-
platelet therapies for intracranial vascular atherostenosis (CAPTIVA) clinical trial is
set to compare different dual antithrombotic regimens, including combination clopi-
dogrel and ticagrelor with aspirin, as well as a combination of aspirin and low-dose
rivaroxaban. The results are anticipated to provide further insights into the optimal
antithrombotic strategies for patients with ICAD https://www.clinicaltrials.gov/study/
NCT05047172.
In addition to the stenting and aggressive medical management for preventing
recurrent stroke in intracranial stenosis (SAMMPRIS), multiple RCTs explored intracra-
nial stenting versus medical therapy. These studies failed to show a benefit for stent-
ing; on the contrary, most studies showed an increased risk of recurrent stroke within
30 days in the stenting arms.45 The recently published balloon angioplasty for symp-
tomatic intracranial artery stenosis (BASIS) trial compared balloon angioplasty without
stenting, in addition to medical therapy, versus medical therapy alone, showing a
benefit in lowering the risk of stroke or death between 30 days and 1 year after the
initial event. However, it also showed an increased risk within the first 30 days.46 In pa-
tients with hemodynamic ischemic strokes or TIAs secondary to symptomatic severe
ICAD or occlusion of ICA or MCA, extracranial-intracranial bypass surgery was
comparing to standard medical therapy. Both the carotid occlusion surgery study
(COSS) trial and carotid and middle cerebral artery occlusion surgery study (CMOSS)
trials showed no significant difference is stroke recurrence, with a higher rate of stroke
recurrence within 30 days in the surgical arms.47

Extracranial atherosclerosis
In patients with symptomatic carotid stenosis, the risk for recurrent stroke or TIA is
highest in the first few days after the initial event. Multiple RCTs compared carotid
revascularization to medical therapy after a mild stroke or TIA with ipsilateral carotid
artery stenosis. A pooled analysis of the North American Symptomatic Carotid Endar-
terectomy Trial (NASCET), European Carotid Surgery Trial (ECST), and Veterans
Affairs Cooperative Study (VACS) trials found robust benefit for carotid endarterec-
tomy (CEA) in patients with severe (70%–99%) symptomatic ipsilateral carotid steno-
sis compared to medical therapy. In patients with moderate (50%–69%) symptomatic
carotid stenosis, the benefit was modest, with an absolute stroke recurrence reduc-
tion of 16% and 4.6% over 5 years for severe stenosis and moderate stenosis, respec-
tively.48 Carotid revascularization within 2 weeks from onset is preferred and carries
lower overall risk of recurrent ischemia.49
Multiple RCTs compared CEA to carotid artery stenting (CAS). A meta-analysis of the
Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid
Stenosis (EVA-3S), stent-protected angioplasty versus carotid endarterectomy
(SPACE), International Carotid Stenting Study (ICSS), and Carotid Revascularization
Endarterectomy Versus Stenting Trial (CREST) trials found that CEA carries a lower
early stroke recurrence rate or death rate when compared to CAS.50 Transcarotid

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 Secondary Risk Reduction after TIA and Minor Stroke 365

artery revascularization (TCAR) is a relatively new endovascular technique. An obser-

vational study showed a lower rate of in-hospital stroke or death with TCAR compared
to CAS; however, no RCT has compared TCAR with CEA or intensive medical
therapy.51
Extracranial vertebral artery stenosis accounts for approximately 10% of posterior
circulation strokes. A combined analysis of the Vertebral Artery Stenting Trial
(VAST), Vertebral Artery Ischaemia Stenting Trial (VIST), and SAMMPRIS trials, the first
2 having predominantly patients with symptomatic moderate (>50%) extracranial
vertebral stenosis, investigated the utility of vertebral artery stenting. It demonstrated
no benefit of stenting over medical therapy for both extracranial and intracranial ste-
noses, while also raising concerns about high periprocedural stroke risk.52 Antiplatelet
therapy is recommended for symptomatic vertebral artery stenosis, with multimodal
medical therapy, including antihypertensives and statins.

Small Vessel Disease

Small vessel disease, also referred to as lacunar stroke, accounts for approximately
25% of ischemic strokes.53 Risk factors such as hypertension, diabetes, and smoking
play significant roles in the pathogenesis of small vessel disease. Lacunar strokes
often present with mild symptoms, and short-duration DAPT may be utilized if patients
meet the criteria for minor stroke RCTs. The Secondary Prevention of Small Subcor-
tical Strokes (SPS3) trial investigated long-term DAPT with clopidogrel plus aspirin in
patients with small vessel disease and found no long-term benefit over aspirin mono-
therapy.35 Cilostazol has been compared to aspirin in Japanese patients with noncar-
dioembolic strokes, with majority having small vessel strokes in the Cilostazol for
prevention of secondary stroke (CSPS) II trial. The trial demonstrated that cilostazol
was noninferior to aspirin, with fewer hemorrhagic events.54 Following that, an RCT
from the CSPS group in 2019 compared DAPT with aspirin and cilostazol against
aspirin monotherapy for duration longer than 6 months in patients with noncardioem-
bolic stroke, with approximately half of the patients having small vessel strokes. Re-
sults showed a lower recurrent stroke rate in the DAPT group without an increase in
hemorrhagic events.55 Studies are further exploring the use of cilostazol as well as va-
sodilators such as isosorbide mononitrate in patients with small vessel disease.

Cardioembolism
Cardioembolic strokes accounts for 25% to 30% of acute ischemic infarcts. AF is the
most common cause of cardioembolic events, making its diagnosis and treatment
critical for reducing recurrent events. Patients with a prior stroke or TIA are at higher
risk of recurrent events than the general population of patients with AF. Long-term
anticoagulation is recommended stroke or TIA prevention in patients with AF, with
the CHADS-VASC risk calculator indicating treatment of the majority of the patients,
including those with a prior stroke or TIA alone.56 Warfarin was shown to reduce the
risk of stroke in patients with AF compared to antiplatelet therapy. Four trials
comparing direct oral anticoagulants (DOACs) to warfarin demonstrated a 19% reduc-
tion in stroke or systemic embolism with DOAC, driven by a significantly lower risk of
hemorrhagic stroke.57 The timing of anticoagulation initiation after an ischemic stroke
is challenging due to the need to balance the risk of hemorrhagic transformation early
after an infarct and the risk of recurrent stroke or TIA if treatment is delayed.58 The
recently published early versus late initiation of direct oral anticoagulants in post-
ischemic stroke patients with atrial fibrillation (ELAN) RCT compared early versus
late initiation of anticoagulation after AF-related stroke. The trial found that starting
anticoagulation within 48 hours for mild-to-moderate stroke decreased the risk of

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 366 Ahmad & Bhatt

composite recurrent stroke, hemorrhage, systemic embolism, and vascular death

compared with starting on day 3 or 4.59
For patients at high risk of bleeding from oral anticoagulation, left atrial appendage
closure is an option to reduce the long-term bleeding risk with a similar risk of ischemic
stroke.60 In patients with valvular AF and/or mechanical heart valve, warfarin is recom-
mended over DOACs.61
In patients with TIA or ischemic stroke and a left ventricular thrombus, treatment
with DOAC or a vitamin K antagonist is recommended for a duration of 3 to 6 months.
In patients with a left ventricular thrombus and persistently low ejection fraction or
persistent apical akinesis, indefinite oral anticoagulant may be considered.62 Other
uncommon causes of cardioembolic strokes include primary cardiac tumors such
as myxoma and fibroelastoma. Surgical excision of left-sided cardiac tumors may
reduce the risk of recurrent stroke.63

Other Stroke Etiologies

 Patent foramen ovale
Substantial evidence links PFO with strokes or TIAs of unknown origin. Multiple
RCTs have explored PFO closure in adult patients aged under 60 years, demon-
strating significant benefit over antithrombotic therapy in reducing risk of recurrent
stroke or TIA. A meta-analysis of these trials found that the number needed to treat
was 13 over a 10 person-years of follow-up, with greater benefit in patients with an
atrial septal aneurysm or large shunt.64 However, the benefit of PFO closure in patients
with low-risk PFO or those aged over 60 years is not well established.
 Cervical artery dissection
Extracranial carotid or vertebral artery dissections are uncommon and may occur
spontaneously or due to trauma, with a higher incidence in younger individuals.
Although most dissections heal spontaneously, they carry a high risk of early stroke.
Antithrombotic therapy plays an important role in reducing the rate of ischemic stroke.
Two randomized trials compared antithrombotic agents in patients with cervical artery
dissection, with the Cervical Artery Dissection in Stroke Study (CADISS) trial showed
similar stroke risks between antiplatelet therapy and anticoagulation. However, the
Treatment in cervical artery dissection trial (Treat-CAD) trial did not find aspirin to
be noninferior to vitamin K antagonists. The AHA suggests individualized antithrom-
botic therapy for at least 3 to 6 months.65
 Hypercoagulable conditions
I. Thrombophilic states: Conditions such as deficiencies in protein C, protein S,
or antithrombin, prothrombin 20210A mutation, and elevated factor VIII have
been associated with a higher risk of stroke; however, the ideal treatment re-
mains unknown. These conditions are associated with an increased risk of
venous thromboembolism (VTE) and may be linked with paradoxic emboli
in patients with a right-to-left shunt, especially those with PFO.
II. Antiphospholipid syndrome: In patients with stroke or TIA meeting full criteria
for antiphospholipid syndrome, treatment with warfarin is reasonable to
reduce the risk of recurrent stroke or TIA. DOACs are associated with higher
thrombotic events and a greater risk of stroke when compared to warfarin
and are not currently recommended for treating patients with antiphospholi-
pid syndrome.66,67
III. Sickle cell disease: In patients with sickle cell disease-associated stroke or
TIA, chronic blood transfusions to reduce hemoglobin S may be considered.

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 Secondary Risk Reduction after TIA and Minor Stroke 367

If transfusions are unavailable, treatment with hydroxyurea may be consid-

ered to reduce the risk of recurrent ischemic stroke.16 There are no clear
guidelines regarding the use of antiplatelets for secondary stroke prevention,
but they have been associated with reduced risk and severity of vaso-
occlusive events, stroke, and acute chest syndrome in patients with sickle
cell disease, particularly with aspirin use.68
IV. Cancer-associated stroke: Patients with cancer are at risk for stroke due to
an acquired hypercoagulable state. Among patients with an ischemic stroke
secondary to potential cancer-related hypercoagulability, antiplatelets or an-
ticoagulation may be used for secondary prevention. Low molecular-weight
heparin and DOACs have been studied for preventing cancer-related VTE,
but data on their use in stroke patients are limited.
 Nonatherosclerotic vasculopathies
Nonatherosclerotic vasculopathies include conditions such as Moyamoya disease,
reversible cerebrovascular constriction syndrome, fibromuscular dysplasia, and sys-
temic and cerebral vasculitis. Treatment is tailored to the underlying mechanism
and may involve revascularization procedures, vasodilators, and immunosuppression.

Cryptogenic and Embolic Stroke of Unknown Source

Cryptogenic strokes, or strokes of uncertain cause, comprise about 20% to 30% of all
ischemic strokes, with most believed to be of embolic origin.69 In patients with TIA and
stroke not attributed to a cardioembolic or large-vessel atherosclerotic source, anti-
platelet therapy is indicated for secondary stroke prevention. Anticoagulation with
vitamin K antagonists is not more efficacious than antiplatelet therapy and carries a
higher risk of bleeding.30
A recently adopted subtype, embolic stroke of unknown source (ESUS), refers to
strokes suspected to be of embolic nature but without an obvious source after
completing evaluation. For patients with ESUS, multiple RCTs have compared antico-
agulation to antiplatelet therapy for secondary stroke prevention. The (new approach
rivaroxaban inhibition of factor Xa in a global trial versus ASA to prevent embolism in
embolic stroke of undetermined source [Navigate-ESUS]) and (randomized, double-
blind, evaluation in secondary stroke prevention comparing the efficacy and safety of
the oral thrombin inhibitor dabigatran etexilate versus acetylsalicylic acid in patients
with embolic stroke of undetermined source [RESPECT-ESUS]) trials compared
rivaroxaban and dabigatran to aspirin, respectively, and found that neither DOAC
was superior to aspirin in preventing recurrent stroke, with an associated increase in
bleeding risk.70,71 The atrial cardiopathy and antithrombotic drugs in prevention after
cryptogenic stroke (ARCADIA) trial compared apixaban to aspirin in patients with
ESUS and evidence of atrial cardiopathy, thought to be a marker of underlying cardi-
oembolic source. Recurrent stroke risk was similar in both groups with no difference
in major hemorrhage.72

SUMMARY

TIA and minor strokes carry a high risk of recurrence and long-term disability. Identi-
fying the underlying stroke etiology and mechanism is crucial for determining both
early and long-term treatment strategy. Management of modifiable risk factors is
essential for effective secondary stroke prevention. Antithrombotic therapy should
be initiated early, with the duration tailored to the workup and underlying stroke
mechanism.

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 368 Ahmad & Bhatt

CLINICS CARE POINTS

 TIA and minor stroke are associated with significant morbidity; however, effective
management strategies are available to reduce the risk of recurrence that leads to such
morbidity.
 The NIHSS and ABCD2 scores are useful to identify patients who are likely to benefit from
early DAPT.
 Short-term DAPT is recommended following a minor stroke or TIA of noncardioembolic
origin. The risk-to-benefit ratio is higher when continued for longer than 21 to 90 days.
 Early vessel imaging is essential for identifying patients with carotid or intracranial stenosis.
Patients with carotid stenosis may be considered for early revascularization through CEA or
CAS. However, revascularization for intracranial stenosis is generally not recommended.
 Antithrombotic regimen should be tailored to the stroke etiology and should be
accompanied with aggressive management of modifiable risk factors.

DISCLOSURE

The authors have nothing to disclose.

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