Original Contribution

Efficacy of Antiplatelet Therapy in Secondary

Prevention Following Lacunar Stroke
Pooled Analysis of Randomized Trials
Chun Shing Kwok, MBBS*; Ashkan Shoamanesh, MD*; Hannah Charlotte Copley, MBBChir;
Phyo Kyaw Myint, MD; Yoon K. Loke, MD; Oscar R. Benavente, MD

Background and PurposeLacunar stroke accounts for 25% of ischemic stroke, but optimal antiplatelet regimen to
prevent stroke recurrence remains unclear. We aimed to evaluate the efficacy of antiplatelet agents in secondary stroke
prevention after a lacunar stroke.
MethodsWe searched MEDLINE, Embase, and the Cochrane library for randomized controlled trials that reported risk of
recurrent stroke or death with antiplatelet therapy in patients with lacunar stroke. We used random effects meta-analysis
and evaluated heterogeneity with I2.
ResultsWe included 17 trials with 42234 participants (mean age 64.4 years, 65% male) and follow up ranging from 4
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017

weeks to 3.5 years. Compared with placebo, any single antiplatelet agent was associated with a significant reduction in
recurrence of any stroke (risk ratio [RR] 0.77, 0.620.97, 2 studies) and ischemic stroke (RR 0.48, 0.300.78, 2 studies),
but not for the composite outcome of any stroke, myocardial infarction, or death (RR 0.89, 0.751.05, 2 studies). When
other antiplatelet agents (ticlodipine, cilostazol, and dipyridamole) were compared with aspirin, there was no consistent
reduction in stroke recurrence (RR 0.91, 0.751.10, 3 studies). Dual antiplatelet therapy did not confer clear benefit
over monotherapy (any stroke RR 0.83, 0.681.00, 3 studies; ischemic stroke RR 0.80, 0.621.02, 3 studies; composite
outcome RR 0.90, 0.801.02, 3 studies).
ConclusionsOur results suggest that any of the single antiplatelet agents compared with placebo in the included trials is
adequate for secondary stroke prevention after lacunar stroke. Dual antiplatelet therapy should not be used for long-term
stroke prevention in this stroke subtype.(Stroke. 2015;46:00-00. DOI: 10.1161/STROKEAHA.114.008422.)
Key Words: antiplatelet agent aspirin lacunar stroke mortality stroke

L acunar stroke or small vessel ischemic stroke represents

25% of all ischemic strokes.1 Although the functional
prognosis of single episode of lacunar stroke is generally good,
recurrence is not uncommon.2,3 The underlying pathogenesis
is believed to be cerebral small vessel disease in the form of
arteriolosclerosis of deep penetrating arteries. This mechanism
is thought to be the most frequent cause of vascular cognitive
impairment.4 Therefore, preventing progression of cerebral
small vessel disease is extremely important. Current therapeutic
options are, however, limited, and the comparative efficacy of
available antiplatelet agents remains uncertain.
Until recently, all of the evidence supporting the use of anti-
platelet agents as secondary prevention after lacunar stroke
came from subgroup analysis from randomized controlled
trials designed to assess the efficacy of these agents in all isch-
emic stroke subtypes. However, these subgroups generally
have small sample sizes. The Secondary Prevention of Small
Subcortical Strokes (SPS3) trial was the first to address the
question at hand in a randomized controlled trial with a large
(n=3020) well-defined population of magnetic resonance
imaging-confirmed lacunar stroke, comparing aspirin mono-
therapy to dual antiplatelet therapy (DAPT) with aspirin and
clopidogrel. This trial was, however, terminated early because
of lack of efficacy and increased mortality among participants
randomized to DAPT.3 In view of the paucity of data, differing
vascular pathology underlying lacunar stroke, and the recent
SPS3 trial results, the utility of antiplatelet monotherapy has
been questioned in this population.5

Received December 19, 2014; final revision received January 26, 2015; accepted February 2, 2015.
From the Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK (C.S.K.); Institute of Applied Health Sciences, School of
Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK (C.S.K., P.K.M.); Department of Medicine, McMaster University/Population
Health Research Institute, Hamilton, Ontario, Canada (A.S.); Department of Surgery, Addenbrookes Hospital, Cambridge, UK (H.C.C.); Department of
Medicine and Health Sciences, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK (Y.K.L.); and Department of
Medicine, Brain Research Centre, University of British Columbia, Vancouver Stroke Program, Vancouver, Canada (O.R.B.).
*Drs Kwok and Shoamanesh are joint first authors.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.
008422/-/DC1.
Correspondence to Chun Shing Kwok, MBBS, C/o Room 4:013 Polwarth Bldg, School of Medicine and Dentistry, Division of Applied Health Sciences,
Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK. E-mail shingkwok@doctors.org.uk
2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.008422

1
 2StrokeApril 2015

Table. Study Design and Participant Characteristics

No. of Patients
Midyear of With Lacunar
Study Study Years of Study Design; Country Stroke (%) Intervention
AICLA8 1976 Oct 1975 to Dec 1978 Double blind, multicenter randomized trial; 98 (16%) ASA/ASA+dipyridamole/
4 centers in France. placebo

CATS9 Before Before 1989 Double blind, multicenter randomized 274 (26%) Ticlopidine/placebo
1989 controlled trial; 25 centers in Canada.

ESPS-219 1992 Feb 1989 to Mar 1995 Double blind, multicenter randomized 2600 (59%) ASA/dipyridamole/
controlled trial; 16 centers, 6 countries. ASA+dipyridamole/placebo
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017

IST11 1993 Jan 1991 to May 1996 Open randomized trial; international 467 4616 (24%) ASA/control
hospital from 36 countries.

Matsumoto 200514 1994 Apr 1992 to Mar 1996 Double blind randomized control trial; 183 794 (74%) Cilostazol/placebo
institutes in Japan.

CAST10 1995 Nov 1993 to Mar 1997 Multicenter randomized controlled trial; 6263 (30%) ASA/placebo
413 hospitals in China.

Uchiyama 200923 1999 July 1996 to Nov 2003 Double blind, multicenter randomized trial; 1341 (73%) Clopidogrel/ticlopidine
Japan.
MATCH13 2001 Dec 2000 to Apr 2002 Double blind, multicenter randomized 3148 (53%) ASA+clopdiogrel/clopidogrel
controlled trial; International 507 centers in
28 countries.

ESPRIT15 2001 Jul 1997 to Dec 2005 Multicenter randomized controlled trial; 1377 (50%) ASA+dipyridamole/ASA
International 79 hospital from 14 countries.

S-ACCESS17 2002 Apr 2001 to Nov 2003 Double blind, multicenter randomized trial; 963 (64%) Sarpogrelate/ASA
113 institutes in Japan.
PRoFESS16 2005 Sept 2003 to Feb 2008 Double blind, multicenter randomized 10578 (52%) ASA+dipyridamole/
controlled trial; International, 695 centers clopidogrel
in 35 countries.

CSPS218 2005 Dec 2003 to Oct 2006 Double blind, multicenter randomized trial; 1743 (65%) Cilostazol/ASA
278 sites in Japan.

AAASPS12 2006 Dec 1992 to Oct 2001 Double blind, multicenter randomized trial; 1221 (68%) Ticlodipine/ASA
62 centers in the United States

SPS33 2007 2003 to 2011 Double blind, multicenter randomized trial; 3020 (100%) ASA+clopidogrel/ASA
international, 8 countries.
 Kwok et al Antiplatelet Therapy in Lacunar Stroke 3

Definition of Lacunar Stroke

Mean Age % Male Participant Selection Stroke Ascertainment Specified
63 70% Participants had 1 cerebral or retinal Neurological assessment with history and No
atherothrombotic ischemic event whether CT scan and cerebral angiography was
transient or complete. optional.
65 62% Patients with thromboembolic stroke no <1 week Diagnosis was based on a neurological No
or >4 months before entry to the study. evaluation and assessment of clinical
course and required a sudden onset of a
new neurological deficit with demonstrable
residual effects at time of randomization.
66 61% Participants with minor ischemic stroke or TIA. Ischemic vascular accident is defined as Yes. Small vessel disease had
neurological deficit because of involvement signs and symptoms of 1 of the
of the brain or brain stem without classical lacunar syndromes
symptoms or signs of hemorrhage or tumor. (pure motor stroke, pure sensory
stroke, ataxic hemiparesis
or dysarthria clumsy hand
syndrome).
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017

61% >70 54% Participants with acute stroke with onset <48
years h previously and no evidence of intracranial
hemorrhage.
65 66% Participants aged <80 years with onset of
cerebral infarction between 1 and 6 months
confirmed on CT or MRI scan and no serious
complications were present.
63 64% Participants were within 48 h of onset of
symptoms of suspected acute ischemic
stroke and had no clear indication for or
contraindications to aspirin.
65 71% Participants had recent ischemic stroke (must
have occurred > 8 days before enrollment).
66 63% Participants had ischemic stroke or TIA in the
previous 3 months with 1 of 5 additional risk
factors within 3 years.
63 65% Participants had TIA within 6 months or minor
stroke of arterial origin.
65 72% Participants with cerebral infarction based on
NINDS criteria.
66 64% Participants had recent ischemic stroke (within
90 days of randomization) with symptoms lasting
>24 h or evidence of cerebral infarction on CT or
MRI scan, clinical and neurological stability before
randomization and age >55 years. Excluded were
those with contraindication for antiplatelet agents.
63 NA Participants with noncardioembolic cerebral
infarction (NINDS-III classification) with evidence
on CT or MRI scan and age 2079 years.
61 53% Participants were black race of age 2985
years of age with noncardioembolic ischemic
stroke with onset 7 days but not >90 days
with neurological imaging and measurable
neurological deficits consistent with cerebral
infarction.
63 63% Participants had recent lacunar stroke.
All patients were CT scanned and eligibility
was based on view of responsible
physician. Classification of stroke type was
based on neurological deficits.
Diagnosis confirmed on CT or MRI imaging.
Patient judged to be within 48 h of onset
of symptoms of suspected acute ischemic
stroke and had CT scan.
Brain infarcts were documented by
computed tomography or MRI.
Diagnosis and stroke type according to
TOAST criteria with MRI or CT imaging.
Data collected by checklist and
classification was on basis of CT or MR
scan and clinical features.
Symptoms, signs, and evidence on CT or
MR imaging.
Symptoms of ischemic stroke with evidence
of a recent brain infarction on CT or MRI
scan.
NINDS-III classification with evidence on CT
or MRI scan of noncardioembolic cerebral
infarction.
Cranial computed tomographic scan or
MRI of the brain consistent with cerebral
infarction.
Clinical diagnosis with investigations,
including an MRI, ECG, ECHO, standard
blood tests, and imaging of cervical and
intracranial arteries.
No
No
No
No
Yes. Small vessel occlusion
defined as one of the traditional
clinical lacunar syndromes and
should not have evidence of
cerebral cortical dysfunction.
Small vessel disease was
used as lacunar stroke but not
defined.
No
No
No
No
Yes. Clinical lacunar syndrome
that corresponded to an
ischemic lesion measuring 2.0
cm in diameter on MRI on DWI
or <1.5 cm on FLAIR/T1.
(Continued)
 4StrokeApril 2015

Table.Continued
No. of Patients
Midyear of With Lacunar
Study Study Years of Study Design; Country Stroke (%) Intervention
PERFORM21 2007 Feb 2006 to Apr 2008 Double blind, multicenter randomized 1733 (9%) Tetroban/ASA
controlled trial; International 802 centers in
46 countries.

ECLIPse20 2007 Nov 2006 to Oct 2008 Double blind, multicenter randomized trial; 203 (100%) ASA+cilostazol/ASA
8 hospitals in Korea.

TRA 2P-TIMI 5022 2009 Sept 2007 to Dec 2011 Double blind, multicenter randomized trial; 2262 (47%) Vorapaxar/placebo and
international, 1032 sites, 32 countries. concomitant medications

AAASPS indicates African American Antiplatelet Stroke Prevention Study; AICLA, Accidents Ischemiques Cerebraux Lies a l'Atherosclerose; CAST, Chinese Acute
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017

Stroke Trial; CATS, Canadian American Ticlopidine Study; CSPS 2, Cilostazol Stroke Prevention Study; CT, computed tomography; ECG, electrocardiogram; ECHO,
echocardiogram; ECLIPse, Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler; ESPRIT, European/Australasian Stroke
Prevention in Reversible Ischaemia Trial; ESPS-2, European Stroke Prevention Study; IST, International Stroke Trial; MATCH, Management of Atherothrombosis
With Clopidogrel in High-Risk Patients; MRI, magnetic resonance imaging; NINDS, National Institute of Neurological Disorders and Stroke; PERFORM, Prevention of
Cerebrovascular and Cardiovascular Events of Ischaemic Origin With Terutroban in Patients With a History of Ischaemic Stroke or Transient Ischaemic Attack; PRoFESS,
Prevention Regimen for Effectively Avoiding Second Strokes; S-ACCESS, Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention
of Cerebral Infarction; SPS3, Secondary Prevention of Small Subcortical Strokes; and TRA 2P-TIMI 50, Trial to Assess the Effects of Vorapaxar (SCH 530348; MK-5348)
in Preventing Heart Attack and Stroke in Patients With Atherosclerosis.

The primary aim of this study is to evaluate the evidence for
antiplatelet therapy as secondary stroke prevention in patients
with lacunar stroke. We performed a systematic review and
pooled meta-analysis of randomized controlled trials.
Methods
Eligibility Criteria
We included randomized controlled trials that evaluated the use of an-
tiplatelet therapy as secondary prevention after acute stroke. Among
these trials, only those which reported outcomes separate for lacunar
stroke were included. For certain trials, additional data were obtained
via personal correspondence from the authors.
participant characteristics, types of interventions, outcomes, results,
and risk of bias onto a spreadsheet. The 2 extractions were compared
and differences were resolved by consensus. Where there was uncer-
tainty, journal authors were contacted for clarification.
Assessment of Risk of Bias
Two reviewers (C.S. Kwok and H.C. Copley) independently assessed
the individual studies risks of bias in accordance with the recom-
mendations of the Cochrane Collaboration, which included baseline
differences, blinding, lost to follow up, exposure and outcome ascer-
tainment, and conflicts of interest. We planned to assess publication
bias using funnel plots if there were >10 studies included in the meta-
analysis, and there was no significant statistical heterogeneity.6

Outcomes Statistical Analysis

Primary outcome of interest was any stroke recurrence (ischemic
or hemorrhagic). Secondary outcomes of interest were (1) recurrent
ischemic stroke and (2) composite of any stroke, myocardial infarc-
tion, and death. We accepted composite outcomes as specified by trial
investigators so long as strokes and deaths were captured in the com-
posite end point.
Search Strategy
MEDLINE and Embase searches with no date limitations or lan-
guage restrictions were conducted in December 2013 using the broad
search terms as shown in Supplementary Data I in the online-only
Data Supplement. Furthermore, we reviewed the bibliography of in-
cluded trials, Cochrane Reviews, and the most recent review by the
antithrombotic trialist collaboration for additional studies.
Study Selection and Data Extraction
Two reviewers (C.S. Kwok and A. Shoamanesh) considered all titles
and abstracts retrieved from the search for potential eligibility. Where
there was disagreement, study inclusion or exclusion was agreed upon
by consensus with the other authors. Two reviewers (C.S. Kwok and
H.C. Copley) independently extracted information on study design,
Fixed effects meta-analysis of dichotomous events was per-
formed using RevMan 5.3 (Nordic Cochrane Center, Kbenhavn,
Denmark) to estimate pooled risk ratios (RRs). Statistical hetero-
geneity was assessed using I2 statistic, with values of 30% to 60%
representing a moderate level of heterogeneity.7 We performed
secondary analysis considering only ischemic stroke as the out-
come. Annual event rates per 100 patient years of follow-up were
estimated by adjusting the studies event rate according to the trials
mean follow-up duration.
Results
We included a total of 17 randomized trials that included
42234 participants with lacunar stroke treated with anti-
platelet therapy (mono or dual) or placebo.3,823 We did not
include 4 trials (IST [International Stroke Trial],11 PERFORM
[Prevention of Cerebrovascular and Cardiovascular Events
of Ischaemic Origin With Terutroban in Patients With a
History of Ischaemic Stroke or Transient Ischaemic Attack],21
S-ACCESS [Sarpogrelate-Aspirin Comparative Clinical Study
for Efficacy and Safety in Secondary Prevention of Cerebral
 Kwok et al Antiplatelet Therapy in Lacunar Stroke 5

Definition of Lacunar Stroke

Mean Age % Male Participant Selection
67 63% Participants were aged 55 years, who had had
an ischemic stroke or arterial retinal ischemic
event >48 h and <3 months preceding inclusion
or a TIA in the previous 8 days.
65 75% Participants were eligible for the trial if they
experienced their first lacunar infarction within
the preceding 7 days and were 45 years of age.
65 67% Patients had previous ischemic stroke who were
hospitalized or evaluated in an acute stroke clinic
with a final diagnosis of ischemic stroke within 2
weeks to 12 months before randomization.
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017
Stroke Ascertainment
Ischemic stroke was confirmed by brain
imaging.
All registered patients had a brain CT and
MRI to exclude hemorrhages and other
causes.
Ischemic stroke based on history of
hospitalization with final diagnosis of
nonhemorrhagic stroke.
Specified
Yes. Ischemic stroke was
categorized into lacunar stroke
based on prior defined criteria.
Yes. Lacunar infarction was
classified according the Trial of
Org 10 172 in the Acute Stroke
Treatment (TOAST) classification
system.
Yes. Small artery occlusion
defined by lacunar stroke
generally <15 mm subcortical
size according to TOAST criteria.

Infarction],17 and TRA 2P-TIMI 50 [Trial to Assess the
Effects of Vorapaxar (SCH 530348; MK-5348) in Preventing
Heart Attack and Stroke in Patients With Atherosclerosis]22)
in our pooled analysis. ISTs composite outcome of death and
dependency did not match our criteria, and TRA 2PTIMI50
did not provide number of events. Novel less-established
agents were excluded from the analysis in an attempt to
reduce the level heterogeneity between the different agents
mechanisms of action, but their results are reported separately
(Saprogelate [S-ACCESS]17 and Terutroban [PERFORM]21
trials). The process of study selection is shown in Figure I in
the online-only Data Supplement. Table shows the summary
characteristics of the study populations of included studies.
Of these, 14 were double-blind randomized trials. The mean
age was 64 years, and 65% of participants were male across
16 studies; one study (IST) reported 61% of participants
>70 years of age and one study (CSPS2 [Cilostazol Stroke
Prevention Study])18 did not report the number of male and
female participants. All the studies included participants with
suspected ischemic stroke or transient ischemic attack, and
neuroimaging was performed to confirm diagnosis in all but
one study (CATS [Canadian American Ticlopidine Study]),9
which relied on neurological evaluation for diagnosis. Only
6 of the studies formally defined lacunar stroke using criteria,
such as the TOAST Criteria, modified Fisher criteria, or other
predefined criteria, and only 1 used magnetic resonance imag-
ing to verify the diagnosis of lacunar stroke.3
Table I in the online-only Data Supplement shows the qual-
ity assessment of the studies included. Sequence generation
of randomization was described in 10 studies and allocation
concealment was described in 13 studies. Fourteen trials were
double blind trials, and some means to assess treatment expo-
sure or compliance was considered in 8 trials. All but one
study had some form of outcome ascertainment, and 4 studies
had unclear participant lost to follow-up.
The treatments received, crude events rate, outcomes,
and results are shown in Table II in the online-only Data
Supplement. The follow-up of the studies ranged from 4
weeks to 3.5 years.
Any Single Antiplatelet Agent Versus Placebo
Overall, patients on antiplatelet monotherapy had signifi-
cantly lower rates of any stroke as compared with placebo
(RR 0.77, 0.620.97, 2 trials, CATS,9 ESPS-2 [European
Stroke Prevention Study]19). There was a significant reduc-
tion in ischemic stroke (RR 0.48, 0.300.78, 2 trials, AICLA
[Accidents Ischemiques Cerebraux Lies a l'Atherosclerose],8
Matsumoto14) but not in the composite outcome (RR
0.89, 0.751.05, 2 trials CAST [Chinese Acute Stroke
Trial],10 ESPS-219). Results of these analyses are shown in
Figure1A1C.
Cilostazol, Ticlopidine, Dipyridamole, Terutobran,
Sarpogrelate Versus Aspirin Alone
Overall, the meta-analysis shows no significant advantage
of other single agents above aspirin alone. These analyses
are shown in Figure2A and 2B. Two trials, PERFORM21
and S-ACCESS,17 evaluating terutroban and sarpogrelate
also found no significant benefit above aspirin alone
(terutroban HR 0.90, 0.621.31; sarpogrelate HR 1.31,
0.842.04).
Dual Antiplatelet Therapy Versus Aspirin Alone
The results of DAPT versus aspirin are shown in Figure3.
Overall, DAPT may possibly have a modest advantage over
 6StrokeApril 2015
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017

Figure 1. Risk of outcome with antiplatelet versus placebo. AICLA indicates Accidents Ischemiques Cerebraux Lies a l'Atherosclerose;
CAST, Chinese Acute Stroke Trial; CATS, Canadian American Ticlopidine Study; and ESPS-2, European Stroke Prevention Study.

aspirin, but this is driven mainly by the aspirin/dipyridamole data stroke, and the composite outcome were RR 0.83, 0.68 to 1.00;
from ESPS-2.19 The pooled risk ratio for any stroke, ischemic RR 0.80, 0.62 to 1.02; and RR 0.95,0.85 to 1.07, respectively.
 Kwok et al Antiplatelet Therapy in Lacunar Stroke 7
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017
Figure 2. Risk of outcome with antiplatelet monotherapy versus aspirin. AAASPS indicates African American Antiplatelet Stroke Preven-
tion Study; CSPS 2, Cilostazol Stroke Prevention Study; and ESPS-2, European Stroke Prevention Study.
Dipyridamole/Aspirin, Clopidogrel/Aspirin, and
Ticlopidine Versus Clopidogrel Alone
We observed no significant advantage of DAPT versus clopido-
grel or ticlopidine versus clopidogrel. For this analysis, aspirin/
dipyridamole did not seem to be superior to clopidogrel alone.
Results are shown in Figure4. Finally, DAPT using vorapaxar
in addition to aspirin or clopidogrel use showed no significant
benefit on vascular end points (HR 0.99,0.751.31).22
Discussion
The current American Heart Association guidelines24 state
that 4 antiplatelet regimens (aspirin, clopidogrel, ticlopidine,
or the combination of dipyridamole and aspirin) have been
shown to reduce the risk of ischemic stroke after stroke or
TIA. The guidelines further suggest that several factors should
be considered, such as patient comorbidities, side effects, and
costs, when choosing an agent at an individual level. Suitably,
our findings suggest that antiplatelet monotherapy (ie, aspirin,
dipyridamole, clopidogrel, cilostazol, and ticlopidine) should
be recommended as secondary prevention of stroke among
patients with lacunar stroke. Aspirin seems to be as good as
any other antiplatelet agents and is likely the appropriate first
line in most because it is less expensive and generally well tol-
erated, which may increase long-term adherence to therapy.24
Cilostazol showed a nonsignificant trend in reducing strokes
when compared with aspirin; however, further larger studies
are needed to validate these findings and ensure generalizabil-
ity to non-East Asian populations.
Unfortunately, in view of the limited number of studies
which evaluate the role of DAPT, we are unable to separate
out individual agents and maintain a meaningful pooled analy-
sis. Accordingly, we identified substantial heterogeneity in the
effects of DAPT, which vary depending on the choice of the com-
bination and the comparator drugs. Only one trial shows DAPT
to be favorable (ESPS-2), but the superiority of dipyridamole
and aspirin was not replicated when clopidogrel was used as
the control rather than aspirin. Moreover, long-term DAPT with
clopidogrel/aspirin led to significantly higher rates of major
bleeding in MATCH (Management of Atherothrombosis With
Clopidogrel in High-Risk Patients) and all-cause mortality in
SPS3. Therefore, current evidence does not justify the use of
long-term DAPT in patient with lacunar stroke.
Our results are in line with those of the SPS3 trial regard-
ing the lack of benefit from clopidogrel and aspirin therapy
in lacunar stroke patients. We, however, did not notice any
significant increase in our composite outcome of any stroke,
myocardial infarction, and death. Limited by the available
published data, we were unable to consider mortality rates in
isolation; however, long-term DAPT (mean 3.4 years) led to
increased all-cause mortality (HR 1.52, 1.142.04, P=0.004)
in comparison to monotherapy with aspirin within SPS3.3
 8StrokeApril 2015
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017

Figure 3. Risk of outcome with dual antiplatelet therapy versus aspirin. AICLA indicates Accidents Ischemiques Cerebraux Lies a
l'Atherosclerose; ECLIPse, Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler; ESPRIT,
European/Australasian Stroke Prevention in Reversible Ischaemia Trial; ESPS-2, European Stroke Prevention Study; and SPS3, Second-
ary Prevention of Small Subcortical Strokes.
 Kwok et al Antiplatelet Therapy in Lacunar Stroke 9
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017
Figure 4. Risk of outcome with other antiplatelet regimens versus clopidogrel. MATCH indicates Management of Atherothrombosis With
Clopidogrel in High-Risk Patients; and PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes.
Our study has limitations. There were a limited number of
trials, and there was insufficient data to investigate particular
outcomes, such as hemorrhagic stroke or all-cause mortal-
ity in isolation. Additionally, lacunar stroke was defined in a
heterogeneous manner among the trials, with only one study
using a strict clinical criteria and magnetic resonance imaging
verification of the infarct,3 and we were unable to consider the
effect-specific DAPT regimens in isolation. A final limitation
is that our analysis is unable to account for possible differ-
ences in treatment-effects between the acute/semiacute phase
after stroke and the chronic phase.
In conclusion, our results suggest that at present, antiplate-
let monotherapy of the agents included in the trials should be
indicated for secondary stroke prevention after a lacunar stroke.
Furthermore, current data are insufficient to justify using one
antiplatelet agent over another in this particular population.
Acknowledgments
C.S. Kwok and A. Shoamanesh was involved in design, screening,
study selection, data extraction, data analysis, and preparation of ar-
ticle. H.C. Copley was involved in screening and data extraction. P.K.
Myint was involved in the design, screening, and preparation of the
article. Y.K. Loke was involved in the design, study selection, data ex-
tractions, data analysis, and preparation of the article. O.R. Benavente
was involved in design and preparation of the article.
Disclosures
Dr Benavente received grant support from National Institutes of
Health (NIH)/National Institute of Neurological Disorders and Stroke
(NINDS) as coprincipal investigators of the Secondary Prevention of
Small Subcortical Stroke trial.
References
1. Schulz UG, Rothwell PM. Differences in vascular risk factors
between etiological subtypes of ischemic stroke: importance of pop-
ulation-based studies. Stroke. 2003;34:20502059. doi: 10.1161/01.
STR.0000079818.08343.8C.
2. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, OFallon WM, Wiebers
DO. Ischemic stroke subtypes: a population-based study of functional
outcome, survival, and recurrence. Stroke. . 2012;367:817825.
3. SPS3 Investigators. Effects of clopidogrel added to aspirin in patients
with recent lacunar stroke. N Engl J Med. 2012;367:8178.
4. Ross GW, Petrovitch H, White LR, Masaki KH, Li CY, Curb JD, et al.
Characterization of risk factors for vascular dementia: the Honolulu-Asia
Aging Study. Neurology. 1999;53:337343.
5. Braun H, Schreiber S. Microbleeds in cerebral small vessel disease.
Lancet Neurol. 2013;12:735736. doi: 10.1016/S1474-4422(13)70148-0.
6. Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for
publication bias in meta-analyses: a large survey. CMAJ. 2007;176:1091
1096. doi: 10.1503/cmaj.060410.
7. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring incon-
sistency in meta-analyses. BMJ. 2003;327:557560. doi: 10.1136/
bmj.327.7414.557.
8. Bousser MG, Eschwege E, Haguenau M, Lefaucconnier JM, Thibult N,
Touboul D, et al. AICLA controlled trial of aspirin and dipyridamole in
the secondary prevention of athero-thrombotic cerebral ischemia. Stroke.
1983;14:514.
9. Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW,
et al. The Canadian American Ticlopidine Study (CATS) in thromboem-
bolic stroke. Lancet. 1989;1:12151220.
10. Chen ZM; CAST (Chinese Acute Stroke Trial) Collaborative
Group. CAST: randomised placebo-controlled trial of early aspi-
rin use in 20,000 patients with acute ischaemic stroke. Lancet.
1997;349:16411649.
11. International Stroke Trial Collaborative Group. The International Stroke
Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both,
or neither among 19435 patients with acute ischaemic stroke. Lancet.
1997;349:15691581.
12. Gorelick PB, Richardson D, Kelly M, Ruland S, Hung E, Harris Y, et al;
African American Antiplatelet Stroke Prevention Study Investigators. Aspirin
 10StrokeApril 2015
and ticlopidine for prevention of recurrent stroke in black patients: a random-
ized trial. JAMA. 2003;289:29472957. doi: 10.1001/jama.289.22.2947.
13. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M,
et al; MATCH investigators. Aspirin and clopidogrel compared with clopi-
dogrel alone after recent ischaemic stroke or transient ischaemic attack in
high-risk patients (MATCH): randomised, double-blind, placebo-controlled
trial. Lancet. 2004;364:331337. doi: 10.1016/S0140-6736(04)16721-4.
14. Matsumoto M. Cilostazol in secondary prevention of stroke: impact of
the Cilostazol Stroke Prevention Study. Atheroscler Suppl. 2005;6:33
40. doi: 10.1016/j.atherosclerosissup.2005.09.003.
15. The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin
alone after cerebral ischaemia of arterial origin (ESPRIT): randomised
controlled trial. Lancet. 2006;367:16651673.
16. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, et
al; PRoFESS Study Group. Aspirin and extended-release dipyridamole
versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238
1251. doi: 10.1056/NEJMoa0805002.
17. Shinohara Y, Nishimaru K, Sawada T, Terashi A, Handa S, Hirai S, et al;
S-ACCESS Study Group. Sarpogrelate-Aspirin Comparative Clinical Study
for Efficacy and Safety in Secondary Prevention of Cerebral Infarction
(S-ACCESS): A randomized, double-blind, aspirin-controlled trial. Stroke.
2008;39:18271833. doi: 10.1161/STROKEAHA.107.505131.
18. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S,
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017
Matsuoka K, et al; CSPS 2 group. Cilostazol for prevention of second-
ary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised
non-inferiority trial. Lancet Neurol. 2010;9:959968. doi: 10.1016/
S1474-4422(10)70198-8.
19. Ariesen MJ, Algra A, Kappelle LJ. Antiplatelet drugs in the secondary
prevention after stroke: differential efficacy in large versus small vessel
disease? A subgroup analysis from ESPS-2. Stroke. 2006;37:134138.
doi: 10.1161/01.STR.0000195045.40409.85.
20. Han SW, Lee SS, Kim SH, Lee JH, Kim GS, Kim OJ, et al. Effect of cilo-
stazol in acute lacunar infarction based on pulsatility index of transcranial
Doppler (ECLIPse): a multicenter, randomized, double-blind, placebo-
controlled trial. Eur Neurol. 2013;69:3340. doi: 10.1159/000338247.
21. Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Fox KM, et
al; PERFORM Study Investigators. Terutroban versus aspirin in patients
with cerebral ischaemic events (PERFORM): a randomised, double-
blind, parallel-group trial. Lancet. 2011;377:20132022. doi: 10.1016/
S0140-6736(11)60600-4.
22. Morrow DA, Alberts MJ, Mohr JP, Ameriso SF, Bonaca MP, Goto
S, et al; Thrombin Receptor Antagonist in Secondary Prevention of
Atherothrombotic Ischemic EventsTIMI 50 Steering Committee
and Investigators. Efficacy and safety of vorapaxar in patients with
prior ischemic stroke. Stroke. 2013;44:691698. doi: 10.1161/
STROKEAHA.111.000433.
23. Uchiyama S, Fukuuchi Y, Yamaguchi T. The safety and efficacy of
clopidogrel versus ticlopidine in Japanese stroke patients: combined
results of two Phase III, multicenter, randomized clinical trials. J Neurol.
2009;256:888897. doi: 10.1007/s00415-009-5035-4.
24. Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al;
American Heart Association Stroke Council, Council on Cardiovascular
Nursing, Council on Clinical Cardiology, and Interdisciplinary Council
on Quality of Care and Outcomes Research. Guidelines for the preven-
tion of stroke in patients with stroke or transient ischemic attack: a guide-
line for healthcare professionals from the american heart association/
american stroke association. Stroke. 2011;42:227276. doi: 10.1161/
STR.0b013e3181f7d043.
 Efficacy of Antiplatelet Therapy in Secondary Prevention Following Lacunar Stroke:
Pooled Analysis of Randomized Trials
Chun Shing Kwok, Ashkan Shoamanesh, Hannah Charlotte Copley, Phyo Kyaw Myint, Yoon
K. Loke and Oscar R. Benavente
Downloaded from http://stroke.ahajournals.org/ by guest on February 12, 2017

Stroke. published online February 26, 2015;

Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2015 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/early/2015/02/26/STROKEAHA.114.008422

Data Supplement (unedited) at:

http://stroke.ahajournals.org/content/suppl/2015/03/03/STROKEAHA.114.008422.DC1
http://stroke.ahajournals.org/content/suppl/2016/04/06/STROKEAHA.114.008422.DC2
http://stroke.ahajournals.org/content/suppl/2016/04/07/STROKEAHA.114.008422.DC3

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Stroke is online at:

http://stroke.ahajournals.org//subscriptions/
SUPPLEMENTAL MATERIAL

1
Supplementary Figure I: Flow diagram of study selection

2
Supplementary Table I: Quality of included trials
Study Sequence generation
AICLA [1] Patients were randomized using a
established randomization
schedule, balanced for every 6
patients.
CATS [2] Randomization code used for
randomization.
ESPS-2 [3] Treatment group allocation was
determined by a randomization
system based on the minimization
technique and taking into account
various factors.
IST [4] Computer allocated the study
treatments using a minimization
algorithm which reduced any
imbalance in recorded prognostic
features between treatment groups.
Matsumoto Randomization was performed by
2005 [5] the dynamic balancing method
adjusted for several variables.
CAST [6] Randomization was by prepacked,
sequentially numbered trial
envelopes.
Uchiyama Unclear.
2009 [7]
Allocation concealment
Unclear.
Unclear.
Unclear.
Adequate allocation concealment
where patients were allocated by
telephoning the central
randomization service at Clinical
Trial Service Unit, Oxford, UK.
Adequate allocation concealment
by central Registration and
Analysis Center, an independent
organization set up at Tokyo
University for the present study.
Adequate allocation concealment
with prepacked sealed envelopes
produced centrally.
Unclear.
Blinding Treatment; exposure;
ascertainment
Double- 330 mg ASA, placebo, 330 mg
blind. ASA and 75 mg dipyridamole,
three times a day; exposure for
duration of study; at each follow
up patients were asked about drug
habits and urine salicylate
measurements were performed.
Double- 500 mg ticlopidine, placebo;
blind. ascertained by pill counting.
Double- Aspirin 50 mg, modified-release
blind. dipyridamole 400 mg, aspirin and
dipyridamole combined and
placebo; exposure for 2 years;
unclear ascertainment.
Not fully 300 mg ASA or control (avoid
double- aspirin); exposure for study
blind. duration; medication in hospital
so compliance not an issue.
Double- 100 mg cilostazol twice daily vs.
blind. placebo; exposure duration of
study; unclear ascertainment.
Unclear 160 mg ASA, placebo; exposure
blind. duration of study; compliance not
an issue because nurse
administered medication.
Double- 75 mg clopidogrel or ticlopidine
blind. 200 mg; exposure for 26 weeks or
Outcome; outcome Follow up; lost to
ascertainment follow up
Ischemic stroke; 3 years; 11%
clinical diagnosis with withdrew from study
CT scan. not related to health
problems, 41%
discontinued
treatment, and 8%
withdrew from study.
Any stroke; events 2 years; 4 patients
were classified by loss to follow up.
steering committee.
Any stroke. Unclear Up to 2 years; unclear
ascertainment. loss to follow up.
Death or dependence; 6 months (0.5 years);
outpatient collection of 74 lost at 6 months.
data, coordinating
centre mail a validated
questionnaire, or
telephone call
interview (coordinated
centrally).
Ischemic stroke; 2 years (1.8 years in
Evaluation Committee cilostazol, 1.6 years in
classified all events. placebo); unclear lost
to follow up.
Death or non-fatal 4 weeks (0.08 years);
stroke; clinical unclear loss to follow
diagnosis with CT up.
scan.
Combined ischemic 26 and 52 weeks; 7
stroke, MI and vascular excluded from
3
 52 weeks; unclear ascertainment. death; follow up with analysis but 562
examination in clinic discontinued
visit or telephone call. treatment.
MATCH Sequence generation was based on Adequate allocation concealment Double- 75 mg clopidogrel daily with 75 Ischemic stroke; 1.5 years; 13
[8] a computer-generated list of which was done centrally, with an blind. mg of aspirin or placebo daily; follow-up visit and participants were lost
treatment numbers. interactive voice response system unclear ascertainment. telephone calls. to follow up.
(by phone).
ESPRIT Treatment allocation was by means Adequate allocation concealment Non- 30-325 mg ASA daily with or Ischemic stroke and all 3.5 years; 106
[9] of computer generated with randomization by means of a blinded. without 200 mg dipyridamole cardiac events (MI, participants were lost
randomization codes stratified by telephone call, fax, or email to the twice daily, exposure for duration sudden death and death to follow up, 554
hospital before the start of the trial. central trial office. of study; medication compliance from cardiac causes); 3 discontinued
asked a follow-up. member committee treatment.
audited outcome events
and independently
classified events.
S- Patients were randomly assigned Adequate allocation concealment Double- 100 mg sarpogrelate three times a Ischemic stroke; 1.59 years; 11 not
ACCESS according to an allocation table that with web-based randomization. blind. day vs. 81 mg ASA once daily; diagnosis by clinical included in efficacy
[10] was generated by using random exposure for duration of study; evaluation with analysis.
numbers by a person who was not unclear ascertainment. Efficacy End Point
part of this study. Committee.
PROFESS Unclear. Adequate allocation concealment Double- 25 mg aspirin and 200 mg Any stroke; ascertained 2.5 years; 0.6% were
[11] by a central telephone blind. extended release dipyridamole by central committee lost to follow up in
randomization system. twice daily or 75 mg clopidogrel using TOAST criteria each arm.
daily; exposure for duration of to classify event.
study; compliance was questioned
at follow up visits.
CSPS2 The randomization table was Adequate allocation concealment Double- 100 mg cilostazol twice daily vs. Any stroke; 2.42 years; 85 not
[12] generated with SAS and random with remote randomization by blind. 81 mg ASA daily; exposure study independent data included in analysis,
allocation was done with a contract research organisation at the duration, unclear ascertainment. monitoring committee. 793 discontinued drug
dynamic balancing method to registration centre. and 4 lost to follow
minimize differences in the up.
distribution of baseline variables
between the two groups.
AAASPS Patients were randomized using a Adequate allocation concealment Double- 650 mg ASA, 500 mg ticlopidine; Any stroke; blinded 1.54 years; 522
[13] algorithm using a length of block with automated phone registration. blind exposure duration of study; adjudication participants withdrew
varying from 2 to 8 with a ratio of ascertained by pill counting. committee. from study but all
patients receiving ticlopidine to were included in
aspirin of 1:1. analysis.
SPS3 [14] Randomization assignments were Adequate allocation concealment Double- 325 mg ASA daily with or Any stroke, ischemic 3.4 years; no loss to

4
 generated using a permuted-block using central web-based system. blind. without 75 mg clopidogrel daily; stroke, death and MI; follow up.
design (variable block size). exposure for duration of study; ascertained by the
adherence measured by pill count. blinded Events
Adjudication
Committee.
PERFOR The allocation sequence was Adequate allocation concealment Double- 30 mg terutroban daily vs. 100 g Ischemic stroke, MI, 28.3 months; 20
M [15] generated by the sponsor through by a central interactive response blind. aspirin daily; unclear vascular death. excluded, 58 lost to
in-house application software. The system (telephone or internet). ascertainment. Independent Data follow up and 382
randomization was balanced, non- Monitoring Committee. withdrew consent.
adaptive, and stratified by country,
with blocks of size four.
ECLIPSE A blocked randomization Adequate allocation concealment Double- 100 mg cilostazol BD or placebo Any stroke (ischemic 90 days; no lost to
[16] procedure generated by a with randomization by central trial blind. and ASA 100 mg daily; study stroke data also follow up.
statistician was used by the central pharmacist who produced identical duration of 90 days; unclear provided); follow up
trial pharmacist randomized study kits. ascertainment. with transcranial
patients. doppler and
examination.
TRA 2P- Unclear. Adequate allocation concealment Double- 2.5 mg vorapaxar daily vs. Cardiovascular death, Median 24 months
TIMI 50 by a central computerized telephone blind. placebo added to standard MI or stroke; (up to 3 years). 32 lost
[17] system. antiplatelet therapy; unclear ascertained by a to follow up and 532
ascertainment. Clinical Events withdrew consent for
Committee blinded to follow up.
treatment allocation.

5
Supplementary Table II: Treatments, outcomes, crude events and follow up of studies included
Study Midyear Treatment Outcome Experi Total Adjusted to Control Total Adjusted to Trial follow-up Reported HRs
of study experimental/contr mental time events time duration (mean) (95% CI) for
ol events (outcome/yr) (outcome/yr) outcome
AICLA [1] 1976 ASA/placebo Ischemic stroke 3 30 3.33% 9 34 8.82% 3 years -
1976 ASA+dipyridamole/ Ischemic stroke 2 34 1.96% 3 30 3.33% 3 years -
ASA
CATS [2] Prior to Ticlopidine/placebo Any stroke 14 137 5% 27 137 10% 2 years
1989
ESPS-2 [3] 1992 ASA/placebo Any stroke 70 609 6.4% 93 681 7.9% 1.7-1.8 years 0.82 (0.60-1.11)
1992 Dipyridamole/place Any stroke 73 651 6.3% 93 681 7.9% 1.7 years 0.80 (0.59-1.08)
bo
1992 ASA+dipyridamole/ Any stroke 52 659 4.4% 93 681 7.9% 1.7-1.8 years 0.56 (0.40-0.78)
placebo
1992 ASA+dipyridamole/ Any stroke 52 659 4.4% 70 609 6.4% 1.8 years 0.68 (0.48-0.97)
ASA
1992 ASA/placebo Composite 101 609 9.4% 128 681 11.0% 1.7-1.8 years 0.86 (0.66-1.11)
vascular events*
1992 Dipyridamole/place Composite 108 651 9.5% 128 681 11.0% 1.7 years 0.86 (0.67-1.12)
bo vascular events*
1992 ASA+dipyridamole/ Composite 82 659 7.0% 128 681 11.0% 1.7-1.8 years 0.64 (0.48 0.84)
placebo vascular events*
1992 ASA+dipyridamole/ Composite 82 659 7.0% 101 609 9.4% 1.8 years 0.74 (0.55-0.99)
ASA vascular events*
IST [4] 1993 ASA/control Death or 1112 2308 - 1116 2308 - 6 months = 0.5 -
dependence years
Matsumoto 1994 Cilostazol/placebo Ischemic stroke 20 400 2.97% 39 394 5.25% 2 years (1.8 years -
2005 [5] in cilostazol, 1.6
years in placebo)
CAST [6] 1995 ASA/placebo Any (non-fatal) 78 3117 - 88 3146 - 4 weeks = 0.08
stroke or death years
Uchiyama 1999 Clopidogrel/ticlopid Ischemic stroke, 19 677 2.8% 22 664 3.3% Up to 1 year.
2009 [7] ine MI, vascular
death
MATCH [8] 2001 ASA+clopdiogrel/cl Ischemic stroke 160 1590 7.70% 161 1558 8.10% 18 months = 1.5
opidogrel years

6
 ESPRIT [9] 2001 ASA+dipyridamole/ Ischemic stroke 96 687 3.99% 106 690 4.39% 3.5 years
ASA and all cardiac
events (MI,
sudden death
and death from
cardiac causes)
S-ACCESS 2002 Sarpogrelate/ASA Ischemic stroke 46 484 5.95% 35 479 4.53% 1.59 years HR 1.31 (0.84-
[10] 2.04)
PROFESS 2005 ASA+dipyridamole/ Any stroke 418 5292 3.16% 437 5286 3.31% 2.5 years
[11] clopidogrel
CSPS2 [12] 2005 cilostazol/ASA Any stroke 59 869 3.06% 85 874 4.07% 2.42 years HR 0.752 (0.542-
1.042)
AAASPS 2006 Ticlodipine/ASA Any stroke 55 600 6% 48 621 5% 1.54 years
[13]
SPS-3 [14] 2007 ASA+clopidogrel/A Ischemic stroke 100 1517 2.00% 124 1503 2.40% 3.4 years 0.82 (0.63-1.09)
SA
2007 ASA+clopidogrel/A Any stroke 125 1517 2.50% 138 1503 2.70% 3.4 years 0.92 (0.72-1.16)
SA
2007 ASA+clopidogrel/A Any stroke, MI, 269 1517 - 253 1503 - 3.4 years -
SA death.
PERFORM 2007 Tetroban/ASA. Ischemic stroke, 54 856 2.55% 61 877 2.98%% 28.3 months = 2.35 0.90 (0.62-1.13)
[15] MI and vascular years
death.
ECLIPSE 2007 ASA+cilostazol/AS Any stroke (all 1 100 - 1 103 - 0.25 years -
[16] A events
ischemic)
TRA 2P- 2009 Vorapaxar/placebo Any stroke, MI, - 2262 3.80% - 2262 3.77 % 3 years 0.99 (0.75-1.31)
TIMI 50 and concomitant cardiovascular (total) (total)
[17] medications death.

*Composite vascular events defined as nonfatal stroke, nonfatal MI, a nonfatal vascular events (DVT, PE, peripheral artery occlusion, venous retinal vascular event) or vascular death.

7
Supplementary Data I: Search Strategy

Database: Embase <1974 to 2013 Week 50>, Ovid MEDLINE(R) In-Process & Other Non-
Indexed Citations and Ovid MEDLINE(R) <1946 to Present>
Search Strategy:
--------------------------------------------------------------------------------
1 Aspirin or Clopidogrel or Ticlopidine or Dipyridamole or Prasugrel or Ticagrelor or
Cilostazol or Dipyridamole {No Related Terms} (6084)
2 Platelet aggregation inhibitors or Antiplatelet {No Related Terms} (69182)
3 Platelet Aggregation Inhibitors {No Related Terms} (5716)
4 Stroke or cerebrovascular disease or cerebrovascular accident {No Related Terms}
(8654)
5 Stroke/ (186298)
6 Brain Ischemia/ (112183)
7 Cerebrovascular Disorders/ (91210)
8 randomised controlled trial or randomized controlled trial or randomised controlled study
or randomized controlled study {No Related Terms} (9836)
9 Randomized Controlled Trial/ (755711)
10 1 or 2 or 3 (77570)
11 4 or 5 or 6 or 7 (355197)
12 8 or 9 (755716)
13 10 and 11 and 12 (536)
14 remove duplicates from 13 (431)

***************************

8
References

[1] Bousser MG, Eschwege E, Haguenau M, Lefaucconnier JM, Thibult N, Touboul D, et

al. "AICLA" controlled trial of aspirin and dipyridamole in the secondary prevention of

athero-thrombotic cerebral ischemia. Stroke 1983;14:5-14.

[2] Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, et al. The

Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet

1989;1:1215-20.

[3] Ariesen MJ, Algra A, Kappelle LJ. Antiplatelet drugs in the secondary prevention of

stroke: differential efficacy in large versus small vessel disease? A subgroup analysis from

the ESPS-2. Stroke 2006;37:134-8.

[4] International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a

randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with

acute ischaemic stroke. Lancet 1997;349:1569-81.

[5] Matsumoto M. Cilostazol in secondary prevention of stroke: impact of the Cilostazol

Stroke Prevention Study. Atheroscler Suppl 2005;6:33-40.

[6] Chen ZM, CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST:

randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute

ischaemic stroke. Lancet 1997;349:1641-9.

[7] Uchiyama S, Fukuuchi Y, Yamaguchi T. The safety and efficacy of clopidogrel versus

ticlopidine in Japanese stroke patients: combined results of two Phase III, multicenter,

randomized clinical trials. J Neurol 2009;256:888-897.

[8] Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al.

Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or

transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind,

placebo-controlled trial. Lancet 2004;364:331-7.

9
[9] The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after

cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet

2006;367:1665-73.

[10] Shinohara Y, Nishimaru K, Sawada T, Terashi A, Handa S, Hayashi K, et al.

Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary

Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-

controlled trial. Stroke 2008;39:1827-33.

[11] Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, et al. Aspirin and

extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;

359: 1238-51.

[12] Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, et al.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind,

randomised non-inferiority trial. Lancet Neurol 2010;9:959-68.

[13] Gorelick PB, Richardson D, Kelly M, Ruland S, Hung E, Harris Y, et al. Aspirin and

ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA

2003;289:2947-57.

[14] SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent

lacunar stroke. N Engl J Med 2012;367:817-25.

[15] Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Hennerici MG, et al.

Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a

randomised, double-blind, parallel-group trial. Lancet 2011;377:2013-22.

[16] Han SW, Lee SS, Kim SH, Lee JH, Kim GS, K OJ, et al. Effect of cilostazol in acute

lacunar infarction based on pulsatility index of transcranial doppler (ECLIPse): a multicenter,

randomized, double-blind, placebo-controlled trial. Eur Neurol 2013;69:33-40.

10
[17] Morrow DA, Alberts MJ, Mohr JP, Ameriso SF, Bonaca MP, Goto S, et al. Efficacy and

safety of vorapaxar in patients with prior ischemic stroke. Stroke 2013;44:691-698.

11
 26 Stroke Vol. 10, No. 2

Abstract

Efficacy of Antiplatelet Therapy in Secondary Prevention Following Lacunar Stroke
Pooled Analysis of Randomized Trials

Chun Shing Kwok, MBBS1,2; Ashkan Shoamanesh, MD3; Hannah Charlotte Copley, MBBChir4, et al.
1
Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK; 2 Institute of Applied Health Sciences, School of Medicine
and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK; 3 Department of Medicine, McMaster University/Population Health Research
Institute, Hamilton, Ontario, Canada; and 4 Department of Surgery, Addenbrookes Hospital, Cambridge, UK.

25%
RR 0.890.75 1.052


RR 0.910.75 1.10
MEDLINEEmbase 3 2
RR 0.83
0.68 1.003 RR 0.800.62
I 2 1.023 RR 0.900.80 1.023

42,234 64.4
65% 4 3.5 17

RR 0.770.62 2
0.972 RR 0.480.30
0.782

Stroke 2015; 46: 1014-1023. DOI: 10.1161/STROKEAHA.114.008422.

M-H
M-H
95%CI
95% CI M-H
M-H 95%
95% CI

AAASPS 55 600 48 621 23.1% 1.19 [0.82, 1.72]
95% CI 600 621 23.1% 1.19 [0.82, 1.72]
55 48

Z 0.90 P 0.37

CSPS2 59 869 85 874 41.5% 0.70 [0.51, 0.96]
95% CI 869 874 41.5% 0.70 [0.51, 0.96]
59 85

Z 2.21 P 0.03

ESPS-2 73 651 70 609 35.4% 0.98 [0.72, 1.33]
95% CI 651 609 35.4% 0.98 [0.72, 1.33]
73 70

Z 0.16P 0.88

95% CI 2120 2104 100.0% 0.91 [0.75, 1.10]

187 203
Chi2 4.82df 2 P 0.09I2 58%
0.01 0.1 1 10 100
Z = 0.99 ( P = 0.32)

Chi2 4.82df 2 P 0.09I2 58.5%

AAASPSAfrican American Antiplatelet Stroke Prevention Study

2 CSPS 2Cilostazol Stroke Prevention Study
ESPS-2European Stroke Prevention StudyStroke

STR-J_10-2_ab4_main.indd
STR-J 10-2 ab4 main.indd 26 2015-8-25 14:53:31
24 Stroke Vol. 8, No. 3

Abstract 2

Efficacy of Antiplatelet Therapy in Secondary Prevention Following Lacunar Stroke

Pooled Analysis of Randomized Trials

Chun Shing Kwok, MBBS*; Ashkan Shoamanesh, MD*; Hannah Charlotte Copley, MBBChir;
Phyo Kyaw Myint, MD; Yoon K. Loke, MD; Oscar R. Benavente, MD
(Stroke. 2015;46:1014-1023.)
Key Words: antiplatelet agent aspirin lacunar stroke mortality stroke

(RR 0.77, 0.62-0.96, 2 ) (RR,

25% . , 0.48, 0.30-0.78, 2 ) ,
, (RR 0.89,
. 0.75-1.05, 2 ) .
. (, ,
) (RR
0.91, 0.75-1.10, 3 ).
MEDLINE, Embase, the Cochrane library (
RR 0.83, 0.68-1.00, 3 ; RR 0.80, 0.62-
. 1.02, 3 ; RR 0.90, 0.80-1.02, 3 ).
, I2 .


42234 ( 64.4, 65% ) 17 .
4 3.5 ,
. .

Abstract 3

Rates of Ischemic Stroke During Warfarin Treatment for Atrial Fibrillation
Jennifer M. Tung, PharmD; Muhammad M. Mamdani, PharmD; David N. Juurlink, PhD; J. Michael Paterson, MSc; Moira K. Kapral, MD; Tara Gomes, MHSc
(Stroke. 2015;46:1120-1122.)
Key Words: anticoagulants epidemiology

1997 4 1 2010 3 31 66
. (Ontario)
. . 30
 Tung et al Warfarin Initiation and Ischemic Stroke 1121

Table 1. Baseline Characteristics (n=2,917) after 1 year, 2.7% (n=4067) after 2 years, and 4.0%
25
New Warfarin Users (%)
1122 (n=6006)Stroke April
after 5 years. The risk was2015
highest during the first 30
1122 Stroke April 2015 n=148 446 days of warfarin therapy: 6.0% PPY (95% confidence inter-
5 .Age,
y (median, IQR) 77 (7282)
, ,
val, 5.5%6.4%) PPY
versus 1.6% )interval,
(95% confidence .
1.5%1.6%) during the remainder of the 5-year follow-up
. Men 73 492 (49.5)
(Table 2; .
Figure).
Comorbidities
Crude 5-year rates of ischemic stroke increased significantly
Myocardial infarction 23 605 (15.9) as CHADS2 scores increased (P<0.0001; Table 2; Figure I in
Peripheral vascular disease 6257 (4.2)
the online-only Data Supplement) and among those with a
Valvular disease 8351 (5.6) history of stroke (P<0.001; Table 2; Figure II in the online-
5 ,
Hemorrhagic event (n=148446) 6632 (4.5)
only Data Supplement). analysis
A sensitivity ,
demonstrated
Thromboembolism 2395 (1.6) no difference in stroke rates according to timing of warfarin
4.0% (n=6006). 30
Medication use initiation after atrial fibrillation diagnosis (Table 2). Relative
30 acid
Acetylsalicylic (1 - 6.0%; 25 984 (17.5) .
to patients who did not a
experience stroke,
those who did
were less likely to have received an international normalized
95% CI 5.5%-6.4%), Ticlopidine
(1 1132 (0.8)
,
ratio test in the preceding 14 days (Table II in the online-only
Clopidogrel 6062 (4.1)
- 1.6%; 95% CI 1.5%-1.6%) . Data Supplement).
Few patients received heparin or antiplate-
Acetylsalicylic acid and dipyridamole 1289 (0.9)
let therapy (Table 1).
Heparins and anticoagulants as bridging therapy 2371 (1.6)
CHADS 2
(, , 75
Digoxin 46 252 (31.2)
1122 Stroke April 2015 Discussion
CHADS2 score components
In this population-based study, the rate of ischemic stroke in
Congestive heart failure 51 831 (34.9)
older patients with atrial fibrillation starting warfarin was sig-
Hypertension 113 713 (76.6) nificantly elevated during the first month of treatment. This
Age >75 y 93 770 (63.2) early elevated risk increased with previous stroke history and
Diabetes mellitus 38,077 (25.7) higher baseline CHADS2 score.
Stroke in past 5 y 9977 (6.7) The overall 5-year risk of stroke observed in our study
CHADS2 score (1.8% PPY) is comparable with the annual incidence rate
0 9555 (6.4) of 1.66% (95% confidence interval, 1.41%1.91%) reported
1 33 985 (22.9) in a meta-analysis of 8 randomized controlled trials and an
23 86 325 (58.9)
observational study by Azoulay et al,3,5 but higher than the
rate of 1.17% PPY reported in another observational study of
46 16 581 (11.3)
younger patients with lower CHADS2 scores.1 The explana-
CHADS2 indicates score comprised of congestive heart failure, hypertension,
tion for our findings is likely multifactorial. The results may
age 75 years, diabetes, previous stroke; and IQR, interquartile range.
reflect the high-risk period after a transient ischemic attack,6
and the time required to achieve therapeutic anticoagula-
the patients who experienced an event, 27.3% (n=1639) died
Figure.
tion.Rate of ischemic
Less frequent stroke
international among
normalized new
ratio warfarin
testing may users with atrial fibrillation.
in hospital or within 7 days of discharge.
Figure. Rate of ischemic stroke among new warfarin users with atrial have fibrillation.
been a contributor. More research is needed to elucidate
The 30-day cumulative incidence of ischemic stroke among whether a transient hypercoagulable state seen immediately
Figure. Rate of ischemic stroke among new warfarin users with atrial fibrillation.
new users of warfarin was 0.5% (n=721), increasing to 2.0% after warfarin initiation explains our findings.7 Our sensitivity
analysis stratifying patients by timing of warfarin initiation intended or should be inferred. Dr Kapral holds a career investigator
analysis stratifying patients by timing of warfarin initiation intended o
analysis stratifying patients by timing of warfarin initiation
Table 2.award
after atrial fibrillation diagnosis found similar stroke rates Rates of Stroke
from the Heart andby Duration
Stroke Foundationof of
Warfarin
Ontario. Therapy
after atrial intended or shoulddiagnosis
fibrillation be inferred. foundDr Kapral holds
similar a career
stroke investigator
rates award from
after atrial fibrillation diagnosis found similar stroke rates
in both groups. This suggests our findings are not simply award from the Heart and Stroke Foundation of Ontario.
influenced by elevated rates of stroke after atrial fibrillation Disclosures
Ischemic Stroke During 5-y in both groups. This suggests our findings are not simply
Rate of Stroke, % per Person-Year (95% CI)

in both groups. This suggests our findings are not simply

diagnosis, as has been previously reported.8 Moreover, few
patients received heparins or antiplatelet agents before ini-
T. Gomes, M.M. Mamdani, J.M. Paterson,n and
Follow-Up, (%) D.N. Juurlink have re-
ceived grant funding from the Ontario Ministry of Health and Long-
First 30 d Remainder of 5-y Follow-Up
influenced by elevated rates of stroke after atrial fibrillation
Overall
Overall Term Care (MOHLTC). J.M. Paterson
influenced by elevated rates of stroke after atrial fibrillation
tiating warfarin. Studies are needed to determine whether
6006 is an employee of Institute
for Clinical Evaluative Sciences, which is funded by the MOHLTC.
6.0 (5.56.4) 1.6 (1.51.6)
diagnosis, as has been previously reported.8 Moreover, few Disclosures
1.8 (1.71.8)
T. Gomes,
CHADS2 score
bridging therapy, antiplatelet therapy, or use of direct-acting M.M. Mamdani is a consultant for AstraZeneca, Bristol-Myers
diagnosis, as has been previously reported. Moreover, few 8 T. Gomes, M.M. Mamdani, J.M. Paterson, and D.N. Juurlink have re-
ceived gra
anticoagulants mitigate this early increased stroke risk. 0 Squibb, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Novartis,
146 (2.4) 2.7 (1.84.1) patients received heparins or antiplatelet
0.5 (0.50.6) 0.6 (0.50.7) agents before ini-
Strengths of this study include its large, population- Novo Nordisk and Pfizer. The other authors report no conflicts.
patients received heparins or antiplatelet agents before ini- ceived grant funding from the1.1Ontario Ministry of Health and Long- Term Car
based sample and long follow-up. Limitations include our1 874 (14.6) 3.8 (3.24.6) 0.9 (0.91.0)
tiating warfarin. Studies are needed (1.01.1)
to determine whether
inability to assess the quality of anticoagulation. We also23 References
3609 (60.1) 5.6 (5.16.2)Term Care 1.6 (MOHLTC).
(1.61.7) J.M.1.8Paterson
(1.81.9) is an employee of Institute
for Clinica
tiating
could not capture warfarin.
stroke events that did notStudies
result in hos-are needed
1. Go AS, Hylek to determine
EM, Chang Y, Phillips KA, Henault whether bridging
LE, Capra AM, et
therapy,
for Clinicalantiplatelet
Evaluative therapy,
Sciences, or useisof
which direct-acting
funded by the MOHLTC. M.M. Ma
46 al. Anticoagulation therapy for 1377
stroke(22.9) 14.2 (12.316.4)
prevention in atrial fibrillation: 3.6 (3.43.8) 4.2 (4.04.4)
bridging therapy, antiplatelet
pitalization or some important risk factors for stroke, such
as hypertension.
therapy,
Stroke history
how well do or use of direct-acting
randomized trials translate
2003;290:26852692. doi: 10.1001/jama.290.20.2685.
into clinical practice?
anticoagulants
JAMA.
M.M. Mamdani mitigate this is aearly
consultant
increased for AstraZeneca,
stroke risk. Bristol-Myers Squibb, E
anticoagulants mitigate thisNo previous early increased stroke
stroke 4900 (81.6) risk.
2. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C,
Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial
5.0 (4.65.4)Squibb, Eli 1.4
Strengths of Lilly,
this GlaxoSmithKline,
study
(1.31.4)
include 1.6 (1.51.6) Hoffmann-La Roche, Novartis,
its large, population- Novo Nor
Conclusions
Strengths cohort of
study this study include
Previous stroke
its large, S, Simon TA,population-
fibrillation. CMAJ. 2013;185:E121E127.
1106 (18.4) doi: 10.1503/cmaj.121218. Novo Nordisk
19.6 (16.823.0) and Pfizer. The4.9other
4.2 (4.04.5) (4.65.2)authors report no conflicts.
In this large, population-based of older patients 3. Azoulay L, DellAniello
Timing of atrialoffibrillation
with atrial fibrillation, we observed the highest rate of ischemic warfarin in diagnosis,
based
Renoux C, Suissa S. Initiation
patients with datrial fibrillation: early effects on ischaemic
sample and long follow-up. Limitations include our
stroke in the based
first 30 dayssample
after warfarinand long follow-up. Limitations include our
Boechler M, Rich MW, inability 6.1 (5.56.8) to assess1.5the quality of1.7anticoagulation. We also
strokes. Eur Heart J. 2014;35:18811887. doi: 10.1093/eurheartj/eht499.
initiation. Although 30 72 385W,(48.8) (1.51.6) (1.71.8)
4. Gage BF, Waterman AD, Shannon Radford
this does not provide evidence of a causal link between war-
inability to assess the
farin initiation and stroke, the persistence of thromboembolic quality
>30 of anticoagulation. 76 061 (51.2) We
results from the National Registry of Atrial Fibrillation.could also
MJ. Validation of clinical classification schemes for predicting stroke:
not
5.8 (5.36.5)
JAMA. capture 1.6stroke
(1.61.7) events References
that
1.8 did
(1.81.9) not result in hos- 1. Go A
age 751. Go AS,previous
Hylekstroke;
EM, andChang Y, interval.
Phillips KA, Henault LE, Capra AM, et al. An
2001;285:28642870.
could not capture stroke events
risk despite anticoagulation highlights the need for futureCHADS indicates
research in this area.
2 that
5. Agarwal
score did not
comprised
S, Hachamovitch result
ofR,congestive
Menon V. Currentin
heart failure, hos-
hypertension,
pitalization
trial-associated out-
years,
or
diabetes,
some important
CI, confidence
risk factors for stroke, such
comes with warfarin in prevention of stroke in patients with nonvalvular
al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how w
pitalization or some important atrial risk factors
fibrillation: forArchstroke,
a meta-analysis. such as hypertension.
Intern Med. 2012;172:623631,
how well do randomized trials translate into clinical practice? JAMA. 2003;
Acknowledgments discussion 631. doi: 10.1001/archinternmed.2012.121.
We thank Broganas Inc,hypertension.
Ottawa for use of their Drug Product and
Therapeutic Class Database.
6. Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA.
Early risk of stroke after transient ischemic attack: a systematic review 2003;290:26852692. doi: 10.1001/jama.290.20.2685. 2. Gome
and meta-analysis. Arch Intern Med. 2007;167:24172422. doi: 10.1001/
2. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurli
Juurlink DN.Conclusions
archinte.167.22.2417.
Sources of Funding 7. Vigan S, Mannucci PM, Solinas S, Bottasso B, Mariani G. Decrease in
Rates of hemorrhage during warfarin therapy for atrial fibrill
This study was supported by the Ontario Drug Policy Research Conclusions
Network which is funded by grants from the Ontario Ministry of population-based Abstract 4
protein C antigen and formation of an abnormal protein soon after start-
In this large,fibrillation. cohort study ofdoi:
ing oral anticoagulant therapy. Br J Haematol. 1984;57:213220.
CMAJ. 2013;185:E121E127.
8. Lehto M, Snapinn S, Dickstein K, Swedberg K, Nieminen MS;
older patients
10.1503/cmaj.121218. 3. Azoul
In this large, population-based cohort study of older patients
Health and Long-Term Care (MOHLTC), and supported by the
Institute for Clinical Evaluative Sciences (ICES). Opinions, results, with atrial3.fibrillation,
Azoulay L, we observed
DellAniello S, the highest
Simon rate ofC,ischemic
TA, Renoux
OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute
myocardial infarction complicated by left ventricular dysfunction: the
Suissa S. Initiation of wa
with atrial fibrillation, we observed the highest rate of ischemic
and conclusions reported are those of the authors and independent
from funding sources. No endorsement by ICES or the MOHLTC is stroke in theoffirst
warfarin in patients with atrial fibrillation: early effects on ischaemic
OPTIMAAL experience. Eur Heart J. 2005;26:350356. doi: 10.1093/
eurheartj/ehi064. 30 days after warfarin initiation. Although stroke
strokes. Eur Heart J. 2014;35:18811887. doi: 10.1093/eurheartj/eht499. 4. Gage
stroke in the first 30 days after warfarin initiation. Although
, this does not provide evidence ofShannon
a causal
4. Gage BF, Waterman AD, W, link between
Boechler M, Richwar-MW, Radford MJ. V
this does not provide evidence of a causal link between war- farin initiationMJ.and stroke,ofthe
Validation persistence
clinical of thromboembolic
classification schemes for predicting stroke: result
farin initiation and stroke, the persistence of thromboembolic risk despite results from the National
anticoagulation highlightsRegistry
the ofneedAtrialforFibrillation.
future JAMA. 2001;
Long-Term Exposure to Fine Particulate Matter, Residential Proximity to Major Roads and Measures
risk despite anticoagulation highlights the need for future 2001;285:28642870.
research in5.this area.S, Hachamovitch R, Menon V. Current trial-associated out-
5. Agarw
Agarwal come
research in this area. of Brain Structure comes with warfarin in prevention of stroke in patients with nonvalvular atrial
Elissa H. Wilker, ScD; Sarah R. Preis, ScD; Alexa S. Beiser, PhD; Philip A. Wolf, MD; Rhoda Au,atrial
PhD; Acknowledgments
fibrillation: a meta-analysis.
Itai Kloog, PhD; WenyuanArch Intern
Li, MS; Med.
Joel 2012;172:623631,
Schwartz, PhD; discus
Acknowledgments
Petros Koutrakis, PhD; Charles DeCarli, MD; Sudha Seshadri, MD;
We thank Brogan
discussion
Murray 631.
A. doi: 10.1001/archinternmed.2012.121.
Mittleman,
Inc,McLaughlin
Ottawa for MD, DrPH
use of their DrugMD, Product andGhali WA.
6. Wu C
6. Wu CM, K, Lorenzetti DL, Hill Manns BJ, Early
We thank Brogan Inc, Ottawa for use of their Drug Product and Therapeutic Class
(Stroke. 2015;46:1161-1166.) EarlyDatabase.
risk of stroke after transient ischemic attack: a systematic review and m
Therapeutic Class Database. and meta-analysis. Arch Intern Med. 2007;167:24172422. doi: 10.1001/ archin
Key Words: air pollution brain infarcts neuroimaging
archinte.167.22.2417.
Sources of Funding 7. Vigan
Sources of Funding 7. Vigan S, Mannucci PM, Solinas S, Bottasso B, Mariani G. Decrease in
This study was supported
protein C antigenbyandthe Ontarioof an
formation Drug Policyprotein
abnormal Research
soon after start-
protei
ing or
This study was supported by the Ontario Drug Policy Research Network which ingisoral
funded by grants
anticoagulant from
therapy. Br the Ontario1984;57:213220.
J Haematol. Ministry of 8. Lehto
Network
which is funded by grants from the Ontario Ministry of Health
and8.
Long-Term
Lehto . Care
,
M, Snapinn (MOHLTC),
S,
Dickstein and supported
K,
K, Swedberg byNieminen
the MS; OPTI
Health and Long-Term Care (MOHLTC), and supported by the
Institute for .
Clinical
OPTIMAAL Evaluative
Sciences
investigators. (ICES).
Prognostic
Opinions,
risk of atrial results,
fibrillation
in acute myoc
Institute for Clinical Evaluative Sciences (ICES). Opinions, results, and conclusions reportedinfarction
myocardial are those of the authors
complicated by leftand independent
ventricular dysfunction: the OPTI
and conclusions reported are those of the authors and independent from funding sources.
OPTIMAAL No experience.
endorsement Eurby ICES
Heart or the MOHLTCdoi:
J. 2005;26:350356. is 10.1093/ eurhe
from funding sources. No endorsement by ICES or the MOHLTC is eurheartj/ehi064.