Hindawi

Cardiovascular erapeutics
Volume 2019, Article ID 1607181, 12 pages
https://doi.org/10.1155/2019/1607181

Review Article
Benefits and Risks of Clopidogrel vs. Aspirin Monotherapy after
Recent Ischemic Stroke: A Systematic Review and Meta-Analysis

Maurizio Paciaroni ,1 Birsen Ince,2 Bo Hu,3 Jiann-Shing Jeng,4 Kursad Kutluk,5

Liping Liu ,6 Min Lou,7 Vladimir Parfenov,8 Ka Sing Lawrence Wong,9 Babak Zamani,10
Dara Paek,11 Jung Min Han,11 Michael del Aguila,11 and Shalini Girotra12
1
Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy
2
Department of Neurology, Division of Cerebrovascular Diseases, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
3
Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
4
Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
5
Department of Neurology, Dokuz Eylul University, Izmir, Turkey
6
Department of Neurology and Stroke Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
7
The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
8
Department of Nervous Diseases and Neurosurgery, Sechenov First Moscow State Medical University, Moscow, Russia
9
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
10
Iranian Stroke Society, Tehran, Iran
11
Doctor Evidence, Santa Monica, CA, USA
12
Sanofi, General Medicines and Emerging Markets, Singapore

Correspondence should be addressed to Maurizio Paciaroni; [email protected]

Academic editor: Joel C. Marrs

Received 16 May 2019; Revised 16 August 2019; Accepted 17 September 2019; Published 1 December 2019

Copyright © 2019 Maurizio Paciaroni et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Aim. Though combination of clopidogrel added to aspirin has been compared to aspirin alone in patients with stroke or transient
ischemic attack, limited data exists on the relative efficacy and safety between clopidogrel and aspirin monotherapy in patients with a
recent ischemic stroke. We aimed to compare clopidogrel versus aspirin monotherapy in this population. Methods. PubMed, Embase,
and CENTRAL databases were searched from inception to May 2018 to identify clinical trials and observational studies comparing
clopidogrel versus aspirin for secondary prevention in patients with recent ischemic stroke within 12 months. Pooled effect estimates
were calculated using a random effects model and were reported as risk ratios with 95% confidence intervals. Results. Five studies
meeting eligibility criteria were included in the analysis. A total of 29,357 adult patients who had recent ischemic stroke received
either clopidogrel (𝑛 = 14, 293) or aspirin (𝑛 = 15, 064) for secondary prevention. Pairwise meta-analysis showed a statistically
significant risk reduction in the occurrence of major adverse cardiovascular and cerebrovascular events (risk ratio 0.72 [95% CI,
0.53–0.97]), any ischemic or hemorrhagic stroke (0.76 [0.58, 0.99), and recurrent ischemic stroke (0.72 [0.55, 0.94]) in patients
who received clopidogrel versus aspirin. The risk of bleeding was also lower for clopidogrel versus aspirin (0.57 [0.45, 0.74]). There
was no difference in the rate of all-cause mortality between the two groups. Conclusions. The analysis showed lower risks of major
adverse cardiovascular or cerebrovascular events, recurrent stroke, and bleeding events for clopidogrel monotherapy compared to
aspirin. These findings support clinical benefit for single antiplatelet therapy with clopidogrel over aspirin for secondary prevention
in patients with recent ischemic stroke.

1. Introduction year, of which 87% are ischemic strokes [2]. Additionally,

approximately 20% of patients with a primary diagnosis of
Stroke is the second most common cause of death and the third stroke have a second stroke within two years, accounting for
most common cause of disability worldwide [1]. Approximately 185,000 annual cases in the United States [2, 3]. Those with
795,000 people in the United States experience a stroke each recurrent strokes have higher costs per patient and are more
2 Cardiovascular Therapeutics

Table 1: Study inclusion and exclusion criteria in PICOTSS format.

(i) Patients with recent ischemic stroke within the previous year
Population
(ii) Subgroup data for ischemic stroke patients in studies with mixed stroke/TIA populations
Interventions Clopidogrel monotherapy (any dosage) for at least four weeks
Comparators Aspirin monotherapy (any dosage) for at least four weeks
Efficacy outcomes
(i) MACCE
 (a) Defined as any composite outcomes that included two or more of the following: recurrent stroke, myocardial infarc-
tion, unstable angina, coronary revascularization, aortic aneurysm rupture, peripheral artery disease, vascular death and
sudden death
(ii) Recurrent stroke (ischemic and hemorrhagic)
Outcomes (iii) Recurrent ischemic stroke
(iv) Mortality
Safety outcome
(i) Bleeding risk
 (a) Intracranial
 (b) Gastrointestinal
 (c) Any reported
Timing Minimum study duration/follow-up of at least four weeks (one month)
Setting No restriction
(i) Randomized controlled trials
Study design
(ii) Comparative observational studies
MACCE: major adverse cardiovascular and cerebrovascular events; TIA: transient ischemic attack.

likely to experience poor outcomes as compared to patients and the Cochrane Central Register of Controlled Trials for
with primary stroke [2, 4–6]. Therefore, secondary stroke pre- studies published from inception to May 2018. Search strategies
vention in patients with a history of ischemic stroke is critical are provided in Supplemental Table I. Search results were
in reducing the overall burden of stroke. It is estimated that exported to Digital Outcome Conversion (DOC™) Library
nearly 80% of secondary strokes can be prevented with anti- Management System (LMS, version 2.0), and duplicates were
platelet therapy when combined with lifestyle changes [2, 7]. removed (Doctor Evidence, Santa Monica, CA) [16]. To ensure
Current guidelines from the American Heart Association that potentially relevant studies were not overlooked, reference
and American Stroke Association recommend antiplatelet lists from other reviews and meta-analyses on the current topic
therapy with aspirin for patients with ischemic stroke [7, 8]. were searched by hand. The Preferred Reporting Items for
Other approved antiplatelet treatment options including clopi- Systematic review and Meta-Analysis protocols (PRISMA)
dogrel, aspirin/dipyridamole, and ticlopidine have been shown guidelines were followed [17].
to be safe and effective for secondary prevention in this pop-
ulation, however, the relative safety and effectiveness among 2.2. Study Selection.  Medical librarians screened titles and
the different antiplatelet agents has still not been clearly estab- abstracts based on a standardized review protocol that
lished [9–13]. Dual antiplatelet therapy with clopidogrel in defined study eligibility criteria using the PICOTSS format,
combination with aspirin has been compared to aspirin in which outlines the participants, interventions, comparators,
reducing recurrent stroke in patients with minor stroke outcomes, timing, setting, and study designs of interest (Table
(within 12–24 hours from onset) or transient ischemic attack 1). Eligible studies were those that compared the beneficial and
(TIA) [14, 15], but data on the efficacy and safety of clopi- harmful effects of clopidogrel and aspirin monotherapies for
dogrel compared to aspirin as single antiplatelet agents exclu- the prevention of recurrent stroke and other cardiovascular
sively in patients with recent ischemic stroke is limited. The complications in patients who experienced ischemic stroke
aim of this study was to conduct a systematic review and in the previous year. Studies that also enrolled patients with
meta-analysis to compare the efficacy and safety of clopidogrel TIA were included only if data for ischemic stroke patients
versus aspirin used as a monotherapy for secondary preven- were reported separately. Randomized controlled trials (RCT)
tion in patients with recent ischemic stroke. Findings from and comparative observational studies with at least 1-month
this comprehensive update on the available body of evidence follow-up were included. There was no restriction for study
will guide healthcare professionals and decision makers on setting. Studies were required to report at least one outcome
the selection of optimal antiplatelet agent for preventative use of interest.
in patients with recent ischemic stroke. Efficacy outcomes included recurrent stroke of any type,
recurrent ischemic stroke, and all-cause mortality. Also col-
lected were major adverse cardiovascular and cerebrovascular
2. Methods events (MACCE). MACCE was defined as a composite out-
come that included two or more of the following: recurrent
2.1. Data Sources and Searches. Literature searches were stroke, myocardial infarction, unstable angina, coronary revas-
performed by a medical librarian (HT) in PubMed, Embase, cularization, aortic aneurysm rupture, peripheral artery
Cardiovascular Therapeutics 3

Records identified through

database searching Additional records identified

Identification
PubMed (n = 1,694) through manual searching
Embase (n = 1,986) (n = 1)
Cochrane (n = 49)

Records after duplicates removed

(n = 2,790)
Screening

Records screened Records excluded

(n =2,790) (n = 2,742)

Full-text articles assessed Full-text articles excluded,

for eligibility with reasons
Eligibility

(n = 48) (n = 42)

Not population of interest (n = 9)

Not intervention of interest (n = 4)
No outcome of interest (n = 22)
No comparison of interest (n = 5)
Studies included in Not a comparative study (n = 1)
qualitative synthesis Duplicate (n = 1)
(n = 6)
Included

Studies included in
quantitative synthesis
(meta-analysis)
(n = 5)

Figure 1: PRISMA flow diagram showing study identification and selection.

disease, vascular death, and sudden death. Safety outcomes (characteristics and outcomes) were collected as reported by
included any reported bleeding events, including intracranial study authors and synonyms were “bound” before analysis
hemorrhage and gastrointestinal bleeding. Only studies pub- using the DOC™ Ontology System. Detailed methods are
lished in English were included for review of the full text. described elsewhere [16].
Studies presented only in conference abstracts without an Quality assessment of the included studies was per-
associated publication were excluded, as this data is not peer formed by two independent reviewers using the Cochrane
reviewed and there is often limited information available on Collaboration tool for assessing the risk of bias for rand-
the details of the study and patient characteristics. A PRISMA omized trials and the Newcastle-Ottawa Scale for cohort
flow diagram was created based on the search results and study studies [18, 19].
selection.
2.4. Statistical Analysis. Pairwise meta-analysis for outcomes
2.3. Data Extraction and Quality Assessment. Relevant were performed using the inverse-variance weighted random
information was extracted by two independent reviewers effects model based on the DerSimonian and Laird 1986
using the Doctor Evidence software platform version 2.0 method to estimate the risk ratio (RR) and 95% confidence
[16]. The following information was collected: study design, interval (CI) [20]. A random effects model took into account
study location, publication year, number of patients in each both within-study and between-study variability. Heterogeneity
arm, intervention, comorbidities, outcomes of interest, was assessed using the 𝐼-squared (𝐼2) statistic, which describes
and study inclusion/exclusion criteria. When available, the the percentage of variation across the studies that is due
definitions and descriptions of stroke and outcomes provided to heterogeneity rather than chance [21]. Percentages of
by the authors were also captured. Any discrepancies in approximately 25%, 50%, and 75% were considered to have
data extraction were resolved by discussion. All terms low, moderate, or high heterogeneity, respectively. Patient and
4 Cardiovascular Therapeutics

study characteristics were visually assessed for any potential 3.2. Quality Assessment. The quality assessment for the
heterogeneity across studies that might have affected pooled included studies is presented in Supplemental Table II. The
effect estimates. Publication bias could not be assessed due risk of bias was rated as low for all seven domains for the RCT.
to the limited number of studies available for all outcomes. All of the observational studies were rated as of high quality,
Multiple analyses were also conducted to consider varying with Newcastle Ottawa Scale scores of eight or nine. The 𝐼2
definitions for the composite MACCE outcome in the event statistic for each outcome is shown in Figures 2 and 3.
that studies reported more than one composite outcome that
could qualify as MACCE. If a study reported multiple composite 3.3. Study and Patient Characteristics. One RCT and four
vascular outcomes, the most inclusive composite outcome was retrospective cohort studies met the PICO criteria for inclusion.
selected for the main analysis [22]. All analyses were performed Study and patient characteristics of the studies are shown in
on DOC™ Data, using R (metaphor package [v.2.0.0]) [23]. Table 2. All retrospective cohort studies were conducted in
a single country (Denmark, Greece, and Taiwan), whereas
the RCT was conducted across 16 countries. All studies were
3. Results published in peer-reviewed journals.
A total of 29,357 adult patients who had recent ischemic
3.1. Literature Search. Of the 2,790 records identified in stroke received either clopidogrel (𝑛 = 14, 293) or aspirin
our search, 2,742 were excluded through title and abstract (𝑛 = 15, 064) for secondary prevention. The proportion of
screening. One additional study was identified manually males ranged from 48% to 73%. The mean age ranged from
after the initial search [24]. Among the 48 full texts reviewed, 64.5 years to 77.6 years. The length of study follow-up ranged
six studies met eligibility criteria (Figure 1). One paper [21] from one year to five years. Comorbidities such as diabetes,
reported on diabetic patients for the same retrospective cohort hypertension, hyperlipidemia, coronary artery disease, myo-
[22] and was therefore excluded, resulting in a total of five cardial infarction, congestive heart failure, and peripheral
studies included in the meta-analysis. artery disease were prevalent at baseline (Table 2). There was

Clopidogrel Aspirin

Author, Year Events Patients (N) Events Patients (N) Weight RR (95% CI)

CAPRIE, 1996 433 3233 461 3198 37.19% 0.93 (0.82, 1.05)

Lee, 2014 155 384 799 1500 36.51% 0.76 (0.67, 0.86)

Milonis, 2011 60 348 249 880 26.30% 0.61 (0.47, 0.78)

RE Model (Q = 10.72, df = 2, p = 0.00; I2 = 81.3%) 100.00% 0.77 (0.63, 0.95)

0.1 0.2 0.5 1 2 5 10

Risk ratio (log scale)
(a)

Clopidogrel Aspirin

Author, Year Events Patients (N) Events Patients (N) Weight RR (95% CI)

Lee, 2014 81 378 520 1500 35.07% 0.62 (0.50, 0.76)

Milonis, 2011 46 348 153 880 28.00% 0.76 (0.56, 1.03)

Chi NF, 2018 244 7611 223 6443 36.93% 0.93 (0.77 1.11)

RE Model (Q = 8.52, df = 2, p = 0.01; I2 = 76.5%) 100.00% 0.76 (0.58, 0.99)

0.5 0.75 1 1.5

Risk ratio (log scale)
(b)

Figure 2: Continued.
Cardiovascular Therapeutics 5

Clopidogrel Aspirin

Author, Year Events Patients (N) Events Patients (N) RR (95% CI)

Lee 2014 75 384 470 1500 0.62 (0.50, 0.77)

Christiansen, 2015 291 3885 360 3043 0.63 (0.55, 0.73)

CAPRIE, 1996 315 3233 338 3198 0.92 (0.80, 1.07)

RE Model (Q = 15.49, df = 2, p = 0.00; I2 = 87.09%) 0.72 (0.55, 0.94)

0.45 0.67 1
Risk ratio (log scale)
(c)

Clopidogrel Aspirin

Author, Year Events Patients (N) Events Patients (N) Weight RR (95% CI)

Lee, 2014 64 384 229 1500 36.22% 1.09 (0.85, 1.41)

Milonis, 2011 17 348 75 880 20.28% 0.57 (0.34, 0.96)

Chi NF, 2018 362 6443 302 6443 43.50% 1.20 (1.03, 1.39)

RE Model (Q = 7.42, df = 2, p = 0.02; I2 = 73.1%) 100.00% 1.00 (0.74, 1.35)

0.3 0.5 0.75 1 1.5 2

Risk ratio (log scale)
(d)

Figure 2: Forest plots showing pooled risk ratio of (a) MACCE, (b) any ischemic or hemorrhagic stroke, (c) recurrent ischemic stroke, and
(d) all-cause mortality.

Clopidogrel Aspirin

Author, Year Events Patients (N) Events Patients (N) RR (95% CI)

Milionis, 2011 3 348 21 880 0.36 (0.11, 1.20)

Lee, 2014 6 384 40 1500 0.59 (0.25, 1.37)

Christiansen, 2015 92 3885 123 3043 0.59 (0.45, 0.76)

RE Model (Q = 0.59, df = 2, p = 0.74; I2 = 0.00%) 0.57 (0.45, 0.74)

0.05 0.14 0.37 1 2.72 7.39

Risk ratio (log scale)

Figure 3: Forest plot showing pooled risk ratio for bleeding events.
6 Cardiovascular Therapeutics

no observed trend in different patient characteristics between may underestimate the true preventative effects of
two treatment groups upon inspection. Two studies did not clopidogrel.
enroll patients with a history of atrial fibrillation [22, 25] and Bleeding event data was only available from retrospective
three studies did not enroll patients who had received anti- cohort studies. Any reported bleeding events including both
coagulation therapy [24–26]. The average daily dose of clopi- composite bleeding events and specific bleeding events were
dogrel was similar across the studies that reported the combined (e.g., intracranial hemorrhage and gastrointestinal
average daily dose (~75 mg/day), whereas the average daily bleeding). These bleeding events were captured from insurance
dosage of aspirin varied from 102 mg/day to 325 mg/day. The databases or national registries, and it is reasonable to assume
reported outcome definitions varied across studies, most that these events were severe enough to require medical atten-
notably for MACCE and bleeding events (Supplemental tion (e.g., office visit or hospitalization). However, due to the
Table III). nature of the claim-based database and national registries, we
were unable to compare bleeding events by severity. In one
3.4. Comparative Efficacy and Effectiveness. Results of the study [22], the authors noted that clopidogrel was prescribed
pairwise meta-analysis showed a statistically significantly only for those with pre-existing gastrointestinal ulcers or
lower risk of MACCE among patients who received clopidogrel bleeding issues or for those who have already failed on aspirin.
compared to those who received aspirin (RR 0.77 [95% CI, This is important to note as the results may not reflect the true
0.63, 0.95]; Figure 2(a)). The risks of stroke of any type, rate of bleeding events associated with clopidogrel use.
ischemic or hemorrhagic, (0.76 [0.58, 0.99]; Figure 2(b)), and Selecting optimal therapy for secondary stroke prevention
recurrent ischemic stroke (0.72 [0.55, 0.94]; Figure 2(c)) were requires careful attention, as these patients often present with
statistically significantly lower with clopidogrel therapy. There comorbidities and other risk factors which may influence pre-
was no difference found for the rate of all-cause mortality scription and treatment effectiveness. The boxed label warning
(Figure 2(d)). for clopidogrel cautions against use of clopidogrel in patients
Sensitivity analysis using a more restrictive definition for with impaired platelet reactivity due to known genetic poly-
MACCE reported in Lee et al. 2014 (i.e., ischemic or hemor- morphisms of CYP2C19 [28]. The majority of studies in this
rhagic stroke or MI) showed a similar result; patients receiving review included data from before 2010 and genotype testing
clopidogrel experienced a lower rate of MACCE (0.72 [0.47, or platelet monitoring via platelet function tests may not have
0.78]) compared to aspirin (Supplemental Table IV and been performed, as routine testing is still not included in any
Supplemental Figure I). current guideline recommendations. The included observa-
tional studies used claim-based or registry data, and in such
3.5. Safety. Bleeding events were reported in three studies real-world settings, the selection of antiplatelets was based on
(Supplemental Table V). Statistically significant reduction in physicians’ preference and receipt of clopidogrel often
risk of bleeding events was shown for clopidogrel (0.57 [0.45, depended on insurance or drug formularies and requirements
0.74]) compared to aspirin (Figure 3). by country. However, this information was not reported in the
studies. Due to the nature of the retrospective cohort studies
included in this analysis, clinicians should be aware that
4. Discussion unknown and therefore unmeasured confounders might have
affected our effect estimates differentially.
The results of our review suggest clinical benefit for single Aspirin remains the recommended antiplatelet therapy for
antiplatelet therapy with clopidogrel over aspirin in recent patients with ischemic stroke in current guidelines [8].
ischemic stroke patients. Pooled relative risk estimates for Published trial data suggests clopidogrel as single antiplatelet
major composite cardiovascular and cerebrovascular events, therapy is safe and effective for secondary prevention com-
recurrence of ischemic stroke, or any ischemic or hemorrhagic pared to aspirin and the combination of aspirin/dipyridamole
stroke were all significantly lower for clopidogrel monotherapy [27, 29]. However, the strength of the evidence in support of
compared to aspirin. Risk of bleeding events were also signif- clopidogrel over other antiplatelet agents is limited by the few
icantly lower with clopidogrel therapy. numbers of studies that make direct comparison to clopidogrel
Although broad searches were conducted to identify and as single antiplatelet therapy, and more recent data is based on
include all available literature and sensitivity analyses were the combination of clopidogrel and aspirin in mixed popula-
run to test the robustness of our findings, there are some lim- tions with ischemic stroke or TIA. In the absence of further
itations to be considered when interpreting these results. clinical trials, indirect evidence obtained through further
Studies often reported composite outcomes as their primary meta-analysis and data from prospective patient registries may
outcome because a smaller sample size is required to ade- provide valuable insights on the efficacy and safety of clopi-
quately power a composite outcome as compared to individual dogrel relative to aspirin for secondary prevention patients
outcomes. Definitions of MACCE and recurrent stroke that with ischemic stroke.
most closely resembled the definitions reported in other stud- To our knowledge, this is the first systematic review and
ies were used, but data collection was limited to the published meta-analysis conducted in patients with recent ischemic
study-level results. The between-study heterogeneity found in stroke specifically, as most of the current evidence is based on
our analyses remain unexplained due to the nature of obser- stroke and TIA populations. We included all published clinical
vational studies. Thus, the pooled preventative effects of clopi- trials and observational studies that made direct comparison
dogrel over aspirin shown for MACCE and recurrent stroke of clopidogrel and aspirin monotherapy for secondary
 Table 2: Study and patient characteristics of the included studies.

Study, design,
Inclusion criteria Exclusion criteria Follow-up duration Treatment groups (𝑁) Age (yr)* Male, % Comorbidities, %
location
Patients (≥21 years) with
(i) Severe cerebral deficit likely to
CAPRIE (1996) ischemic stroke (retinal and Minimum of 1 year and Clopidogrel (3,233) 75
lead to patient being bedridden or 64.7 ± 11.0 63 Angina: 17
[27]† lacunar infarction) with the maximum of 3 year mg/d
demented
following:
(i) focal neurological
(ii) Carotid endarterectomy after Mean follow-up: 1.91
RCT deficit likely to be of Atrial fibrillation: 4
qualifying stroke years
Cardiovascular Therapeutics

atherothrombotic origin
(iii) Qualifying stroke induced Total person-time:
(ii) onset ≥ 1 week and ≤ 6
16 countries by carotid endarterectomy or Clopidogrel: 6,054 Cardiomegaly: 5
months before randomization
angiography person-years at risk;
(iii) neurological signs
(iv) Unlikely to be discharged alive Aspirin: 5,979
persisting ≥1 week from CHF: 4
after qualifying event person-years at risk
stroke onset
(iv) CT or MRI ruling out (v) Severe co-morbidity likely to
hemorrhage or non-relevant limit patient’s life expectancy to Diabetes: 26
disease <3 years
(vi) Uncontrolled hypertension Hyperlipidemia: 38
Hypertension: 65
Ischemic stroke: 19
Myocardial infarction:
11
TIA/RIND: 19
Aspirin (3,198) 325
64.5 ± 11.2 64 Angina: 17
mg/d
Atrial fibrillation: 4
Cardiomegaly: 6
CHF: 4
Diabetes: 25
Hyperlipidemia: 37
Hypertension: 65
Ischemic stroke: 17
Myocardial infarction:
13
TIA/RIND: 19
Adult patients from the
Taiwanese Stroke Registry
For 1 year after the
Chi et al. who had ischemic stroke and (i) Received a combination of
diagnosis of ischemic Clopidogrel (6,443) 71.4 ± 13.2 60.5 Atrial fibrillation: 4.3
(2018) [24] whose survival statuses one aspirin and clopidogrel,
stroke
year after the index stroke
were confirmed
7
 8
Table 2: Continued.

Study, design,
Inclusion criteria Exclusion criteria Follow-up duration Treatment groups (𝑁) Age (yr)* Male, % Comorbidities, %
location
CHD: 2.20
(ii) Received other medicine CVA/TIA: 32.7
Retrospective
including Aggrenox, ticlopidine,
cohort Diabetes: 42.1
cilostazol, or warfarin
Heart disease: 34.4
(iii) Died during hospitalization
Hyperlipidemia: 45.9
for acute ischemic stroke
Taiwan
(iv) With missing data Hypertension: 78.6
(v) Died at discharge IHD: 17.1
(vi) Had recurrent stroke before Myocardial infarction:
Aspirin (6,443)
discharge 0.34
71.8 ± 16.3 60.2 Atrial fibrillation: 4.33
CHD: 2.20
CVA/TIA: 34.6
Diabetes: 42.3
Heart disease: 33.0
Hyperlipidemia: 45.0
Hypertension: 79.2
IHD: 17.9
Myocardial infarction:
0.25
From 30 days after
Patients with first-time
discharge until patients
ischemic stroke discharged Atrial fibrillation or anticoagu-
Christiansen et had an outcome, died, 68.6 (59.2–
from Jan. 2017 to Dec. 2010 lation therapy before or up to 30 Clopidogrel (3,885) 49 Diabetes: 11.7
al. (2015) [25] emigrated, or 1 year 77.6)
and those who survived the days after discharge
after discharge, which-
first 30 days after stroke
ever comes first
Retrospective
Bleeding: 8.2
cohort
Median follow-up: 335
Cancer: 6.3
days [335–335]
Total person-time:
Denmark
Clopidogrel: 3,364
COPD: 7.1
person-years; Aspirin:
2,475 person-years
Heart failure: 5.9
Hypertension: 42.3
Myocardial infarction:
13.5
Aspirin (3,043) PAD: 4.6
Cardiovascular Therapeutics
 Table 2: Continued.

Study, design,
Inclusion criteria Exclusion criteria Follow-up duration Treatment groups (𝑁) Age (yr)* Male, % Comorbidities, %
location
75.3 (64.5–
48 Bleeding: 13.3
83.7)
Cancer: 6.8
COPD: 8.4
Diabetes: 12.5
Heart failure: 7.3
Cardiovascular Therapeutics

Hypertension: 43.2
Myocardial infarction:
11
PAD: 4.1
Hospitalized adults who were
admitted with a primary
diagnosis of ischemic stroke
Lee et al. (i) Atrial fibrillation, valvular heart Mean follow up: 2.4
(index stroke) between 2003 Clopidogrel‡ (384) 70.8 ± 9.5 60 Diabetes: 44.0
(2014) [22] disease, or coagulopathy years
and 2009 and received con-
tinuous aspirin treatment ≥30
days before the index stroke
(ii) Those with poor drug adher-
Retrospective Average daily dose: GI bleeding/peptic
ence (medication possession ratio
cohort 74.6 mg ulcer: 18.8
≤80%)
Taiwan Hyperlipidemia: 20.3
Hypertension: 57.3
IHD: 16.7
Aspirin (1,500) Stroke/TIA: 22.7
Average daily dose:
71.1 ± 10.2 60 Diabetes: 49.1
101.9 mg
GI bleeding/peptic
ulcer: 2.6
Hyperlipidemia: 21.8
Hypertension: 52.0
IHD: 18.9
Stroke/TIA: 18.7
Patients who were hospital-
ized due to an acute ischemic
Clopidogrel (348)
Milionis et al. stroke (atherothrombotic, Those who were treated with For 5 years from index
Average daily dose: 75 77.6 ± 11.0 73 CAD:18.4
(2011) [26] lacunar, cryptogenic) and coumadin stroke
mg/d
had an indication to receive
antiplatelet therapy
9
 10

Table 2: Continued.

Study, design,
Inclusion criteria Exclusion criteria Follow-up duration Treatment groups (𝑁) Age (yr)* Male, % Comorbidities, %
location
Mean follow-up:
Retrospective
Clopidogrel: 38.5 ± 20.4 Diabetes: 66.1
cohort
months;
Aspirin: 40.9 ± 22.2
Greece Hyperlipidemia: 46.3
months
Hypertension: 31.3
PAD: 6.1
Aspirin (880) TIA: 14.1
Average daily dose:
67.6 ± 11.8 70 CAD: 18.9
104 mg/d
Diabetes: 71.4
Hyperlipidemia: 38.4
Hypertension: 29.5
PAD: 5.5
TIA: 14.7
*
Age presented as mean age ± standard deviation or median age with interquartile range. †Only subgroup of patients with ischemic stroke at baseline are presented. ‡The Taiwan National Health Insurance Bureau
provided reimbursement for the use of clopidogrel in patients with ischemic stroke who are allergic to aspirin, have peptic ulcer, or aspirin treatment failure. CAD: coronary artery disease; CHF: congestive heart
failure; COPD: chronic obstructive pulmonary disease; CT: computed tomography; CVA: cerebrovascular attack; IHD: ischemic heart disease; MRI: magnetic resonance imaging; PAD: peripheral artery disease;
RCT: randomized controlled trial; RIND: reversible ischemic neurological deficit; TIA: transient ischemic attack.
Cardiovascular Therapeutics
Cardiovascular Therapeutics 11

prevention in patients with ischemic stroke. Data from obser- Supplementary Materials
vational studies were included to explore the benefits and
harms for this population in the real-world setting. Because The supplementary PDF includes summaries of the search
there is limited data on the relative efficacy and safety of clopi- strings, in addition to further information on methodology
dogrel compared to aspirin alone, these findings can add val- and results. (Supplementary Materials)
uable information to help clinicians and policymakers in
selection of antiplatelet therapy for secondary prevention
following recent ischemic stroke.
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