Stroke

BRIEF REPORT

Dual Antiplatelet Therapy Versus Aspirin in

Patients With Stroke or Transient Ischemic Attack
Meta-Analysis of Randomized Controlled Trials
Kirtipal Bhatia, MD*; Vardhmaan Jain, MD*; Devika Aggarwal, MD; Muthiah Vaduganathan , MD, MPH;
Sameer Arora, MD, MPH; Zeeshan Hussain , MD; Guneesh Uberoi, MD; Alfonso Tafur , MD, MSc; Cen Zhang , MD;
Mark Ricciardi, MD; Arman Qamar , MD, MPH

BACKGROUND AND PURPOSE: Antiplatelet therapy is key for preventing thrombotic events after transient ischemic attack or
ischemic stroke. Although the role of aspirin is well established, there is emerging evidence for the role of short-term dual
antiplatelet therapy (DAPT) in preventing recurrent stroke.

METHODS: We conducted a systematic review and study-level meta-analyses of randomized controlled trials comparing outcomes
of early initiation of short-term DAPT (aspirin+P2Y12 inhibitor for up to 3 months) versus aspirin alone in patients with acute
stroke or transient ischemic attack. Primary efficacy outcome was risk of recurrent stroke and primary safety outcome was
incidence of major bleeding. Secondary outcomes studied were risk of any ischemic stroke, hemorrhagic stroke, major adverse
cardiovascular events, and all-cause death. Pooled risk ratios (RRs) and CIs were calculated using a random-effects model.

RESULTS: Four trials with a total of 21 459 patients were included. As compared to aspirin alone, DAPT had a lower risk of
recurrent stroke (RR, 0.76 [95% CI, 0.68–0.83]; P<0.001; I2=0%) but a higher risk of major bleeding events (RR, 2.22 [95%
CI, 1.14–4.34], P=0.02, I2=46.5%). Patients receiving DAPT had a lower risk of major adverse cardiovascular events (RR,
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0.76 [95% CI, 0.69–0.84], P<0.001, I2=0%) and recurrent ischemic events (RR, 0.74 [95% CI, 0.67–0.82], P<0.001, I2=0%).
CONCLUSIONS: As compared to aspirin alone, short-term DAPT within 24 hours of high-risk transient ischemic attack or mild-
moderate ischemic stroke reduces the risk of recurrent stroke at the expense of higher risk of major bleeding.

GRAPHIC ABSTRACT: An online graphic abstract is available for this article.

Key Words: aspirin ◼ hemorrhage ◼ incidence ◼ ischemic attack, transient ◼ ischemic stroke

P
atients who experience a transient ischemic attack
(TIA) or minor ischemic stroke face a high risk of
recurrent thrombotic events, especially within 3
months of the index event.1–3 The efficacy and safety
of aspirin in preventing the incidence and lessening the
severity of recurrent stroke is well established.2,4,5 Plate-
let inhibition with dipyridamole alone or with aspirin is not
superior to aspirin alone,5 and triple antiplatelet therapy
with aspirin, clopidogrel, and dipyridamole increases the
risk of major bleeding.6 Although dual antiplatelet ther-
apy (DAPT) with combination of aspirin with a P2Y12
inhibitor has become the cornerstone of antithrombotic
therapy in patients with acute coronary syndromes, the
role of this approach in patients presenting with isch-
emic stroke or TIA is not definitively established. The
recently published THALES study (Acute Stroke or
Transient Ischaemic Attack Treated With Ticagrelor and
Aspirin for Prevention of Stroke and Death) is the largest

Correspondence to: Arman Qamar, MD, MPH, Section of Interventional Cardiology and Vascular Medicine, NorthShore University Health System, 2650 Ridge Ave,
Evanston, Illinois. Email aqamar@alumni.harvard.edu.
*K. Bhatia and V. Jain contributed equally
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.033033.
For Sources of Funding and Disclosures, see page e222.
© 2021 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

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 Bhatia et al
Nonstandard Abbreviations and Acronyms
Brief Report
CHANCE Clopidogrel in High-Risk Patients With
Acute Nondisabling Cerebrovascular
Events
DAPT dual antiplatelet therapy
FASTER Fast Assessment of Stroke and Tran-
sient Ischemic Attack to Prevent Early
Recurrence
MACE major adverse cardiovascular events
POINT Platelet-Oriented Inhibition in New TIA
and Minor Ischemic Stroke
RR risk ratio
THALES Acute Stroke or Transient Ischaemic
Attack Treated With Ticagrelor and Aspi-
rin for Prevention of Stroke and Death
TIA transient ischemic attack
randomized controlled trial comparing aspirin with DAPT
in patients with minor stroke. This trial compared aspi-
rin monotherapy to aspirin plus ticagrelor, rather than
clopidogrel. This has renewed the interest in optimizing
antithrombotic therapy after ischemic stroke or TIA. In
this meta-analysis, we compare the safety and efficacy
of aspirin plus a P2Y12 inhibitor with aspirin alone for
the prevention of recurrent stroke in patients with minor
ischemic stroke or high-risk TIA.
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METHODS
Search Strategy and Study Characteristics
We searched Medline, EMBASE, Web of Science, and
Cochrane Central from inception through July 2020 for eli-
gible studies with the terms “ischemia,” “stroke,” “cerebral
infarction,” “transient ischemic attack,” “aspirin,” “clopidogrel,”
“ticagrelor,” “prasugrel,” and “antiplatelets.” We also searched
the references of the included studies to identify any addi-
tional studies. We considered trials that included adult patients
with acute stroke or TIA randomized to receive antiplatelet
therapy within 24 hours of symptom onset and compared
safety and efficacy outcomes between DAPT with aspirin and
a P2Y12 inhibitor versus aspirin alone. We excluded observa-
tional studies for the purpose of this analysis. Two reviewers
screened the title and abstracts of the retrieved studies to
select studies that met the inclusion criteria. In case of any
disagreement, a third reviewer (A.Q.) helped in establishing
consensus. The authors declare that all supporting data are
available within the article or Data Supplement.
Outcome Measures
Primary efficacy outcomes of interest was recurrent stroke
(hemorrhagic or ischemic) with DAPT compared with aspi-
rin monotherapy. Primary safety outcome was the occur-
rence of major bleeding, defined as any bleed that resulted in
hemodynamic compromise, hypovolemic shock requiring an
e218   June 2021
Dual Antiplatelet Therapy in Minor Stroke or TIA
intervention, requirement of blood transfusion, or symptom-
atic intracranial hemorrhage. Table I in the Data Supplement
addresses the different definitions of major bleeds across
the included trials. Secondary outcomes of interest were risk
of any ischemic stroke, hemorrhagic stroke, all-cause death,
and major adverse cardiovascular events (MACE), defined as
a composite of myocardial infarction, any stroke, and cardio-
vascular death.
Statistical Analysis
We calculated pooled risk ratios (RRs) using a random-effects
model.7 A random-effects model was used to account for inter-
study heterogeneity due to variation in the included population.
Heterogeneity among studies was assessed using the Higgins
I2 value.8 I2 values of 25%, 50%, and 75% were considered
to represent low, moderate, and high levels of heterogeneity,
respectively. We conducted a meta-regression analysis using
mixed-effects modeling to explain any heterogeneity observed
secondary to the duration of DAPT in the intervention arm of
each trial. To address heterogeneity secondary to differences in
the duration of follow-up, we pooled prespecified hazard ratios
and the 95% CI for the primary efficacy and safety outcomes.
Publication bias was assessed visually with funnel plots. All
P values were 2-tailed with statistical significance specified
at 0.05 and CI reported at 95% level. Stata version 16 and
R package, metafor, version 3.6.2 (R Foundation) were used
for analyses. This study was reported in accordance with the
Preferred Reporting Items for Systematic reviews and Meta-
Analyses amendment to the Quality of Reporting of Meta-
analyses statement.
RESULTS
Study Population
The initial literature search retrieved 8211 citations.
After title, abstract, and full-text review, 4 randomized
controlled trials with a total of 21,459 patients were
included in this study-level meta-analysis (Figure I in
the Data Supplement).9–12 The design and characteris-
tics of patients enrolled in these trials are described in
the Table. The studies excluded patients if they had a
presumed cardioembolic stroke, received thrombolytics,
were planned for endovascular therapy, or had underly-
ing indications for anticoagulation. Three trials compared
the combination of clopidogrel to aspirin versus aspirin
monotherapy, whereas the THALES study compared
the combination of ticagrelor with aspirin versus aspirin
alone. All included patients had mild to moderate non-
cardioembolic ischemic stroke (National Institutes of
Health Stroke Scale score 0–5) or TIA, and the duration
of DAPT ranged between 21 and 90 days. Duration of
follow-up ranged from 30 to 90 days. Patients’ mean age
was 62 to 68 years and 3% to 47% of participants were
female. Most patients had hypertension (50.1%–77.3%).
Current or previous smoking history (26%–43%), prior
stroke or TIA (21%–23%), and diabetes (10%–28%)
were the other common comorbidities.
Stroke. 2021;52:e217–e223. DOI: 10.1161/STROKEAHA.120.033033
 Bhatia et al Dual Antiplatelet Therapy in Minor Stroke or TIA

Table. Study Designs, Treatment Protocols, and Baseline Characteristics of the Included Studies

Trial name FASTER 20079 CHANCE 201310 POINT 201811 THALES 202012

Brief Report
Study characteristics
No. of patients randomized 392 5170 4881 11 016
Study design Double blind Double blind Double blind Double blind
Location North America China Multinational Multinational
Treatment arm Aspirin+clopidogrel Aspirin+clopidogrel Aspirin+clopidogrel Aspirin+ticagrelor
Dose Aspirin: loading dose 162 mg Aspirin: 75 mg/d for 21 d, Aspirin: 162 mg/d for 5 d Aspirin: loading dose 325 or
then 81 mg/d, clopidogrel: clopidogrel: loading dose 300 then 81 mg/d,* clopidogrel: 300 mg then 75–100 mg/d,
loading dose 300 mg then mg then 75 mg/d loading dose 600 mg then ticagrelor: loading dose 180
75 mg/d 75 mg/d mg then 90 mg twice a day
Comparison Aspirin alone Aspirin alone Aspirin alone Aspirin alone
Comparison arm dose Aspirin: loading dose 162 mg Aspirin: 75 mg/d for 90 d Aspirin: 162 mg/d for 5 d Aspirin: loading dose 325 or
then 81 mg/d then 81 mg/d 300 mg then 75–100 mg/d
Duration of antiplatelets 90 d 21 d 90 d 30 d
Inclusion NIHSS score 0–3 0–3 0–3 0–5
Initiation of antiplatelets Within 24 h Within 24 h Within 12 h Within 24 h
Primary outcome Recurrent stroke (ischemic or Recurrent stroke (ischemic or Major ischemic events Composite of stroke or death
hemorrhagic) hemorrhagic)
Duration of follow-up 90 d 90 d 90 d 30 d
Baseline characteristics
Mean age (SD) 68.1 (13.1) 62.8 (12.6) 64.8 (13.7) 65.2 (11.0)
Females 47.2% 33.9% 45 % 38.8%
Hypertension 50.1% 65.7% 69.4% 77.3%
Diabetes 10.8% 21.1% 27.5% 28.6%
Dyslipidemia 7.1% 11.1% n/r n/r
Current or previous smoker 26.0% 42.9% 20.6% 26.6%
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Myocardial ischemia 4.8% 1.9% n/r n/r

Previous stroke/TIA 23.5% 23.3% n/r 21.2%
Qualifying events
TIA 2.6% 28.0% 43.2% 9.4%
Stroke 97.4% 72.1% 56.8% 90.6%

CHANCE indicates Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events; FASTER, Fast Assessment of Stroke and Transient Ischemic
Attack to Prevent Early Recurrence; NIHSS, National Institutes of Health Stroke Scale; n/r, not reported; POINT, Platelet-Oriented Inhibition in New TIA and Minor Ischemic
Stroke; THALES, Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death; and TIA, transient ischemic attack.
*This was the recommended regimen in the trial; however the dose of aspirin was determined by the treating physicians and ranged between 50 and 325 mg/d.

Outcomes P=0.13; I2=14.7%; [Figure 2D]). For patients receiving

DAPT with clopidogrel and aspirin, the number needed to
In comparison to aspirin monotherapy, patients treated with
treat to prevent an additional ischemic stroke ranged from
DAPT had a lower risk of recurrent stroke (RR, 0.76 [95%
21 to 58, compared with patients taking aspirin alone. The
CI, 0.68–0.83]; P<0.001; I2=0%; [Figure 1A]). However,
number needed to harm ranged from 40 in the FASTER
patients receiving DAPT had a higher risk of major bleed-
trial (Fast Assessment of Stroke and Transient Ischemic
ing (RR, 2.22 [95% CI, 1.14–4.34], P=0.02, I2=46.5%;
Attack to Prevent Early Recurrence) to 186 in the POINT
[Figure 1B]). Similar magnitudes of relative risk reduc-
trial (Platelet-Oriented Inhibition in New TIA and Minor
tion were obtained when outcomes were pooled using
Ischemic Stroke) for major bleeding. In the CHANCE trial
prespecified hazard ratios (Figure IIA and IIB in the Data
(Clopidogrel in High-Risk Patients With Acute Nondis-
Supplement). Among the secondary outcomes assessed,
abling Cerebrovascular Events), patients receiving DAPT
patients on DAPT had a lower risk of MACE (RR, 0.76
experienced lower bleeding events compared to patients
[95% CI, 0.69–0.84], P<0.001, I2=0%; [Figure 2A]) and
treated with aspirin. DAPT using ticagrelor resulted in a
recurrent ischemic events (RR, 0.74 [95% CI, 0.67–0.82],
number needed to treat of 78 to prevent an additional
P<0.001, I2=0%; [Figure 2B]) during the follow-up period.
ischemic stroke and a number needed to harm of 221 for
There was no difference in the risk of hemorrhagic stroke
major bleeding. Thus, in terms of absolute risk, in all trials,
(RR, 1.82 [95% CI, 0.83–3.98], P=0.13, I2 =14.7%; [Fig-
the absolute benefits of DAPT appear to be greater than
ure 2C]) or all-cause death (RR, 1.30 [95% CI, 0.90–1.89],
the significantly elevated bleeding risk.

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 Bhatia et al Dual Antiplatelet Therapy in Minor Stroke or TIA
Brief Report

Figure 1. Pooled risk-ratios and 95% confidence intervals.

A, Recurrent ischemic or hemorrhagic stroke. B, Major bleeding. CHANCE indicates Clopidogrel in High-Risk Patients With Acute Nondisabling
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Cerebrovascular Events; DAPT, dual antiplatelet therapy; FASTER, Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early
Recurrence; POINT, Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke; RR, risk ratio; and THALES, Acute Stroke or Transient
Ischaemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death.

The degree of heterogeneity between the studies
was low to moderate (I2=0–46.5). Mixed-effects meta-
regression models demonstrated a nonsignificant posi-
tive correlation with the increasing duration of DAPT and
risk of major bleeding (Figure III in the Data Supplement).
However, this meta-regression analysis is limited by the
low number of trials included in this study. Visual analysis
of the funnel plots suggested no publication bias (Online
Supplement Figure IVA and IVB); however, Egger test
was not performed due to lack of sufficient trials. All
studies were judged to have a low risk of bias (Figure V
in the Data Supplement).
DISCUSSION
Our meta-analysis supports the use of DAPT with aspirin
and a P2Y12 inhibitor as compared with aspirin mono-
therapy in patients presenting with minor ischemic stroke
or TIA, with the recognition of increased risk of major
bleeding. Pooled analysis of trial-level data revealed
a statistically significant reduction in recurrent stroke,
driven mainly by a reduction in ischemic stroke. In addi-
tion, treatment with DAPT resulted in a significantly lower
risk of MACE. Although there was no significant increase
in the risk of hemorrhagic stroke, DAPT was associated
with an increased risk of major bleeding.
The FASTER trial was the first study to examine the
efficacy of early DAPT (aspirin and clopidogrel) com-
pared with aspirin monotherapy in patients with minor
stroke or TIA. In this trial, the patients in the DAPT arm
had a numerically lower but statistically nonsignifi-
cant reduction in recurrent strokes at the expense of
increase in symptomatic bleeding at 90 days follow-up.
After the preliminary insights from the FASTER trial,
the efficacy and safety of the combination of aspirin
and clopidogrel in preventing recurrent stroke in minor
stroke (National Institutes of Health Stroke Scale score
≤3) or high-risk TIA (ABCD2 score ≥4) was established
by 2 large scale multicenter studies: the CHANCE and
POINT trials. The CHANCE trial was a multicenter trial
that was conducted in China. Patients randomized to the
DAPT arm received a combination of aspirin and clopi-
dogrel for 21 days. Patients with DAPT had a significant
reduction in recurrent stroke and MACE events with no
significant difference in the risk of severe or moderate
bleeding. In contrast to CHANCE, the POINT trial was

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 Bhatia et al Dual Antiplatelet Therapy in Minor Stroke or TIA

Brief Report
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Figure 2. Pooled risk-ratios and 95% confidence intervals.

A, Major adverse cardiovascular events. B, Recurrent ischemic stroke. C, Hemorrhagic stroke. D, All-cause death. H2 and I2 values are measures for
quantifying heterogeneity in a metanalysis. CHANCE indicates Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events;
DAPT, dual antiplatelet therapy; FASTER, Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence; POINT, Platelet-
Oriented Inhibition in New TIA and Minor Ischemic Stroke; RR, risk ratio; and THALES, Acute Stroke or Transient Ischaemic Attack Treated With
Ticagrelor and Aspirin for Prevention of Stroke and Death.

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 Bhatia et al
a multinational trial that randomized patients within 12
hours of symptom onset and continued aspirin and clop-
idogrel in the DAPT arm for 90 days. Although DAPT
Brief Report
proved superior to aspirin monotherapy in preventing
recurrent ischemic strokes, the risk of major and minor
hemorrhage was significantly increased. A second-
ary analysis of the treatment effect stratified by differ-
ent time points demonstrated that the combination of
aspirin and clopidogrel significantly reduced the rate of
ischemic events largely during the initial 7 to 30 days
whereas the risk of hemorrhage increased significantly
between 8 and 90 days after starting treatment. Pos-
sible causes for the low bleeding events in CHANCE
included a shorter duration DAPT (21 days in CHANCE
versus 90 days in POINT) and increased prevalence of
genetic polymorphism of CYP2C19 in the Asian popula-
tion resulting in decreased antiplatelet effect.
Ticagrelor is a direct antagonist of the P2Y12 inhibi-
tor and has a more consistent and potent antiplate-
let effect compared with clopidogrel. The THALES
trial tested the efficacy of adding ticagrelor to aspirin
monotherapy in preventing recurrent strokes. 11 016
patients with mild to moderate stroke (National Insti-
tutes of Health Stroke Scale score ≤5) or high-risk TIA
(ABCD2 score ≥6) were included and DAPT was given
for 30 days. Patients receiving DAPT had a lower rate
of recurrent stroke or all-cause death. Incidence of
overall disability (modified Rankin Scale score >1) was
similar between the treatment arms. Although bleed-
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ing events occurred infrequently, patients on DAPT
had an increased risk of moderate to severe bleeding
driven by an increase in intracranial or fatal bleeding
when compared with aspirin monotherapy. This was in
contrast to the POINT trial, where the increased risk
of major hemorrhage was driven by nonfatal extracra-
nial bleeding events in the DAPT arm. However, the
POINT and CHANCE trials utilized lower loading dos-
ing of aspirin (75 and 162 mg, respectively) compared
with the THALES trial. Taken together, in patients with
minor stroke or high-risk TIA, short-term DAPT for at
least 21 days resulted in significant reduction in recur-
rent stroke, albeit at a small but significantly increased
risk of major bleeding. Current data are insufficient to
suggest one P2Y12 agent over the other. The ongoing
CHANCE-2 trial comparing different DAPT strategies
may provide further insight.
Our meta-analysis has certain limitations. Differences
in the definition of major bleeding and doses used, along
with variation in the duration of follow-up likely contrib-
uted to the moderate heterogeneity associated with the
primary safety outcome of major bleeding. There was
residual heterogeneity even after adjusting for the fol-
low-up period and duration of DAPT. Due to the lack of
patient-level data, we were also unable to investigate the
effect of background therapies on the primary efficacy
and safety end points. All trials enrolled patients with
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Dual Antiplatelet Therapy in Minor Stroke or TIA
minor strokes or high-risk TIAs, so these meta-analytic
findings do not generalize to patients with moderate to
severe strokes, low-risk TIA, presumed cardioembolic
strokes, and patients receiving anticoagulation or intra-
venous fibrinolytics.
CONCLUSIONS
DAPT with aspirin and ticagrelor or clopidogrel given
within 24 hours of high-risk TIA or noncardioembolic mild
to moderate stroke effectively reduces the risk of recur-
rent stroke and MACE compared with aspirin monother-
apy. DAPT is associated with a higher risk of bleeding
events, but there is no difference in the risk of all-cause
death. Thus, the decision to use DAPT with the addition
of clopidogrel or ticagrelor to aspirin must be individual-
ized and guided by the patient’s underlying thrombotic
and bleeding risk profile.
ARTICLE INFORMATION
Received October 16, 2020; final revision received February 12, 2021; accepted
March 19, 2021.
Affiliations
Department of Medicine, Icahn School of Medicine at Mount Sinai, NY (K.B.).
Department of Medicine, Cleveland Clinic, Cleveland, OH (V.J.). Department of
Medicine, Beaumont Hospital, Royal Oak, MI (D.A.). Cardiovascular Division,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (M.V.). Car-
diovascular Division, University of North Carolina School of Medicine, Chapel Hill
(S.A.). Division of Cardiology, Loyola University School of Medicine, Maywood, IL.
Department of Medicine, Emory University School of Medicine, Atlanta, GA (G.U.).
Section of Interventional Cardiology and Vascular Medicine, NorthShore Univer-
sity Health System, Evanston, IL (A.T., M.R., A.Q.). Department of Neurology, New
York University Grossman School of Medicine (C.Z.).
Disclosures
Dr Vaduganathan has received research grant support or served on advisory
boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare,
Boehringer Ingelheim, Cytokinetics, and Relypsa, and participates on clinical end
point committees for studies sponsored by Galmed, Novartis, and the National
Institutes of Health (NIH). Dr Qamar reports receiving institutional grant support
from the NorthShore Auxiliary research scholar fund, Daiichi-Sankyo, American
Heart Association, and fees for educational activities from the American College
of Cardiology, Society for Vascular Medicine, Society for Cardiovascular Angi-
ography and Interventions, Janssen and Janssen, Pfizer, Medscape, and Clini-
cal Exercise Physiology Association. Dr Tafur reports nonfinancial support from
Recovery Force, grants from JANSSEN, and grants from Bristol Myers Squibb
outside the submitted work. The other authors report no conflicts.
Supplemental Materials
Online Table I
Online Figures I–V
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