Antiplatelet Treatment After TIA and Ischemic Stroke

Antiplatelet Treatment After Transient Ischemic Attack and
Ischemic Stroke in Patients With Cerebral Microbleeds

in 2 Large Cohorts and an Updated Systematic Review
Kui Kai Lau, DPhil*; Caroline E. Lovelock, DPhil*; Linxin Li, MD, DPhil;
Michela Simoni, DPhil; Sergei Gutnikov, DPhil; Wilhelm Küker, MD;
Henry Ka Fung Mak, MD; Peter M. Rothwell, MD, PhD, FMedSci
Background and Purpose—In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts
intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous
cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic
use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke.
Methods—In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/
mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of
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microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were
determined and stratified by microbleed burden (0 versus 1, 2–4, and ≥5), adjusting for age, sex, and vascular risk factors.
Results—Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P<0.0001), but risk
associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of
major extracranial bleeds was unrelated to microbleed burden (Ptrend=0.87), but the 5-year risk of ICH was steeply related
(Ptrend<0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of
ischemic stroke also increased with microbleed burden (Ptrend=0.013), such that risk of ischemic stroke and coronary
events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds
(11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic
events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke
was due mainly to nondisabling events (Ptrend=0.007), the association with ICH was accounted for (Ptrend<0.0001) by
disabling/fatal events (≥5 microbleeds: 82% disabling/fatal ICH versus 40% disabling/fatal ischemic stroke; P=0.035).
Conclusions—In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after
transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit
thereafter. (Stroke. 2018;49:1434-1442. DOI: 10.1161/STROKEAHA.117.020104.)
Key Words: cerebral small vessel disease ◼ magnetic resonance imaging ◼ stroke ◼ transient ischemic attack
C erebral microbleeds are markers of severe small ves-

sel disease.1–3 Recent systematic reviews of mainly
small studies have shown that a high burden of microbleeds
(TIA)/ischemic stroke in reducing the early risk of recurrent
ischemic events,8 and this benefit outweighs the risks of ICH,9
antiplatelet-related ICH is associated with a high risk of mor-
is associated with an increased risk of intracerebral hemor- bidity and mortality on longer-term treatment.10 However, in
rhage (ICH) and possibly also of ischemic stroke.4–6 Other TIA/ischemic stroke patients with microbleeds, current guide-
retrospective studies have reported an increased risk of ICH lines make no recommendations on the safety of antiplatelet
among aspirin users with microbleeds.7 Although aspirin treatments11 although there is clinical uncertainty, particularly
is highly effective in patients with transient ischemic attack in those with ≥5 microbleeds.12,13 Clinicians, therefore, face
Received November 11, 2017; final revision received April 3, 2018; accepted April 10, 2018.
From the Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom
(K.K.L., C.E.L., L.L., M.S., S.G., W.K., P.M.R.); and Division of Neurology, Department of Medicine (K.K.L.) and Department of Diagnostic Radiology
(H.K.F.M.), Li Ka Shing Faculty of Medicine, University of Hong Kong.
Guest Editor for this article was Gregory W. Albers, MD.
*Drs Lau and Lovelock contributed equally.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
117.020104/-/DC1.
Correspondence to Peter M. Rothwell, MD, PhD, Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, John
Radcliffe Hospital, Level 6, W Wing, Oxford, United Kingdom. E-mail peter.rothwell@ndcn.ox.ac.uk
© 2018 The Authors. Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article
under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original
work is properly cited.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.117.020104
1434
Lau et al Microbleeds in TIA and Ischemic Stroke 1435
a treatment dilemma14 and may err on the side of caution by using T2*-weighted gradient-recalled echo (GRE) in OXVASC
not prescribing antiplatelets in patients with multiple micro- and using susceptibility weighted imaging (SWI) in HKU. Details
of scan parameters are provided in Table I in the online-only Data
bleeds, potentially jeopardizing the early benefits of antiplate- Supplement.
let treatment after TIA/ischemic stroke.8 Two neurologists, supervised by 2 consultant neuroradiolo-
The treatment dilemma might be solved by reliable data gists (H.K.F.M. and W.K.), interpreted all MRIs. Microbleeds were
on the prognostic implications of microbleeds, but the cur- defined according to current guidelines,21 the location scored using
rent evidence base has several shortcomings.4–6 First, meta- the Microbleed Anatomical Rating Scale,22 and burden graded as
absent, 1, 2 to 4, and ≥5.6 The intrarater κ for interpretation of micro-
analyses have combined cohorts including patients who were bleed burden in 50 randomly selected scans was 0.88 (OXVASC) and
variously on antiplatelets, anticoagulants, or no antithrom- 0.81 (HKU), and the interrater κ was 0.84. White matter hyperin-
botic drugs.5,6 Second, although microbleeds are much more tensity severity, enlarged perivascular space burden, and presence of
prevalent in Asians than whites, racial differences in progno- lacunes were also determined based on previously validated scales
sis remain uncertain. Third, although the balance of risk and (online-only Data Supplement).23–25
All patients in OXVASC were followed-up regularly by a
benefits from antiplatelet agents in patients with microbleeds research nurse or physician at 1, 3, 6, 12, 24, 60, and 120 months
who present with a TIA/ischemic stroke might well vary over after the index event. Patients recruited from HKU were followed-
time, particularly if the risk of recurrent ischemic events is up by a clinician every 3 to 6 months or more frequently if clinically
highest early whereas the risk of ICH and extracranial bleed- indicated. All patients were assessed for the following clinical out-
comes: (1) recurrent stroke (ischemic and hemorrhagic), (2) acute
ing accrue more gradually, the time course of risk of ICH ver-
coronary events (acute coronary syndrome and sudden cardiac
sus ischemic stroke has not been addressed previously. The death), (3) major extracranial bleeding, and (4) mortality (vascular
particularly high early risk after TIA versus ischemic stroke
and nonvascular). The definition of recurrent stroke required a sud-

might also be relevant here.15 den new neurological deficit fitting the definition of ischemic stroke
To improve the reliability of previous estimates of risk or ICH, occurring after a period of unequivocal neurological stabil-
ity and not attributable to cerebral edema, mass effect, or hemor-
of recurrent stroke from meta-analyses of small studies and rhagic transformation of the incident cerebral infarction. Modified
to address these unanswered questions, we studied the time Rankin Scale (mRS) at 1 month after recurrent stroke was deter-
course and severity of recurrent events in TIA/ischemic stroke mined and disabling stroke defined as mRS >2 (refer to online-only
patients with microbleeds from OXVASC (Oxford Vascular Data Supplement for definitions of other clinical outcomes). Where
Study), as well as a large prospective cohort of Chinese with needed, details of clinical outcomes were supplemented by medical
records from primary care practices, hospitals, as well as the Deaths
ischemic stroke. General Register Office.
We performed an updated systematic review according to the
PRISMA guidelines (Preferred Reporting Items for Systematic
Methods Reviews and Meta-Analyses) and searched Medline and Embase
Request for access to data will be considered by the corresponding from April 2015 (date last systematic review6 on this topic was per-
author. formed) to September 2017 with the following search strategy:
We prospectively studied 2156 patients with a probable or definite 1. Cerebral microbleed* or CMB or cerebral microh?emorr* or
TIA/ischemic stroke recruited from 2 study centers—OXVASC and brain microbleed* or brain microh?emorr*
The University of Hong Kong (HKU). In brief, OXVASC is an on- 2. Stroke or isch?emic stroke or TIA or intrac* adj2 h?emorrhag*
going population-based study of all acute vascular events occurring or ICH
within a predominantly white population of all 92 728 individuals, 3. 1 and 2
irrespective of age, who are registered with 100 general practitio- We included published and unpublished studies that fulfilled the
ners in 8 general practices of Oxfordshire, United Kingdom.16 The following criteria: (1) included a study population of patients with
analysis herein includes 1080 consecutive cases of TIA/ischemic TIA or ischemic stroke, (2) performed MRI T2*-GRE or SWI
stroke recruited from November 2004 to September 2014 who had sequences at baseline to detect presence of microbleeds and had isch-
a cerebral magnetic resonance imaging (MRI) incorporating a hemo- emic stroke or ICH as an outcome, (3) had a prospective study design
siderin-sensitive sequence and was subsequently diagnosed to have with at least 3 months of follow-up, and (4) subjects were predomi-
a TIA/ischemic stroke. The imaging protocol of OXVASC has been nantly (≥70% of the study population) on antiplatelet agents.
described in detail elsewhere.17,18 A further 1076 consecutive patients
who were predominantly Chinese with a diagnosis of acute ischemic
stroke who received an MRI scan incorporating a hemosiderin-sensi- Statistical Analysis
tive sequence at the HKU MRI Unit was recruited from March 2008 We first conducted separate analyses for the OXVASC and HKU
to September 2014.13 Both cohorts had similar antiplatelet treatment cohorts. Because there was no significant heterogeneity (micro-
policies, and antiplatelet treatment was started routinely irrespective bleed burden by cohort interaction P=0.52 for prediction of recurrent
of microbleed burden. However, patients with a diagnosis of cerebral stroke), these were then combined in a pooled analysis. The clini-
amyloid angiopathy, defined according to the modified Boston crite- cal and imaging predictors of ≥5 microbleeds were determined using
ria,19 presenting with a transient focal neurological episode,20 were logistic regression model. Variables, including age, male sex, vascular
not considered as having TIAs and were not included in this study. risk factors (hypertension, hyperlipidemia, diabetes mellitus, smok-
All patients gave written informed consent, or assent was obtained ing, atrial fibrillation), glomerular filtration rate,26 premorbid use of
from a relative of patients who were unable to provide consent. The 2 antiplatelets, and anticoagulants, were entered into a univariate analy-
studies were approved by the local research ethics committee. sis model, and all variables were subsequently entered into a multi-
We collected demographic data, atherosclerotic risk factors, pre- variate analysis model to determine the independent predictors of ≥5
morbid antithrombotic use, details of hospitalization of index event, microbleeds. The associations of ≥5 microbleeds with other neuroim-
and medications on discharge during face-to-face interview and aging markers of severe small vessel disease were also determined.
cross-referenced these with primary care and hospital records in In the primary analysis, we used Kaplan–Meier survival analysis
both cohorts. to calculate the 5-year risk of adverse events among 1811 antiplatelet
Patients with TIA/ischemic stroke recruited from OXVASC were users from OXVASC and HKU, censored at death or March 31, 2015.
scanned with a 1.5-T or 3-T MRI scanner. All 1076 HKU patients Risks of adverse events by microbleed burden were compared with log-
were scanned using a 3-T MRI scanner. Microbleeds were detected rank test. We determined by Cox-regression analysis the unadjusted
1436 Stroke June 2018
Table. Characteristics and Outcomes of OXVASC and HKU Table. Continued

Cohorts
OXVASC, UK
OXVASC, UK TIA/Ischemic
TIA/Ischemic Stroke, HKU, HK
Stroke, HKU, HK N=1080 Ischemic
N=1080 Ischemic (572 TIA/508 Stroke,
(572 TIA/508 Stroke, Stroke) N=1003 P Value
Stroke) N=1003 P Value
Combined anticoagulant and 7 (1) 19 (1) 0.010
Baseline clinical characteristics antiplatelet (%)
Mean (SD), age, y 68 (14) 69 (12) 0.17 Not on antithrombotic 13 (1) 37 (4) <0.0001
agents (%)
Males (%) 566 (52) 601 (60) 0.001
Outcome
Hypertension (%) 588 (55) 657 (66) <0.0001
Mean follow-up time, mo 47±27 38±20
Diabetes mellitus (%) 143 (13) 284 (28) <0.0001
Patient-years follow-up 4265 3168
Hyperlipidemia (%) 399 (37) 256 (26) <0.0001
Recurrent stroke (%) 97 (9) 113 (11) 0.084
Ever-smokers (%) 543 (50) 297 (30) <0.0001

Ischemic (%) 87 (8) 93 (9) 0.32
Atrial fibrillation (%) 167 (16) 130 (13) 0.10
Fatal (%)
9 (10) 13 (14) 0.30
Prior transient ischemic 201 (19) 154 (15) 0.047

attack /stroke (%) Intracerebral hemorrhage
10 (1) 20 (2) 0.041
(%)
Angina or myocardial 146 (14) 92 (9) 0.002
infarction (%)
Fatal (%) 3 (30) 6 (30) 0.27
Prior antiplatelet use (%) 137 (13) 218 (22) <0.0001 Acute coronary event (%) 26 (2) 52 (5) 0.001
Prior warfarin use (%) 12 (1) 20 (2) 0.10 Extracranial bleed* (%) 80 (7) 64 (6) 0.36
Prior NOAC use (%) 1 (0.1) 3 (0.3) 0.28 Major bleed (%) 19 (24) 21 (33) 0.58
Imaging characteristics Deaths (%) 161 (15) 130 (13) 0.20
Magnet strength, Tesla 1.5 (N=628) 3 3 Vascular deaths (%) 41 (25) 60 (46) 0.20
(N=452) GRE indicates gradient-recalled echo; HKU, University of Hong Kong; NOAC,
nonvitamin K antagonist oral anticoagulant; OXVASC, Oxford Vascular Study;
Method of detecting T2* GRE SWI
SWI, susceptibility weighted imaging; and TIA, transient ischemic attack.
microbleeds
*Bleeding events from oral and nasal cavity excluded.
Median delay (interquartile 3 (0–29) 4 (3–6) 0.71
range) to scan, days
and adjusted (age, sex, and vascular risk factors) risks of adverse out-
N with microbleeds (%) 165 (15) 450 (45) <0.0001 come among patients with 1, 2 to 4, and ≥5 microbleeds compared
with no microbleeds as reference. We obtained the Ptrend by analyzing
N with 1 microbleed (%) 79 (7) 184 (18) <0.0001
0, 1, 2 to 4, ≥5 microbleeds as a noncategorical variable. The follow-
N with 2–4 microbleeds (%) 46 (4) 147 (15) <0.0001 ing outcomes were studied: recurrent stroke, recurrent ischemic stroke,
ICH, acute coronary events, major extracranial hemorrhage, death, and
N with ≥5 microbleeds (%) 40 (4) 119 (12) <0.0001 vascular death. We also examined the risk of adverse events of patients
N with strictly deep 14 (1) 61 (6) <0.0001 with <5 and ≥5 microbleeds, within 1 year versus those occurring from
microbleeds (%) 1 to 5 years of index event using the Kaplan–Meier method. To deter-
mine whether the risk of recurrent ischemic stroke and ICH in patients
N with strictly lobar 73 (7) 161 (16) <0.0001 with ≥5 microbleeds was time dependent, we inserted a time-depen-
microbleeds (%) dent variable (within 1 year versus 1–5 years) into the Cox-regression
model. Finally, we compared the severity of recurrent ischemic stroke
N with strictly infratentorial 16 (2) 41 (4) <0.0001
and ICH based on mRS with ordinal regression (mRS shift) analysis.
microbleeds (%)
Because there were no new studies from April 2015 to September
N with microbleeds of mixed 54 (5) 187 (19) <0.0001 2017 that matched our systematic review search criteria (Figure I in
location (%) the online-only Data Supplement), we performed a meta-analysis
using a random-effects analysis by pooling the results from our 2
Postevent antithrombotic use cohorts with those from the most recent systematic review6 and cal-
Antiplatelets only culated the risk ratios of recurrent ischemic stroke and ICH among
patients with 1, 2 to 4, and ≥5 microbleeds compared with no micro-
Single antiplatelet (%) 677 (63) 725 (72) <0.0001 bleeds as reference. TIA/ischemic stroke cohorts that were predomi-
nantly (≥70% of the study population) on antiplatelets were included.
Dual antiplatelet (%) 272 (25) 137 (14) <0.0001
We stratified our analysis by ethnicity (whites versus Asians), MRI
Anticoagulants only strength (0.5T/1T/1.5T versus 3T), and sequence (T2*GRE versus
SWI). Heterogeneity was determined with χ2 tests.

Warfarin (%) 105 (10) 50 (5) 0.001 Sensitivity analyses was also performed to include all 2083

NOAC (%) 6 (1) 35 (4) <0.0001 patients, regardless of antithrombotic status, from OXVASC and
HKU and all studies from the systematic review.6
(Continued ) All analyses were done with SPSS version 22.
Role of the Funding Source in patients with or without antithrombotic treatment (Table
The funding source had no role in study design, data collection, data III in the online-only Data Supplement; P=0.58).
analysis, data interpretation, or writing of the report. The correspond- Microbleeds were more frequent in the HKU cohort versus
ing author had full access to all the data in the study and had the final OXVASC (45% versus 15%; P<0.0001), but risk factors for
responsibility for the decision to submit for publication.
microbleeds were similar (Table IV in the online-only Data
Supplement). On multivariate analysis, only age (adjusted
Results odds ratio, 1.02; 95% confidence interval, 1.00–1.03;
After excluding 73 patients with incomplete follow-up data, P=0.035) and premorbid anticoagulation use (2.77; 1.00–
a total of 2083 patients were included in the final analysis. 7.70; P=0.05) remained significant independent predictors of
Characteristics and outcomes of the 1080 patients from a high burden (≥5) of microbleeds (Table IV in the online-
OXVASC (572 TIA, 508 ischemic stroke) and 1003 patients only Data Supplement). Lacunes and an increasing burden of
with ischemic stroke from HKU are shown in the Table. HKU enlarged basal-ganglia perivascular spaces and white matter
patients were more often men and were more likely to have hyperintensity were all associated with ≥5 microbleeds after
hypertension and diabetes mellitus whereas OXVASC patients adjusting for age and sex (all P<0.05; Table V in the online-
were more likely to have hyperlipidemia or were ever-smok- only Data Supplement).
ers (all P<0.05). The median delay from event to MRI was 3 On 4265 patient-years follow-up in OXVASC and 3168
days in OXVASC and 4 days in HKU. Cause of TIA/ischemic patient-years in HKU, associations between microbleed bur-
stroke, according to the modified TOAST criteria (Trial of den and risk were similar in the 2 cohorts for all outcomes
ORG 10172 in Acute Stroke Treatment), is provided in Table (Table VI in the online-only Data Supplement), and so further
II in the online-only Data Supplement. Antithrombotic treat- analyses are pooled. After mean follow-up of 43±25 months
ment on discharge in the 2 cohorts was similar (Table), with (7433 patient-years), 220 patients developed a recurrent stroke
86.9% on antiplatelets only, 9.4% anticoagulants only, 1.3% (82% ischemic; Table). One patient developed a subarachnoid
anticoagulant plus antiplatelet, and 2.4% on no antithrom- hemorrhage because of an underlying cerebral aneurysm.
botic agents. There were no differences in microbleed burden Seventy-eight patients developed an acute coronary event and
Figure 1. Risk of recurrent stroke (A), recurrent ischemic stroke (B), intracerebral hemorrhage (C), and intracerebral hemorrhage and major
extracranial bleeding (D) among patients with transient ischemic attack/ischemic stroke on antiplatelets.
Figure 2. Risk of disabling or fatal (A) and nondisabling (B) ischemic stroke and intracerebral hemorrhage by microbleed burden in
patients with transient ischemic attack/ischemic stroke on antiplatelets.
144 patients an extracranial bleed. A total of 291 patients died anticoagulant use excluded), the 5-year risks of recurrent isch-
during follow-up (34% vascular deaths). emic stroke and ICH in patients with 0, 1, 2 to 4, and ≥5 micro-
Among 1811 patients (OXVASC n=949; HKU n=862) who bleeds were 8.7%, 14.1%, 13.7%, and 17.4% (Figure 1B;
were prescribed with antiplatelet agents (26 with concomitant log-rank test P=0.002) and 0.6%, 0.9%, 3.7%, and 10.2%,
Figure 3. Risk of ischemic and hemor-

rhagic events in transient ischemic attack/
ischemic stroke patients with <5 and ≥5
microbleeds on antiplatelets, within 1 year
of index event and between 1 and 5 years
after index event. ICH indicates intracere-
bral hemorrhage.
respectively (Figure 1C; P<0.0001). After adjusting for age, during the first year after TIA/ischemic stroke as compared
sex, and vascular risk factors, a high microbleed burden was an with years 1 to 5 (P=0.030). However, there was no evi-
independent predictor of recurrent ischemic stroke, ICH, all- dence of time dependence of ICH risk in TIA/ischemic stroke
cause mortality, and nonvascular death (all Ptrend<0.05; Table patients with ≥5 microbleeds (P=0.74).
VII in the online-only Data Supplement). A high microbleed We pooled the results from OXVASC and HKU with those
burden was not associated with risk of coronary events, major from a recent meta-analyses (Table IX in the online-only Data
extracranial bleed, or vascular death (all Ptrend>0.05). Similar Supplement).6 After excluding cohorts with <70% of the study
findings were noted in 1403 patients (OXVASC n=677; HKU population on antiplatelet agents, the pooled unadjusted rela-
n=726) on single antiplatelets (Table VIII in the online-only tive risk estimates of recurrent ischemic stroke in patients with
Data Supplement). 1, 2 to 4, and ≥5 versus no microbleeds were 1.68 (95% con-
In patients with microbleeds, the 5-year absolute risks of fidence interval, 1.14–2.48; P=0.009; Phet=0.18), 2.51 (1.41–
a nondisabling ischemic stroke exceeded that of a nondis- 4.47; P=0.002; Phet=0.0003), and 2.75 (1.75–4.34; P<0.0001;
abling ICH (9.4% versus 1.2%; P<0.0001), even among those Phet=0.031; Figure III in the online-only Data Supplement). The
with ≥5 microbleeds (9.8% versus 2.1%; P=0.008; Figure 2). pooled relative risk estimates of ICH in patients with 1, 2 to 4,
Similarly, the 5-year risk of a disabling/fatal ischemic stroke and ≥5 versus no microbleeds were 3.14 (1.17–8.42; P=0.023;
exceeded that of a disabling/fatal ICH in patients with 1 to Phet=0.52), 5.81 (2.63–12.84; P<0.0001; Phet=0.85), and 13.35
4 microbleeds (8.3% versus 1.3%; P=0.0004; Figure 2). (6.75–26.39; P<0.0001; Phet=0.92; Figure IV in the online-only
However, in patients with ≥5 microbleeds, risks of a disabling/ Data Supplement). No significant heterogeneity was noted
fatal ICH increased substantially, such that the 5-year absolute between our 2 cohorts and pooled relative risk estimates of pre-
risks of a disabling/fatal ischemic stroke and ICH were similar vious cohorts and when all studies were stratified by ethnicity,
(9.0% versus 9.4%; P=0.81; Figure 2). Moreover, in patients MRI magnet strength, or sequence (Figure 4). However, risk
with ≥5 microbleeds, a greater proportion of patients who of recurrent ischemic stroke in patients with microbleeds ver-
developed a subsequent ICH were disabled or dead compared sus no microbleeds was significantly greater in the 2 TIA-only
with those who developed a recurrent ischemic stroke (81.8% cohorts that had ≤1-year follow-up compared with the other
versus 40.0%; mRS shift odds ratio, 6.75; 95% confidence TIA/ischemic stroke cohorts that had >1-year follow-up (rela-
interval, 1.14–39.80; P=0.035; Figure II in the online-only tive risk, 4.80; 2.35–9.76 versus 1.62; 1.32–1.99; Phet=0.004;
Data Supplement). Figure V in the online-only Data Supplement). Sensitivity
In a time-course analysis, among patients with <5 micro- analysis of all patients revealed broadly similar results (Table
bleeds, the absolute risks of ischemic stroke and coronary VI in the online-only Data Supplement; Figures VI and VII in
events combined exceeded that of an ICH and major extracra- the online-only Data Supplement).
nial bleed both within and beyond 1 year of the index event
(1-year risk: 4.8% versus 1.3%; 1–5 year risk: 10.8% versus Discussion
2.4%; Figure 3). In patients with ≥5 microbleeds, risks of a Our study comprises the 2 largest cohorts to date from the
combined ischemic event also exceeded that of a combined west and the east to report the long-term prognostic impli-
hemorrhagic event during the first year (11.6% versus 3.9%). cations of microbleed burden in patients with TIA/ischemic
However, in years 1 to 5, the risks of ICH increased steeply stroke, adding ≈6500 patient-years of follow-up data to the
such that the risks of ICH matched that of ischemic stroke 9534 patient-years included in a recent systematic review of
(11.2% versus 12.0%; Figure 3). This was mainly because of 15 smaller studies.6 Our study is also the first to report the
the expected frontloading of recurrent ischemic stroke risk other nonstroke determinants of the balance of risks and
Figure 4. Pooled analyses of relative risk estimates from the current and previous studies showing risk of recurrent ischemic stroke (A)
and of intracerebral hemorrhage (B) among patients with transient ischemic attack/ischemic stroke on antiplatelet agents with micro-
bleeds vs those without, stratified by geographical origin, magnetic resonance imaging (MRI) scanner magnet strength, MRI sequence,
and number of microbleeds. CI indicates confidence interval; GRE, gradient-recalled echo; HKU, University of Hong Kong; OXVASC,
Oxford Vascular Study; RR, relative risk; and SWI, susceptibility weighted imaging.
benefits of antiplatelet drugs (extracranial bleeds and coronary TIA, in whom the prevalence of microbleeds is known to be
events) stratified by microbleed burden, the first to determine lower.1 However, when individuals from OXVASC and HKU
the severity and time course of recurrent events, and the first were stratified by microbleed burden, risk of recurrent stroke
to determine whether risks of microbleeds differ in TIA versus was similar regardless of ethnicity, and no heterogeneity
ischemic stroke cohorts. was observed when all cohorts were pooled and stratified by
Our results support those from previous studies that micro- ethnicity.
bleeds represent an imaging biomarker of severe cerebral Compared with patients with no microbleeds, TIA/ischemic
small vessel disease.6,27,28 Similar to previous studies,1 we stroke patients with ≥5 microbleeds on antiplatelet agents
showed that prevalence and burden of microbleeds were sig- were at 3-fold increased risk of recurrent ischemic stroke and
nificantly greater in Chinese than whites. While this may be at 13-fold increased risk of ICH. However, the relative risk of
because of a greater proportion of hypertension among the ischemic versus hemorrhagic events was time dependent, with
Chinese, patients from HKU also consisted entirely of patients a 3-fold excess of risk of recurrent ischemic stroke versus ICH
with ischemic stroke while ≈53% of OXVASC patients had in the first year (9.5% versus 3.7%) but an increasing relative
risk of ICH thereafter. Furthermore, the disability accrued of cerebral amyloid angiopathy (either cortical superficial sid-
because of ICH was significantly greater than that because erosis or numerous microbleeds). Fourth, we were only able
of recurrent ischemic stroke. Our relative risk estimates for to provide preliminary insights as to whether risks of adverse
ICH in relation to microbleed burden were fairly consistent events among patients with ≥5 microbleeds were time depen-
with the pooled estimates from previous meta-analyses, but dent. Although our results were significant, our sample size
our relative risk estimates for recurrent ischemic stroke were was small, and confirmation of our results by pooling data
more modest.6 The pooled estimates from previous meta-anal- from multiple cohorts34 would be required before formal clini-
yses were nevertheless undermined by substantial heterogene- cal recommendations could be made. Fifth, we were not able
ity (Figure 4A) because of a 3-fold higher risk of ischemic to determine the prognostic implications of microbleed burden
stroke in TIA-only cohorts compared with cohorts that con- based on location because of small numbers in each subgroup.
sisted predominantly of patients with ischemic stroke (Figure Previous meta-analysis have nevertheless shown that patients
V in the online-only Data Supplement). Excluding the TIA- with microbleeds of mixed location are at greatest risk of a
only cohorts29,30 substantially reduced the heterogeneity of recurrent stroke.6 Finally, our cohort did not provide data on
pooled relative risk estimates of previous studies on recurrent the prognostic implications of microbleeds among patients on
ischemic stroke risk in 1, 2 to 4, and ≥5 microbleeds versus anticoagulants. Several clinical trials are currently underway
no microbleeds (Phet=0.095 to 0.24; Phet=0.0005 to 0.99; and to answer this question.
Phet=0.025 to 0.52, respectively). In conclusion, in TIA/ischemic stroke patients with ≥5
Our findings, therefore, have clinical implications on anti- microbleeds, antiplatelets are likely to be beneficial for sec-
platelet use in TIA/ischemic stroke patients with a high micro- ondary prevention of ischemic events within 1 year of index
bleed burden. Taken together with the recent evidence of event, especially among those presenting with a TIA where the
the considerable early benefit of aspirin in reducing the risk early ischemic risks are high. However, the associated hemor-
and severity of recurrent ischemic events after TIA/ischemic rhagic risks seem to outweigh its benefits thereafter. Although
stroke,8 our results suggest that patients with noncardioembolic withholding antiplatelet drugs during the acute phase of TIA/
TIA/ischemic stroke with <5 microbleeds could reasonably be ischemic stroke based on microbleed burden may be inap-
prescribed antiplatelet drugs unless contraindicated or unless propriate, the benefits of gradual withdrawal of antiplatelets
future research identifies a clearer hazard. In patients with ≥5 afterwards needs to be further studied.
microbleeds however, in view of the high early risk of ischemic
events, particularly in patients presenting as a TIA, antiplatelet Acknowledgments
agents should also be prescribed within the first year of index We are grateful to all the staff in the general practices that collabo-
event. Antiplatelet agents should perhaps be withdrawn there- rated with the Oxford Vascular Study: Abingdon Surgery, Stert St,
after because of the increasing long-term risks of ICH that are Abingdon; Malthouse Surgery, Abingdon; Marcham Road Family
more likely to be disabling/fatal than ischemic events. Health Centre, Abingdon; The Health Centre, Berinsfield; Key
Although we consider our findings to be valid, our study Medical Practice, Kidlington; 19 Beaumont St, Oxford; East Oxford
Health Centre, Oxford; Church Street Practice, Wantage. We also
has limitations. First, several different MRI scanners with dif- acknowledge the use of the facilities of the Acute Vascular Imaging
ferent field strengths, echo times, and hemosiderin-sensitive Centre, Oxford, and magnetic resonance imaging unit, Department
sequences were used for detection of microbleeds. Although of Diagnostic Radiology, University of Hong Kong. Dr Lau obtained
all these factors may have affected the sensitivity of micro- funding, collected data, did the statistical analysis and interpretation,
bleed detection,31–33 we have shown that scanner strength and wrote and revised the article. Dr Lovelock collected data, did the
statistical analysis and interpretation, wrote and revised the article.
sequence did not result in significant heterogeneity of the Dr Li acquired data and did the statistical analysis. Drs Simoni and
results (Figure 4). Although there appeared to be a trend toward Gutnikov acquired data. Dr Küker provided study supervision and
a greater risk of ICH in TIA/ischemic stroke patients with 1 to acquired imaging data. Dr Mak provided study supervision and fund-
4 microbleeds scanned with T2*-GRE as compared with SWI, ing, acquired, analyzed, and interpreted imaging data. Dr Rothwell
studies utilizing SWI are scarce (2 versus 13 studies; 3433 conceived and designed the overall study, provided study supervision
and funding, acquired, analyzed, and interpreted data, and wrote and
versus 11 234 patient-years), and power to demonstrate het- revised the article.
erogeneity between MRIs performed using SWI or T2*-GRE
may be limited. Second, the OXVASC and HKU cohorts were
different in several aspects—OXVASC was a population-
Sources of Funding
The Oxford Vascular Study is funded by the National Institute for
based study, consisting predominantly of whites with 50% Health Research (NIHR) Oxford Biomedical Research Centre,
being TIAs while the HKU cohort was a hospital-based study Wellcome Trust, Wolfson Foundation, British Heart Foundation, and the
comprising predominantly of Chinese with ischemic stroke, European Union’s Horizon 2020 programme (grant 666881, SVDs@
which is likely to have accounted for some of the differences target). Professor Rothwell is in receipt of a NIHR Senior Investigator
in stroke subtypes between the 2 populations. Third, it should award. Magnetic resonance imaging studies from University of Hong
Kong (HKU) are funded by the SK Yee Medical Foundation Grant
be noted that the generalizability of our results are restricted to and HKU Strategic Theme in Neurosciences. Dr Lau is funded by a
patients with a probable or definite diagnosis of TIA or isch- University of Oxford Croucher Scholarship. The views expressed are
emic stroke of mild-moderate severity who were fit for a MRI those of the author(s) and not necessarily those of the National Health
(mean mRS on discharge being 2 for ischemic stroke patients). Service (NHS), the NIHR, or the Department of Health.
Also, our results may not be applicable to patients presenting
with a transient neurological episode consistent with an amy- Disclosures
loid spell and who had clear neuroimaging features suggestive None.
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Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients
With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review
Kui Kai Lau, Caroline E. Lovelock, Linxin Li, Michela Simoni, Sergei Gutnikov, Wilhelm
Küker, Henry Ka Fung Mak and Peter M. Rothwell
Stroke. 2018;49:1434-1442; originally published online May 10, 2018;

doi: 10.1161/STROKEAHA.117.020104
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SUPPLEMENTAL*MATERIAL*
Supplementary*methods**
Enlarged"perivascular"spaces"(PVSs)"were"defined"as"small"(<3mm)"punctate"(if"perpendicular"to"the"
plane"of"scan)"or"linear"(if"longitudinal"to"the"plane"of"scan)"hyperintensities"on"T2"images"in"the"basal"
ganglia"(BG)"or"centrum"semiovale"(CS)."Burden"of"enlarged"PVSs"were"then"stratified"into"3"groups:"
<11,"11H20"and">20."The"severity"of"white"matter"disease"was"determined"for"each"patient"according"
to"the"Fazekas"scale."Subcortical"white"matter"hyperintensity"(WMH)"was"graded"as"0"(absent),"1"
(puntate"foci),"2"(beginning"confluence"of"foci)"and"3"(large"confluent"areas)Q"whilst"periventricular"
WMH"was"graded"as"0"(no"WMH"except"for"small"triangular"foci"surrounding"the"frontal"horns),"1"
(periventricular"hyperintensity"surrounding"the"anterior"and"posterior"horns"±"discrete"WMHs),"2"
(extensive"patchy"WMHs"and"their"early"confluent"stages),"and"3"(confluent,"completely"surrounding"
lateral"ventricles)."Lacunes"were"defined"as"rounded"or"ovoid"lesions,">3"and"<20mm"in"diameter,"in"
the"BG,"internal"capsule,"CS"or"brainstem,"of"cerebrospinal"fluid"signal"density"on"T2"and"fluidH
attenuated"inversion"recovery"(FLAIR)"and"no"increased"signal"on"diffusion"weighted"imaging"(DWI).""
Acute"coronary"syndrome"(ACS)"was"defined"as"nonHST"or"STHsegment"elevation"myocardial"
infarction"based"on"current"guidelines,1,"2"and"sudden"cardiac"death"was"defined"as"a"sudden"
pulseless"condition,"presumed"to"be"due"to"a"cardiac"arrhythmia,"in"a"previously"stable"individual"
without"a"nonHcardiac"cause"of"cardiac"arrest."Severity"of"extracranial"bleeding"was"classified"
according"to"the"CURE"trial.3"Vascular"death"was"defined"as"death"due"to"lethal"cardiac"arrhythmias,"
ACS,"congestive"heart"failure,"fatal"stroke,"pulmonary"embolism,"aortic"dissection"or"unexplained"
sudden"death.""
" *
1"
!
Supplementary*Tables**
*
Supplementary"Table"I."Imaging"sequence"parameters"of"the"OXVASC"and"HKU"cohorts"
"
Supplementary"Table*II."Cause"of"TIA"or"ischaemic"stroke"according"to"the"modified"TOAST"criteria""
Supplementary"Table*III."Burden"of"microbleeds"in"patients"with"or"without"antiHthrombotic"
medications"after"TIA"or"ischaemic"stroke"
Supplementary"Table*IV."Clinical"predictors"of"a"highHburden"(≥5)"of"cerebral"microbleeds"versus"<5"
microbleeds"
Supplementary"Table*V."Associations"of"a"highHburden"(≥5)"of"cerebral"microbleeds"with"other"
neuroimaging"markers"of"small"vessel"disease"versus"<5"microbleeds""
Supplementary"Table*VI."Cox"regression"analyses"of"risk"of"adverse"events"in"all"TIA"/"ischaemic"
stroke"patients"with"increasing"burden"of"microbleeds"versus"no"microbleeds"
Supplementary"Table*VII."Cox"regression"analyses"of"risk"of"adverse"events"amongst"antiplatelet"
users"with"increasing"burden"of"microbleeds"versus"no"microbleeds"
Supplementary"Table*VIII."Cox"regression"analyses"of"risk"of"adverse"events"amongst"single"
antiplatelet"users"with"increasing"burden"of"microbleeds"versus"no"microbleeds"
Supplementary"Table*IX."Summary"of"studies"included"in"metaHanalysis"
""
2"
!
Supplementary,Table,I.,Imaging,sequence,parameters,of,the,OXVASC,and,HKU,cohorts,
MR,parameters, HKU,, OXVASC,scanner,1, OXVASC,scanner,2, OXVASC,scanner,3, OXVASC,scanner,4,,

Achieva,,Philips,Healthcare, Magnetom,Verio,, Discovery,MR750,,GE, Achieva,,Philips, Signa,HDxt,,GE,
Siemens,Healthcare, Healthcare, Healthcare, Healthcare,
Patients,scanned, 1076" 388" 62" 493" 137"
Field,strength,(T), 3" 3, 3, 1.5, 1.5,
T1W,TR/TE/TI,(ms), 2000/20/800" 2000/1.94/880" ." 701/16" ."
T2W,TR/TE,(ms), 2377/80" 6000/96" 5800/94" 5061/100" 3760/100"
FLAIR,TR/TE/TI,(ms), 4800/282/1650" 9000/88/2500" 9600/130/2350" 11000/140/2800" 8080/112/2200"
(3D),
Diffusion,TR/TE,(ms), 2874/46" 5300/91" 6000/84" 2891/73" 6100/71"
GRE,/,SWI,TR/TE,(ms), SWI"28/23" GRE"504/15" GRE"500/20" GRE"694/23" GRE"560/25"
(3D),
Pixel,bandwidth,(Hz), 218.5"(T1W)" 240"(T1W)" ." 87.4"(T1W)" ."
350.7"(T2W)" 220"(T2W)" 50"(T2W)" 88.5"(T2W)" 47.6"(T2W)"
144.7"(FLAIR)" 202"(FLAIR)"" 41.7"(FLAIR)" 375"(FLAIR)" 31.3"(FLAIR)"
40.2"(Diffusion)" 1374"(Diffusion)" 250"(Diffusion)" 25.3"(Diffusion)" ."
455.7"(SWI)" 200"(GRE)" 31.3"(GRE)" 109.3"(GRE)" 75"(GRE)"
Matrix, 308x207"(T1W)" 256x256"(T1W)" ." 118x214"(T1W)" 416x256"(T2W)"
308x235"(T2W)" 320x320"(T2W)" 512"(T2W)" 356x193"(T2W)" 256x224"(FLAIR)"
228x227"(FLAIR)" 192x192"(FLAIR)" 384x224"(FLAIR)" 236x159"(FLAIR)" 128x128"(Diffusion)"
112x87"(Diffusion)" 130x130"(Diffusion)" 128x128"(Diffusion)" 97x84"(Diffusion)" 288x192"(GRE)"
256x224"(SWI)" 320x256"(GRE)" 288x224"(GRE)" 256x163"(GRE)"
No.,of,slices, 25"(T1W)" 208"(T1W)" 25" 25"(T1W)" 25"
25"(T2W)" 25"(T2W)" 25"(T2W)"
30"(FLAIR,"reconstructed)" 50"(FLAIR)" 28"(FLAIR)"
25"(Diffusion)" 25"(Diffusion)" 25"(Diffusion)"
25"(SWI,"reconstructed)" 25"(GRE)" 22"(GRE)"
"
Slice,thickness,(mm), 5"(T1W)" 1"(T1W)" 5" 5" 5"
5"(T2W)" 5"(T2W)"
5"(FLAIR"coronal),"2.5"(FLAIR" 3"(FLAIR)"
axial)"(reconstructed)"" 5"(Diffusion)"
5"(Diffusion)" 5"(GRE)"
5"(SWI,"reconstructed)"
Inter\slice,gap,(mm), 0.5"(T1W)" 0"(T1W)" 1" 1" 1"
0.5(T2W)" 1"(T2W)"
0.5"(FLAIR"coronal)" 0"(FLAIR"coronal)"
0"(FLAIR"axial)"" 1"(Diffusion)"
0.5"(Diffusion)" 1"(GRE)"
0.5"(SWI)"
3"
!
MR,parameters, HKU,, OXVASC,scanner,1, OXVASC,scanner,2, OXVASC,scanner,3, OXVASC,scanner,4,,
Achieva,,Philips,Healthcare, Magnetom,Verio,, Discovery,MR750,,GE, Achieva,,Philips, Signa,HDxt,,GE,
Siemens,Healthcare, Healthcare, Healthcare, Healthcare,
Voxel,size,(mm3), 0.75x0.95x5.0"(T1W)" 1.0x1.0x1.0"(T1W)" ." 0.53x0.53x5.0"(T1W)" ."
0.75x0.76x5.0"(T2W)" 0.8x0.8x5.0"(T2W)" 0.65x0.65x5.0"(T2W)"
1.10x1.10x0.56"(FLAIR)" 1.0x1.0x3.0"(FLAIR)" 0.82x0.81x5.0"
2.05x2.64x5.0"(Diffusion)" 1.8x1.8x5.0"(Diffusion)" (FLAIR)"
0.90x0.90x1.00"(SWI)" 0.9x0.8x5.0"(GRE)" 1.74x1.73x5.0"
" " (Diffusion)"
0.90x0.90x5.0"(GRE)"
,
, ,
4"
!
Supplementary,Table,II.,Cause,of,TIA,or,ischaemic,stroke,according,to,the,modified,TOAST,criteria,,
, OXVSAC, HKU,
(n=1080), (n=1003),
Small,vessel,occlusion,(%), 132"(12.2)" 425"(42.4)"
Large,artery,atherosclerosis,(%), 145"(13.4)" 342"(34.1)"
Cardio\embolism,(%), 167"(15.5)" 124"(12.4)"
Multiple,causes,(%), 36"(3.3)" 28"(2.8)"
Others,(%), 34"(3.2)" 18"(1.8)"
Undetermined,(%), 539"(50.0)" 44"(4.4)"
Unknown,(%), 26"(2.4)" 22"(2.2)"
,
,
Supplementary,Table,III.,Burden,of,microbleeds,in,patients,with,or,without,anti\thrombotic,medications,after,TIA,or,ischaemic,stroke,
, On,anti\thrombotic, Not,on,anti\thrombotic,
medications,(n=2032), medications,(n=50),
Microbleeds,, , ,
0,(%), 1442"(71.0)" 33"(66.0)"
1\4,(%), 436"(21.5)" 11"(22.0)"
5\9,(%), 79"(3.9)" 2"(4.0)"
10\24,(%), 49"(2.4)" 3"(6.0)"
≥25,(%), 26"(1.3)" 1"(2.0)"
,
, ,
5"
!
Supplementary,Table,IV.,Clinical,predictors,of,a,high\burden,(≥5),of,cerebral,microbleeds,versus,<5,microbleeds"
, Univariate, Age,and,sex,adjusted,, Multi\variateb,adjusted,
a
, OXVASC, p, HKU, p, Combined , p, Combineda, p, Combineda, p,
OR,(95%,CI), OR,(95%,CI), OR,(95%,CI), OR,(95%,CI), OR,(95%,CI),
Age" 1.05"" 0.001" 1.01"" 0.096" 1.02"" 0.001" 1.02"" 0.001" 1.02"" 0.035"
(1.02.1.08)" (1.00.1.03)" (1.01.1.04)" (1.01.1.04)" (1.00.1.03)"
Male"sex" 1.00"" 1.00" 1.26"" 0.26" 1.18"" 0.33" 1.27"" 0.16" 1.25"" 0.24"
(0.53.1.89)" (0.85.1.88)" (0.84.1.65)" (0.91.1.79)" (0.86.1.80)"
Hypertension" 1.14"" 0.70" 1.65"" 0.024" 1.47"" 0.034" 1.32"" 0.14" 1.38"" 0.11"
(0.60.2.15)" (1.07.2.55)" (1.03.2.10)" (0.92.1.90)" (0.93.2.03)"
Diabetes" 1.41"" 0.42" 0.88"" 0.56" 0.96"" 0.84" 0.92"" 0.66" 0.83"" 0.39"
(0.61.3.25)" (0.57.1.36)" (0.65.1.42)" (0.62.1.35)" (0.55.1.26)"
Hyperlipidaemia" 1.27"" 0.46" 0.93"" 0.76" 1.03"" 0.88" 1.02"" 0.92" 0.89"" 0.57"
(0.67.2.41)" (0.60.1.46)" (0.72.1.48)" (0.71.1.47)" (0.61.1.31)"
Ever.smoker" 1.09"" 0.78" 1.04"" 0.87" 1.05"" 0.77" 1.02"" 0.90" 0.99"" 0.96"
(0.58.2.06)" (0.68.1.57)" (0.74.1.49)" (0.71.1.49)" (0.68.1.45)"
Atrial"fibrillation" 1.38"" 0.42" 0.96"" 0.90" 1.08"" 0.74" 0.90"" 0.68" 0.74"" 0.26"
(0.63.3.06)" (0.54.1.72)" (0.68.1.73)" (0.56.1.46)" (0.43.1.26)"
Glomerular"filtration"rate" 1.23"" 0.58" 1.95"" 0.002" 1.72"" 0.003" 1.47"" 0.049" 1.37"" 0.12"
<60ml/min/1.73m2" (0.60.2.50)" (1.28.2.98)" (1.20.2.47)" (1.00.2.15)" (0.93.2.03)"
Premorbid"antiplatelet"use" 1.76"" 0.16" 1.38"" 0.15" 1.46"" 0.055" 1.28"" 0.22" 1.42"" 0.10"
(0.80.3.91)" (0.89.2.14)" (0.99.2.14)" (0.87.1.90)" (0.93.2.15)"
Premorbid"anticoagulation"use" 2.19"" 0.46" 2.11"" 0.15" 2.13"" 0.10" 1.94"" 0.16" 2.77"" 0.050"
(0.28.17.30)" (0.77.5.79)" (0.86.5.27)" (0.78.4.81)" (1.00.7.70)"
"
a
Adjusted"for"centre"
b
Adjusted"for"all"variables"in"univariate"analysis""
OR,"odds"ratioX"CI,"confidence"interval"
"
, ,
6"
!
Supplementary,Table,V.,Associations,of,a,high\burden,(≥5),of,cerebral,microbleeds,with,other,neuroimaging,markers,of,small,vessel,
disease,versus,<5,microbleeds"
, Univariate, Age,and,sex,adjusted,,
, OXVASC, p, HKU, p, Combineda, p, Combineda, p,
OR,(95%,CI), OR,, OR,(95%,CI), OR,(95%,CI),
(95%,CI),
Periventricular"white"matter" 3.25"" <0.0001" 3.32"" <0.0001" 3.30"" <0.0001" 3.45"" <0.0001"
hyperintensity" (2.28.4.65)" (2.66.4.14)" (2.73.3.98)" (2.82.4.21)"
Subcortical"white"matter" 3.05"" <0.0001" 2.77"" <0.0001" 2.86"" <0.0001" 2.87"" <0.0001"
hyperintensity" (2.17.4.28)" (2.18.3.52)" (2.35.3.48)" (2.35.3.51)"
Lacunes" 2.74"" 0.003" 1.28"" 0.21" 1.53"" 0.016" 1.49"" 0.023"
(1.39.5.38)" (0.87.1.89)" (1.08.2.15)" (1.06.2.11)"
Basal.ganglia"perivascular" 2.56"" <0.0001" 2.87"" <0.0001" 2.77"" <0.0001" 2.80"" <0.0001"
spacesb" (1.71.3.84)" (2.18.3.76)" (2.21.3.48)" (2.18.3.60)"
Centrum.semiovale"perivascular" 1.88"" 0.011" 0.76"" 0.074" 1.01"" 0.92" 0.96"" 0.72"
spacesb" (1.16.3.06)" (0.56.1.03)" (0.80.1.29)" (0.75.1.22)"
"
a
Adjusted"for"centre"
b
Missing"data"in"81"patients""
OR,"odds"ratioX"CI,"confidence"interval"
"
,
, ,
7"
!
Supplementary,Table,VI.,Cox,regression,analyses,of,risk,of,adverse,events,in,all,TIA,/,ischaemic,stroke,patients,with,increasing,
burden,of,microbleeds,versus,no,microbleeds,
, Unadjusted,HR,(95%,CI)*, HR,(95%,CI)*,adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,risk,
factorsa,,
Microbleed, 1,, 2\4, ≥5, 1, 2\4, ≥5, 1, 2\4, ≥5, ptrend,
number,
Recurrent, " " " " " " " " " "
stroke,
""OXVASC" 2.06"" 2.32"" 3.02"" 1.75"" 2.01"" 2.49"" 1.70"" 1.83"" 2.41"" 0.0005"
(1.09.3.89)" (1.07.5.05)" (1.45.6.28)" (0.92.3.34)" (0.92.4.41)" (1.18.5.23)" (0.89.3.24)" (0.83.4.03)" (1.14.5.10)"
""HKU" 1.32"" 1.59"" 2.86"" 1.25"" 1.38"" 2.54"" 1.30"" 1.36"" 2.81"" 0.0002"
(0.79.2.21)" (0.93.2.70)" (1.77.4.61)" (0.74.2.09)" (0.81.2.36)" (1.57.4.11)" (0.78.2.19)" (0.79.2.33)" (1.73.4.57)"
""Combinedb" 1.56"" 1.82"" 3.03"" 1.40"" 1.56"" 2.59"" 1.38"" 1.46"" 2.67"" <0.0001"
(1.04.2.33)" (1.17.2.83)" (2.04.4.51)" (0.93.2.09)" (1.00.2.43)" (1.74.3.86)" (0.93.2.07)" (0.94.2.28)" (1.80.3.98)"
Ischaemic, " " " " " " " " " "
stroke,
""OXVASC" 1.98"" 1.34"" 2.84"" 1.72"" 1.16"" 2.42"" 1.65"" 0.98"" 2.32"" 0.060"
(1.02.3.86)" (0.49.3.68)" (1.30.6.19)" (0.88.3.39)" (0.42.3.21)" (1.09.5.35)" (0.84.3.24)" (0.35.2.74)" (1.04.5.16)"
""HKU" 1.41"" 1.49"" 1.78"" 1.33"" 1.29"" 1.58"" 1.40"" 1.28"" 1.83"" 0.054"
(0.83.2.41)" (0.84.2.65)" (0.99.3.21)" (0.78.2.27)" (0.72.2.30)" (0.88.2.86)" (0.82.2.39)" (0.71.2.30)" (1.01.3.33)"
""Combinedb" 1.61"" 1.52"" 2.10" 1.44"" 1.30"" 1.81"" 1.42"" 1.19"" 1.87"" 0.015"
(1.06.2.44)" (0.93.2.49)" "(1.31.3.38)" (0.95.2.19)" (0.79.2.14)" (1.13.2.91)" (0.94.2.16)" (0.73.1.96)" (1.16.3.01)"
Intracerebral, " " " " " " " " " "
haemorrhage,
""OXVASC" 2.69"" 14.37"" 4.94"" 1.96"" 14.40"" 3.09"" 1.95" 15.43"" 3.80"" 0.011"
(0.31. (3.42.60.34)" (0.58.42.41)" (0.22. (3.28.63.11)" (0.35.27.16)" (0.21.18.04)" (3.21.74.31)" (0.41.35.33)"
23.06)" 17.11)"
""HKU" 0.58"" 2.33"" 11.13"" 0.54"" 2.08"" 10.12"" 0.59"" 2.14"" 9.51"" <0.0001"
(0.07.4.92)" (0.56.9.73)" (3.86.32.04)" (0.06.4.65)" (0.49.8.78)" (3.49.29.35)" (0.07.5.05)" (0.50.9.12)" (3.25.27.81)"
""Combinedb" 1.05"" 4.53"" 11.35"" 0.93"" 3.93"" 9.52"" 0.91"" 4.09"" 9.81"" <0.0001"
(0.22.4.93)" (1.57.13.10)" (4.66.27.65)" (0.20.4.34)" (1.35.11.42)" (3.89.23.30)" (0.20.4.26)" (1.40.11.95)" (3.98.24.15)"
,
8"
!
,

factorsa,,
number,
Acute, " " " " " " " " " "
coronary,
event,
""OXVASC""" 1.27"" ." 3.64"" 0.82"" ." 2.03"" 0.90"" ." 1.96"" 0.75"
(0.30.5.43)" (1.08.12.26)" (0.19.3.52)" (0.59.6.94)" (0.21.3.87)" (0.57.6.81)"
""HKU" 0.80"" 1.11"" 1.19"" 0.73"" 0.89"" 0.95"" 0.75"" 0.88"" 1.01"" 0.86"
(0.36.1.74)" (0.51.2.43)" (0.52.2.71)" (0.33.1.60)" (0.40.1.95)" (0.42.2.18)" (0.34.1.64)" (0.40.1.95)" (0.44.2.33)"
""Combinedb" 0.88"" 0.99"" 1.53" 0.73"" 0.76"" 1.15"" 0.73"" 0.72"" 1.23"" 0.98"
(0.44.1.77)" (0.46.2.13)" (0.76.3.08)" (0.37.1.47)" (0.36.1.63)" (0.58.2.30)" (0.36.1.46)" (0.33.1.55)" (0.61.2.47)"
Ischaemic, " "" " " " " " " " "
stroke,and,
acute,
coronary,
event,
""OXVASC" 1.72"" 1.05"" 3.17"" 1.39"" 0.83"" 2.48"" 1.35"" 0.74"" 2.33"" 0.066"
(0.92.3.23)" (0.39.2.86)" (1.65.6.11)" (0.74.2.62)" (0.30.2.26)" (1.27.4.84)" (0.72.2.55)" (0.27.2.05)" (1.19.4.56)"
""HKU" 1.15"" 1.32"" 1.39"" 1.08"" 1.11"" 1.20"" 1.11"" 1.10"" 1.37"" 0.27"
(0.74.1.80)" (0.82.2.11)" (0.84.2.31)" (0.69.1.68)" (0.69.1.78)" (0.72.2.00)" (0.71.1.74)" (0.68.1.77)" (0.82.2.28)"
""Combinedb" 1.33"" 1.33"" 1.80"" 1.16"" 1.09"" 1.50"" 1.15"" 1.02"" 1.56"" 0.085"
(0.92.1.92)" (0.88.2.03)" (1.20.2.73)" (0.81.1.68)" (0.72.1.67)" (0.99.2.25)" (0.80.1.66)" (0.67.1.55)" (1.04.2.34)"
Major, " " " " " " " " " "
extracranial,
bleedingc,
""OXVASC" 0.77"" 1.34"" 1.47"" 0.53" 1.05"" 0.96" 0.47"" 1.02"" 1.00"" 0.85"
(0.10.5.82)" (0.18.10.10)" (0.20.11.07)" (0.07.4.06)" (0.14.8.05)" (0.13.7.33)" (0.06.3.64)" (0.13.7.90)" (0.13.7.73)"
""HKU" 0.49"" 0.64"" 2.03"" 0.46"" 0.56"" 1.81"" 0.42"" 0.70"" 2.19"" 0.36"
(0.11.2.17)" (0.14.2.88)" (0.72.5.77)" (0.10.2.05)" (0.13.2.53)" (0.63.5.15)" (0.09.1.91)" (0.15.3.18)" (0.75.6.38)"
""Combinedb" 0.57"" 0.79"" 1.93"" 0.49"" 0.67"" 1.57"" 0.47"" 0.71"" 1.71"" 0.59"
(0.17.1.90)" (0.23.2.67)" (0.77.4.80)" (0.15.1.64)" (0.20.2.25)" (0.63.3.91)" (0.14.1.58)" (0.21.2.40)" (0.69.4.26)"
,
9"
!
,

factorsa,,
number,
All\cause, " " " " " " " " " "
mortality,
""OXVASC" 2.22"" 2.20"" 2.21"" 1.44"" 1.62" 1.24"" 1.30"" 1.41"" 1.26"" 0.20"
(1.37.3.61)" (1.22.4.00)" (1.16.4.21)" (0.88.2.35)" (0.89.2.95)" (0.65.2.38)" (0.79.2.14)" (0.76.2.62)" (0.65.2.43)"
""HKU" 0.97"" 1.48"" 1.81"" 0.86"" 1.16"" 1.48"" 0.89"" 1.19"" 1.54"" 0.094"
(0.59.1.59)" (0.92.2.39)" (1.12.2.92)" (0.52.1.41)" (0.72.1.88)" (0.92.2.39)" (0.54.1.46)" (0.73.1.93)" (0.95.2.49)"
""Combinedb" 1.43"" 1.80"" 2.07"" 1.10" 1.33"" 1.43"" 1.05"" 1.24"" 1.46"" 0.041"
(1.00.2.04)" (1.24.2.63)" (1.41.3.04)" (0.77.1.56)" (0.92.1.94)" (0.98.2.09)" (0.74.1.50)" (0.85.1.81)" (1.00.2.14)"
Vascular, " " " " " " " " " "
death,
""OXVASC" 1.54"" ." 1.46"" 1.01"" ." 0.84"" 0.98"" ." 0.81"" 0.34"
(0.55.4.35)" (0.35.6.09)" (0.36.2.87)" (0.20.3.52)" (0.34.2.80)" (0.19.3.41)"
""HKU" 1.15"" 1.74"" 1.59"" 1.04"" 1.39"" 1.27"" 1.09"" 1.37"" 1.38"" 0.29"
(0.57.2.31)" (0.88.3.42)" (0.75.3.37)" (0.52.2.10)" (0.70.2.73)" (0.60.2.70)" (0.54.2.20)" (0.69.2.74)" (0.65.2.95)"
""Combinedb" 1.21"" 1.38"" 1.53"" 1.00"" 1.07"" 1.11"" 1.00"" 1.02"" 1.17"" 0.71"
(0.68.2.17)" (0.73.2.61)" (0.79.2.96)" (0.56.1.79)" (0.57.2.03)" (0.58.2.14)" (0.56.1.78)" (0.54.1.93)" (0.61.2.25)"
Non\vascular, " " " " " " " " " "
death,
""OXVASC" 2.42"" 3.17"" 2.10"" 1.57"" 2.30"" 1.20"" 1.41"" 2.08"" 1.28"" 0.084"
(1.34.4.36)" (1.68.5.99)" (0.91.4.82)" (0.87.2.85)" (1.21.4.37)" (0.52.2.78)" (0.77.2.59)" (1.07.4.05)" (0.55.2.99)"
""HKU" 0.81"" 1.26"" 1.95"" 0.68"" 0.97"" 1.59"" 0.70"" 1.04"" 1.57"" 0.24"
(0.40.1.63)" (0.64.2.48)" (1.05.3.62)" (0.34.1.39)" (0.49.1.91)" (0.86.2.97)" (0.34.1.42)" (0.52.2.07)" (0.84.2.93)"
""Combinedb" 1.48"" 2.05"" 2.27"" 1.11"" 1.48"" 1.56"" 1.06"" 1.41"" 1.60"" 0.037"
(0.93.2.35)" (1.27.3.29)" (1.39.3.72)" (0.70.1.76)" (0.92.2.38)" (0.96.2.54)" (0.67.1.68)" (0.87.2.28)" (0.98.2.61)"
,
*
0"microbleeds"as"reference"
a
Hypertension,"hyperlipidemia,"diabetes,"atrial"fibrillation,"smoking"
b
Also"adjusted"for"centre"
c
Oral"and"nasal"bleeds"excluded"
HR,"hazards"ratioX"CI,"confidence"interval"
"
" "
10"
!
Supplementary,Table,VII.,Cox,regression,analyses,of,risk,of,adverse,events,amongst,antiplatelet,users,with,increasing,burden,of,
microbleeds,versus,no,microbleeds,
, Unadjusted,HR,(95%,CI)*, HR,(95%,CI)*,adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,
risk,factorsa,,
Microbleed, 1, 2\4, ≥5, 1, 2\4, ≥5, 1, 2\4, ≥5, ptrend,
number,
Recurrent,stroke, " " " " " " " " " "
""OXVASC" 2.00"" 2.63"" 3.47"" 1.72"" 2.27"" 2.92"" 1.55"" 1.83"" 2.81"" 0.003"
(0.99.4.03)" (1.14.6.08)" (1.66.7.24)" (0.85.3.50)" (0.97.5.30)" (1.38.6.17)" (0.76.3.15)" (0.78.4.31)" (1.31.6.00)"
""HKU" 1.38"" 1.44"" 3.07"" 1.27"" 1.27"" 2.71"" 1.30"" 1.28"" 2.89"" 0.001"
(0.79.2.41)" (0.78.2.66)" (1.83.5.15)" (0.72.2.22)" (0.69.2.36)" (1.61.4.56)" (0.74.2.29)" (0.69.2.38)" (1.70.4.90)"
""Combinedb" 1.61"" 1.77"" 3.35"" 1.43" 1.53"" 2.87"" 1.38"" 1.39"" 2.89"" <0.0001"
(1.03.2.50)" (1.07.2.92)" (2.20.5.10)" (0.92.2.22)" (0.93.2.53)" (1.88.4.39)" (0.89.2.13)" (0.84.2.30)" (1.89.4.41)"
Ischaemic,stroke, " " " " " " " " " "
""OXVASC" 2.13"" 1.76"" 3.24"" 1.88"" 1.51"" 2.80"" 1.66"" 1.13"" 2.65"" 0.025"
(1.06.4.31)" (0.64.4.84)" (1.48.7.09)" (0.92.3.83)" (0.54.4.21)" (1.26.6.21)" (0.81.3.40)" (0.40.3.21)" (1.18.5.95)"
""HKU" 1.41"" 1.34"" 1.81"" 1.30"" 1.18"" 1.60"" 1.35"" 1.21"" 1.81"" 0.096"
(0.79.2.52)" (0.69.2.57)" (0.96.3.43)" (0.73.2.33)" (0.61.2.27)" (0.84.3.03)" (0.75.2.42)" (0.62.2.36)" (0.95.3.45)"
""Combinedb" 1.69"" 1.53"" 2.29"" 1.51"" 1.32"" 1.98"" 1.44"" 1.16"" 2.01"" 0.013"
(1.08.2.66)" (0.88.2.65)" (1.39.3.79)" (0.96.2.38)" (0.76.2.30)" (1.20.3.28)" (0.92.2.26)" (0.67.2.02)" (1.22.3.32)"
Intracerebral, " " " " " " " " " "
haemorrhage,
""OXVASC" ." 12.90"" 6.35"" ." 12.74"" 4.20"" ." 10.02"" 4.51"" 0.042"
(2.36.70.47)" (0.71.56.99)" (2.22.72.97)" (0.46.38.62)" (1.67.60.18)" (0.43.47.36)"
""HKU" 0.95"" 2.57"" 16.62"" 0.86"" 2.30"" 14.91"" 0.88"" 2.22"" 13.15"" <0.0001"
(0.10.9.12)" (0.43.15.40)" (4.57.60.41)" (0.09.8.32)" (0.38.13.85)" (4.07.54.65)" (0.09.8.55)" (0.37.13.42)" (3.54.48.93)"
""Combinedb" 0.73"" 4.21"" 14.34"" 0.63"" 3.67"" 11.86"" 0.62"" 3.81"" 11.52"" <0.0001"
(0.09.6.05)" (1.16.15.27)" (5.22.39.39)" (0.08.5.24)" (1.01.13.33)" (4.29.32.81)" (0.07.5.13)" (1.04.13.96)" (4.09.32.43)"
Acute,coronary, " " " " " " " " " "
event,
""OXVASC""" 1.69"" ." 3.01"" 1.14"" ." 1.76"" 1.18"" ." 1.62"" 0.95"
(0.39.7.34)" (0.69.13.10)" (0.26.4.99)" (0.40.7.76)" (0.27.5.17)" (0.36.7.34)"
""HKU" 1.15"" 1.03"" 1.47"" 1.02"" 0.85"" 1.16"" 1.06"" 0.92"" 1.08"" 0.95"
(0.51.2.61)" (0.39.2.74)" (0.59.3.66)" (0.45.2.33)" (0.32.2.28)" (0.46.2.89)" (0.46.2.42)" (0.34.2.48)" (0.42.2.76)"
""Combinedb" 1.25"" 0.89"" 1.72"" 1.01"" 0.71"" 1.28"" 0.99"" 0.67"" 1.34"" 0.85"
(0.61.2.58)" (0.34.2.32)" (0.78.3.78)" (0.49.2.07)" (0.27.1.83)" (0.58.2.80)" (0.48.2.04)" (0.26.1.74)" (0.61.2.95)"
"
"
"
11"
!
"
"

risk,factorsa,,
number,
Ischaemic,stroke, " " " " " " " " " "
and,acute,
coronary,event,
""OXVASC" 1.92"" 1.40"" 3.33"" 1.59"" 1.09"" 2.68"" 1.43"" 0.88"" 2.46"" 0.041"
(0.99.3.73)" (0.51.3.83)" (1.66.6.65)" (0.82.3.11)" (0.40.3.00)" (1.33.5.42)" (0.73.2.80)" (0.31.2.45)" (1.21.5.03)"
""HKU" 1.29"" 1.25"" 1.48"" 1.18"" 1.08"" 1.27"" 1.22"" 1.10"" 1.40"" 0.28"
(0.80.2.09)" (0.73.2.16)" (0.84.2.58)" (0.73.1.91)" (0.62.1.86)" (0.72.2.22)" (0.75.1.98)" (0.63.1.92)" (0.80.2.48)"
""Combinedb" 1.52"" 1.36"" 1.97"" 1.32"" 1.13"" 1.63"" 1.28"" 1.02"" 1.68"" 0.058"
(1.02.2.25)" (0.84.2.20)" (1.26.3.07)" (0.89.1.95)" (0.70.1.82)" (1.05.2.54)" (0.86.1.89)" (0.63.1.64)" (1.08.2.61)"
Major,extracranial, " " " " " " " " " "
bleedc,
""OXVASC" 1.25"" ." ." 0.92"" ." ." 0.79"" ." ." 0.35"
(0.16.9.81)" (0.12.7.31)" (0.10.6.52)"
""HKU" 0.71"" ." 2.43"" 0.62"" ." 2.08"" 0.66"" ." 2.32"" 0.53"
(0.15.3.36)" (0.73.8.07)" (0.13.2.92)" (0.62.6.94)" (0.14.3.22)" (0.64.8.40)"
""Combinedb" 0.81"" ." 1.85"" 0.68"" ." 1.50"" 0.66"" ." 1.53"(0.49. 0.87"
(0.23.2.85)" (0.60.5.66)" (0.20.2.39)" (0.49.4.60)" (0.19.2.31)" 4.75)"
All\cause, " " " " " " " " " "
mortality,
""OXVASC" 3.00"" 2.16"" 2.42"" 1.97"" 1.55"" 1.42"" 1.66"" 1.22"" 1.54"" 0.10"
(1.83.4.91)" (1.09.4.29)" (1.22.4.80)" (1.20.3.23)" (0.78.3.09)" (0.71.2.83)" (1.00.2.76)" (0.60.2.51)" (0.77.3.08)"
""HKU" 1.08"" 1.73"" 2.18"" 0.88"" 1.42"" 1.75"" 0.90"" 1.56"" 1.63"" 0.046"
(0.61.1.91)" (1.00.3.00)" (1.27.3.74)" (0.49.1.57)" (0.82.2.47)" (1.02.3.01)" (0.51.1.61)" (0.89.2.72)" (0.93.2.86)"
""Combinedb" 1.80" 2.02"" 2.46"" 1.33"" 1.50"" 1.66"" 1.23"" 1.36"" 1.66"" 0.012"
(1.22.2.66)" (1.31.3.10)" (1.61.3.74)" (0.90.1.95)" (0.98.2.30)" (1.09.2.51)" (0.84.1.80)" (0.88.2.09)" (1.09.2.54)"
Vascular,death,, " " " " " " " " " "
""OXVASC" 2.41"" ." 2.16"" 1.62"" ." 1.38"" 1.49"" ." 1.35"" 0.97"
(0.83.6.98)" (0.51.9.17)" (0.56.4.71)" (0.32.5.89)" (0.50.4.40)" (0.31.5.85)"
""HKU" 1.37"" 2.46"" 2.04"" 1.20"" 2.06"" 1.59"" 1.24"" 2.17"" 1.55"" 0.12"
(0.59.3.18)" (1.12.5.37)" (0.84.4.91)" (0.52.2.80)" (0.94.4.51)" (0.66.3.85)" (0.53.2.89)" (0.98.4.81)" (0.63.3.84)"
""Combinedb" 1.59"" 1.92"" 2.03"" 1.29"" 1.56"" 1.45"" 1.27"" 1.50"" 1.48"" 0.18"
(0.81.3.10)" (0.94.3.95)" (0.96.4.28)" (0.66.2.51)" (0.76.3.19)" (0.69.3.05)" (0.65.2.46)" (0.73.3.08)" (0.70.3.14)"
"
12"
!
"

risk,factorsa,,
number,
Non\vascular, " " " " " " " " " "
death,,
""OXVASC" 3.10" 3.26" 2.02"" 2.05"" 2.27"" 1.19"" 1.74"" 1.84"" 1.36"" 0.089"
(1.70.5.65)" (1.61.6.59)" (0.81.5.03)" (1.12.3.75)" (1.11.4.62)" (0.48.2.99)" (0.94.3.23)" (0.88.3.89)" (0.54.3.44)"
""HKU" 0.87"" 1.25"" 2.26"" 0.65"" 1.00"" 1.87"" 0.66"" 1.10"" 1.59"" 0.27"
(0.39.1.92)" (0.57.2.77)" (1.14.4.48)" (0.29.1.45)" (0.45.2.22)" (0.94.3.70)" (0.30.1.48)" (0.49.2.46)" (0.76.3.31)"
""Combinedb" 1.81"" 2.13"" 2.50"" 1.30"" 1.52"" 1.66"" 1.18"" 1.36"" 1.68"" 0.044"
(1.10.2.97)" (1.24.3.65)" (1.46.4.27)" (0.79.2.12)" (0.89.2.60)" (0.98.2.83)" (0.72.1.94)" (0.79.2.35)" (0.98.2.89)"
"
*
0"microbleeds"as"reference"
a
Hypertension,"hyperlipidemia,"diabetes,"atrial"fibrillation,"smoking""
b
Also"adjusted"for"centre""
c
Oral"and"nasal"bleeds"excluded" "
"
,
, ,
13"
!
Supplementary,Table,VIII.,Cox,regression,analyses,of,risk,of,adverse,events,amongst,single,antiplatelet,users,with,increasing,burden,
of,microbleeds,versus,no,microbleeds,
, Unadjusted,HR,(95%,CI)*" HR,(95%,CI)*,adjusted,for,age,and,sex" HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,risk,
factorsa,
number,
Recurrent, 1.83"" 1.92"" 4.17"" 1.62"" 1.64"" 3.53"" 1.52"" 1.52"" 3.46"" <0.0001"
stroke, (1.11.3.02)" (1.09.3.38)" (2.63.6.63)" (0.98.2.66)" (0.93.2.90)" (2.22.5.62)" (0.93.2.49)" (0.86.2.68)" (2.17.5.51)"
Ischaemic, 1.89"" 1.96"" 2.82"" 1.66"" 1.67"" 2.37"" 1.55"" 1.51"" 2.36"" 0.002"
stroke, (1.14.3.16)" (1.09.3.52)" (1.63.4.86)" (1.00.2.76)" (0.93.3.00)" (1.38.4.10)" (0.93.2.57)" (0.84.2.72)" (1.37.4.08)"
Intracerebral, 1.34"" 1.78"" 22.19"" 1.25"" 1.64"" 19.89"" 1.33"" 1.88"" 19.53"" <0.0001"
haemorrhage, (0.14.13.14)" (0.18.17.68)" (5.84.84.28)" (0.13.12.33)" (0.16.16.40)" (5.15.76.82)" (0.13.13.25)" (0.19.19.08)" (4.83.79.02)"
Acute, 1.48"" 0.45"" 1.88"" 1.18"" 0.36"" 1.39"" 1.15"" 0.34"" 1.40"" 0.99"
coronary, (0.68.3.21)" (0.11.1.91)" (0.81.4.41)" (0.55.2.55)" (0.09.1.54)" (0.60.3.23)" (0.53.2.49)" (0.08.1.45)" (0.59.3.30)"
event,
Ischaemic, 1.76"" 1.48"" 2.32"" 1.51"" 1.22"" 1.89"" 1.45"" 1.12"" 1.93"" 0.017"
stroke,and, (1.14.2.72)" (0.87.2.53)" (1.43.3.75)" (0.98.2.33)" (0.71.2.08)" (1.17.3.07)" (0.94.2.22)" (0.65.1.92)" (1.19.3.12)"
acute,
coronary,
event,
Major, 0.65"" ." 2.11"" 0.55"" ." 1.73"" 0.52"" ." 1.64"" 0.95"
extracranial, (0.14.2.91)" (0.67.6.64)" (0.12.2.46)" (0.55.5.44)" (0.12.2.36)" (0.50.5.36)"
bleedingb,
All\cause, 2.10"" 2.05"" 2.84"" 1.52"" 1.55"" 1.90"" 1.40"" 1.56"" 1.98"" 0.002"
mortality, (1.37.3.22)" (1.24.3.39)" (1.78.4.52)" (0.99.2.32)" (0.94.2.55)" (1.20.3.02)" (0.91.2.14)" (0.95.2.59)" (1.24.3.18)"
Vascular, 2.24"" 1.81"" 2.44"" 1.80"" 1.48"" 1.73"" 1.83"" 1.54"" 1.87"" 0.094"
death, (1.10.4.53)" (0.77.4.27)" (1.08.5.51)" (0.89.3.63)" (0.63.3.47)" (0.77.3.89)" (0.90.3.69)" (0.65.3.65)" (0.82.4.25)"
Non\vascular, 1.77"" 2.18"" 2.65"" 1.25" 1.60"" 1.74"" 1.11"" 1.58"" 1.81"" 0.033"
death, (1.00.3.12)" (1.17.4.06)" (1.45.4.82)" (0.71.2.20)" (0.86.2.97)" (0.96.3.16)" (0.63.1.95)" (0.85.2.94)" (0.98.3.31)"
"
*
0"microbleeds"as"reference,"adjusted"for"centre"
a
Hypertension,"hyperlipidemia,"diabetes,"atrial"fibrillation,"smoking"
b
Oral"and"nasal"bleeds"excluded,,
, ,
14"
!
Supplementary,Table,IX.,Summary,of,studies,included,in,meta\analysis"
N,and,disease,type, Mean,age,, Males, Antiplatelets, Anticoagulants, Follow\up,,
Author, Region, Year, MRI,
(%,TIA), yr, (%), (%), (%), (patient,yrs),
Western, " " " " " " " " "
cohorts,
Lau,"Lovelock" UK" 2017" 1080"IS/TIA"(53)" 1.5/3T"T2*"GRE" 68" 53" 88" 11" 4265"
et#al."
CROMIS"Ia"" UK" NA" 68"IS/TIA" 1.5T"T2*GRE" 66" 66" 81" 16" 136"
Heidelberga" NA" NA" 265"IS" SWI" 65" 67" 78" 20" 265"
Kwa"et#al.4" Netherlands" 2013" 397"IS/TIA"(49)" 0.5/1/1.5T"T2*" 65" 58" 90" 10" 1522"
GRE"
Fluri"et#al.5" Switzerland" 2011" 176"TIA" T2*"GRE" 69" 61" 77" 12" 44"
Thijs"et#al.6" Belgium" 2010" 487"IS/TIA"(27)" 1/1.5/3T"T2*" 72" 61" 73" 27" 812"
GRE"
Boulanger"et# Canada" 2006" 236"IS/TIA" 3T"T2*"GRE" NA" 55" NA" NA" 354"
al.7"
Asian,cohorts, " " " " " " " " "
Lau"et#al.8" Hong"Kong," 2017" 1003"IS" 3T"SWI" 69" 60" 88" 10" 3168"
China"
Lim,"et#al.9" Korea" 2015" 500"TIA" NA"T2*"GRE" 64" 58" 91" 15" 125"
Song,"et#al.10" Korea" 2013" 550"IS" 3T"MRI" 70" 59" 35"" 87" 1375"
Mok"et"al.11"" Hong"Kong," 2009" 75"IS" 1.5T"T2*"GRE" 71" 52" 96" 0" 375"
China"
Soo"et#al.12" Hong"Kong," 2008" 908"IS" 1.5T"T2*"GRE" 68" 58" 93" 3" 2059"
China"
Huang"et#al.13" China" 2008" 636"IS"" 1.5T"T2*"GRE" 60" 69" 100" 0" 742"
Naka"et#al.14" Japan" 2006" 183"Lacunar"and" 1T"T2*"GRE" NA" NA" 93" 2" 275"
atherothrombotic"
stroke"
Fan"et#al.15" China" 2003" 121"IS" 1.5T"T2*"GRE" 68" 68" 80" 6" 272"
Imaizumi"et#al.16" Japan" NA" 138"IS" 1.5T"T2*"GRE" 66" 66" 33" 2" 253"
,
a
Unpublished"cohorts"
IS,"ischaemic"strokeX"TIA,"transient"ischaemic"attackX"GRE,"gradient"echoX"SWI,"susceptibility"weighted"imagingX"NA,"not"available
15"
!
Supplementary,Figures,
,
Supplementary#Figure#I.#Flow#chart#of#literature#search#and#additional#study#selection#since#most#recent#meta;analysis#
Supplementary#Figure#II.#Severity#of#recurrent#stroke#(mRS#at#1;month)#in#all#antiplatelet#users#(A)#and#in#antiplatelet#
users#with#!5#microbleeds#(B)#
Supplementary#Figure#III.#Pooled#analyses#of#relative#risk#estimates#from#the#current#and#previous#studies#showing#
risk#of#recurrent#ischaemic#stroke#amongst#TIA#/#ischaemic#stroke#patients#on#antiplatelet#agents#with#microbleeds#
versus#those#without##
Supplementary#Figure#IV.#Pooled#analyses#of#relative#risk#estimates#from#the#current#and#previous#studies#showing#
risk#of#intracerebral#haemorrhage#amongst#TIA#/#ischaemic#stroke#patients#on#antiplatelet#agents#with#microbleeds#
versus#those#without##
Supplementary#Figure#V.#Pooled#analyses#of#relative#risk#estimates#from#the#current#and#previous#studies#showing#risk#
of#recurrent#ischaemic#stroke#(A)#and#intracerebral#hemorrhage#(B)#in#TIA#/#ischaemic#stroke#patients#on#antiplatelet#
agents,#stratified#by#presence#versus#absence#of#microbleeds##
Supplementary#Figure#VI.#Pooled#analyses#of#relative#risk#estimates#from#the#current#and#previous#studies#showing#
risk#of#recurrent#ischaemic#stroke#amongst#TIA#/#ischaemic#stroke#patients#with#microbleeds#versus#those#without##
Supplementary#Figure#VII.#Pooled#analyses#of#relative#risk#estimates#from#the#current#and#previous#studies#showing#
risk#of#intracerebral#haemorrhage#amongst#TIA#/#ischaemic#stroke#patients#with#microbleeds#versus#those#without##
16#
!
Supplemenary,Figure,I.,Flow,chart,of,literature,search,and,additional,study,selection,since,
most,recent,meta9analysis,
17#
!
Supplementary,Figure,II.,Severity,of,recurrent,stroke,(mRS,at,19month),in,all,antiplatelet,
users,(A),and,in,antiplatelet,users,with,!5,microbleeds,(B),
,
OR=odds#ratioN#mRS=modified#Rankin#Scale
18#
!
Supplementary,Figure,III.,Pooled,analyses,of,relative,risk,estimates,from,the,current,and,
previous,studies,showing,risk,of,recurrent,ischaemic,stroke,amongst,TIA,/,ischaemic,
stroke,patients,on,antiplatelet,agents,with,microbleeds,versus,those,without,,
1*vs.*no*microbleeds
Study RR 95%*CI
Huang 1∙46 0∙32-6∙73

Naka 2∙18 0∙33-14∙39
Soo 0∙57 0∙25-1∙28
Fluri 8∙82 1∙93-40∙33
Thijs 1∙40 0∙49-3∙95
Heidelberg 1∙60 0∙20-12∙68
Kwa 2∙12 0∙66-6∙83
Lim 3∙09 0∙22-42∙97
CROMISJI 3∙40 1∙17-9∙89
Prevoius*studies 1∙86 1∙03:3∙34
Significance*p=0∙040,*heterogeneity*p=0∙095
OXVASC*and*HKU* 1∙56 1∙03:2∙38

Overall* 1∙68 1∙14:2∙48

0 5 10 15 20 25
Risk* Ratio*(95%* CI)
2:4*vs.*no*microbleeds
Study RR 95%*CI
Huang 2∙25 0∙75-6∙75

Naka 1∙79 0∙53-5∙98
Soo 2∙21 1∙31-3∙71
Fluri 40∙06 13∙94-115∙13
Thijs 1∙65 0∙64-4∙25
Heidelberg 1∙09 0∙06-18∙39
Kwa 3∙16 0∙81-12∙26
Lim 2∙03 0∙50-8∙27
CROMISJ1 1∙70 0∙25-11∙45
Previous*studies 2∙93 1∙42:6∙04
OXVASC*and*HKU 1∙41 0∙84:2∙37

OVERALL 2∙51 1∙41:4∙47

0 5 10 15 20 25
≥5*vs.*no*microbleeds
Study RR 95%*CI
Huang 3∙76 1∙34-10∙53

Naka 0∙25 0∙02-4∙15
Soo 1∙56 0∙88-2∙75
Fluri 16∙67 2∙36-117∙55
Thijs 2∙69 0∙98-7∙37
Heidelberg 1∙95 0∙25-15∙35
Kwa 3∙42 0∙54-21∙72
Lim 8∙46 3∙63-19∙74
CROMISJ1 2∙13 0∙33-13∙60
Previous*studies 3∙08 1∙65:5∙76
OXVASC*and*HKU 2∙08 1∙25:3∙46

OVERALL 2∙75 1∙75:4∙34

Significance*p<0∙0001,*heterogeneity*p=0∙031
0 5 10 15 20 25

,
19#
!
Supplementary,Figure,IV.,Pooled,analyses,of,relative,risk,estimates,from,the,current,and,
previous,studies,showing,risk,of,intracerebral,haemorrhage,amongst,TIA,/,ischaemic,
stroke,patients,on,antiplatelet,agents,with,microbleeds,versus,those,without,,
Study RR 95%*CI
Huang 17∙33 0∙71+420∙91

Naka 21∙83 1∙55+308∙50
Soo 3∙04 0∙56+16∙38
Thijs 2∙18 0∙09+52∙74
Kwa 1∙30 0∙07+23∙51
Previous*studies 4∙51 1∙48813∙72
Significance:*p=0∙008,*heterogeneity*p=0∙53
OXVASC*and*HKU 0∙84 0∙1087∙02

OVERALL 3∙14 1∙1788∙42

0 5 10 15 20 25
Study RR 95%*CI
Huang 10∙75 0∙44+262∙01

Naka 1∙91 0∙08+45∙54
Soo 7∙57 1∙73+33∙09
Thijs 6∙28 0∙40+99∙00
Kwa 2∙78 0∙16+49∙11
Significance:*p=0∙001,*heterogeneity*p=0∙91

OVERALL 5∙81 2∙63812∙84

0 5 10 15 20 25
Study RR 95%*CI
Huang 44∙65 2∙43+821∙01

Naka 21∙83 2∙55+187∙00
Soo 12∙46 3∙59+43∙19
Thijs 4∙13 0∙17+99∙05
Kwa 14∙54 1∙90+111∙53
Significance:*p<0∙0001,*heterogeneity*p=0∙85
OXVASC*and*HKU 11∙70 3∙91835∙30

OVERALL 13∙35 6∙75826∙39

0 5 10 15 20 25

,
, ,
20#
!
Supplementary,Figure,V.,Pooled,analyses,of,relative,risk,estimates,from,the,current,and,
previous,studies,showing,risk,of,recurrent,ischaemic,stroke,(A),and,intracerebral,
hemorrhage,(B),in,TIA,/,ischaemic,stroke,patients,on,antiplatelet,agents,,stratified,by,
presence,versus,absence,of,microbleeds,,
,
(A)$Ischaemic$stroke$
Study RR 95%$CI
TIA$only$cohorts$with$ ≤1$year$follow@up
Fluri& 7∙69 1∙83.32∙40
Lim& 4∙13 1∙83.9∙34
Overall$ 4∙80 2∙36@9∙76

Significance$p<0∙0001,$heterogeneity$p=0∙46
Previous$TIA/IS$cohorts
Soo 1∙30 0∙87.1∙94
CROMIS&1& 2∙68 0∙99.7∙31
Huang 2∙51 1∙06.5∙97
Fan 1∙51 0∙49.4∙67
Mok 0∙85 0∙10.7∙13
Thijs 1∙90 0∙97.3∙73
Heidelberg 1∙30 0∙27.6∙27
Kwa 2∙57 1∙06.6∙19
Naka 1∙01 0∙33.3∙07
Overall$ 1∙62 1∙24@2∙11

Significance$p=0∙0004,$heterogeneity$p=0∙70
OXVASC$and$HKU 1∙56 1∙15@2∙12

Significance$p=0∙005$,$heterogeneity$p=0∙41$
All$TIA/IS$cohorts 1∙62 1∙32@1∙99

0 5 10 15 20 25
Risk$ Ratio$(95%$ CI)
(B)$Intracerebral$haemorrhage
Study RR 95%$CI
Previous$TIA/IS$cohorts
Soo 7∙16 2∙30.22∙27
Huang 20∙04 1∙13.354∙24
Fan 7∙26 0∙84.62∙88
Mok 13∙65 1∙63.114∙10
Thijs 2∙78 0∙17.44∙04
Kwa 1∙82 0∙21.15∙93
Naka 12∙60 1∙51.105∙24
Overall$ 7∙09 3∙43@14∙65

OXVASC$and$HKU 4∙63 1∙97@10∙85

Significance$p=0∙0004$,$heterogeneity$p=0∙41$
All$TIA/IS$cohorts 5∙80 3∙23@10∙41

0 5 10 15 20 25
Risk$ Ratio$(95%$ CI)

,
, ,
21#
!
Supplementary,Figure,VI.,Pooled,analyses,of,relative,risk,estimates,from,the,current,and,
previous,studies,showing,risk,of,recurrent,ischaemic,stroke,amongst,TIA,/,ischaemic,
stroke,patients,with,microbleeds,versus,those,without,,
Study RR 95%*CI
Huang 1∙46 0∙32-6∙73

Imaizumi 2∙46 0∙24-25∙35
Naka 2∙18 0∙33-14∙39
Song 0∙45 0∙11-1∙85
Soo 0∙57 0∙25-1∙28
Fluri 8∙82 1∙93-40∙33
Thijs 1∙40 0∙49-3∙95
Heidelberg 1∙60 0∙20-12∙68
Kwa 2∙12 0∙66-6∙83
Lim 3∙09 0∙22-42∙97
CROMISK1 3∙40 1∙17-9∙89

Overall* 1∙57 1∙0882∙29

0 5 10 15 20 25
Study RR 95%*CI
Huang 2∙25 0∙75-6∙75

Imaizumi 0∙67 0∙03-13∙35
Naka 1∙79 0∙53-5∙98
Song 0∙97 0∙34-2∙72
Soo 2∙21 1∙31-3∙71
Fluri 40∙06 13∙94-115∙13
Thijs 1∙65 0∙64-4∙25
Heidelberg 1∙09 0∙06-18∙39
Kwa 3∙16 0∙81-12∙26
Lim 2∙03 0∙50-8∙27
CROMISK1 1∙70 0∙25-11∙45

OVERALL 2∙19 1∙2983∙70

0 5 10 15 20 25
≥5**vs.*no*microbleeds
Study RR 95%*CI
Huang 3∙76 1∙34-10∙53

Imaizumi 1∙97 0∙29-13∙41
Naka 0∙25 0∙02-4∙15
Song 0∙32 0∙02-5∙18
Soo 1∙56 0∙88-2∙75
Fluri 16∙67 2∙36-117∙55
Thijs 2∙69 0∙98-7∙37
Heidelberg 1∙95 0∙25-15∙35
Kwa 3∙42 0∙54-21∙72
Lim 8∙46 3∙63-19∙74
CROMISK1 2∙13 0∙33-13∙60

OVERALL 2∙53 1∙6483∙90

0 5 10 15 20 25

,
22#
!
Supplementary,Figure,VII.,Pooled,analyses,of,relative,risk,estimates,from,the,current,and,
previous,studies,showing,risk,of,intracerebral,haemorrhage,amongst,TIA,/,ischaemic,
stroke,patients,with,microbleeds,versus,those,without,,
Study RR 95%*CI
Huang 17∙33 0∙71+420∙91

Imaizumi 14.00 0∙60+327∙25
Naka 21∙83 1∙55+308∙50
Song 3∙67 0∙84+16∙08
Soo 3∙04 0∙56+16∙38
Thijs 2∙18 0∙09+52∙74
Kwa 1∙30 0∙07+23∙51

OVERALL 3∙30 1∙5786∙95

0 5 10 15 20 25
Study RR 95%*CI
Huang 10∙75 0∙44+262∙01

Imaizumi 16∙67 0∙83+333∙74
Naka 1∙91 0∙08+45∙54
Song 1∙33 0∙15+11∙70
Soo 7∙57 1∙73+33∙09
Thijs 6∙28 0∙40+99∙00
Kwa 2∙78 0∙16+49∙11

OVERALL 5∙07 2∙6089∙88

0 5 10 15 20 25
Study RR 95%*CI
Huang 44∙65 2∙43+821∙01

Imaizumi 25∙28 1∙46+436∙22
Naka 21∙83 2∙55+187∙00
Song 11∙31 2∙68+47∙79
Soo 12∙46 3∙59+43∙19
Thijs 4∙13 0∙17+99∙05
Kwa 14∙54 1∙90+111∙53

OVERALL 11∙81 6∙68820∙88

0 5 10 15 20 25
23#
!
Supplementary,references,
1.# Anderson#JL,#Adams#CD,#Antman#EM,#Bridges#CR,#Califf#RM,#Casey#DE,#Jr.,#et#al.#2012#
accf/aha#focused#update#incorporated#into#the#accf/aha#2007#guidelines#for#the#management#
of#patients#with#unstable#angina/non;st;elevation#myocardial#infarction:#A#report#of#the#
american#college#of#cardiology#foundation/american#heart#association#task#force#on#practice#
guidelines.#Circulation.#2013N127:e663;828#
2.# O'Gara#PT,#Kushner#FG,#Ascheim#DD,#Casey#DE,#Jr.,#Chung#MK,#de#Lemos#JA,#et#al.#2013#
accf/aha#guideline#for#the#management#of#st;elevation#myocardial#infarction:#Executive#
summary:#A#report#of#the#american#college#of#cardiology#foundation/american#heart#
association#task#force#on#practice#guidelines.#Circulation.#2013N127:529;555#
3.# Mehta#SR,#Yusuf#S,#Peters#RJ,#Bertrand#ME,#Lewis#BS,#Natarajan#MK,#et#al.#Effects#of#
pretreatment#with#clopidogrel#and#aspirin#followed#by#long;term#therapy#in#patients#undergoing#
percutaneous#coronary#intervention:#The#pci;cure#study.#Lancet.#2001N358:527;533#
4.# Kwa#VI,#Algra#A,#Brundel#M,#Bouvy#W,#Kappelle#LJ,#Group#MS.#Microbleeds#as#a#predictor#of#
intracerebral#haemorrhage#and#ischaemic#stroke#after#a#tia#or#minor#ischaemic#stroke:#A#
cohort#study.#BMJ0Open.#2013N3#
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patients#with#transient#ischaemic#attack.#European0journal0of0neurology0:0the0official0journal0of0
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Antiplatelet Treatment After TIA and Ischemic Stroke

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Antiplatelet Treatment After TIA and Ischemic Stroke

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Antiplatelet Treatment After Transient Ischemic Attack and

Ischemic Stroke in Patients With Cerebral Microbleeds

C erebral microbleeds are markers of severe small ves-

and nonvascular). The definition of recurrent stroke required a sud-

Table. Characteristics and Outcomes of OXVASC and HKU Table. Continued

Prior transient ischemic 201 (19) 154 (15) 0.047

Imaging characteristics Deaths (%) 161 (15) 130 (13) 0.20

Figure 3. Risk of ischemic and hemor-

Matsumoto M. Antiplatelet therapy as a risk factor for microbleeds

Stroke. 2018;49:1434-1442; originally published online May 10, 2018;

Data Supplement (unedited) at:

Reprints: Information about reprints can be found online at:

Subscriptions: Information about subscribing to Stroke is online at:

MR,parameters, HKU,, OXVASC,scanner,1, OXVASC,scanner,2, OXVASC,scanner,3, OXVASC,scanner,4,,

, Unadjusted,HR,(95%,CI)*, HR,(95%,CI)*,adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,risk,

, Unadjusted,HR,(95%,CI)*, HR,(95%,CI)*,adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,risk,

, Unadjusted,HR,(95%,CI)*, HR,(95%,CI)*,adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,

, Unadjusted,HR,(95%,CI)*, HR,(95%,CI)*,adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,

Huang 1∙46 0∙32-6∙73

OXVASC*and*HKU* 1∙56 1∙03:2∙38

Overall* 1∙68 1∙14:2∙48

Risk* Ratio*(95%* CI)

Huang 2∙25 0∙75-6∙75

OXVASC*and*HKU 1∙41 0∙84:2∙37

OVERALL 2∙51 1∙41:4∙47

Risk* Ratio*(95%* CI)

Huang 3∙76 1∙34-10∙53

OXVASC*and*HKU 2∙08 1∙25:3∙46

OVERALL 2∙75 1∙75:4∙34

Risk* Ratio*(95%* CI)

Huang 17∙33 0∙71+420∙91

OXVASC*and*HKU 0∙84 0∙1087∙02

OVERALL 3∙14 1∙1788∙42

Risk* Ratio*(95%* CI)

Huang 10∙75 0∙44+262∙01

OXVASC*and*HKU 5∙76 1∙22827∙10

OVERALL 5∙81 2∙63812∙84

Risk* Ratio*(95%* CI)

Huang 44∙65 2∙43+821∙01

OXVASC*and*HKU 11∙70 3∙91835∙30

OVERALL 13∙35 6∙75826∙39

Risk* Ratio*(95%* CI)

Overall$ 4∙80 2∙36@9∙76

Overall$ 1∙62 1∙24@2∙11

OXVASC$and$HKU 1∙56 1∙15@2∙12

All$TIA/IS$cohorts 1∙62 1∙32@1∙99

Risk$ Ratio$(95%$ CI)

Overall$ 7∙09 3∙43@14∙65

OXVASC$and$HKU 4∙63 1∙97@10∙85

All$TIA/IS$cohorts 5∙80 3∙23@10∙41

Risk$ Ratio$(95%$ CI)

Huang 1∙46 0∙32-6∙73

OXVASC*and*HKU 1∙55 1∙0582∙30

Overall* 1∙57 1∙0882∙29

Risk* Ratio*(95%* CI)

Huang 2∙25 0∙75-6∙75

OXVASC*and*HKU 1∙37 0∙8582∙21

OVERALL 2∙19 1∙2983∙70

Risk* Ratio*(95%* CI)

Huang 3∙76 1∙34-10∙53

OXVASC*and*HKU 1∙92 1∙2482∙97

OVERALL 2∙53 1∙6483∙90

Risk* Ratio*(95%* CI)

Huang 17∙33 0∙71+420∙91

Prior transient ischemic 201 (19) 154 (15) 0.047

Imaging characteristics Deaths (%) 161 (15) 130 (13) 0.20

, Unadjusted,HR,(95%,CI), HR,(95%,CI),adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,risk,

, Unadjusted,HR,(95%,CI), HR,(95%,CI),adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,risk,

, Unadjusted,HR,(95%,CI), HR,(95%,CI),adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,

, Unadjusted,HR,(95%,CI), HR,(95%,CI),adjusted,for,age,and,sex, HR,(95%,CI)*,adjusted,for,age,,sex,and,vascular,

OXVASCandHKU* 1∙56 1∙03:2∙38

Risk* Ratio(95% CI)

OXVASCandHKU 1∙41 0∙84:2∙37

Risk* Ratio(95% CI)

OXVASCandHKU 2∙08 1∙25:3∙46

Risk* Ratio(95% CI)

OXVASCandHKU 0∙84 0∙1087∙02

Risk* Ratio(95% CI)

OXVASCandHKU 5∙76 1∙22827∙10

Risk* Ratio(95% CI)

OXVASCandHKU 11∙70 3∙91835∙30

Risk* Ratio(95% CI)

OXVASCandHKU 1∙55 1∙0582∙30

Risk* Ratio(95% CI)

OXVASCandHKU 1∙37 0∙8582∙21

Risk* Ratio(95% CI)

OXVASCandHKU 1∙92 1∙2482∙97

Risk* Ratio(95% CI)

OXVASCandHKU 1∙18 0∙2685∙38

Risk* Ratio(95% CI)

OXVASCandHKU 5∙21 1∙02826∙60

Risk* Ratio(95% CI)

OXVASCandHKU 8∙75 3∙44822∙24

Risk* Ratio(95% CI)