JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
15, 2023
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VOL. 82, NO.
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THE PRESENT AND FUTURE
JACC STATE-OF-THE-ART REVIEW
Antithrombotic Therapy for Primary and
Secondary Prevention of Ischemic Stroke
JACC State-of-the-Art Review
Antonio Greco, MD, Giovanni Occhipinti, MD, Daniele Giacoppo, MD, MSC, PHD, Federica Agnello, MD,
Claudio Laudani, MD, Marco Spagnolo, MD, Maria Sara Mauro, MD, Carla Rochira, MD, Simone Finocchiaro, MD,
Placido Maria Mazzone, MD, Denise Cristiana Faro, MD, Davide Landolina, MD, Nicola Ammirabile, MD,
Antonino Imbesi, MD, Carmelo Raffo, MD, Davide Capodanno, MD, PHD
ABSTRACT
Stroke is a devastating condition with significant morbidity and mortality worldwide. Antithrombotic therapy plays a
crucial role in both primary and secondary prevention of stroke events. Single or dual antiplatelet therapy is generally
preferred in cases of large-artery atherosclerosis and small-vessel disease, whereas anticoagulation is recommended in
conditions of blood stasis or hypercoagulable states that mostly result in red thrombi. However, the benefit of antith-
rombotic therapies must be weighed against the increased risk of bleeding, which can pose significant challenges in the
pharmacological management of this condition. This review provides a comprehensive summary of the currently available
evidence on antithrombotic therapy for ischemic stroke and outlines an updated therapeutic algorithm to support phy-
sicians in tailoring the strategy to the individual patient and the underlying mechanism of stroke.
(J Am Coll Cardiol 2023;82:1538–1557) © 2023 by the American College of Cardiology Foundation.
S troke is a prominent contributor to global mor-
tality, accounting for >7 million deaths in 2020
and leading to significant
sequelae.1,2 Based on the Global Burden of Disease
long-term
strokes can be classified into 5 subtypes: 1) strokes
due to cardioembolic events (w27%); 2) cryptogenic
strokes (w35%); 3) strokes from large-artery athero-
sclerosis (w13%); 4) strokes due to small-vessel dis-
Study, the numbers of incident and prevalent cases ease (w23%); and 5) strokes of other determined
of stroke in 2020 were approximately 12 million and etiology (w2% of cases).1,4
1
83 million, respectively. The economic burden of Ischemic stroke survivors are at a high risk of
stroke disease is also considerable, with a global recurrence, which can vary depending on ethnicity,
cost estimated at $891 billion in 2017. With growing sex, and stroke subtype. 5 However, the rates of
and aging populations, this burden is expected to recurrent ischemic strokes and major vascular events
rise significantly in the future.3 have substantially declined over the last 6 decades,
Ischemic strokes account for approximately 62% of mainly due to better blood pressure control and
all strokes, whereas intracranial and subarachnoid antithrombotic agents, which play a crucial role in
hemorrhages make up 28% and 10%, respectively.1 both primary and secondary prevention. 6 The choice
Based on the etiological TOAST (Trial of Org 10172 in of the appropriate antithrombotic agent requires
Acute Stroke Treatment) classification, ischemic identifying modifiable risk factors for stroke and
From the Division of Cardiology, Azienda Ospedaliero-Universitaria Policlinico “G. Rodolico–San Marco,” University of Catania,
Catania, Italy.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received April 20, 2023; revised manuscript received July 5, 2023, accepted July 12, 2023.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2023.07.025
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JACC VOL. 82, NO. 15, 2023
OCTOBER 10, 2023:1538–1557
HIGHLIGHTS

For primary or secondary prevention of
stroke due to large-artery extracranial
atherosclerosis or intracranial small-
vessel disease, single or dual antiplatelet
therapy is generally preferred, whereas
anticoagulation is recommended in cases
of cardiogenic embolism associated with
atrial fibrillation, mural thrombus, me-
chanical prosthetic heart valves, or hy-
percoagulable states.

In patients with acute ischemic stroke
due to arterial disease or in those with
carotid artery stents, the incremental
benefit of dual antiplatelet therapy is
greatest in the first few weeks or months,
following which antiplatelet mono-
therapy is generally recommended.

More research is needed to define opti-
mum antithrombotic regimens for pa-
tients with embolic stroke of
undetermined source, arterial dissection,
and specific forms of nonatherosclerotic
vascular disease.
understanding the pathophysiology of the initial
ischemic injury. Antiplatelet therapy is generally
preferred in cases of large-artery atherosclerosis and
small-vessel disease, where arterial plaque disruption
or endothelial injury might be involved. Conversely,
anticoagulation is recommended in conditions of
blood stasis (eg, atrial fibrillation) or hypercoagulable
states (eg, thrombophilia) that mostly result in red
thrombi. 7
Importantly, the benefit of antithrombotic thera-
pies in terms of ischemic protection comes with an
increased risk of bleeding. To balance this tradeoff,
several considerations should be taken into account,
ranging from the overlap in risk factors for ischemic
and bleeding events to the potential risk of hemor-
rhagic transformation of ischemic stroke. Thus, the
pharmacological management of this condition is
complex and challenging.
In this review, we summarize the current evidence
and indications for the use of antiplatelet and anti-
coagulant therapies for primary and secondary pre-
vention of various subtypes of ischemic stroke
(Central Illustration). A summary of key trials in the
field is provided in Figure 1. Also, we provide an
updated therapeutic algorithm to support physicians
in tailoring the strategy to the patient and the
mechanism of stroke. The acute management of
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Greco et al 1539
Antithrombotic Therapy for Ischemic Stroke
ischemic stroke and the management of ABBREVIATIONS
AND ACRONYMS
hemorrhagic stroke are beyond the scope of
this paper.
DAPT = dual antiplatelet
therapy
CARDIOEMBOLIC STROKES
DOAC = direct oral
anticoagulant
Cardioembolic stroke occurs when a clot or
ESUS = embolic stroke of
debris from the heart obstructs the cerebral
undetermined source
blood flow. Predisposing conditions are those
INR = international normalized
that result in blood stasis and clot formation
ratio
in the heart chambers, such as atrial fibrilla- TIA = transient ischemic attack
tion, heart failure, presence of mechanical VKA = vitamin K antagonist
prostheses, infective endocarditis, and para-
doxical embolism from the venous circulation
through a patent foramen ovale. Antithrombotic
therapy is the cornerstone of primary and secondary
prevention for some causes of cardioembolic stroke,
and different surgical or device approaches may be
also considered depending on the etiology.
PRIMARY PREVENTION. Atrial fibrillation is the most
common high-risk condition for ischemic stroke, and
it requires anticoagulation unless contraindicated. 8
In fact, aspirin monotherapy is ineffective for this
indication,9,10 and dual antiplatelet therapy (DAPT)
with aspirin and clopidogrel has limited efficacy.11
Vitamin K antagonists (VKAs) such as warfarin have
been the mainstay of anticoagulant therapy for pa-
tients with atrial fibrillation and additional risk fac-
tors for stroke, but the need for frequent monitoring
and dose adjustments has led to low patient adher-
ence and underuse.9-13 Direct oral anticoagulants
(DOACs) have emerged as safer and more convenient
options for most patients thanks to their rapid onset
and offset of action, fewer drug and dietary in-
teractions, and the ability to administer fixed doses
without routine monitoring. The activated factor II
inhibitor dabigatran and the activated factor X in-
hibitors rivaroxaban, apixaban, and edoxaban have
been shown to be at least as safe and effective as
warfarin for preventing stroke and systemic embolism
in patients with nonvalvular atrial fibrillation.14-17
Rivaroxaban was also noninferior to VKA in patients
with atrial fibrillation and mitral valve bio-
prostheses, 18 whereas warfarin remains indicated in
patients with atrial fibrillation and rheumatic heart
disease (Table 1).19 Overall, in patients with non-
valvular atrial fibrillation, DOACs have been associ-
ated with a risk reduction of 19% for ischemic stroke or
systemic embolism, 51% for hemorrhagic stroke, and
10% for all-cause mortality compared with warfarin;
however, with the possible exception of apixaban,
they have also been associated with a 25% higher risk
of gastrointestinal bleeding. 20 For patients with con-
traindications to oral anticoagulation, DAPT reduced
1540 Greco et al JACC VOL. 82, NO. 15, 2023

Antithrombotic Therapy for Ischemic Stroke OCTOBER 10, 2023:1538–1557

C E NT R AL IL L U STR AT IO N Types of Ischemic Strokes and Recommended Antithrombotic Strategies

Greco A, et al. J Am Coll Cardiol. 2023;82(15):1538–1557.

Ischemic strokes are classified into five etiological subtypes according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification, including strokes from
cardioembolic events (approximately 27%), large-artery atherosclerosis (approximately 13%), or small-vessel disease (approximately 23%), with strokes of other
determined etiology accounting for approximately 2% and cryptogenic strokes for approximately 35% of cases. Cryptogenic strokes encompass embolic stroke of
undetermined source (ESUS) (50% of cases) and non-ESUS (50% of cases). Specific evidence on the optimal antithrombotic regimen for each ischemic stroke subtype
is reported. DAPT ¼ dual antiplatelet therapy; DOAC ¼ direct oral anticoagulant; LV ¼ left ventricle; OAC ¼ oral anticoagulation; SAPT ¼ single antiplatelet therapy;
VKA ¼ vitamin K antagonist.

the risk of stroke at the cost of increased major Patients with heart failure are also at risk for car-
bleeding and intracranial hemorrhage,21 and left dioembolic stroke, particularly if a thrombus de-
atrial appendage occlusion may represent a valid velops within the left heart chambers. Several trials
alternative.22,23 Advances in pharmacology such as showed significant stroke reduction with warfarin
factor XI inhibitors hold promise for improving the compared with antiplatelet therapy in patients with
safety profiles of VKAs and DOACs by uncoupling heart failure in sinus rhythm.26-28 In the
thrombosis from hemostasis.24 Asundexian resulted COMMANDER-HF (A Study to Assess the Effective-
in lower rates of bleeding compared with apixaban ness and Safety of Rivaroxaban in Reducing the Risk
in a dose-finding study,25 and the OCEANIC-AF (A of Death, Myocardial Infarction or Stroke in Partici-
Study to Learn How Well the Study Treatment pants With Heart Failure and Coronary Artery Disease
Asundexian Works and How Safe it is Compared to Following an Episode of Decompensated
Apixaban to Prevent Stroke or Systemic Embolism Heart Failure) trial, low-dose rivaroxaban (ie, 2.5 mg
in People With Irregular and Often Rapid Heartbeat twice daily) on top of standard therapy was no more
[Atrial Fibrillation], and at Risk for Stroke; effective than placebo in preventing ischemic events
NCT05643573) trial is ongoing to test the efficacy among patients with worsening chronic heart failure
and safety of asundexian vs apixaban on a and coronary artery disease in sinus rhythm,
larger scale. although stroke (a nonpowered secondary endpoint)

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JACC VOL. 82, NO. 15, 2023 Greco et al 1541
OCTOBER 10, 2023:1538–1557 Antithrombotic Therapy for Ischemic Stroke

F I G U R E 1 Landmark Trials of Antithrombotic Strategies for Ischemic Stroke Secondary Prevention

R
R R

NAVIGATE R

ESUS RE-SPECT ARCADIA

ESUS ESUS ATTICUS
A A
A

R A
FASTER R
IST R
CHANCE-2
ESPS P R CSPS 2
SOCRATES
CSPS.com
ESPS-2 MATCH R A

A A
R
ESPRIT A
THALES
Large-Artery WARSS CHANCE
CAST A
Disease R POINT
DATAS II
R
P
A
PRoFESS
R
CSPS R PRASTRO-II
R
TARDIS
SPIRIT ESPRIT
PRASTRO-I

R R

SPS3 LACI-2
Small-Vessel
Disease

1990 1995 2000 2005 2010 2015 2020

Sample Size <1,000 1,000 - 10,000 >10,000 Timing of Stroke A Acute R Recent P Prior

Aspirin Ticagrelor Dipyridamole VKA Rivaroxaban

Study
Drug Clopidogrel Prasugrel Cilostazol Dabigatran Apixaban

Trials are categorized according to their sample size, the investigational strategy, and the timing of the index ischemic stroke. ARCADIA ¼ Atrial Cardiopathy and
Antithrombotic Drugs in Prevention After Cryptogenic Stroke study; ATTICUS ¼ Apixaban for Treatment of Embolic Stroke of Undetermined Source study;
CAST ¼ Chinese Acute Stroke Trial; CHANCE ¼ Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events study; CHANCE-2 ¼ Ticagrelor or
Clopidogrel With Aspirin in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events II study; CSPS ¼ Cilostazol Stroke Prevention Study; CSPS 2 ¼ Post-
marketing Study of Cilostazol (Cilostazol Stroke Prevention Study 2); CSPS.com ¼ Cilostazol Stroke Prevention Study for Antiplatelet Combination study; DATAS
II ¼ Dabigatran Following Transient Ischemic Attack and Minor Stroke study; ESPRIT ¼ European/Australasian Stroke Prevention in Reversible Ischaemia Trial;
ESPS ¼ European Stroke Prevention Study; ESPS-2 ¼ European Stroke Prevention Study 2; ESUS ¼ embolic stroke of undetermined source; FASTER ¼ Fast Assessment
of Stroke and Transient Ischemic Attack to Prevent Early Recurrence study; IST ¼ International Stroke Trial; LACI-2 ¼ Lacunar Intervention-2 study;
MATCH ¼ Management of Atherothrombosis With Clopidogrel in High-Risk Patients study; NAVIGATE ESUS ¼ Rivaroxaban Versus Aspirin in Secondary Prevention of
Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source study; POINT ¼ Platelet-Oriented Inhibition in New TIA
and Minor Ischemic Stroke study; PRASTRO-I ¼ Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke study; PRASTRO-II ¼ Safety and Efficacy of
Prasugrel in Elderly and/or Low Body Weight Japanese Patients With Ischemic Stroke study; PRoFESS ¼ Prevention Regimen for Effectively Avoiding Second Strokes
study; RE-SPECT ESUS ¼ Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source study; SOCRATES ¼ Acute
Stroke or Transient Ischaemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes study; SPIRIT ¼ Stroke Prevention in Reversible Ischemia Trial;
SPS3 ¼ Secondary Prevention of Small Subcortical Strokes Trial; TARDIS ¼ Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke study; THALES ¼ Acute
Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death study; VKA ¼ vitamin K antagonist; WARSS ¼ Warfarin–
Aspirin Recurrent Stroke Study.

was significantly reduced.29 Due to its increased risk
of bleeding, routine anticoagulation is not recom-
mended for primary prevention in heart failure pa-
tients in sinus rhythm.
Patients with mechanical heart valves require
lifelong treatment with VKAs, targeting an interna-
tional normalized ratio (INR) between 2.5 and 3.5,
depending on prosthesis thrombogenicity.30,31
The risk of thromboembolism is higher during the
first 6 months, and VKA administration should be
started on the first day. The addition of antiplatelet
therapy may be considered in patients at very high
risk of thromboembolism. 32 For patients who have
undergone mitral or tricuspid bioprosthetic valve
implantation without another indication for oral
anticoagulation, VKA therapy for 3 months should be
administered to reduce the risk of thromboembo-
lism. 33 For aortic surgical bioprostheses, aspirin is a

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1542 Greco et al JACC VOL. 82, NO. 15, 2023

Antithrombotic Therapy for Ischemic Stroke OCTOBER 10, 2023:1538–1557

T A B L E 1 Trials of DOACs in Patients With AF

Primary
Efficacy Follow-Up,
Trial (Year) Sample Population Intervention Control Outcome Median Result

RE-LY14 18,113 AF Dabigatran Warfarin Ischemic stroke 2.0 y RR: 0.91; 95% CI: 0.74 to 1.11; P < 0.001
(2009) 110 mg or or SE for NI (110 mg); RR: 0.66; 95% CI: 0.53
150 mg to 0.82; P < 0.001 (150 mg)
ROCKET-AF15 14,264 AF Rivaroxaban Warfarin Ischemic stroke 1.9 y HR: 0.88; 95% CI: 0.74 to 1.03; P < 0.001
(2011) or SE for NI
ARISTOTLE16 18,201 AF Apixaban Warfarin Ischemic stroke 1.8 y HR: 0.79; 95% CI: 0.66 to 0.95; P ¼ 0.01
(2011) or SE
AVERROES44 5,599 AF Apixaban Aspirin Ischemic stroke 1.1 y HR: 0.45; 95% CI: 0.32 to 0.62; P < 0.001
(2011) or SE
ENGAGE-AF17 21,105 AF Edoxaban 60 mg Warfarin Ischemic stroke 2.8 y HR: 0.79; 97.5% CI: 0.63 to 0.99;
(2013) or 30 mg or SE P ¼ 0.02 (60 mg); HR: 1.07; 97.5% CI:
0.87 to 1.31; P ¼ 0.005 for NI (30 mg)
RIVER18 1,005 AF and BMV Rivaroxaban Warfarin NACCE 0.9 y Difference in RSMT: 7.4 d; 95% CI: 1.4 to
(2020) 16.3; P < 0.001 for NI
INVICTUS19 4,531 AF and RHD Rivaroxaban Warfarin MACCE 3.1 y HR: 1.25; 95% CI: 1.10 to 1.41; P < 0.001
(2022)
PACIFIC-AF25 441 AF Asundexian Apixaban Major or CRNM 84 d HR: 0.50: 90% CI: 0.14 to 1.68 (20 mg);
(2022) 20 mg or bleeding HR: 0.16; 90% CI: 0.01 to 0.99
50 mg (50 mg)

AF ¼ atrial fibrillation; ARISTOTLE ¼ Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation study; AVERROES ¼ A Phase III Study of Apixaban in Patients With Atrial Fibrillation study;
BMV ¼ bioprosthetic mitral valve; CRNM ¼ clinically relevant nonmajor; DOACs ¼ direct oral anticoagulants; ENGAGE-AF ¼ Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs
Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation; INVICTUS ¼ Investigation of Rheumatic AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-
Inferiority study; MACCE ¼ major adverse cerebrovascular or cardiac events; NACCE ¼ net adverse cerebrovascular or cardiac events; NI ¼ noninferiority; PACIFIC-AF ¼ Study to Gather Information
About the Proper Dosing of the Oral FXIa Inhibitor BAY 2433334 and to Compare the Safety of the Study Drug to Apixaban, a Non-vitamin K Oral Anticoagulant (NOAC) in Patients With Irregular Heartbeat
(Atrial Fibrillation) That Can Lead to Heart-related Complications; RE-LY ¼ Randomized Evaluation of Long Term Anticoagulant Therapy With Dabigatran Etexilate study; RHD ¼ rheumatic heart disease;
RIVER ¼ Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation Trial; ROCKET-AF ¼ An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous
System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation study; RR ¼ relative risk; RSMT ¼ restricted mean survival time; SE ¼ systemic embolism.

potential alternative and represents the standard of
care after transcatheter aortic valve implantation in
patients who do not have baseline conditions that
33,34
require anticoagulation. In patients with a bio-
prosthetic valve and a baseline indication to anti-
coagulation, DOACs are not inferior to VKA in
reducing major adverse cardiovascular events. 18,35-37
In case of bioprosthetic valve thrombosis, VKA or
unfractionated heparin is the first-line therapy,
whereas the management of mechanical heart valve
thrombosis is complex and may require surgery.33
Migration of vegetation fragments into the cerebral
circulation is a potential complication of infective
endocarditis and is associated with higher mortal-
ity. 38 This stroke subtype is often symptomatic and
leads to diagnosis, but silent cerebral embolism is not
39
uncommon. Antibiotic therapy is a pillar of the
treatment of infective endocarditis, whereas cardiac
surgery is recommended for patients at high risk of
40
embolism. Current evidence does not support the
use of antiplatelet therapy after the diagnosis of
infective endocarditis, and there are few data about
the effects of oral anticoagulants. 41,42
Finally, paradoxical embolization through a patent
foramen ovale is the cause of a significant proportion
of cardioembolic strokes referred to as cryptogenic.
Neither medical therapy nor percutaneous closure is
generally recommended for primary prevention in
this setting.43
SECONDARY PREVENTION. The treatment effects of
the DOACs were generally consistent across sub-
groups of patients with and without prior stroke,
suggesting their benefits in both primary and sec-
ondary prevention.14-17,44 After an acute stroke in
patients with atrial fibrillation, the optimal timing to
initiate DOACs is an area of uncertainty and depends
on the risk of hemorrhagic transformation, infarct
size, and other factors (eg, uncontrolled hyperten-
sion). A randomized trial showed that early initiation
(ie, within 4 days) was noninferior to delayed start of
DOACs (ie, between 5 and 10 days).45 However, the
risk of hemorrhagic transformation should be
considered and current guidelines recommend initi-
ating oral anticoagulation between 2 and 14 days
(Class 2b) or beyond 14 days (Class 2a) in case of low
and high risk, respectively. 43 Accounting also for the
infarct size, the ELAN (Early Versus Late Initiation of
Direct Oral Anticoagulants in Post-Ischaemic Stroke
Patients With Atrial Fibrillation) trial compared early
(ie, within 48 hours after a minor or moderate stroke
or at 6 or 7 days after a major stroke) to late initiation

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JACC VOL. 82, NO. 15, 2023 Greco et al 1543
OCTOBER 10, 2023:1538–1557 Antithrombotic Therapy for Ischemic Stroke

T A B L E 2 Trials of PFO Closure vs Antithrombotic Therapy

Primary Efficacy
Sample Population Intervention Control Outcome Follow-Up Result

CLOSURE I49 909 Cryptogenic stroke or TIA PFO closure plus Warfarin, aspirin, or Ischemic stroke 1.7 y (mean) HR: 0.78; 95% CI: 0.45-
(2012) antiplatelet therapy both or TIA 1.35; P ¼ 0.37
PC50 414 Cryptogenic stroke or PFO closure plus Antiplatelet or oral MACCE 4.1 y (mean) HR: 0.63; 95% CI: 0.25-
(2013) peripheral antiplatelet therapy anticoagulation 1.62; P ¼ 0.34
thromboembolism therapy
RESPECT51 980 Cryptogenic stroke PFO closure plus Antiplatelet or oral MACCE 5.9 y (median) HR: 0.55; 95% CI: 0.31-
(2013) antiplatelet therapy anticoagulation 0.999; P ¼ 0.046
therapy
CLOSE53 663 Cryptogenic stroke and PFO closure plus Anticoagulation Ischemic stroke 5.3 y (mean) HR: 0.03; 95% CI: 0.00-
(2017) high-risk PFO antiplatelet therapy therapy 0.26; P < 0.001
REDUCE54 664 Cryptogenic stroke PFO closure plus Antiplatelet therapy Ischemic stroke 5.0 y (median) HR: 0.31; 95% CI: 0.13-
(2017) antiplatelet therapy 0.76; P ¼ 0.007
DEFENSE PFO55 120 Cryptogenic stroke and PFO closure plus Antiplatelet or oral NACCE 2.8 y (mean) 0% vs 12.9%; P ¼ 0.013
(2018) high-risk PFO antiplatelet therapy anticoagulation
therapy

CLOSE ¼ Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence; CLOSURE I ¼ Evaluation of the STARFlex Septal Closure System in Patients With a Stroke
or TIA Due to the Possible Passage of a Clot of Unknown Origin Through a Patent Foramen Ovale (PFO); DAPT ¼ dual antiplatelet therapy; DEFENSE PFO ¼ Device Closure Versus Medical Therapy for
Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale; PC ¼ PC-Trial: Patent Foramen Ovale and Cryptogenic Embolism; PFO ¼ patent foramen ovale; REDUCE ¼ GORE Septal Occluder Device for
Patent Foramen Ovale (PFO) Closure in Stroke Patients; RESPECT ¼ Patent Foramen Ovale Closure or Medical Therapy After Stroke; TIA ¼ transient ischemic attack; VKA ¼ vitamin K antagonists; other
abbreviations as in Table 1.

(ie, on day 3 or 4 after a minor stroke, day 6 or 7 after a
moderate stroke, or day 12 to 14 after a major stroke),
showing similar efficacy and safety
2 strategies.46
No specific evidence is available on secondary
stroke prevention among patients with heart failure,
and general strategies for secondary prevention of
recurrent cardioembolism should be considered (eg,
anticoagulation if atrial fibrillation coexists).43 Add-
ing antiplatelet therapy may be considered in pa-
tients with an ischemic stroke despite adequate
INR.32 In patients with endocarditis who experience
an ischemic stroke, cardiac surgery is an option
depending on a thorough evaluation of neurological
damage, cardiac function, and the burden of infective
endocarditis. 33
Finally, in the context of paradoxical embolization,
percutaneous device closure of the
variant may be of benefit for selected patients beyond
medical therapy, particularly for those with high-risk
anatomical features (eg, large defect, multiple open-
ings, atrial septal aneurysm, shunt at rest), a high
RoPE (Risk of Paradoxical Embolism) score or with a
stroke likely related to patent foramen ovale based on
the PASCAL (PFO-Associated Stroke Causal Likeli-
hood) classification.47,48 Six randomized controlled
trials have collectively shown a high relative risk
reduction and a low absolute risk reduction of
ischemic stroke recurrence compared with anticoag-
ulant or antiplatelet therapy, with benefits out-
weighing periprocedural complications (Table 2).
Most studies enrolled patients aged 18 to 60 years
with cryptogenic stroke, making patent foramen
ovale closure generally restricted to young patients,
especially those with moderate-to-high risk. In older
of the patients, patent foramen ovale closure is condition-
ally suggested over long-term antiplatelet therapy
alone. 56
CRYPTOGENIC STROKES
The term cryptogenic means that the origin of the
ischemic stroke remains unknown despite extensive
diagnostic evaluation. Approximately one-half of
cryptogenic strokes are caused by embolic events and
are referred to as embolic stroke of undetermined
source (ESUS).4,43
ESUS refers to an ischemic stroke that has been
diagnosed after appropriate diagnostic work-up has
excluded cardioembolism and proximal arterial ste-
anatomical nosis, and is a more heterogeneous condition than
thought in the past.57,58 Although covert atrial fibril-
lation was previously considered the primary etiology
of ESUS, recent research has revealed other potential
sources of embolism, including atrial cardiopathy (ie,
left atrium disease with no atrial fibrillation), non-
stenotic plaques, hypercoagulability associated with
malignancy, and aortic arch atherosclerosis
(Figure 2).59 The identification of distinct thrombo-
embolic sources has led to the investigation of alter-
native antithrombotic therapies for secondary
prevention, including anticoagulant and antiplatelet
drugs. 60
49-55
Four randomized clinical trials of DOACs in ESUS
did not demonstrate a significant benefit of anti-
coagulation over aspirin (Table 3, Figure 1).61-64 The

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1544 Greco et al JACC VOL. 82, NO. 15, 2023

Antithrombotic Therapy for Ischemic Stroke OCTOBER 10, 2023:1538–1557

F I G U R E 2 Common Sources of ESUS

Atherothrombosis Atrial cardiopathy

or arrhythmia

Ventricular Patent
disease foramen ovale

Valvular disease Neoplasm

Embolic stroke of undetermined source (ESUS) is typically the acute manifestation of an underlying disease that has not been previously
diagnosed. Potential cardiac sources of embolism include conditions where blood stasis in the heart chambers induces coagulation (eg,
dilated cardiomyopathy, atrial cardiopathy or covert atrial fibrillation), congenital defects that allow for the passage of blood clots from the
venous to the arterial bed (eg, patent foramen ovale), and valvular diseases that can cause embolisms from local turbulent flow, calcium
debris, or vegetations. Systemic diseases not directly involving the heart, such as atherosclerosis and neoplasms, may also contribute to
clotting.

NAVIGATE ESUS (Rivaroxaban Versus Aspirin in
Secondary Prevention of Stroke and Prevention of
Systemic Embolism in Patients With Recent Embolic
Stroke of Undetermined Source) trial was designed to
test the comparative efficacy and safety of rivarox-
aban and aspirin. However, the trial was terminated
prematurely due to higher rates of major bleeding and
intracranial hemorrhage with rivaroxaban, and the
absence of benefit for the prevention of recurrent
ischemic stroke. 61
Similarly, the RE-SPECT ESUS (Dabigatran Etex-
ilate for Secondary Stroke Prevention in Patients With
Embolic Stroke of Undetermined Source) trial failed
to demonstrate the superiority of dabigatran over
aspirin during a median follow-up of 19 months, but
interestingly, the event curves started to diverge in
favor of dabigatran after 450 days of follow-up.62
Although the subgroup analyses were exploratory in
nature, a treatment effect was noted in patients who
received dabigatran at a lower dose (ie, 110 mg) or a
proton pump inhibitor as a background therapy.62 In
contrast to NAVIGATE ESUS, the rate of major
bleeding was similar between dabigatran and aspirin
in RE-SPECT ESUS. It should be noted, however, that
this discrepancy was unexpectedly caused by the
safety profile of aspirin in the 2 trials (ie, lower rates
of major bleeding yearly in NAVIGATE ESUS) rather
than by the safety profile of rivaroxaban and
dabigatran.
The proof-of-concept ATTICUS (Apixaban for
Treatment of Embolic Stroke of Undetermined
Source) trial, which aimed to compare apixaban vs

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JACC VOL. 82, NO. 15, 2023 Greco et al 1545
OCTOBER 10, 2023:1538–1557 Antithrombotic Therapy for Ischemic Stroke

T A B L E 3 Trials of Direct Oral Anticoagulation in Patients With ESUS

NAVIGATE ESUS 61 RE-SPECT ESUS62 ATTICUS63 ARCADIA64

Sample, n 7,213 5,390 352 1,015

Population ESUS ESUS ESUS and risk factor profile for cardiac ESUS and atrial cardiopathy (atrial
thromboembolism and mandatory abnormalities at ECG, enlarged
continuous AF monitoring left atrium at echocardiography,
or high NT-proBNP)
NIHSS score in the control 1 1 NR 1
arm, median
Time from index event to 36 d 43 d 8d 2 mo
randomization in the
control arm, median
Blinded Yes Yes No Yes
Intervention Rivaroxaban 15 mg Dabigatran 150 mg or Apixaban 5 mg twice daily (or reduced Apixaban 5 mg twice daily (or
once daily 110 mg twice daily dose according to IFU) reduced dose according to IFU)
Control Aspirin 100 mg once Aspirin 100 mg once daily Aspirin 100 mg once daily with switch Aspirin 81 mg once daily
daily to apixaban in case of AF detection
Follow-up, median 11 mo 19 mo 12 mo 1.8 y
Primary efficacy outcome Ischemic stroke or Ischemic stroke New ischemic lesions on MRI Any recurrent stroke
systemic
embolism
Result HR: 1.07; 95% CI: HR: 0.85; 95% CI: 0.69- 13.6% vs 16.0%; P ¼ 0.57 HR: 1.00; 95% CI: 0.64-1.55
0.87-1.33; 1.03; P ¼ 0.10
P ¼ 0.52
Primary safety outcome Major bleeding Major bleeding Any bleeding Symptomatic intracranial
hemorrhage and major
hemorrhage other than
intracranial
Result HR: 2.72; 95% CI: HR: 1.19; 95% CI: 0.85- 16.9% vs 10.3%: P ¼ 0.075 0.0% vs 1.1% for symptomatic
1.68-4.39; 1.66 intracranial hemorrhage; HR:
P < 0.001 1.02; 95% CI: 0.29-3.51 for
major hemorrhage

AF ¼ atrial fibrillation; ARCADIA ¼ Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke study; ATTICUS ¼ Apixaban for Treatment of Embolic Stroke of
Undetermined Source study; ECG ¼ electrocardiogram; ESUS ¼ embolic stroke of undetermined source; IFU ¼ instructions for use; MRI ¼ magnetic resonance imaging; NAVIGATE
ESUS ¼ Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source study;
NIHSS ¼ National Institutes of Health Stroke Scale; NR ¼ not reported; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; RE-SPECT ESUS ¼ Dabigatran Etexilate for Secondary Stroke
Prevention in Patients With Embolic Stroke of Undetermined Source study.

aspirin for the prevention of new ischemic lesions
documented by brain magnetic resonance imaging,
was terminated prematurely for futility after an
interim analysis at a time when 352 patients of the
500 patients initially planned were
Compared with NAVIGATE ESUS and RE-SPECT
ESUS, ATTICUS enrolled an enriched ESUS popula-
tion with additional risk factors for cardiac thrombo-
embolism. In particular, the mandatory continuous
cardiac monitoring detected subclinical episodes of
atrial fibrillation in 26% of the study population. Pa-
tients found to have atrial fibrillation in the aspirin
arm were switched to receive apixaban, which may
have contributed to the neutral result. 63 In those that
did not show atrial fibrillation, apixaban and aspirin
were similar in preventing recurrent events. Apix-
aban almost doubled numerically the risk of minor
bleeding, but major bleeding was similar despite the
earlier initiation of anticoagulation compared with
the trials of rivaroxaban and dabigatran.
Mirroring the experience with atrial fibrillation,
DOACs were also hypothesized to prevent stroke
recurrencies in patients with atrial cardiopathy. In
the ARCADIA (Atrial Cardiopathy and Antithrombotic
enrolled. 63 Drugs in Prevention After Cryptogenic Stroke) trial,
patients with ESUS in the past 6 months, evidence of
atrial cardiopathy (ie, either atrial abnormalities at
electrocardiogram, enlarged left atrium at echocar-
diography, or high N-terminal pro–B-type natriuretic
peptide levels) and no overt sources of car-
dioembolism were randomized to apixaban or aspirin.
There were no differences between the 2 strategies in
terms of stroke recurrence, with similar rates of death
and intracranial hemorrhage, and the trial was
stopped prematurely for futility. 64
Based on these results, anticoagulation therapy
cannot be recommended for the secondary preven-
tion of stroke in unselected patients with ESUS.
Interestingly, exploratory analyses have suggested
that the treatment effect of anticoagulation therapy

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1546 Greco et al
Antithrombotic Therapy for Ischemic Stroke
may differ with age. Specifically, a significant benefit
of aspirin was observed only in patients aged #60
years in NAVIGATE ESUS, whereas dabigatran and
apixaban were better than aspirin in patients
aged $75 years in RE-SPECT ESUS and ATTICUS,
respectively. In the context of the neutral results of
the 3 trials, these subgroup analyses must be inter-
preted with caution. However, it is possible that
anticoagulation works better in older patients with
multiple concomitant embolic sources, including
covert atrial fibrillation.
The hypothesis of multiple embolic causes in pa-
tients with ESUS, including atherothrombotic and
thromboembolic sources (Figure 2), and the concept
that emboli arising from nonstenotic athero-
thrombotic plaques may benefit from both anti-
platelets and anticoagulants due to coexistence of red
and white thrombi have gained further support from
a secondary analysis of the COMPASS (Rivaroxaban
for the Prevention of Major Cardiovascular Events in
Coronary or Peripheral Artery Disease) trial. Specif-
ically, the use of low-dose rivaroxaban plus aspirin
was associated with a significant reduction in car-
dioembolic stroke and ESUS compared with treatment
with rivaroxaban or aspirin alone. 65
Although current data do not provide conclusive
evidence in support of anticoagulation with a DOAC
over antiplatelet therapies, ongoing trials hold
promise for providing further insights into the
optimal treatment for patients with ESUS. The
AREST-ESUS (Rivaroxaban Plus ASA in Embolic
Stroke of Undetermined Source; NCT04273516) trial is
currently underway and will randomize patients with
ESUS to low-dose rivaroxaban and aspirin vs aspirin
and placebo.
STROKES FROM LARGE-ARTERY ATHEROSCLEROSIS
Large-artery atherosclerosis pertains to the manifes-
tation of atheromatous plaques in the intracranial
arteries (specifically the anterior cerebral, middle
cerebral, and basilar arteries) or the extracranial ar-
teries (namely the carotid and vertebral arteries),
which result in stenosis of 50% or more, or complete
4
vessel occlusion. The prevention and management
of this type of stroke are primarily dependent on
antithrombotic therapy, wherein a diverse array of
drugs (including antiplatelet and anticoagulant
agents), combinations, and durations have been
subjected to investigation (Table 4, Figure 1).66
Importantly, the evidence on this stroke subtype in
the available trials is confounded by inclusion of
varying proportions of patients with strokes from
other etiologies (eg, small-vessel disease,
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JACC VOL. 82, NO. 15, 2023
OCTOBER 10, 2023:1538–1557
cryptogenic), with clinical presentation of “ischemic
stroke" representing the common denominator and
main entry criterion. In addition, other inclusion
criteria largely differed between trials in this group as
it relates, for example, to stroke severity, timing from
symptoms onset, and duration of the investigational
antithrombotic regimen. Studies that included, but
were not limited to, patients with large-artery
atherosclerosis are reported in the following para-
graphs for descriptive purpose. The generalizability
of these trials to patients with large-artery athero-
sclerosis cannot be conclusively established. Yet,
despite large-artery atherosclerosis sometimes rep-
resenting a minor or unknown proportion of the
study samples, these trials embody the evidence basis
of guideline recommendations for this indication.
PRIMARY PREVENTION. The potential benefits of
using aspirin for primary prevention of ischemic
stroke must be considered alongside the risk of
bleeding.67 Other strategies to prevent adverse car-
diovascular events, including ischemic stroke, were
compared with aspirin in trials that mixed individuals
at high risk and patients with manifestations of
atherosclerotic vascular disease, including cerebro-
vascular disease. 68-70 In the CAPRIE (Clopidogrel
Versus Aspirin in Patients at Risk of Ischemic Events)
trial, the benefit of clopidogrel compared with aspirin
was less pronounced in patients without a previous
history of ischemic events. 71 Significant reductions in
stroke were noted with the addition of clopidogrel to
aspirin in CHARISMA (Clopidogrel for High Athero-
thrombotic Risk and Ischemic Stabilization, Manage-
ment and Avoidance)69 and with the addition of low-
dose rivaroxaban in COMPASS, 70 but these trials
cannot be considered pure studies of primary pre-
vention and were not powered for stroke reduction.
SECONDARY PREVENTION. Initial studies of anti-
platelet strategies for acute ischemic stroke have
focused on aspirin monotherapy, with 2 large trials
producing mixed results. 72,73 However, a pooled
analysis of these trials demonstrated that the in-
hospital initiation of aspirin reduced the recurrence
of stroke by 30%.74 In CAPRIE, one-third of patients
had experienced an ischemic stroke within the pre-
vious 6 months; when the analysis was restricted to
these patients, clopidogrel was not shown to be better
than aspirin. 68 In the SOCRATES (Acute Stroke or
Transient Ischaemic Attack Treated With Aspirin or
Ticagrelor and Patient Outcomes) trial, ticagrelor was
compared with aspirin in 13,199 patients with acute
nonsevere ischemic stroke or high-risk transient
ischemic attack (TIA), with no apparent benefit. 75
Additionally, 2 small Japanese trials failed to prove
JACC VOL. 82, NO. 15, 2023 Greco et al 1547
OCTOBER 10, 2023:1538–1557 Antithrombotic Therapy for Ischemic Stroke

T A B L E 4 Landmark Randomized Clinical Trials of Contemporary Antiplatelet Strategies for Patients With Ischemic Stroke

Primary
Efficacy
Sample NIHSS Intervention Control Outcome Follow-Up Result

Acute or recent
ischemic stroke
IST72 (1997) 19,435 NR SAPT (aspirin) No aspirin Death 14 d 9.0% vs 9.4%; P ¼ NR
CAST73 (1997) 21,106 NR SAPT (aspirin) Placebo Death 4 wk 3.3% vs 3.9%; P ¼ 0.04
SPIRIT107 (1997) 1,316 NR OAC (vitamin K SAPT (aspirin) Death 14 mo (mean) HR: 2.40; 95% CI: 1.30-4.40; P ¼ NR
antagonists)
WARSS109 (2002) 2,206 NR OAC (warfarin) SAPT (aspirin) Death or 2y HR: 1.13; 95% CI: 0.92-1.38; P ¼ 0.25
ischemic
stroke
ESPRIT108 (2007) 1,068 NR OAC (vitamin K SAPT (aspirin) Death 4.6 y (mean) HR: 1.36; 95% CI: 0.92-2.01; P ¼ NR
antagonists)
FASTER83 (2007) 392 1 (median) SAPT (clopidogrel) Placebo Ischemic stroke 90 d RR: 0.7; 95% CI: 0.3-1.2; P ¼ 0.19
CHANCE85 (2013) 5,170 #3 DAPT (aspirin þ SAPT (aspirin) Ischemic stroke 90 d HR: 0.68; 95% CI: 0.57-0.81;
clopidogrel) P < 0.001
SOCRATES75 13,199 #3 in SAPT (ticagrelor) SAPT (aspirin) MACCE 90 d HR: 0.89; 95% CI: 0.78-1.01; P ¼ 0.07
(2016) 67.4%
TARDIS106 (2017) 3,096 2.7 (mean) TAPT (dipyridamole þ DAPT Ischemic stroke 90 d HR: 0.98; 95% CI: 0.67-1.20; P ¼ 0.47
aspirin þ clopidogrel) (dipyridamole þ or TIA
aspirin or
clopidogrel)
POINT89 (2018) 4,881 2 (median) DAPT (aspirin þ SAPT (aspirin) MACCE 90 d HR: 0.75; 95% CI: 0.59-0.95;
clopidogrel) P ¼ 0.02
PRASTRO-I76 3,747 NR SAPT (prasugrel) SAPT (clopidogrel) MACCE 2y RR: 1.05%; 95% CI: 0.76-1.44; P ¼ NR
(2019)
DATAS II112 (2020) 305 1 (median) OAC (dabigatran) SAPT (aspirin) Ischemic stroke 90 d HR: 0.62; 95% CI: 0.26-1.48; P ¼ NR
THALES92 (2020) 11,016 #3 in DAPT (aspirin þ SAPT (aspirin) Death or 30 d HR: 0.83; 95% CI: 0.71-0.96; P ¼ 0.02
60.3% ticagrelor) ischemic
stroke
CHANCE-293 11,255 2 (median) DAPT (aspirin þ DAPT (aspirin þ Ischemic stroke 90 d HR: 0.77; 95% CI: 0.64-0.94;
(2021) ticagrelor) clopidogrel) P ¼ 0.008
Prior or remote
ischemic stroke
ESPS100 (1990) 2,500 NA DAPT (dipyridamole þ Placebo Death or 24 mo z-stat ¼ 4.75; P < 0.01
aspirin) ischemic
stroke
ESPS-278 (1996) 6,602 NA SAPT (dipyridamole or Placebo Ischemic stroke 24 mo OR: 0.61; 95% CI: 0.67-0.99
aspirin) or DAPT (dipyridamole); OR: 0.79; 95% CI:
(dipyridamole þ 0.65-0.97 (aspirin); OR: 0.59;
aspirin) 95% CI: 0.48-0.73
(dipyridamole þ aspirin)
CSPS79 (2000) 1,095 NA SAPT (cilostazol) Placebo Ischemic stroke 1y RR reduction: 41.7%; CI 9.2%-62.5%;
P ¼ 0.0150
MATCH82 (2004) 7,599 NA DAPT (aspirin þ SAPT (clopidogrel) MACCE 1.5 y RR: 0.94; 95% CI: 0.84-1.05; P ¼ NR
clopidogrel)
ESPRIT102 (2006) 2,739 NA DAPT (dipyridamole þ SAPT (aspirin) NACCE 3.5 y HR: 0.80; 95% CI: 0.66-0.98
aspirin)
PRoFESS103 20,332 NA DAPT (dipyridamole þ SAPT (clopidogrel) Ischemic stroke 2.5 y HR: 1.01; 95% CI: 0.92-1.11; P ¼ NR
(2008) aspirin)
CSPS 280 (2010) 2,757 NA SAPT (cilostazol) SAPT (aspirin) Ischemic stroke 29 mo HR: 0.74; 95% CI: 0.56-0.98;
P ¼ 0.0357
CSPS.com98 (2019) 1,879 NA DAPT (cilostazol þ aspirin SAPT (aspirin or Ischemic stroke 1.4 y HR: 0.49; 95% CI: 0.31-0.76;
or clopidogrel) clopidogrel) P ¼ 0.0010
77
PRASTRO-II 654 NA SAPT (prasugrel) SAPT (clopidogrel) MACCE 48 wk RR: 4.2%: 95% CI: 1.9-7.8; P ¼ NR
(2020)

NIHSS was reported about the control arm of each study of acute or recent ischemic stroke.
CAST ¼ Chinese Acute Stroke Trial; CHANCE ¼ Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events study; CHANCE-2 ¼ Ticagrelor or Clopidogrel With Aspirin in High-Risk
Patients With Acute Non-Disabling Cerebrovascular Events II study; CSPS ¼ Cilostazol Stroke Prevention Study; CSPS 2 ¼ Post-marketing Study of Cilostazol (Cilostazol Stroke Prevention Study 2);
CSPS.com ¼ Cilostazol Stroke Prevention Study for Antiplatelet Combination; DATAS II ¼ Dabigatran Following Transient Ischemic Attack and Minor Stroke study; ESPRIT ¼ European/Australasian Stroke
Prevention in Reversible Ischaemia Trial; ESPS ¼ European Stroke Prevention Study; ESPS-2 ¼ European Stroke Prevention Study 2; FASTER ¼ Fast Assessment of Stroke and Transient Ischemic Attack to
Prevent Early Recurrence study; IST ¼ International Stroke Trial; MATCH ¼ Management of Atherothrombosis With Clopidogrel in High-Risk Patients study; NA ¼ not applicable; OAC ¼ oral anticoagulation;
POINT ¼ Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke study; PRASTRO-I ¼ Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke study; PRASTRO-II ¼ Safety and Efficacy
of Prasugrel in Elderly and/or Low Body Weight Japanese Patients With Ischemic Stroke study; PRoFESS ¼ Prevention Regimen for Effectively Avoiding Second Strokes study; SAPT ¼ single antiplatelet
therapy; SOCRATES ¼ Acute Stroke or Transient Ischaemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes study; SPIRIT ¼ Stroke Prevention in Reversible Ischemia Trial; SPS3 ¼ Secondary
Prevention of Small Subcortical Strokes Trial; TAPT ¼ triple antiplatelet therapy; TARDIS ¼ Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke study; THALES ¼ Acute Stroke or Transient
Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death study; TIA ¼ transient ischemic attack; WARSS ¼ Warfarin–Aspirin Recurrent Stroke Study; other abbreviations as in
Tables 1 and 2.

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1548 Greco et al
Antithrombotic Therapy for Ischemic Stroke
a significant benefit of low-dose prasugrel. 76,77
Dipyridamole and cilostazol were also investigated
with some positive evidence but little uptake in
clinical practice. 78-81
Numerous trials have tested the combination of 2
antiplatelet drugs. DAPT with aspirin and clopidogrel
has been compared with aspirin or clopidogrel mon-
otherapies in trials that varied in population, timing
of enrollment from the index event, treatment dura-
tion, and study endpoints, yielding mixed re-
sults.69,82-89 Specifically, the MATCH (Management of
Atherothrombosis With Clopidogrel in High-Risk Pa-
tients) trial randomized 7,599 high-risk patients due
to a recent ischemic stroke or TIA to aspirin or placebo
on a background of clopidogrel therapy. DAPT was
not associated with a reduction in ischemic events
compared with aspirin alone, and it increased the risk
of life-threatening, major, and minor bleeding. 82
Conversely, the evidence on DAPT is more
convincing in patients with acute minor stroke or
high-risk TIA, although it should be noted that the
available trials mixed populations of patients and
were not just limited to those with large-artery
atherosclerosis.85,89 The CHANCE (Clopidogrel in
High-Risk Patients With Acute Non-Disabling Cere-
brovascular Events) trial randomized 5,170 Chinese
patients with recent ischemic stroke (34% from large-
artery disease) or TIA to DAPT with aspirin and clo-
pidogrel (for 21 days, followed by clopidogrel mono-
therapy) or aspirin plus placebo. After 90 days, DAPT
significantly reduced the incidence of stroke by 32%
without any increase in moderate or severe
bleeding. 85 Similarly, the POINT (Platelet-Oriented
Inhibition in New TIA and Minor Ischemic Stroke)
trial, where the specific cause of stroke was not re-
ported, randomly allocated 4,881 patients to 90-day
DAPT with aspirin and clopidogrel or aspirin alone.
Despite a 25% reduction in ischemic events at 90 days
with DAPT, the trial was prematurely halted by the
data and safety monitoring board due to excess major
bleeding in this group.89 When interpreting these
findings, it is important to take into account the
temporal trends in the risks of ischemia and bleeding
as the DAPT benefit was highest in the initial 3 weeks
following an ischemic stroke, during which the po-
tential advantages may outweigh the risk of intra-
cranial hemorrhage. Differences with the CHANCE
trial might have reflected disparities in population (ie,
Chinese patients in CHANCE, Westerners in POINT),
loading dose of clopidogrel (ie, lower in CHANCE),
and DAPT duration (ie, 21 days in CHANCE vs 90 days
in POINT). A pooled analysis of the CHANCE and
POINT trials showed a 34% benefit with DAPT within
the first 21 days, but not thereafter.90 DAPT with
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JACC VOL. 82, NO. 15, 2023
OCTOBER 10, 2023:1538–1557
aspirin and clopidogrel was used in both the arms of
the SAMMPRIS (Stenting vs. Aggressive Medical
Management for Preventing Recurrent Stroke in
Intracranial Stenosis) trial, a study where intensive
medical management alone was superior to carotid
stenting plus intensive medical management in pa-
tients with a recent stroke or TIA and a 70% to 99%
intracranial artery stenosis.91
DAPT with aspirin and ticagrelor was also consid-
ered an option. 92-94 The THALES (Acute Stroke or
Transient Ischaemic Attack Treated With Ticagrelor
and ASA for Prevention of Stroke and Death) trial,
where the specific cause of stroke was not reported,
randomized 11,016 patients with mild-to-moderate
acute ischemic stroke to receive DAPT with aspirin
and ticagrelor or aspirin alone. At 30 days, DAPT
reduced the composite of ischemic stroke or death by
21% at the price of increased severe bleeding. 92 In the
CHANCE-2 (Ticagrelor or Clopidogrel With Aspirin in
High-Risk Patients With Acute Non-Disabling Cere-
brovascular Events II) trial, which enrolled 11,255
Chinese patients with minor stroke or TIA who carried
cytochrome P450 2C19 loss-of-function alleles (ie,
poor metabolizers of clopidogrel), there was a 23%
reduction in the risk of stroke with ticagrelor-based
DAPT paralleled by an increase in bleeding; howev-
er, there were no between-group differences in se-
vere or moderate bleeding.93
Several investigations have also been conducted
on the combination of aspirin and cilostazol, but
these were mainly impaired by methodological limi-
tations and low statistical power for clinical end-
points. 95-97 In the CSPS.com (Cilostazol Stroke
Prevention Study for Antiplatelet Combination) trial,
which randomized 1,879 Japanese patients with high-
risk ischemic stroke (42% from large-artery disease),
cilostazol-based DAPT reduced the risk of stroke by
51% compared with aspirin or clopidogrel mono-
therapy, without any increase in severe or life-
threatening bleeding. 98
The combination of aspirin and dipyridamole has
been investigated with mixed results. 78,99-103 In
particular, this regimen proved better than placebo in
patients with recent ischemic stroke, and better than
aspirin or dipyridamole monotherapy in patients with
recent or prior ischemic stroke.78,100,102 Conversely,
noninferiority to clopidogrel could not be demon-
strated in patients with recent ischemic stroke.103
However, clinical use of this combination has been
limited by the occurrence of severe headache, leading
to dipyridamole discontinuation in approximately 6%
of patients.104 The combination of clopidogrel and
dipyridamole has been tested among diabetic pa-
tients with peripheral artery disease, with significant
JACC VOL. 82, NO. 15, 2023
OCTOBER 10, 2023:1538–1557
reductions in ischemic events and stroke or TIA
compared with clopidogrel alone.105 The TARDIS
(Triple Antiplatelets for Reducing Dependency after
Ischaemic Stroke) trial enrolled 3,096 patients with
acute ischemic stroke or TIA (16% from large-artery
disease) to randomly investigate a triple antiplatelet
regimen with aspirin, clopidogrel, and dipyridamole.
The trial was stopped prematurely due to evidence of
increased major bleeding, without any difference in
recurrent ischemic stroke or TIA.106
Overall, these trials suggest benefits of a limited
course of DAPT (ie, up to 90 days) over single anti-
platelet therapy in the acute phase of ischemic stroke,
particularly within the first 21 days from symptom
onset. However, bleeding is a major concern, espe-
cially when antiplatelet drugs are stacked or if tica-
grelor is part of the prescribed regimen; as such, the
risk–benefit ratio for longer durations of DAPT or its
use beyond the acute period is unfavorable.
Various strategies of oral anticoagulation have
been proposed for secondary prevention of non-
cardioembolic ischemic stroke.66 Several randomized
trials have evaluated the use of VKA over aspirin in
patients at high risk of or with acute or recent
ischemic stroke, but yielded neutral or negative re-
sults in the prevention of ischemic events, with
similar or even higher bleeding complications. 107-111
The DATAS II (Dabigatran Following Transient
Ischemic Attack and Minor Stroke) trial randomized
305 patients with minor acute ischemic stroke or TIA
to dabigatran or aspirin, but was not informative due
to the lack of primary endpoint events (ie, symp-
tomatic hemorrhagic transformation) in both arms. 112
More recently, factor XI inhibitors were tested in 2
phase II trials of patients with acute non-
cardioembolic stroke.24 In the PACIFIC-STROKE
(Study to Gather Information About Proper Dosing
and Safety of the Oral FXIa Inhibitor BAY 2433334 in
Patients Following a Recent Non Cardioembolic
Ischemic Stroke Which Occurs When a Blood Clot Has
Formed Somewhere in the Human Body [But Not in
the Heart] Travelled to the Brain) trial (where only
18% of patients had a stroke from large-artery dis-
ease), asundexian did not reduce the incidence of
covert brain infarction or ischemic stroke, but
decreased the risk of a post hoc composite of ischemic
stroke or TIA. 113 In the AXIOMATIC-SSP (A Study on
BMS-986177 for the Prevention of a Stroke in Patients
Receiving Aspirin and Clopidogrel) trial, milvexian
showed a numerical reduction of ischemic stroke with
all but 1 of the tested doses.114 Although specific trials
on strokes from large-artery disease are lacking, these
drugs feature a potentially favorable safety profile
and are promising options for patients with acute
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Greco et al 1549
Antithrombotic Therapy for Ischemic Stroke
ischemic stroke, where the risk of hemorrhagic
transformation is a major concern; however, larger
investigations powered for efficacy and safety are
needed.24
In treatment recommendations, antiplatelet ther-
apy is considered a fundamental component for pa-
tients with stroke related to large-artery
atherosclerosis.115 According to American guidelines,
aspirin is recommended within 24 to 48 hours from
symptoms onset in patients not eligible for throm-
bolysis (Class 1), whereas it is delayed until 24 hours
later for those treated with intravenous alteplase
(Class 1).116 Conversely, ticagrelor and triple anti-
platelet therapy with aspirin, clopidogrel, and dipyr-
idamole are not recommended (Class 3). In patients
with minor noncardioembolic ischemic stroke, DAPT
with aspirin and clopidogrel is recommended within
24 hours and continued for 21 to 90 days (Class 1).116
DAPT with aspirin and clopidogrel should be consid-
ered for 3 months in patients with recent stroke or
TIA and a 70% to 99% intracranial artery stenosis
(Class 2a). DAPT with aspirin and ticagrelor may be
considered for 30 days in patients with acute minor
stroke or high-risk TIA and a 30% or greater intra-
cranial artery stenosis (Class 2b). European guidelines
recommend aspirin, dipyridamole plus aspirin, or
clopidogrel alone in patients with noncardioembolic
ischemic stroke or TIA (Class I).117 Finally, guidelines
from the European Stroke Organisation on the man-
agement of TIA recommend short-term DAPT with
aspirin and clopidogrel in high-risk patients, whereas
DAPT is not recommended over antiplatelet mono-
therapy in those at low risk. 118
Despite significant progress in the field, some
questions remain unanswered, and several ongoing
trials are currently evaluating novel therapeutic ap-
proaches or regimens. The INSPIRES (Intensive
Medical Therapy for High-risk Intracranial or Extra-
cranial Atherosclerosis; NCT03635749) trial is
enrolling patients with acute minor ischemic stroke
or mild TIA to explore different combinations of
antiplatelets and statins.119 The ATAMIS (Antiplatelet
Therapy in Acute Mild-Moderate Ischemic Stroke;
NCT02869009) trial is investigating DAPT with
aspirin and clopidogrel over aspirin alone in patients
with acute ischemic stroke. The EAST (Early Anti-
platelet for Minor Stroke Following Thrombolysis;
NCT05193071) trial is investigating the effectiveness
and safety of early antithrombotic treatment after
intravenous thrombolysis in minor stroke. Two phase
3 trials of factor XI inhibitors are ongoing, namely the
OCEANIC-STROKE (A Study to Learn More About
Asundexian [Also Called BAY2433334] for Prevention
of Ischemic Stroke in Male and Female Participants
1550 Greco et al
Antithrombotic Therapy for Ischemic Stroke
Aged 18 Years and Older Who Already Had Such a
Stroke Due to a Blood Clot That Formed Outside the
Heart and Travelled to the Brain, or Temporary
Stroke-like Symptoms; NCT05686070) with asundex-
ian and the LIBREXIA-STROKE (A Study of Milvexian
in Participants After an Acute Ischemic Stroke or
High-Risk Transient Ischemic Attack; NCT05702034)
with milvexian. The ATIS-NVAF (Optimal Antith-
rombotic Therapy in Ischemic Stroke Patients With
Non-Valvular Atrial Fibrillation and Athero-
thrombosis; NCT03062319) trial is investigating
whether an antiplatelet agent should be added to oral
anticoagulation therapy in patients with both athe-
rothrombotic stroke and atrial fibrillation. In addi-
tion, in the AA-ICAS (Anticoagulation Using
Rivaroxaban on Top of Aspirin in Intracranial Athe-
rostenosis Stenosis; NCT05700266) and CATIS-ICAD
(Combination Antithrombotic Treatment for Preven-
tion of Recurrent Ischemic Stroke in Intracranial
Atherosclerotic Disease; NCT04142125) trials, dual-
pathway inhibition will be compared with DAPT
with aspirin and clopidogrel or to aspirin alone,
respectively, in patients with recent ischemic stroke
or TIA. Finally, the CAPTIVA (Comparison of Anti-
coagulation and Anti-Platelet Therapies for Intracra-
nial Vascular Atherostenosis; NCT05047172) trial will
compare different antithrombotic regimens (ie,
aspirin plus clopidogrel vs aspirin plus ticagrelor vs
aspirin plus low-dose rivaroxaban) in patients with
acute or recent stroke due to an intracranial artery
stenosis. These ongoing trials will help to further
refine our understanding of antithrombotic therapy
for ischemic stroke prevention and may inform future
treatment guidelines.
STROKES FROM SMALL-VESSEL DISEASE
Strokes from small-vessel disease are characterized
by small subcortical infarcts caused by occlusion of
small deep perforating arterioles.120 Although the
pathogenesis is poorly understood, they seem most
frequently caused by lipohyalinosis, a condition
121
linked to multiple factors. Hypertension is the most
relevant risk factor for all stroke subtypes and
particularly for small-vessel disease stroke; behavior
change interventions to control blood pressure and
other modifiable risk factors are critical to reduce
further events and cognitive impairment.43
Evidence for antithrombotic therapy in stroke from
small-vessel disease comes mostly from subgroup
analyses of trials with heterogeneous stroke pop-
ulations, with few dedicated trials (Table 5,
Figure 1). 122-124 In the SPS3 (Secondary Prevention of
Small Subcortical Strokes) trial, adding clopidogrel to
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JACC VOL. 82, NO. 15, 2023
OCTOBER 10, 2023:1538–1557
aspirin in patients with a recent stroke from small-
vessel disease did not reduce recurrent stroke and
was associated with more bleeding and death. 122 The
LACI-2 (Lacunar Intervention-2) was a 2  2 ran-
domized trial that investigated the role of cilostazol
and isosorbide mononitrate in patients with a stroke
from small-vessel disease, showing that both these
drugs were associated with improved clinical out-
comes.124 Small-vessel disease is frequently associ-
ated with cerebral microbleeds, a condition that
makes patients more prone to bleeding with antico-
agulants.125 Consequently, anticoagulation has been
discouraged in recent guidelines, supported by
studies that showed more major bleeding and no
difference in recurrent stroke with warfarin
compared with aspirin.43,109 Whether factor XI in-
hibitors may make a difference is unknown. In
PACIFIC-STROKE, asundexian failed especially in
reducing covert brain infarcts, which are largely due
to small-vessel disease (45% of trial participants). 113
Conversely, there is strong evidence supporting
antiplatelet therapy, especially aspirin. 72,73 A sub-
analysis of the PRASTRO (Prasugrel and Clopidogrel
in Japanese Patients With Ischemic Stroke) trial on
strokes from small-vessel disease showed no signifi-
cant difference in efficacy and safety between pra-
sugrel and clopidogrel. 126 In SOCRATES, where
ticagrelor was not superior to aspirin, stroke from
small-vessel disease was the qualifying diagnosis in
only 29%.75 Although the results of dipyridamole are
conflicting, 78,102,103 2 trials of cilostazol vs placebo
and aspirin (including 74% and 64% patients with
stroke from small-vessel disease, respectively)
showed hints of efficacy and significantly reduced
hemorrhagic events. 79,80 Cilostazol has desirable ef-
fects in small-vessel disease due to its action on
endothelial function on top of the mild antiplatelet
effect.127 In a trial of patients with extensive small-
vessel disease and high risk of intracranial hemor-
rhage, cilostazol was not inferior to aspirin for the
prevention of ischemic events but did not reduce the
risk of hemorrhagic stroke. 81 Cilostazol was more
effective when used long term (ie, >6 months) and in
trials with higher proportions of stroke from small-
vessel disease. 128 A network meta-analysis investi-
gating several regimens and strategies for stroke from
small-vessel disease showed that cilostazol was the
most effective agent.129
Based on data from the CHANCE and POINT trials,
which also included patients with stroke from small-
vessel disease, DAPT with aspirin and clopidogrel
has been indicated in selected patients with stutter-
ing capsular stroke.130 However, the optimal antith-
rombotic regimen is still uncertain, because DAPT
JACC VOL. 82, NO. 15, 2023 Greco et al 1551
OCTOBER 10, 2023:1538–1557 Antithrombotic Therapy for Ischemic Stroke

T A B L E 5 Randomized Clinical Trials of Antiplatelet Therapy in Patients With Stroke From Small-Vessel Disease

SPS3122 LACI-2 124

Sample, n 3,020 363

Population Patients with recent symptomatic stroke from Patients with recent stroke from small-vessel
small-vessel disease identified by magnetic disease identified by magnetic resonance
resonance imaging imaging
NIHSS score in the control arm NR 0
(median)
Time from index event to 62 d 77 d
randomization in the control arm
(median)
Blinded Yes No
Intervention DAPT with aspirin 325 mg once daily and Cilostazol 100 mg twice daily  isosorbide
clopidogrel 75 mg once daily mononitrate 25 mg twice daily
Control Aspirin 325 mg once daily Neither cilostazol nor isosorbide mononitrate
Follow-up 3.4 y (mean) 12 mo
Primary efficacy outcome Ischemic stroke Ischemic stroke, TIA, myocardial ischemia,
cognitive impairment, and dementia
Result HR: 0.92; 95% CI: 0.72-1.16; P ¼ 0.48 Adjusted HR: 0.58; 95% CI: 0.36-0.92; P ¼ NR
Primary safety outcome Major extracranial hemorrhage Systemic or intracranial bleeding
Result HR: 2.15; 95% CI: 1.49-3.11; P < 0.001 2.2% vs 0%

LACI-2 ¼ Lacunar Intervention-2 study; SPS3 ¼ Secondary Prevention of Small Subcortical Strokes Trial; other abbreviations as in Tables 2 and 3.

actually failed in showing a reduction of recurrent
ischemic strokes in patients with small-vessel dis-
ease, and increased major bleeding compared with
aspirin.122,131,132 This evidence is limited to the acute
setting and mainly to high-risk TIA and minor stroke.
However, there is also evidence that prolonged DAPT
with aspirin and clopidogrel increases the risk of
bleeding with no added benefit. 83,89 The TARDIS trial,
which showed no significant differences in recurrent
ischemic stroke or TIA and increased major bleeding
with triple antiplatelet therapy (aspirin, clopidogrel,
and dipyridamole), included 42% of patients with
stroke from small-vessel disease. 106 In a CSPS.com
subgroup analysis (stroke from small-vessel disease
in 49%), DAPT with cilostazol showed significant
benefits on ischemic stroke recurrence and no added
133
bleeding. As noted above, the combination of cil-
ostazol and isosorbide mononitrate showed promise
in patients with stroke from
123,124
disease.
STROKES OF OTHER DETERMINED ETIOLOGY
This category is highly heterogeneous as different
conditions potentially causing ischemic stroke can
be enumerated. There is no standard strategy for
antithrombotic prevention of this stroke subtype,
and the treatment should be selected based on the
specific etiology (Central Illustration).43
while antiplatelet therapy is recommended
certain diseases (eg, moyamoya disease, several
hypercoagulable states, fibromuscular dysplasia, or
carotid web), other conditions (eg, several congen-
ital heart diseases, cancer, or antiphospholipid
syndrome) require anticoagulation for secondary
prevention of ischemic stroke.43 Of note, extracra-
nial carotid or vertebral dissections represent a
relatively common cause of stroke in young
adults.134 The CADISS (Cervical Artery Dissection in
Stroke Study) trial compared 3-month antiplatelet
and anticoagulant regimens in patients with acute
extracranial dissection, showing substantial equi-
poise.135 Accordingly, guidelines recommend either
aspirin or VKA for the first 3 months after an
extracranial dissection (Class 2a).43
PRACTICAL APPROACH
AND CONSIDERATIONS
Primary and secondary prevention of ischemic stroke
necessitates a comprehensive multilevel therapeutic
small-vessel
approach that encompasses lifestyle modifications,
management of cardiovascular risk factors, and spe-
cific interventions.43 In terms of antithrombotic
therapies, several have been investigated and vali-
dated depending on the underlying stroke etiology
(Figure 3).
Established causal associations of cardioembolic
stroke often require specific medical and interven-
tional treatments to remove or mitigate their effects.
Indeed, Atrial fibrillation, for instance, requires long-term
for anticoagulation in the majority of patients and, in
selected cases, left atrial appendage closure.136,137
DOACs have become the preferred preventive

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1552 Greco et al JACC VOL. 82, NO. 15, 2023

Antithrombotic Therapy for Ischemic Stroke OCTOBER 10, 2023:1538–1557

F I G U R E 3 Antithrombotic Prevention Strategies After Ischemic Stroke

Small-Vessel
Cardioembolic Cryptogenic Large-Artery Atherosclerosis
Disease

Nonvalvular Stroke and

AF DOAC 50%-99% Aspirin 325
stenosis mg
Valvular AF
ESUS Small-vessel
(MS or any mechanical
Cilostazol disease
valve) Warfarin
(INR 2.0-3.0)
SAPT Recent
Nonrheumatic (aspirin) DAPT (A+C)
stroke and for up to Cilostazol
mitral and 70%-99%
Intracranial 3 months
aortic valve stenosis
atherosclerotic
disease
SAPT disease Long-term
aspirin

Mechanical
mitral Acute minor DAPT (A+T)
valve Warfarin
Valvular stroke and for up to
(INR 2.5-3.5)
disease >30% stenosis 30 days
and aspirin
Long-term
aspirin
Mechanical
Warfarin
aortic valve Vertebral
(INR 2.5-3.5)
and aspirin stenosis
SAPT
Carotid
Bioprosthetic stenosis (not
mitral and revascularized)
aortic valve SAPT
SAPT (aspirin) Class 1 (strong)

Extracranial DAPT (A+C) Benefit >>> Risk

Carotid
atherosclerotic artery for at least
disease
Class 2a (moderate)
LV/LA Warfarin for at stenting 30 days
thrombus least 3 months Benefit >> Risk
Long-term
SAPT Class 2b (weak)
PFO closure
PFO (<60 Y/o) and Carotid Benefit ≥ Risk
APT endarterectomy
SAPT

This algorithm for the choice of antithrombotic prevention strategies according to etiological subtypes in patients with ischemic stroke is based on the 2021 American
Heart Association/American Stroke Association guidelines on the prevention of stroke in patients with stroke and transient ischemic attack.43 A ¼ aspirin; AF ¼ atrial
fibrillation; APT ¼ antiplatelet therapy; C ¼ clopidogrel; DAPT ¼ dual antiplatelet therapy; DOAC ¼ direct oral anticoagulant; ESUS ¼ embolic stroke of undetermined
source; INR ¼ international normalized ratio; LA ¼ left atrium; LV ¼ left ventricle; MS ¼ mitral stenosis; PFO ¼ patent foramen ovale; SAPT ¼ single antiplatelet
therapy; T ¼ ticagrelor.

treatment in the absence of absolute contraindica-
tions, 14-17 with VKA remaining an alternative for pa-
tients with absolute or relative contraindications to
DOACs. 138 Heart failure with
thrombus is another important cause of embolic
stroke, and oral anticoagulation is indicated with an
individualized duration based on the relationship
with acute myocardial infarction, thrombus recur-
rence, and risk conditions for
thrombus.139 Prosthetic mechanical heart valves and
rheumatic heart disease with moderate-to-severe
mitral stenosis are also associated with thromboem-
bolism and require long-term anticoagulation. 33 In
these cases, VKA are recommended due to the higher
risk of events associated with DOACs for primary
stroke prevention. 19 Less common cardiac conditions
at high risk for cerebral embolism, such as endo-
left ventricular carditis, atrial myxoma, and papillary fibroelastoma,
may require surgical treatment to remove the source
of cardioembolism. 38
ESUS is likely the most challenging pattern. The
reasons for the absence of favorable effects of oral
left ventricular anticoagulation in trials comparing DOACs with an-
tiplatelet therapy are multifactorial.61-63 A substantial
proportion of ESUS patients may have multiple
embolic sources, some of which are more responsive
to antiplatelet therapy than oral anticoagulation.
Thus, patients with ESUS should not be treated

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JACC VOL. 82, NO. 15, 2023 Greco et al 1553
OCTOBER 10, 2023:1538–1557 Antithrombotic Therapy for Ischemic Stroke

empirically with oral anticoagulation, and mono-
therapy with aspirin continues to be recommended
over other treatments.43
For patients with ischemic stroke and no other
plausible explanation other than patent foramen
ovale, transcatheter closure can be an effective
treatment, particularly when the risk of stroke by
paradoxical embolism is high, with a significant
reduction of events compared with antithrombotic
therapy.49-55,140
Stroke recurrence is particularly high within the
first year after a stroke from large-artery disease. 6,116
To minimize this risk, antiplatelet therapy is gener-
ally recommended, whereas oral anticoagulation is
not recommended unless there is a clear association
between stroke and thromboembolic
tions. 109,116 After brain imaging has excluded intra-
cranial hemorrhage, aspirin should be administered
within 24 to 48 hours after symptom onset.116
The highest benefit of DAPT is limited to the first
few weeks following ischemic stroke, as subsequent
major bleedings outweigh the reduced incidence of
recurrent ischemic events.82,85,89,90 Conversely,
DAPT is not recommended for thromboembolic pat-
terns. 43 In patients with symptomatic intracranial
artery disease and TIA or minor stroke, short-term
DAPT with aspirin and clopidogrel followed by
aspirin monotherapy is recommended.85,89,141 For
early-presenting minor stroke not undergoing
thrombolysis or thrombectomy, short-term DAPT
with aspirin and ticagrelor may be a reasonable
option.92
The rationale for using aspirin is also strong for
aortic arch, cervical, or intracranial atherosclerosis,
carotid artery stenting, or endoarterectomy. 43,116
Although there is evidence that clopidogrel mono-
therapy may be more effective than aspirin in these
settings, there is still a lack of focused high-quality
evidence. 68,142 In patients with symptomatic carotid
atherosclerosis, intensive medical therapy
revascularization (either surgical or endovascular) are
recommended.43 After carotid artery stenting, short-
term DAPT with aspirin and clopidogrel is the stan-
pathophysiology. Antiplatelet agents are generally
recommended, but their effectiveness in preventing
recurrent events has been questioned. In this context,
cilostazol has emerged as a potential treatment op-
tion due to multiple desirable effects that go beyond
antithrombotic protection. 43 However, further
research is needed to determine the optimal antith-
rombotic therapy for stroke from small-vessel
disease.
Cancer- and hypercoagulable state–related strokes
pose therapeutic issues due to the broader spectrum
of mechanisms causing cerebral ischemia and the
heterogeneous variants of the diseases.144 Addition-
ally, frailty and bleeding risk conditions can be more
common in these settings, which has therapeutic
condi- implications. The treatment of the original diseases
and monotherapy (ie, with either aspirin or an oral
anticoagulant depending on the specific etiology) are
generally the most reasonable approaches for long-
term secondary prevention.43
CONCLUSIONS
Selecting the optimal antithrombotic therapy for pri-
mary and secondary prevention of ischemic stroke
requires careful consideration of the risks and bene-
fits of antithrombotic therapies. The use of anti-
platelet or anticoagulant regimens for the secondary
prevention of ischemic stroke strongly depends on
the underlying etiology. The emergence of novel
therapeutic agents such as factor XI inhibitors may
provide additional options for ischemic stroke pre-
vention, but further research is needed to fully eval-
uate their efficacy and safety. Overall, the
management of ischemic stroke requires a personal-
ized approach that considers the individual patient’s
clinical characteristics, comorbidities, and
preferences.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
and
Prof Capodanno has received speaker honoraria from Daiichi-Sankyo
and Sanofi. All other authors have reported that they have no re-
lationships relevant to the contents of this paper to disclose.

dard antithrombotic strategy.143 However, DAPT is

not recommended for primary and long-term sec- ADDRESS FOR CORRESPONDENCE: Prof Davide
ondary ischemic stroke prevention in all other set- Capodanno, Division of Cardiology, Azienda
tings of intracranial and extracranial artery disease.43 Ospedaliero-Universitaria Policlinico “G. Rodolico–
Antithrombotic therapy for stroke from small- San Marco,” Via Santa Sofia, 78-95123 Catania, Italy.
vessel disease remains a matter of debate due to E-mail: dcapodanno@unict.it. @DFCapodanno,
the uncertainty regarding the underlying @AGrecoMD.

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1554 Greco et al
Antithrombotic Therapy for Ischemic Stroke
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KEY WORDS anticoagulation, antiplatelet
therapy, antithrombotic therapy, prevention,
stroke