Antithrombotic Therapy to Prevent Recurrent Strokes in Ischemic Cerebrovascular Disease

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 74, NO. 6, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE JACC SCIENTIFIC EXPERT PANEL

Antithrombotic Therapy to Prevent Recurrent Strokes in Ischemic Cerebrovascular Disease JACC Scientific Expert Panel Victor J. Del Brutto, MD,a Seemant Chaturvedi, MD,b Hans-Christoph Diener, MD, PHD,c Jose G. Romano, MD,a Ralph L. Sacco, MD, MSa ABSTRACT Stroke survivors carry a high risk of recurrence. Antithrombotic medications are paramount for secondary prevention and thus crucial to reduce the overall stroke burden. Appropriate antithrombotic agent selection should be based on the best understanding of the physiopathological mechanism that led to the initial ischemic injury. Antiplatelet therapy is preferred for lesions characterized by atherosclerosis and endothelial injury, whereas anticoagulant agents are favored for cardiogenic embolism and highly thrombophilic conditions. Large randomized controlled trials have provided new data to support recommendations for the evidence-based use of antiplatelet agents and anticoagulant agents after stroke. In this review, the authors cover recent trials that have altered clinical practice, cite systematic reviews and meta-analyses, review evidence-based recommendations based on older landmark trials, and indicate where there are still evidence-gaps and new trials being conducted. (J Am Coll Cardiol 2019;74:786–803) © 2019 by the American College of Cardiology Foundation.

T

remendous strides have been made in the

due to intracranial atherosclerotic disease (ICAD);

management of cerebrovascular disorders.

25% due to small vessel disease (SVD); 5% from other

Ischemic stroke is more challenging to treat

determined causes; and 25%, labeled cryptogenic,

than coronary artery disease due to the variety of

without a definite understanding of the cause

mechanisms that can lead to cerebral ischemia.

(Figure 1). Some of the latter have been classified as

Stroke subtypes include: 25% due to cardioembolism;

embolic strokes of undetermined source (ESUS)

10% due to extracranial atherosclerotic disease; 10%

where the cause could be an under-recognized

From the aDepartment of Neurology, University of Miami, Miller School of Medicine, Miami, Florida; bDepartment of Neurology, University of Maryland, Baltimore, Maryland; and the cInstitute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Dr. Chaturvedi has received grant support from Boehringer Ingelheim. Dr. Diener has received honoraria for participation in clinical trials, contribution to Advisory Boards, or oral presentations from Abbott, Achelios, Allergan, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daiichi-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Merck Sharp & Dohme, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo Nordisk, Paion, Parke-Davis, Pfizer, Portola, Sanofi, Schering Plough, Servier, Solvay, St. Jude, Syngis, Talecris, Thrombogenics, WebMD Global, and Wyeth; has received financial Listen to this manuscript’s

support for research projects from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag,

audio summary by

Sanofi, Syngis, and Talecris; has served as editor of Neurology International Open, Aktuelle Neurologie, and Arzneimitteltherapie,

Editor-in-Chief

as coeditor of Cephalalgia, and on the editorial board of Lancet Neurology, Current Neurology and Neuroscience Reports, European

Dr. Valentin Fuster on

Neurology, and Cerebrovascular Disorders; and has served as chair of the Treatment Guidelines Committee of the German Society

JACC.org.

of Neurology and contributed to the EHRA and ESC guidelines for the treatment of AF. Dr. Romano receives salary support (to the Department of Neurology at the University of Miami) from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke Multiple Program Director/Principal Investigator (PD/PI) Award (1R01NS084288). Dr. Sacco has received institutional grant support from the NIH, the American Heart Association, and Boehringer Ingelheim. Dr. Del Brutto has reported that he has no relationships relevant to the contents of this paper to disclose. Manuscript received April 7, 2019; revised manuscript received June 11, 2019, accepted June 24, 2019.

ISSN 0735-1097/$36.00

https://doi.org/10.1016/j.jacc.2019.06.039

Del Brutto et al.

JACC VOL. 74, NO. 6, 2019 AUGUST 13, 2019:786–803

AND ACRONYMS

let agents are the therapy of choice to reduce


23% of all ischemic strokes are recurrent events.
Antithrombotic agents are part of a comprehensive risk factor management strategy to prevent stroke recurrence.
Contemporary trials guide management in common stroke causes. However, data for less common stroke etiologies are limited.
Ongoing trials aim to clarify the efficacy of novel pharmacological approaches to reduce stroke recurrence. cardiac source or a nonstenosing arterial lesion (1). Diagnostic imaging of the brain, arteries, and heart have enhanced our ability to identify the most likely mechanism of injury. The immediate period after stroke has been the target of time-sensitive therapies including thrombolysis and endovascular thrombectomy. Beyond this stage, therapeutic goals are to reduce the risk of stroke recurrence and prevent medical complications. The pattern of recurrence varies by stroke subtype, being the highest for large-artery atherosclerosis (LAA) in the early phase, whereas for cardioembolic strokes, the long-term risk is steadily high and is associated with higher mortality (2,3). In addition, particular mechanisms of injury such as SVD presenting with capsular warning syndrome are characterized by early neurodeterioration

(4).

Antithrombotic

agents

contribute to preventing recurrent stroke and vascular events after an ischemic stroke. In this paper, we review the latest evidence for the use of antithrombotic agents in patients who have symptomatic cerebrovascular disease. We organized our discussion on the basis of the likely etiology of the initial stroke. Our aims were to cover recent trials that have altered clinical practice, cite systematic reviews and meta-analyses, review evidence-based recommendations, and indicate where there are still unanswered

ABBREVIATIONS

After noncardioembolic stroke, antiplate-

HIGHLIGHTS

logical

questions

and

new

trials

being

conducted.

recurrent stroke (Table 1). Anticoagulation

AF = atrial fibrillation

has not been found to be superior to anti-

APLS = antiphospholipid

platelet agents and increases the risk of

syndrome

hemorrhagic complications (5). Aspirin is

ARR = absolute risk reduction

widely available and has well-documented efficacy

in

preventing

stroke

CAD = cervical arterial

recurrence

dissection

(6–8). Dipyridamole is a phosphodiesterase

CAS = carotid artery stenting

inhibitor often used in combination with

CEA = carotid endarterectomy

aspirin that has been demonstrated to reduce

CVT = cerebral venous

stroke recurrence when compared with pla-

thrombosis

cebo (9). In addition, a meta-analysis found

DAPT = dual antiplatelet

that aspirin-dipyridamole was superior to

therapy

aspirin alone in preventing major vascular

DOAC = direct oral

events after stroke (10). Notably, aspirin-

anticoagulant agent

dipyridamole has a high discontinuation

ESUS = embolic stroke of

rate, largely due to headaches (9,10). Clopi-

undetermined source

dogrel inhibits the adenosine diphosphate

ICAD = intracranial atherosclerotic disease

receptor resulting in platelet antiaggregation.

ICH = intracerebral

Clopidogrel has not been compared with

hemorrhage

placebo in secondary stroke prevention. Two

INR = international normalized

large randomized controlled trials (RCTs)

ratio

demonstrated benefits of clopidogrel when

LAA = large-artery

compared with aspirin, and the similarity

atherosclerosis

between clopidogrel and the combination of

LMWH = low-molecular-

aspirin and dipyridamole (11,12). For long-

weight heparin

term prevention of stroke recurrence, dual

MI = myocardial infarction

antiplatelet therapy (DAPT) with aspirin plus

NNT = number needed to treat

clopidogrel has not demonstrated benefit and

PFO = patent foramen ovale

led to significantly increased hemorrhagic

RCT = randomized controlled

complications (13–15); whereas 2 recent RCTs

trial

showed DAPT is beneficial in the short term

SVD = small vessel disease

after transient ischemic attack (TIA) and mi-

TIA = transient ischemic attack

nor ischemic stroke (see the following text)

VKA = vitamin K antagonist

(16,17). Cilostazol is a phosphodiesterase-3 inhibitor with vasodilatory as well as antiplatelet effects. A Japanese RCT showed that cilostazol was noninferior to aspirin in preventing stroke recurrence after noncardioembolic stroke and was associated with fewer hemorrhagic complications (18). Similar to clopidogrel, ticagrelor acts on the platelet P2Y 12 pathway, but ticagrelor reversibly binds to the P2Y 12 receptor and is direct acting, whereas clopidogrel requires metabolic activation. In patients with history of

GENERAL CONSIDERATIONS REGARDING

stroke or TIA, ticagrelor was not different than

SELECTION AMONG ANTITHROMBOTIC AGENTS

clopidogrel in preventing vascular events (19). Other antiplatelet agents are almost never used due to

Antithrombotic agents are part of a comprehensive risk factor management strategy to prevent short-

their adverse effect profile or unproven efficacy. Antiplatelet selection should be based on known

and long-term recurrence after stroke and include

efficacy,

safety,

anticoagulant

Current

guidelines

agents.

agents

787

Antithrombotic Agents in Secondary Stroke Prevention

and

platelet

antiaggregant

cost,

and

patient

recommend

preference.

aspirin

mono-

therapy, the combination aspirin-dipyridamole, or

788

Del Brutto et al.

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Antithrombotic Agents in Secondary Stroke Prevention

F I G U R E 1 Prevalence of Stroke Subtypes

(A) Small vessel disease: brain magnetic resonance imaging showing an acute left internal capsule lacunar infarct (<20 mm) on diffusion-weighted imaging (DWI) sequence. (B) Intracranial atherosclerotic disease: cerebral angiogram and computed tomography angiogram showing left middle cerebral artery stenosis (>90%) (arrow) associated with acute infarct on left insula. (C) Extracranial atherosclerotic disease: cerebral angiogram showing right middle cerebral artery occlusion associated with severe stenosis of ipsilateral cervical internal carotid (arrow). (D) Cardioembolic stroke: left frontal cortical infarct on DWI sequence associated with atrial fibrillation on electrocardiogram. (E) Other determined causes of stroke: dissection of the left cervical internal carotid artery (arrows) associated with ischemic stroke on the left frontal lobe. (F) Cryptogenic stroke: right frontal cortical infarct on DWI sequence with no definite cardioembolic source based on cardiac monitoring or echocardiography, and no evidence of large-artery steno-occlusive disease.

clopidogrel after noncardioembolic stroke. Clopi-

Cardioembolic strokes occur primarily in patients

dogrel is recommended in the setting of aspirin al-

with atrial fibrillation (AF), valvular heart disease,

lergy

for

and cardiomyopathies predisposing to intracardiac

patients who have stroke while on appropriate

thrombus formation and are prevented with anti-

therapy has been poorly studied. On the basis of

coagulation. Vitamin K antagonists (VKA) such as

platelet function testing, one-third of patients on

warfarin have been available for almost a century and

aspirin or clopidogrel are deemed to be non-

are the anticoagulant agents most commonly pre-

responders. However, therapy modification in this

scribed worldwide. The newer direct oral anticoagu-

subset of patients resulted in no benefit (21). More

lant agents (DOAC) include direct thrombin inhibitors

recently, a systematic review showed that the

(dabigatran) and factor Xa inhibitors (rivaroxaban,

addition of or a switch to another antiplatelet agent

apixaban, edoxaban). In contrast to VKA, DOACs do

in patients with “aspirin failure” was associated

not require coagulation monitoring, have no food

with fewer vascular events (22). These results,

interactions, and only few drugs interactions. The

however, require confirmation.

role of anticoagulant agents after cardioembolic

(20).

Antithrombotic

agent

selection

Del Brutto et al.

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Antithrombotic Agents in Secondary Stroke Prevention

T A B L E 1 Major Trials in Long-Term Secondary Prevention After Noncardioembolic Stroke

Intervention

Follow-Up

Primary Endpoint

IST (7)

Study (Ref. #)

Ischemic stroke with onset <48 h

Population

19,435

N

Aspirin vs. avoid aspirin

6 months

Mortality at 14 days Mortality, dependence, or incomplete recovery at 6 months

9.0% vs. 9.4% 62.2% vs. 63.5%

NS ARR ¼ 1.3% NNT ¼ 77

CAST (8)

Ischemic stroke with onset <48 h

21,106

Aspirin vs. placebo

4 weeks

Death or nonfatal stroke at 4 weeks

5.3% vs. 5.9%

ARR ¼ 0.7% NNT ¼ 153

ATT Collaboration meta-analyses (6)

Previous stroke or TIA

6,170 (10 trials)

Aspirin vs. control

—

6.78%/yr vs. 8.06%/yr 3.9%/yr vs. 4.7%/yr

ARR ¼ 1.3% NNT ¼ 78 ARR ¼ 1.7% NNT ¼ 128

WARSS (5)

Ischemic stroke within 30 days

2,206

Warfarin vs. aspirin

2 yrs

Death and recurrent ischemic strokes

17.8% vs. 16%

NS

ESPS-2 (9)

Ischemic stroke or TIA in last 3 months

6,602

Aspirin vs. placebo Dipyridamole vs. placebo Aspirin-dipyridamole vs. placebo

2 yrs

Stroke recurrence

12.5% vs. 15.2% 12.8% vs. 15.2% 9.5% vs. 15.2%

ARR ¼ 2.7% NNT ¼ 37 ARR ¼ 2.4% NNT ¼ 42 ARR ¼ 5.7% NNT ¼ 18

ESPRIT (10)

Minor ischemic stroke or TIA in prior 6 months

2,739

Aspirin-dipyridamole vs. aspirin

3.5 yrs

Vascular mortality, nonfatal stroke, nonfatal MI, or nonfatal major bleeding

12.7% vs. 15.7%

ARR ¼ 3% NNT ¼ 33

CAPRIE (11)

Subgroup: ischemic stroke onset $1 week and #6 months

6,431

Clopidogrel vs. aspirin

1.9 yrs

Ischemic stroke, MI, or vascular death

7.2% vs. 7.7%

NS

PRoFESS (12)

Ischemic stroke in prior 90 days

20,332

Aspirin-dipyridamole vs. clopidogrel

2.5 yrs

Stroke recurrence

9.0% vs. 8.8%

NS

MATCH (13)

Ischemic stroke within 3 months and $1 additional cardiovascular risk factor

7,599

Aspirin/clopidogrel vs. clopidogrel

18 months

16% vs. 17%

NS

SPS3 (14)

Lacunar stroke in prior 6 months

3,020

Aspirin/clopidogrel vs. aspirin/ placebo

3.4 yrs

2.7%/yr vs. 2.5%/yr

NS

CHARISMA (15)

Subgroup: diagnosis of stroke or TIA

4,320

Clopidogrel/aspirin vs. placebo/ aspirin

28 months

Stroke recurrence

4.8% vs. 6%

NS

CSPS-2 (18)

Ischemic stroke in previous 26 weeks

2,757

Cilostazol vs. aspirin

29 months

Stroke recurrence

6.1% vs. 8.9%

ARR ¼ 2.9% NNT ¼ 36

PLATO (19)

Subgroup: patients with acute coronary syndrome with history of stroke or TIA

1,152

Ticagrelor vs. clopidogrel

Stroke, MI, vascular death

19% vs. 20.8%

NS

1 yr

Serious vascular events (stroke, MI, or vascular death) Any stroke

Ischemic stroke, MI, vascular death, or hospitalization for acute ischemic event Incident stroke

Results

ARR ¼ absolute risk reduction; ATT ¼ Antithrombotic Trialists; CAPRIE ¼ Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events; CAST ¼ Chinese Acute Stroke Trial; CHARISMA ¼ Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance; CSPS-2 ¼ Cilostazol for prevention of secondary stroke; ESPRIT ¼ European/Australasian Stroke Prevention in Reversible Ischemia Trial; ESPS-2 ¼ European Stroke Prevention Study-2; IST ¼ International Stroke Trial; MATCH ¼ Management of Atherothrombosis With Clopidogrel in High-Risk Patients; MI ¼ myocardial infarctions; NNT ¼ number needed to treat; NS ¼ nonsignificant; PLATO ¼ Platelet inhibition and patient outcomes; PRoFESS ¼ Prevention Regimen for Effectively Avoiding Second Strokes; SPS3 ¼ Secondary Prevention of Small Subcortical Strokes; TIA ¼ transient ischemic attack; WARSS ¼ Warfarin versus Aspirin Recurrent Stroke Study.

strokes and other thrombophilic conditions is dis-

compared with placebo (number needed to treat

cussed in the following text.

[NNT] ¼ 77) (7,8). As a result, initiation of aspirin within 48 h of an ischemic stroke is recommended.

ACUTE ISCHEMIC STROKE AND

Two recent RCTs have evaluated DAPT in acute

TRANSIENT ISCHEMIC ATTACK

cerebral ischemia (15,16). Conducted exclusively in China, the CHANCE (Clopidogrel in High-Risk Pa-

Immediately after ischemic stroke or TIA, there is a

tients With Acute Non-disabling Cerebrovascular

major opportunity to institute treatments that can

Events) trial included patients with high-risk TIA or

prevent stroke recurrence. Within 48 h of an event,

minor stroke within 24 h of onset (16). Subjects in the

aspirin provides benefit compared with placebo. In 2

DAPT arm received a 300-mg loading dose of clopi-

large RCTs that enrolled more than 40,000 patients,

dogrel followed by 75 mg daily for 90 days along with

there was a 1.3% absolute risk reduction (ARR) in the

aspirin 75 mg daily during the first 21 days, whereas

rate of death and disability at 6 months with aspirin

the control group received aspirin alone through

790

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Antithrombotic Agents in Secondary Stroke Prevention

90 days. Stroke recurrence was 8.2% with DAPT

The

SOCRATES

(Acute

Stroke

or

Transient

compared with 11.7% with aspirin (ARR ¼ 3.5%;

Ischemic Attack Treated With Aspirin or Ticagrelor

NNT ¼ 29). In a time-course analysis, stroke reduction

and Patient Outcomes) trial enrolled 13,199 patients

with DAPT was primarily seen in the first 10 days,

with high-risk TIA or mild stroke from 33 countries

whereas the risk of any bleeding (although not sta-

(28). Subjects received a 180-mg loading dose of

tistically significant) was constant during 21 days of

ticagrelor (followed by 90 mg twice daily) or aspirin

DAPT (23). Because stroke subtype distribution (i.e.,

300-mg loading dose (followed by 100 mg daily).

higher prevalence of LAA), as well as the prevalence

Within 90 days, the endpoint of stroke, MI, or death

of

occurred in 6.7% of patients receiving ticagrelor and

genetic

polymorphisms

affecting

clopidogrel

metabolism, differ in China compared with other

7.5% receiving aspirin (p ¼ 0.07), and ischemic

populations, there was uncertainty about generaliz-

stroke occurred in 5.8% patients treated with tica-

ability to non-Chinese patients (24,25).

grelor and 6.7% with aspirin (p ¼ 0.046). No differ-

The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial studied early

ence in bleeding complications was seen among groups.

DAPT in a broader population with mild stroke or

In synthesizing the recent data, short-term DAPT

high-risk TIA (17). Candidates for reperfusion in-

with aspirin plus clopidogrel initiated within 24 h is

terventions, as well as those with carotid stenosis

beneficial for patients with recent TIA or minor stroke

eligible for endarterectomy were excluded. Including

(Table 2), whereas antiplatelet monotherapy is rec-

10 countries, 4,881 patients were enrolled within 12 h

ommended after moderate-to-severe strokes due to

of symptom onset. Patients assigned to DAPT

the potential risk of hemorrhagic transformation. The

received a 600-mg loading dose of clopidogrel, fol-

role of ticagrelor remains the subject of an ongoing

lowed by 75 mg daily. All patients received aspirin (50

RCT (29), which aims to compare ticagrelor combined

to 325 mg). During 90-day follow-up, the primary

with aspirin versus aspirin alone in preventing stroke

endpoint of stroke, myocardial infarction (MI), or

and death after a mild ischemic stroke or high-risk

vascular death occurred in 5% of patients receiving

TIA.

DAPT

and

in

6.5%

receiving

aspirin

alone

(ARR ¼ 1.5%; NNT ¼ 66). Ischemic stroke was also

LARGE-ARTERY ATHEROSCLEROSIS

reduced among patients receiving DAPT (4.6% vs. 6.3%; ARR ¼ 1.7%; NNT ¼ 59). Major hemorrhage was

INTRACRANIAL ATHEROSCLEROTIC DISEASE. ICAD

increased with DAPT compared with aspirin alone

is more prevalent among Asians, Blacks, and His-

(0.9% vs. 0.4%; p ¼ 0.02), but there was no increase

panics, thus is likely the most common vascular

in symptomatic intracerebral hemorrhage (ICH). The

lesion in stroke patients worldwide (30). Even with

event rate was lower than expected, particularly

intensive medical management, individuals with

among patients with TIA, which could be partially

ICAD and high-grade stenosis have a 30-day and

explained by the inclusion of mimics and low-risk

1-year risk of stroke recurrence of 5% and 15%,

patients (17).

respectively (31).

Different time windows were analyzed in the

Anticoagulation was found not to be safe in

POINT trial, and a divergent pattern emerged for

symptomatic ICAD. The WASID (Warfarin-Aspirin

ischemic and hemorrhagic outcomes. Prevention of

Symptomatic Intracranial Disease) trial compared

ischemic events on DAPT was statistically significant

aspirin 1,300 mg daily versus warfarin in individuals

at both 7 days and 30 days. However, major

with stroke or TIA within 90 days due to ICAD (50% to

bleeding was not different at 7 days but signifi-

99% stenosis) (32). The study was stopped early due

cantly increased in days 8 to 90. Given the finding

to excess major hemorrhage (8.3% vs. 3.2%; p ¼ 0.01)

from the CHANCE trial that 3 weeks of DAPT

and death (9.7% vs. 4.3%; p ¼ 0.02) in the warfarin

reduced stroke without an increase in major hem-

arm. With 569 participants followed for 1.8 years, the

orrhagic events, some have argued that 3 weeks

primary endpoint of ischemic stroke, brain hemor-

represents the “sweet spot” to optimize benefits

rhage and vascular death occurred in 22% in both

and reduce risks. A recent meta-analysis also found

groups.

that 3 weeks of DAPT appears to provide the

The SAMMPRIS (Stenting and Aggressive Medical

optimal balance of stroke reduction and bleeding

Management for Preventing Recurrent Stroke in

avoidance (26). More intensive antiplatelet regimen

Intracranial Stenosis) trial was designed to assess

with 3 combined agents (aspirin, clopidogrel, and

endovascular therapy in symptomatic ICAD (31). In-

dipyridamole) showed no benefit over guideline-

dividuals with ICAD (70% to 99% stenosis) within

based therapy (27).

30 days from an index stroke or TIA were randomized

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791

Antithrombotic Agents in Secondary Stroke Prevention

T A B L E 2 Suggested Recommendations on Antithrombotic Therapies for Secondary Prevention in Patients With Common Causes of Cerebral Ischemia

Recommendation

Class* Level†

Endpoint

Results

90 days

Stroke recurrence

8.2% vs. 11.7%

ARR ¼ 3.5% NNT ¼ 29

POINT (17)

Aspirin/clopidogrel vs. aspirin

90 days

Ischemic stroke, MI, or vascular death

5.0% vs. 6.5%

ARR ¼ 1.7% NNT ¼ 59

A

SPS3 (14)

Aspirin/clopidogrel vs. aspirin/ placebo

3.4 yrs

Incident stroke Safety: major hemorrhages

2.5%/yr vs. 2.7%/yr 2.1%/yr vs. 1.1%/yr

NS ARI ¼ 3.2% NNH ¼ 31

III

A

WASID (32)

Warfarin vs. aspirin

36 months

Ischemic stroke, ICH, or vascular death Safety: death

21.8% vs. 22.1% 9.7% vs. 4.3%

NS ARI ¼ 5.4% NNH ¼ 19

DAPT for 90 days in severe stenosis (70%-99%) might be reasonable§

IIb

B

SAMMPRIS (33)

PTAS plus aggressive medical therapy vs. aggressive medical therapy only

32 months

Stoke or death

23% vs. 15%

ARI ¼ 8.2% NNH ¼ 12

Low-dose aspirin is recommended before CEA and may be continued indefinitely

I

A

ACE (48)

Low-dose (81–325 mg) vs. high-dose (650–1,300 mg) aspirin

3 months

Stroke, MI, or death

6.2% vs. 8.4%

ARR ¼ 2.1% NNT ¼ 46

DAPT for at least 30 days after CASk

I

C

McKevitt et al.(52)

Aspirin/clopidogrel vs. 24 h heparin plus aspirin

30 days

Neurological complications

0% vs. 25%

ARR ¼ 25% NNT ¼ 4

Long-term anticoagulation for AF¶

I

A

EAFT (62)

Anticoagulation vs. placebo

2.3 yrs

Stroke, MI, systemic embolism, or vascular death

8%/yr vs. 17%/yr

ARR ¼ 12.2% NNT ¼ 8

DOACs are favored over warfarin in DOAC-eligible patients¶

I

A

Ntaios 2017 et al. (meta-analysis) (69)

DOAC vs. warfarin

1.8 to 2.8 yrs

Stroke or systemic embolism Safety: intracranial hemorrhage

4.9% vs. 5.7% 1.0% vs. 1.9%

ARR ¼ 0.8%; NNT ¼ 127 ARR ¼ 0.9% NNT ¼ 133

DOACs are not recommended over antiplatelets‡

III

A

NAVIGATE-ESUS (80)

Rivaroxaban vs. aspirin

11 months

Stroke or systemic embolism Safety: major bleeding

5.1%/yr vs. 4.8%/yr 1.8%/yr vs. 0.7%/yr

NS ARI ¼ 1.1% NNH ¼ 92

Dabigatran vs. aspirin

19 months

Stroke recurrence Safety: major bleeding

4.1%/yr vs. 4.8%/yr 1.7%/yr vs. 1.4%/yr

NS NS

II

SVD

Long-term DAPT is not recommended§

III

ICAD

Anticoagulation is not recommended over antiplatelet therapy§

ESUS

Follow-Up

Aspirin/clopidogrel vs. aspirin

DAPT within 24 h of onset and continuation for 21 days‡

AF

Intervention

CHANCE (16)

Acute minor stroke or TIA

ECAD

Relevant Studies (Ref. #)

A

RESPECTESUS (81)

*Class of recommendation: I ¼ benefit outweigh risk (strong); IIa ¼ benefit outweigh risk (moderate); IIb ¼ benefit might outweigh risk (weak); and III ¼ no benefit or harm. †Level of Evidence: A ¼ highquality evidence from meta-analyses or high-quality randomized controlled trials; B ¼ moderate-quality evidence, data from single randomized control trial or nonrandomized studies; and C ¼ limited data or expert opinion. ‡Our interpretation based on new evidence released after the publication of pertinent guidelines. §2014 Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association (20). k2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease (50). ¶2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation (61). ACE ¼ Aspirin and Carotid Endarterectomy Trial; AF ¼ atrial fibrillation; ARI ¼ absolute risk increase; ARR ¼ absolute risk reduction; CAS ¼ carotid artery stenting; CEA ¼ carotid endarterectomy; CHANCE ¼ Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events; DOACs ¼ direct oral anticoagulant agents; DAPT ¼ dual antiplatelet therapy; EAFT ¼ European Atrial Fibrillation Trial; ECAD ¼ extracranial atherosclerotic disease; ESUS ¼ embolic stroke of undetermined source; ICAD ¼ Intracranial atherosclerotic disease; NAVIGATE-ESUS ¼ New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus Aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source; NNH ¼ number needed to harm; POINT ¼ Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke; PTAS ¼ percutaneous transluminal angioplasty and stenting; RESPECT-ESUS ¼ Randomized, Double-blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran versus Aspirin in Patients with Embolic Stroke of Undetermined Source; SAMMPRIS ¼ Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis; SPS3 ¼ Secondary Prevention of Small Subcortical Strokes; WASID ¼ Warfarin-Aspirin Symptomatic Intracranial Disease; other abbreviations as in Table 1.

to best medical therapy with or without stenting

(5.8%) (p ¼ 0.002). The primary outcome of stroke

(Wingspan system, Stryker Neurovascular, Fremont,

and death remained better for the medical arm during

California; formerly Boston Scientific Neurovascular).

prolonged follow-up (15% vs. 23%; p ¼ 0.025) (33).

Best medical therapy included DAPT with aspirin and

Better outcomes in the medical arm of the

clopidogrel for 90 days followed by aspirin alone,

SAMMPRIS trial compared with historical controls

aggressive management of blood pressure, lipids and

have been attributed to statins, aggressive risk factor

other vascular risk factors, and a lifestyle modifica-

control, and the use of DAPT (34). Therefore, data

tion program. The study was discontinued due to a

from the SAMMPRIS trial has been extrapolated to

higher 30-day rate of stroke and death in the endo-

support the use of DAPT in ICAD. A subanalysis of the

vascular arm (14.7%) compared with the medical arm

CHANCE trial showed no significant benefit in 90-day

792

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Antithrombotic Agents in Secondary Stroke Prevention

stroke reduction among ICAD patients treated with

2 weeks after the index event, and therefore, prompt

DAPT compared with aspirin alone (11.3% vs. 13.6%;

revascularization should be considered. In data

p ¼ 0.44) (35). However, these results were under-

largely from pre-statin era, 3 RCTs revealed signifi-

powered and could be influenced by clopidogrel

cant benefit of carotid endarterectomy (CEA) over

resistance as mentioned in the preceding text.

medical management for symptomatic stenosis of

Another study that supports DAPT for patients with

70% to 99% (ARR ¼ 16% at 5 years; NNT ¼ 6.3), a lower

LAA found a significant decrease in microembolic

benefit for 50% to 69% stenosis (ARR ¼ 4.6% at 5

signals at 7 days with DAPT compared with aspirin

years; NNT ¼ 22), and no benefit or harm for <50%

alone (36). To date, no RCT focused on ICAD has

stenosis (42). Carotid artery stenting (CAS) has

compared antiplatelet monotherapy with DAPT.

emerged as an alternative to CEA. A pooled analysis

The TOSS (Trial of Cilostazol in Symptomatic

of 3 RCTs comparing CEA with CAS in symptomatic

Intracranial Arterial Stenosis) trial (37) randomized

carotid stenosis showed that CEA was safer than CAS

135 participants to aspirin plus cilostazol versus

(30-day rate of stroke or death: 4.4% vs. 7.7%;

aspirin alone within 2 weeks of their index event and

p < 0.001). However, the short-term outcomes were

found that ICAD progression at 6 months occurred in

similar among patients younger than 70 years of age

7% on combined therapy versus 29% on aspirin alone

(30-day rate of stroke or death: CEA 4.5% vs. CAS

(p ¼ 0.008). A larger study comparing cilostazol plus

5.1%) (43). More recently, the long-term follow-up of

aspirin versus clopidogrel plus aspirin in 457 in-

the ICSS (International Carotid Stenting Study)

dividuals found no difference in ICAD progression at

showed similar cumulative 5-year risk of fatal or

7 months (9.3% vs. 15.5%; p ¼ 0.09) or recurrent

disabling stroke between CEA and CAS (6.5% vs.

stroke (4.7% vs. 2.6%; p ¼ 0.32) (38). Recent results

6.4%) (44).

from the CSPS (Cilostazol Stroke Prevention Study for

The benefit from CEA appears to diminish after

Antiplatelet Combination) trial reported lower stroke

2 weeks (NNT ¼ 5 within 2 weeks vs. NNT ¼ 125 after

recurrence among patients with LAA (or at least 2 risk

12 weeks) (45), but carotid intervention within 48 h is

factors for atherosclerosis) when treated with cil-

associated with greater periprocedural ipsilateral

ostazol plus aspirin or clopidogrel compared with

stroke and death (46). Therefore, it is critical to

aspirin

4.5%;

institute appropriate medical therapy until revascu-

ARR ¼ 2.3%), without an increase in hemorrhagic

larization can be performed and in those not eligible

events. The benefit of DAPT with cilostazol was

for intervention to prevent recurrent carotid-related

maintained in the ICAD subgroup (4% vs. 9.2%;

stroke and decrease procedural vascular complications.

or

clopidogrel

alone

(2.2%

vs.

ARR ¼ 5.2%). However, this open-label study was

Aspirin use before CEA is now standard of care. A

stopped at 47% of planned recruitment and enrolled

RCT comparing aspirin versus placebo before CEA

only Japanese participants (39).

found a significant reduction in stroke and death

Ticagrelor has not been studied specifically in

without an increase in pre-operative bleeding (47).

ICAD, but amongst SOCRATES trial participants with

The ACE (Aspirin and Carotid Endarterectomy) trial

proximal atherosclerotic disease, ticagrelor was su-

compared low-dose (81 mg and 325 mg) to high-dose

perior to aspirin in preventing stroke, MI, or death at

aspirin (650 mg and 1,300 mg) in the periprocedural

90 days (6.7% vs. 9.6%; ARR ¼ 2.9%) (40). For Asian

period and found a lower risk of stroke, MI, or death

participants, among whom ICAD is common, events

with lower doses (3.2% vs. 8.2%; p ¼ 0.002) (48).

recurrence was lower with ticagrelor than aspirin

DAPT before CEA has been traditionally avoided

(9.7% vs. 11.6%; ARR ¼ 1.9%) (41).

because of the increased risk of surgical bleeding. A

For TIA or stroke due to ICAD, RCTs data supports

large registry that included almost 7,000 patients

current recommendations of the use of antiplatelet

who had CEAs for symptomatic disease showed that

therapy, high-intensity statins, good blood pressure

DAPT was not associated with a lower risk of peri-

control, and exercise (20). DAPT beyond the acute

operative stroke and death (1.3% vs. 1.5%; p ¼ 0.7) but

phase in ICAD remains investigational. Endovascular

had a higher risk of neck bleeding requiring surgical

approaches should be reserved for those with recur-

exploration (1.5% vs. 0.6%; p ¼ 0.02) (49).

rent events despite optimal medical management. EXTRACRANIAL

CAROTID

The recommendation to use DAPT before and for at

DISEASE. Extracranial

least 30 days after CAS (50,51) is largely based on the

carotid disease is responsible for 10% to 15% of all

coronary published reports. A small trial comparing

ischemic strokes. Patients with stroke, TIA, and

antithrombotic agents in CAS showed higher neuro-

amaurosis fugax caused by carotid disease often have

logical complications with aspirin plus 24 h of heparin

recurrent symptoms, with the highest risk in the first

compared with aspirin plus clopidogrel (52).

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Beyond the procedural period and among those not

Antithrombotic Agents in Secondary Stroke Prevention

patients with AF (61) (Table 2). The EAFT (European

eligible for intervention, antiplatelet therapy with

Atrial Fibrillation Trial) was the first RCT to show this

aspirin, clopidogrel, or aspirin-dipyridamole is rec-

effect (62). When compared with placebo, this RCT

ommended indefinitely after CEA and CAS (50,51).

found 8% ARR for recurrent stroke with warfarin

Ticagrelor needs further investigation as an option for

(NNT ¼ 12) and 2% ARR in patients receiving aspirin

those with atherosclerotic disease (40).

(NNT ¼ 50). A meta-analysis showed that warfarin

EXTRACRANIAL VERTEBRAL DISEASE. Among pos-

was superior to aspirin for prevention of vascular

terior circulation strokes, 10% to 20% of patients have

events (odds ratio: 0.55; 95% confidence interval: 0.37

proximal atherosclerotic extracranial disease (53).

to 0.82) or recurrent stroke (odds ratio: 0.36; 95%

The same medical management recommended for

confidence interval: 0.22 to 0.58) (63). However,

carotid disease is followed for extracranial vertebral

hemorrhagic risk was significantly increased by anti-

disease (50,51). Two trials failed to show superiority

coagulation. The optimal international normalized

of stenting over medical management (54,55). A

ratio (INR) range for VKA anticoagulation is between

recent trial, unfortunately discontinued due to

2.0 and 3.0 (61).

funding issues, showed that stenting was safe and

DOACs were compared with warfarin in patients

suggested a trend toward better outcomes (56). To

with AF in 4 RCTs (64–67). In addition, 1 trial

date, no data support endovascular intervention for

compared apixaban with aspirin in AF patients not

vertebral artery disease.

suitable for treatment with warfarin (68). All studies

AORTIC ARCH ATHEROSCLEROTIC DISEASE. Semi-

nal studies have identified an association between aortic arch atherosclerosis and ischemic stroke, particularly when large plaques (>4 mm) are present (57,58). Compared with other stroke mechanisms, there are relatively scarce data on antithrombotic treatment for secondary prevention in arch disease. In the observational FSAPS (French Study of Aortic Plaques in Stroke) trial, those on antiplatelet and anticoagulant therapy had similar recurrent events (57). The ARCH (Aortic Arch Related Cerebral Hazard) trial (59) was specifically designed to study aortoembolism. Patients with stroke, TIA, or peripheral embolism from thoracic arch plaques >4 mm were randomized to DAPT versus warfarin. In 349

comparing DOACs with warfarin had subgroups of AF patients with a prior TIA or stroke. In 20,500 patients, DOACs were associated with a marginal benefit as demonstrated by reduction of stroke and systemic embolism (ARR ¼ 0.8%; NNT ¼ 127), any stroke (ARR ¼ 0.7%; NNT ¼ 142), and intracranial hemorrhage (ARR ¼ 0.9%; NNT ¼ 113) over 1.8 to 2.8 years (69). Therefore, DOACs are favored over warfarin in secondary stroke prevention in patients with AF, except in those with moderate-to-severe mitral stenosis or mechanical heart valve (61). In patients with moderate-to-severe kidney disease, adjusted doses of DOACs are required, whereas in those with end-stage renal disease or requiring dialysis, warfarin is recommended instead of DOACs (61).

participants followed for a mean of 3.4 years, the

OTHER CARDIOEMBOLIC SOURCES. Mitral stenosis,

outcome of stroke, MI, peripheral embolism, and

commonly secondary to rheumatic fever, have a high

vascular death occurred in 7.6% on DAPT and 11.3% on

risk of systemic embolism and is frequently compli-

warfarin (p ¼ 0.2); only vascular death was signifi-

cated by AF (70). In the absence of high-quality evi-

cantly more frequent in the anticoagulation group. In

dence,

the SOCRATES post hoc analysis, the subgroup with

anticoagulation is indicated in patients with mitral

known arch disease and/or carotid stenosis <50% had

stenosis and previous stroke or AF (20,70). Patients

a lower rate of stroke, MI, or death within 90 days

with moderate-to-severe mitral stenosis were sys-

when treated with ticagrelor compared with aspirin

tematically excluded from RCTs comparing DOACs

(3.7% vs. 7.1%; ARR ¼ 3.4%; p ¼ 0.02) (60).

and warfarin (71); therefore, long-term VKA therapy

there

is

general

consensus

that

Therefore, the current published reports support as

(INR 2 to 3) is recommended (70). There are scarce

a Class I recommendation treating patients with

data regarding the effect of other valvular heart dis-

aortic arch disease and stroke or TIA with antiplatelet

eases on stroke risk.

agents (20). There is no evidence that warfarin is useful in this condition.

Mechanical heart valves carry a high stroke risk and life-long therapy with VKA (INR 2.3 to 3.5) is mandatory (70). Warfarin was superior to dabigatran

CARDIOGENIC EMBOLISM

in patients with mechanical heart valves, both in terms of efficacy and safety (72). Bioprosthetic valves

ATRIAL FIBRILLATION. Long-term anticoagulation is

have

recommended for secondary stroke prevention in

compared with mechanical valves. For patients with

a

lower

risk

of

thromboembolism

when

793

794

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Antithrombotic Agents in Secondary Stroke Prevention

mitral bioprosthetic valves, anticoagulation with VKA

the risk of hemorrhage was increased (2.1% vs. 1.1%/

(INR 2 to 3) for 3 months followed by antiplatelet

year; p < 0.01) (14). These findings were concordant

therapy is recommended. For aortic bioprosthetic

with the MATCH trial, which found no benefit of

valves, including transcatheter aortic valve bio-

DAPT versus clopidogrel monotherapy (Table 1). Of

prosthesis, antiplatelet therapy is suggested over

note, more than 50% of patients enrolled in the

anticoagulation (70). There are no data to support the

MATCH trial were categorized as SVD (13).

long-term use of anticoagulation in patients with bioprosthetic valves.

Due to its pleiotropic properties such as arteriolar vasodilation and protection of the vascular endothe-

The WARCEF (Warfarin Versus Aspirin in Reduced

lium, cilostazol is potentially effective for preventing

Cardiac Ejection Fraction) trial compared warfarin

cerebral injury among patients with SVD (76,77). The

(INR 2.0 to 3.5) to aspirin (325 mg) among 2,305 pa-

ECLIPse (Effect of Cilostazol in Acute Lacunar

tients with heart failure and low ejection fraction (73).

Infarction Based on Pulsatility Index of Transcranial

The primary outcome of ischemic stroke, ICH, or

Doppler)

death was not significantly different between groups

decreased the pulsatility index, used as a marker of

trial

found

that

cilostazol

effectively

(7.5% vs. 7.9%; p ¼ 0.40) during a mean follow-up of

small vessel resistance (76). The safety and efficacy of

3.5 years. Patients on warfarin had a lower rate of

cilostazol together with isosorbide mononitrate to

ischemic events (0.7% vs. 1.4%; p ¼ 0.005). However,

prevent recurrent strokes and progression of SVD is

as expected, hemorrhages were higher with warfarin

under study (78).

(1.8% vs. 0.9%; p < 0.001). Pooled analysis of 4 studies investigating anticoagulation in patients with heart failure suggest an increased risk of bleeding counterbalanced by a marginal benefit in ischemic stroke prevention (74). Acute MI can lead to formation of a left ventricular thrombus. Anticoagulation with heparin followed by 3 months of VKA is recommended (20). Whether DOACs have a similar efficacy and safety in this situation remains to be proven.

SMALL VESSEL DISEASE

CRYPTOGENIC STROKE EMBOLIC STROKE OF UNDETERMINED SOURCE.

Cryptogenic strokes that are nonlacunar, have no definite cardioembolic source, and no evidence of LAA are thought to have an embolic mechanism (1). These patients are classified as ESUS, and represent 10% to 21% of all ischemic strokes (1,79). ESUS patients are relatively young (65 years of age average), and the rate of recurrence is about 5% annually. Under the assumption of an embolic mechanism, 4 RCTs

were

initiated

comparing

anticoagulation

Cerebral SVD is responsible for 25% of all ischemic

with aspirin after ESUS. The NAVIGATE-ESUS (New

strokes and the annual risk of recurrence is 2-7%

Approach Rivaroxaban Inhibition of Factor-Xa in a

(2,14). Lacunar infarcts are suspected by clinical pre-

Global Trial Versus Aspirin to Prevent Embolism in

sentation (lacunar syndromes), and confirmed on

Embolic Stroke of Undetermined Source) trial ran-

neuroimaging by the presence of small (<20 mm)

domized 7,213 patients to either rivaroxaban 15 mg

subcortical infarcts located in the territory of single

daily or aspirin 100 mg. The trial was terminated early

perforating arteries (14). A pooled analysis of RCTs

due to increased bleeding and the absence of an off-

found that, compared with placebo, any single anti-

setting benefit in the rivaroxaban arm. The median

platelet agent after a lacunar infarct lowers the rate of

follow-up was 11 months. The endpoint of first

any stroke (ARR ¼ 3.5%; NNT ¼ 29) and ischemic

recurrent stroke or systemic embolism occurred in 172

stroke (ARR ¼ 5.9%; NNT ¼ 17) (75).

patients (4.8%) on rivaroxaban and 160 patients

Most of the trials discussed in the preceding text

(4.4%) on aspirin (annualized rate 5.1% vs. 4.8%;

included diverse stroke subtypes, and results cannot

p ¼ 0.52). The rate of major bleeding was higher for

be completely extrapolated to patients with SVD.

rivaroxaban compared with aspirin (annualized rate

Alternatively, the long-term efficacy of DAPT was

1.8% vs. 0.7%; p < 0.001) (80). The RESPECT-ESUS

specifically studied in the SPS3 (Secondary Preven-

(Randomized, Double-blind, Evaluation in Second-

tion of Small Subcortical Strokes) study. This study

ary Stroke Prevention Comparing the Efficacy and

randomized 3,020 patients with magnetic resonance

Safety of the Oral Thrombin Inhibitor Dabigatran

imaging–confirmed lacunar infarcts to receive clopi-

Versus Aspirin in Patients With Embolic Stroke of

dogrel 75 mg plus aspirin 325 mg daily versus the

Undetermined Source) trial randomized 5,390 pa-

same dose of aspirin plus placebo. After a mean

tients to either dabigatran 150 mg or 110 mg twice

follow-up of 3.4 years, stroke recurrence was not

daily depending on age and kidney function or aspirin

reduced by DAPT (2.5% vs. 2.7%/year; p ¼ 0.48), and

100 mg daily. During a mean follow-up of 19 months,

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Antithrombotic Agents in Secondary Stroke Prevention

recurrent stroke occurred in 117 patients (6.6%) on

In summary, PFO closure plus long-term anti-

dabigatran and 207 patients (7.7%) on aspirin (annu-

platelet therapy is superior to antiplatelet agents

alized rate 4.1% vs. 4.8%; p ¼ 0.10). The rate of major

alone in carefully selected patients (i.e., younger than

bleeding was similar in both groups (annualized rate

60 years of age). PFO closure and anticoagulation may

1.7% vs. 1.4%; p ¼ 0.30) (81). Both trials defined major

have similar efficacy in preventing stroke recurrence,

bleeding according to the International Society on

but available data are less robust. When PFO closure

Thrombosis

is contraindicated, the benefit of anticoagulation over

and

Hemostasis:

fatal

bleeding,

or

bleeding in a critical organ, or requiring transfusion of $2 U, or hemoglobin fall $2 g/dl. The ATTICUS (Apixaban for Treatment of Embolic Stroke of Undetermined Source) trial plans to randomize 500 ESUS patients to apixaban 5 mg twice daily or aspirin 100 mg daily. The primary outcome is at least 1 new ischemic lesion identified by magnetic resonance imaging at 12 months (82). The ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke) trial aims to compare apixaban versus aspirin in ESUS patients at high risk of cardioembolism on the basis of atrial cardiopathy detected on 12-lead electrocardiogram abnormalities, left atrium enlargement on echocardiography, or presence of elevated amino terminal pro–B-type natriuretic peptide (83). In conclusion, anticoagulation with DOACs has not

antiplatelet therapy is unclear (85).

OTHER DETERMINED ETIOLOGIES Uncommon stroke etiologies may be recognized after more extensive evaluations among patients with unrevealing initial work up. This category includes nonatherosclerotic

vasculopathies

(i.e.,

arterial

dissection, vasculitis, vasospasm), hypercoagulable states, hematologic disorders, and monogenic etiologies (90). In the absence of RCTs, antiplatelet agents are generally prescribed to prevent stroke recurrence. However, management of many of these conditions is mostly based on treating the underlying disorder. Antithrombotic agents remain the pivotal treatment in some of these conditions, thus worth mentioning in the current review.

been superior to aspirin for stroke prevention in

CERVICAL ARTERIAL DISSECTION. Cervical arterial

patients with ESUS (Table 2). Whether this is also

dissection (CAD) is a common cause of stroke in the

true for selected high-risk subgroups needs to be

young. Stroke recurrence is generally low; however,

shown. CRYPTOGENIC STROKE AND PATENT FORAMEN OVALE. Paradoxical embolism through a patent fo-

ramen ovale (PFO) may be implicated in a proportion of patients with cryptogenic stroke (84). Secondary prevention strategies in these patients include PFO closure, antiplatelet agents, or anticoagulant agents (84,85). A pooled analysis of 6 RCTs comparing PFO closure plus antiplatelet therapy versus any antithrombotic agent (antiplatelet and/or anticoagulation) showed significant stroke reduction in the closure group compared with controls (risk ratio ¼ 0.39; p ¼ 0.01), despite a significant risk of developing AF among

patients

undergoing

intervention

(risk

ratio ¼ 4.33; p < 0.001). All studies except 1 (86) included patients <60 years of age. A subanalysis of 2 studies comparing PFO closure to antiplatelet agents showed that the former remained more effective in preventing stroke recurrence (risk ratio ¼ 0.36; p ¼ 0.01) (85). Another study compared PFO closure versus anticoagulation (VKA or DOACs), and no significant benefit was found (87). Finally, 3 RCTs that compared anticoagulation versus antiplatelet agents

the first few weeks after presentation represents a high-risk time period (91,92). Therefore, 3 to 6 months of antithrombotic agents after diagnosis are recommended (20). A systematic review including 1,285 patients with CAD found no difference between anticoagulant agents and antiplatelet agents in the rate of death (1.2% vs. 2.6%; p ¼ 0.2), or ischemic stroke (1.9% vs. 2%; p ¼ 0.4) (93). The rate of ICH and extracranial hemorrhage in the anticoagulation group was 0.8% and 1.6%, respectively, compared with no hemorrhagic

complications

seen

with

antiplate-

let agents. The CADISS (Cervical Artery Dissection In Stroke Study) is the only RCT of antithrombotic agents in CAD. Patients received either antiplatelet agents or anticoagulation for 3 months after diagnosis of CAD. Ipsilateral stroke occurred in 3 of 101 patients receiving antiplatelet agents versus 1 of 96 on anticoagulation (p ¼ 0.66). There were no deaths, but 1 patient receiving anticoagulation had a subarachnoid hemorrhage

(94). The

infrequency of

endpoint

occurrence precludes any definitive conclusion.

HYPERCOAGULABLE STATES

showed fewer ischemic strokes in patients assigned to anticoagulation; however, none found a significant

INHERITED THROMBOPHILIAS. A causal relationship

difference (87–89).

between stroke and inherited thrombophilias (factor

795

796

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Antithrombotic Agents in Secondary Stroke Prevention

V Leiden, prothrombin G20210A mutation, methyl-

Anticoagulation with either low-molecular-weight

enetetrahydrofolate reductase C677T mutation, pro-

heparin (LMWH) or DOACs may be recommended

tein

for

C

deficiency,

protein

S

deficiency,

and

cancer-associated

thrombosis

(110–112).

The

antithrombin III deficiency) remains poorly estab-

mechanism of injury as well as the overall prognosis

lished, and routine testing is not advised (95).

should be considered when selecting antithrombotic

Long-term anticoagulation with VKA or heparin

therapy. The TEACH (Trial of Enoxaparin Versus

products is recommended for patients with unpro-

Aspirin

voked venous thrombosis and an underlying throm-

showed no difference in the rates of stroke, major

bophilia (95,96), yet some data suggest DOACs are a

bleeding, and survival between enoxaparin and

suitable alternative (97,98). By contrast, published

aspirin (113). However, results were limited by low

reports

arterial

patient enrollment mainly due to aversion to receive

thrombosis (i.e., ischemic stroke) are limited. Current

enoxaparin injections. The OASIS-CANCER (Optimal

guidelines recommend that anticoagulation should

Anticoagulation Strategy In Stroke Related to Can-

be considered in the setting of recurrent cryptogenic

cer) trial is an ongoing RCT that aims to compare the

on

antithrombotic

therapy

for

in

Cancer

Patients With

Stroke)

study

strokes and known inherited thrombophilia (20).

efficacy and safety of VKA, LMWH, and DOACs for

ANTIPHOSPHOLIPID

prevention of recurrent stroke or systemic embolism

SYNDROME. Antiphospholipid

syndrome (APLS) is an antibody-induced thrombo-

in cancer patients.

philia characterized by recurrent thrombosis (venous

CEREBRAL VENOUS THROMBOSIS

and arterial) and pregnancy morbidity. In the EuroPhospholipid Project, 20% of the patients with APLS

Although not from an arterial occlusion, ischemic or

presented with ischemic stroke and 11% with TIAs

hemorrhagic infarctions may occur due to cerebral

(99). Conversely, it is estimated that 1 in 5 strokes in

venous thrombosis (CVT). On the basis of 2 RCTs,

all young patients (<50 years of age) are associated

anticoagulation with heparin products is recom-

with APLS, although all ages can be affected (100).

mended for acute CVT, regardless of the presence of

A systematic review showed that APLS patients

intracranial hemorrhage (114). LMWH has been asso-

with previous stroke had high thrombosis recurrence

ciated with lower mortality, fewer hemorrhagic

despite being on antiplatelet agents or standard

complications,

anticoagulation, and found that <4% of all events

outcome when compared with unfractionated hepa-

occurred with an INR >3.0, thus advocating for an

rin (115,116).

and

better

long-term

functional

aggressive therapeutic target in high-risk patients

After the acute phase, guidelines recommend

(101). Two RCTs with insufficient power compared

anticoagulation with VKA for a variable period of time

high-intensity warfarin (INR 3.1 to 4.0) versus stan-

(3 to 12 months) (20,117). The optimal duration, as

dard anticoagulation and found that high-intensity

well as the effectiveness of DOACs, is uncertain. The

anticoagulation had no significant benefit (102,103).

EXCOA-CVT (Extending Oral Anticoagulation Treat-

Finally, 1 observational study and 1 small randomized

ment After Acute Cerebral Vein Thrombosis) trial is a

trial suggested that the combination of antiplatelet

RCT designed to compare the efficacy of short-term (3

agents and anticoagulation may be more effective

to 6 months) versus long-term (12 months) anti-

than either alone (104,105).

coagulation after CVT (118). Another phase III trial is

More recently, DOACs have been proposed as an alternative for APLS (106). A RCT reported no

comparing dabigatran with warfarin for thrombosis prevention after CVT (119).

thrombosis or major bleeding in low-risk APLS patients treated with rivaroxaban, suggesting similar efficacy to warfarin (107). Various case series showed conflicting results regarding the efficacy of DOACs

ANTITHROMBOTIC THERAPY AFTER INTRACRANIAL HEMORRHAGE

among patients with APLS (108). The use of DOACs in

Antithrombotic agent–associated ICH is associated

thrombotic APLS is the aim of several ongoing RCTs.

with larger hematoma volume, hematoma expansion,

STROKE

AND

MALIGNANCY. Ischemic

is

and worse outcomes (120). All antithrombotic agents

common among cancer patients. Cancer may lead to

should be discontinued at presentation, and rapid

stroke via hypercoagulability, paradoxical emboli,

reversal of anticoagulation is recommended (Table 3)

nonbacterial endocarditis, tumor embolization, and

(121,122). For patients taking antiplatelet agents,

local

by

routine platelet transfusion is not recommended

treatment-related complications such as radiation-

(123). After bleeding cessation, early use of low-dose

related large-vessel arteriopathy (109).

heparin

tumor

compression,

or

stroke

alternatively,

is

considered

safe

and

effective

in

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Antithrombotic Agents in Secondary Stroke Prevention

T A B L E 3 Investigational Questions in the Use of Antithrombotic Therapy in Patients With Cerebrovascular Disease

Investigational Question

Ongoing Trials

Acute ischemic stroke and transient ischemic attack DAPT (ticagrelor and aspirin) after a minor ischemic stroke or TIA DOACs vs. antiplatelet therapy after minor ischemic stroke or TIA

THALES (NCT03354429) ADANCE (NCT01924325) TRACE (NCT01923818) DATAS II (NCT02295826)

DAPT (clopidogrel and aspirin) after mild-to-moderate ischemic stroke

ATAMIS (NCT02869009)

Small vessel disease Cilostazol to prevent recurrent lacunar strokes and progression of cerebral small vessel disease

LACI-2 (NCT03451591)

Large artery atherosclerotic disease Cilostazol plus aspirin or clopidogrel for stroke prevention of in patients with large artery atherosclerosis

CSPS (NCT01995370) DORIC (NCT02983214)

Cardioembolic stroke DOACs for stroke prevention in valvular heart disease and AF

DECISIVE (NCT02982850) INVICTUS-ASA (NCT02832531) INVICTUS-VKA (NCT02832544)

Optimal time to resume anticoagulation in patients with acute ischemic stroke and AF

OPTIMAS (NCT03759938) TIMING (NCT02961348) ELAN (NCT03148457)

Other determined etiologies DOACs for prevention of thromboembolisms in patients with APLS

ASTRO-APS (NCT02295475) TRAPS (NCT02157272) RISAPS (NCT03684564)

Optimal anticoagulation strategy for ischemic stroke related to cancer

OASIS-CANCER (NCT02743052) ENCHASE (NCT03570281)

Embolic stroke of undetermined source (cryptogenic stroke) DOACs for stroke prevention in patients with ESUS and high-risk of cardioembolism

ATTICUS (NCT02427126) ARCADIA (NCT03192215)

Cerebral venous thrombosis Efficacy and safety of a short-term (3-6 months) versus long-term (12 months) anticoagulation after CVT

EXCOA-CVT (ISRCTN25644448)

Dabigatran versus warfarin to prevent thrombotic events after CVT

RE-SPECT CVT (NCT02913326)

Antithrombotic therapy after intracranial hemorrhage Safety of restarting antithrombotic agents in patients with antithrombotic agent–related ICH

RESTART (ISRCTN71907627) RESTART-FR (NCT02966119) APACHE-AF (NCT02565693) NASPAF-ICH (NCT02998905) SoSTART (NCT03153150) A3-ICH (NCT03243175)

Efficacy and safety of DOACs compared with aspirin for stroke prevention in patients AF and previous ICH

NASPAF-ICH (NCT02998905)

Efficacy and safety of cilostazol to prevent stroke recurrence in patients with previous of ICH

PICASSO (NCT01013532)

A3-ICH ¼ Avoiding Anticoagulation After IntraCerebral Haemorrhage; ADANCE ¼ Apixaban Versus Dual-antiplatelet Therapy (Clopidogrel and Aspirin) in Acute Non-disabling Cerebrovascular Events; APACHE-AF ¼ Apixaban After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation; ARCADIA ¼ AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke; ASTRO-APS ¼ Apixaban for Secondary Prevention of Thromboembolism Among Patients With AntiphosPholipid Syndrome; ATAMIS ¼ Antiplatelet Therapy in Acute Mild-Moderate Ischemic Stroke; ATTICUS ¼ Apixaban for Treatment of Embolic Stroke of Undetermined Source; CSPS ¼ Cilostazol Stroke Prevention Study for Antiplatelet Combination; CVT ¼ cerebral venous thrombosis; DATAS II ¼ Dabigatran Following Transient Ischemic Attack and Minor Stroke; DECISIVE ¼ Dabigatran Versus Conventional Treatment for Prevention of Silent Cerebral Infarct in Atrial Fibrillation Associated With Valvular Disease; DORIC ¼ Diabetic Artery Obstruction: is it Possible to Reduce Ischemic Events With Cilostazol?; ELAN ¼ Early Versus Late Initiation of Direct Oral Anticoagulants in Postischaemic Stroke Patients With Atrial fibrillatioN (ELAN): an International, Multicentre, Randomised-controlled, Two-arm, Assessor-blinded Trial; ENCHASE ¼ Edoxaban for the Treatment of Coagulopathy in Patients With Active Cancer and Acute Ischemic Stroke: a Pilot Study; EXCOA-CVT ¼ the benefit of EXtending oral antiCOAgulation treatment after acute Cerebral Vein Thrombosis; INVICTUS-ASA ¼ INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Superiority; INVICTUS-VKA ¼ INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority; LACI-2 ¼ LACunar Intervention Trial-2; NASPAF-ICH ¼ NOACs for Stroke Prevention in Patients With Atrial Fibrillation and Previous ICH; OASIS-CANCER ¼ Anticoagulation in Cancer Related Stroke; OPTIMAS ¼ OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke: a Randomised Controlled Trial; PICASSO ¼ PreventIon of CArdiovascular Events in iSchemic Stroke Patients With High Risk of Cerebral HemOrrhage; RE-SPECT CVT ¼ A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis; RESTART ¼ REstart or STop Antithrombotics Randomised Trial; RESTART-FR ¼ REstart or STop Antithrombotic Randomised Trial in France; RISAPS ¼ RIvaroxaban for Stroke Patients With AntiPhospholipid Syndrome; SoSTART ¼ Start or STop Anticoagulants Randomised Trial; THALES ¼ Acute STroke or Transient IscHaemic Attack Treated With TicAgreLor and ASA for PrEvention of Stroke and Death; TIMING ¼ TIMING of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation; TRACE ¼ Treatment of Rivaroxaban Versus Aspirin for Non-disabling Cerebrovascular Events; TRAPS ¼ Rivaroxaban in Thrombotic Antiphospholipid Syndrome other abbreviations as in Table 2.

797

798

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Antithrombotic Agents in Secondary Stroke Prevention

the observational nature of published data, there is a

T A B L E 4 Recommendations for Oral Anticoagulant Agent Reversal in

lack of evidence-based recommendations. Numerous

Intracranial Hemorrhage

ongoing RCTs target this clinical situation. The Anticoagulant Agent

Vitamin K antagonist (warfarin)

Mechanism of Action

Reversal

Inhibits factors II, Administer Vitamin K 10 mg IV VII, IX, X Clotting factor repletion: First line: 4F-PCC 25–50 U/kg

Monitoring

PT INR

Direct thrombin inhibitor

Idracizumab 5 g IV If above not available: 4F-PCC 50 U/kg IV

TT ECT aPTT

Direct factor Xa inhibitors

Andexanet alfa 400–800 mg IV If above not available: 4F-PCC 50 U/kg IV

starting versus avoiding antiplatelet drugs after a other trials aim to investigate the safety of restarting anticoagulation in patients with AF after a spontaneous ICH. The chief investigators of these RCTs have

Consider hemodialysis Apixaban Rivaroxaban Edoxaban

mised Trial) study is a multicenter RCT comparing antithrombotic agent–associated ICH (133). Several

Second line: FFP 10–15 ml/kg Dabigatran

RESTART (Restart or Stop Antithrombotics Rando-

PT Anti-factor Xa activity (not widely available)

4F-PCC ¼ 4-factor prothrombin complex concentrate; aPTT ¼ activated partial thromboplastin time; ECT ¼ ecarin clotting time; FFP ¼ fresh frozen plasma; INR ¼ international normalized ratio; IV ¼ intravenous; PT ¼ prothrombin time; TT ¼ thrombin time.

created the COCROACH (Collaboration of Controlled Randomized Trials of Oral Antithrombotic Drugs After Intracranial Hemorrhage) study for a prospective preplanned individual-patient data meta-analysis in order to maximize the power of their findings (134).

ONGOING TRIALS AND FUTURE PROSPECTS Well-designed RCTs and meta-analysis have provided

preventing deep venous thrombosis and pulmonary

guidance on the use of antithrombotic agents for

embolism (121).

secondary prevention in common stroke subtypes

The safety of restarting antithrombotic agents after

such as those attributed to SVD, LAA, and AF. How-

ICH remains unclear. Observational studies suggest

ever, data are scarce in less common stroke etiologies.

that antiplatelet resumption does not carry a major

In addition, RCTs are not adequate to address many

hazard (124–126). A single-center study found that

challenging situations, including the coexistence of

aspirin use was associated with ICH recurrence

more than 1 stroke mechanism, high bleeding risk

among patients with lobar ICH, thus exposing the

patients, or patients who had stroke recurrence

higher risk of platelet inhibition among patients with

despite being on the recommended therapy. To date,

ICH associated with cerebral amyloid angiopathy

many questions with respect to antithrombotic agent

(127).

use among patients with cerebrovascular disease

A decision analysis model showed that restarting

remain unanswered (Table 4).

VKA in patients with AF after a lobar ICH was asso-

The best approach to select antithrombotic agents

ciated with lower quality-adjusted life expectancy,

in patients with stroke is to first identify the likely

whereas the difference in patients with deep ICH was

mechanism of injury (Central Illustration). When oc-

minimal (128). A joint analysis of 3 observational

clusion of perforator vessels is suspected to be sec-

studies found that anticoagulation resumption after

ondary to SVD, antiplatelet monotherapy after the

ICH was associated with decreased mortality and

acute phase is effective as long as other risk factors

better functional outcome, regardless of hematoma

such as arterial hypertension are well controlled. In

location (129). A systematic review evaluated anti-

LAA, aggressive platelet antiaggregation is beneficial

coagulation resumption among 5,306 ICH patients

in the acute phase due to the high thrombogenicity

with AF, prosthetic heart valves, previous venous

caused by plaque rupture, whereas the use of statins

thrombosis, and previous ischemic stroke. With a

and strict vascular risk factors control is more rele-

median time for restarting anticoagulation of 10 to

vant in the long term to reduce atherosclerosis pro-

39 days, resumption was associated with lower risk of

gression. When the thromboembolic mechanism is

thromboembolic events (6.7% vs. 17.6%), and no sig-

attributed to blood stasis such as what occurs in AF,

nificant risk of ICH recurrence (8.7% vs. 7.8%) during

or when inherited or acquired thrombophilias are

a mean follow-up ranged from 12 to 43 months (130).

implicated, anticoagulant agents are recommended.

A recent meta-analysis with overlapping inclusion

DOACs have emerged as a convenient alternative to

criteria revealed similar results (131).

VKA among patients with AF. Nevertheless, DOACs

In summary, restarting antithrombotic agents after

efficacy in other thrombophilic conditions predis-

ICH should be considered, particularly in high-risk

posing to stroke remains to be proven in large RCTs.

thromboembolic conditions. It has been suggested

Finally, the stroke mechanism remains undeter-

that avoidance of antithrombotic agents for 2 to

mined in a significant proportion of patients. Two

4 weeks after ICH is reasonable (132). However, given

recent RCTs failed to show that DOACs are beneficial

Del Brutto et al.

JACC VOL. 74, NO. 6, 2019 AUGUST 13, 2019:786–803

Antithrombotic Agents in Secondary Stroke Prevention

C ENTR AL I LL U STRA T I O N Approach to the Use of Antithrombotic Therapy for Secondary Prevention After Ischemic Stroke

Del Brutto, V.J. et al. J Am Coll Cardiol. 2019;74(6):786–803.

AF ¼ atrial fibrillation; CAS ¼ carotid artery stenting; CEA ¼ carotid endarterectomy; CT ¼ computerized tomography; DAPT ¼ dual antiplatelet therapy; DOAC ¼ direct oral anticoagulant agents; ECAD ¼ extracranial atherosclerotic disease; ECG ¼ electrocardiogram; ESUS ¼ embolic stroke of undetermined source; ICAD ¼ intracranial atherosclerotic disease; INR ¼ international normalized ratio; MRI ¼ magnetic resonance imaging; PFO ¼ patent foramen ovale; TEE ¼ transesophageal echocardiogram; TTE ¼ transthoracic echocardiogram; VKA ¼ vitamin K antagonist.

in ESUS, and suggest that covert AF is perhaps not as

understanding on how to evaluate and treat these

common as previously thought. Furthermore, these

patients.

trials have led us to rethink cryptogenic stroke defi-

In conclusion, a rational antithrombotic agent

nition. Ongoing trials that take into account a more

selection based on the suspected mechanism of

refined classification of patients according to high risk

injury is the best approach to select the appro-

versus low risk of embolism may provide us a better

priate therapy to prevent stroke recurrence after

799

800

Del Brutto et al.

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Antithrombotic Agents in Secondary Stroke Prevention

cerebral ischemia. Decisions should be individualized according to the risk of adverse effects such

ADDRESS FOR CORRESPONDENCE: Dr. Victor J. Del

as bleeding. Vascular risk factors and high-risk

Brutto, Don Soffer Clinical Research Center, 1120 NW

behaviors

14th Street, Suite 1383, Miami, Florida 33136. E-mail:

controlled.

must

also

There

are

be

modified

still

many

and

strictly

[email protected].

unanswered

Twitter:

@vdelbrutto.

OR

questions and several ongoing trials aim to clarify

Dr. Ralph L. Sacco, Don Soffer Clinical Research

the efficacy of newer medications with alternative

Center, 1120 NW 14th Street, Suite 1383, Miami,

mechanisms of action and safer pharmacological

Florida

profiles.

Twitter: @DrSaccoNeuro.

33136.

E-mail:

[email protected].

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KEY WORDS anticoagulants, antiplatelets, antithrombotics, ischemic stroke, secondary

aspirin in Chinese after recovery from primary

Stroke 2017;48:1594–600.

prevention

3 trial. Lancet 2016;387:2605–13.

803