Acv Antitromboticos

Cerebrovascular disease
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325249 on 21 June 2022. Downloaded from http://jnnp.bmj.com/ on August 14, 2022 by guest. Protected by copyright.
Review
Antithrombotic dilemmas in stroke medicine: new

data, unsolved challenges
Jonathan G Best,1 Beatrix Cardus,2 Catharina J M Klijn ‍ ‍,3 Gregory Lip,4,5
David J Seiffge ‍ ‍,6 Eric E Smith,7 David J Werring ‍ ‍1
► Additional supplemental ABSTRACT priorities for further research, and giving recom-
material is published online Antithrombotic therapy is a key element of secondary mendations for management where possible.
only. To view, please visit
the journal online (http://dx. prevention in patients who have had an ischaemic
doi.org/10.1136/jnnp-2020- stroke or transient ischaemic attack. However, its use ANTITHROMBOTIC MEDICATION IN PATIENTS
325249). in clinical practice is not always straightforward. This WITH ICH
1
review provides an update on certain difficult scenarios At least one- third of patients presenting with
Stroke Research Centre, UCL
Queen Square Institute of
in antithrombotic management, with a focus on recent ICH use antithrombotic medication: antiplate-
Neurology, London, UK clinical trials and large observational studies. We lets in 15%–40% and oral anticoagulants (OAC)
2
Royal Surrey County Hospital, discuss the approach to patients with an indication in 15%–25% (mainly because of atrial fibrillation
Royal Surrey NHS Foundation for antithrombotic treatment who also have clinical or
Trust, Guildford, UK (AF)).1–5 Case fatality after ICH is approximately
3 radiological evidence of previous intracranial bleeding, 40% at 1 month,6 and even higher in patients on
Department of Neurology,
Radboud University Medical patients with indications for both anticoagulant antithrombotic treatment.2 7 8 In those who survive,
Centre, Donders Institute for and antiplatelet treatment, and patients in whom clinicians face the dilemma if, in whom, and when
Brain, Cognition and Behaviour, antithrombotic treatment fails to prevent stroke. We
antithrombotic medication should be reinitiated.
Nijmegen, Netherlands also review the timing of anticoagulation initiation after
4
Liverpool Centre for As antithrombotic treatment is frequent in the
Cardiovascular Science,
cardioembolic stroke, and the use of antithrombotics elderly and the population continues to age, the
University of Liverpool, Liverpool, in patients with asymptomatic cerebrovascular absolute number of patients with ICH while on
UK disease. Despite a wealth of new evidence, numerous antithrombotic treatment is likely to increase with
5
Aalborg Thrombosis Research uncertainties remain and we highlight ongoing trials
Unit, Aalborg University, time. Although the adoption of non- vitamin K
addressing these. OACs (NOACs) for prevention of thromboembo-
Aalborg, Denmark
6
Department of Neurology, lism in patients with AF might reduce the incidence
Inselspital University Hospital, of OAC-associated ICH,9 the increased uptake of
Bern, Switzerland
7 OAC in the elderly is likely to balance this effect.4 10
Calgary Stroke Program,
Department of Clinical INTRODUCTION Current guidelines provide only weak recommenda-
Neurosciences, Radiology and Antithrombotic therapy remains the cornerstone tions on antithrombotic medication after ICH.11 12
Community Health Sciences, of secondary prevention after ischaemic stroke Many clinicians have been reluctant to reinitiate
Hotchkiss Brain Institute, antithrombotic treatment, in particular OACs, after
University of Calgary, Calgary, or transient ischaemic attack (TIA). Antiplatelet
Alberta, Canada or anticoagulant drugs are prescribed for most ICH, especially in older patients, frail patients at
patients with ischaemic stroke and are indicated in risk of falling, and patients suspected to have cere-
Correspondence to a substantial proportion of those with intracerebral bral amyloid angiopathy (CAA).13 14 In an observa-
Dr David J Werring, Stroke haemorrhage (ICH). These drugs are associated tional cohort study describing patients from four
Research Centre, UCL Queen
with a small yet unpredictable increase in bleeding different countries, the percentage of patients who
Square Institute of Neurology, restarted antithrombotic drugs after ICH varied
London, UK; d.werring@ucl. risk (of which intracranial bleeding is the most
ac.uk lethal or disabling) but in many cases the benefits between 11% and 45%.13 However, increasing
will outweigh the risks. However, stroke is not a awareness that in patients with ICH the long-term
Received 16 July 2021 homogeneous disease, and an important part of risk of ischaemic stroke and other thromboembolic
Accepted 16 May 2022
clinical practice is recognising when a deviation events may be at least as high as the risk of ICH,15
Published Online First 21 June
from routine antithrombotic therapy is necessary, and even higher in those with non-lobar ICH16 or
2022
perhaps due to safety concerns in patients at high AF,17 18 is starting to shift secondary prevention
risk of bleeding, or to balance competing indica- paradigms.
tions for treatment in patients with vascular comor-
bidities. Despite a large body of evidence, practical Current evidence
dilemmas in how best to use antithrombotic treat- Acutely, patients with ICH are often immobile and
ment remain common, including when to start at risk of deep venous thrombosis and pulmonary
© Author(s) (or their
employer(s)) 2022. No anticoagulants after stroke, and what to do when embolism. The optimal time to initiate prophy-
commercial re-use. See rights antithrombotics fail to prevent stroke. Whether lactic low-molecular-
weight heparin (LMWH) is
and permissions. Published antithrombotic treatment might benefit those with uncertain. A Cochrane review identified two small
by BMJ. incidental cerebrovascular disease, an increasingly randomised controlled trials (RCTs) and found
To cite: Best JG, Cardus B, common scenario given the frequent use of brain no differences between treatment groups in the
Klijn CJM, et al. J Neurol CT and MRI, is also unknown. In this review, we occurrence of deep venous thrombosis (relative
Neurosurg Psychiatry discuss each of these areas in turn, summarising the risk (RR) 0.99, 95% CI 0.49 to 1.96; n=121) or
2022;93:939–951. available evidence, highlighting ongoing studies and pulmonary embolism (RR 0.54, 95% CI 0.23 to
Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249 939
1.28; n=121) between those that started LMWH after 2 days underline the need for more evidence to identify subgroups of
or heparin from day four and controls (all patients also received patients with AF and ICH or intracranial haemorrhage in whom
graduated compression stockings).19 Observational data suggest the effect of restarting anticoagulation might be either beneficial
that LMWH started within 48 hours after ICH is probably safe or hazardous.
as it did not result in haematoma expansion compared with There are no randomised comparisons of the timing of recom-
patients who did not receive this treatment or received it later.12 mencing antithrombotics after ICH, nor any ongoing RCTs.
However, practice varies, with some clinicians choosing to defer Observational data from 2619 ICH survivors included in the
LWMH initiation for several days, often with the use of intermit- Swedish Stroke Register suggest that the optimal timing of
tent pneumatic compression in the interim.20 initiation of OACs is 7–8 weeks after the ICH for prevention
The RESTART trial suggests that antiplatelet therapy after of stroke or vascular death and minimising the risk of severe
ICH is safe. In 536 participants with ICH while on antithrom- haemorrhage.27 In patients with mechanical heart valves, earlier
botic medication, over a median follow- up duration of 3.0 reinitiation of anticoagulation (with heparins or VKAs) should
years, the 268 patients allocated to antiplatelet therapy had a be considered due to the high risk of valve thrombosis. Based
similar risk of recurrent ICH (22 participants, 8.2%) as the 268 on a multicentre cohort study, a start time between 6 and 13
allocated to avoid antiplatelet therapy (25 participants, 9.3%, days after ICH, depending on anticipated thromboembolic risk,
adjusted HR (aHR) 0.87, 95% CI 0.49 to 1.55).21 The risks might be optimal.28
of major vascular events were also similar in both groups (HR
0.79, 95% CI 0.58 to 1.08). The median time between onset and Research priorities
randomisation was 76 days (IQR 29–146). The absolute risk of Two further studies of antiplatelet use are ongoing (RESTART-Fr,
major occlusive events was about 1.5 to 2 times higher than the NCT02966119, n=280; STATICH, NCT03186729, n=250),
risk of major haemorrhagic events. as are six further studies addressing whether to restart OACs
The Start or Stop Anticoagulants Randomised Trial (SoSTART) in patients with AF who have had an ICH (table 1), mostly
randomised 203 participants with previous spontaneous intra- testing the use of NOACs against other strategies, including no
cranial haemorrhage (92% intracerebral, 84% OAC-associated) OAC.29 Of these, NASPAF-ICH has completed inclusion, and a
to start or avoid OAC.22 The median time from onset to rando- pooled analysis of SoSTART, APACHE-AF and NASPAF-ICH is
misation was 115 days (IQR 49–265), and nearly all partici- planned.30 A3ICH is a three-arm trial also including left atrial
pants starting anticoagulation received an NOAC. Participants appendage occlusion (LAAO). The potential advantage of LAAO
were followed up for a median of 1.2 years (251 person-years of is that long term antithrombotic medication can be avoided.
follow-up). Participants allocated to start OAC had more intra- However, after implantation of the device antiplatelet therapy
cranial haemorrhage recurrences (8 of 100, 8.0%) than those is needed, initially dual therapy, then monotherapy for about 6
allocated to avoid OAC (4 of 102, 3.9%), but the prespecified months. In STROKECLOSE (NCT 02830152), LAAO (followed
margin for declaring non-inferiority was not met. For the three by aspirin for at least 6 months with or without clopidogrel in
prespecified composite secondary outcomes (any symptom- the first 45 days) is compared with OAC, antiplatelet therapy or
atic major vascular event, any stroke, or any stroke or vascular no antithrombotic therapy at all, for prevention of a composite
death), the aHRs ranged between 0.51 and 0.55, suggesting that of stroke (ischaemic or haemorrhagic), systemic embolism, life-
starting OAC might be superior to avoiding OAC, but none of threatening or major bleeding and all-cause mortality in patients
the analyses reached statistical significance. The APACHE-AF with ICH. In this context one should consider that ischaemic
(Apixaban After Anticoagulation-associated Intracerebral Haem- stroke may arise from other origins than the left atrial appendage
orrhage in Patients with Atrial Fibrillation) trial randomised 101 (in AF) and non-AF sources (eg, arteriosclerosis, small vessel
participants with ICH in the previous 90 days to apixaban or no disease) and it is debatable whether antiplatelet therapy should
anticoagulation, a median of 46 days (IQR 21–74) after onset, be stopped entirely after LAAO in patients at high risk of isch-
and followed participants for a median of 1.9 years (222 person- aemic stroke.
years of follow-up).23 The primary outcome of stroke or vascular
death occurred in 13 (26%) of 50 participants allocated to apix-
aban and in 12 (24%) of 51 allocated to avoid anticoagulation Recommendations
(aHR 1.05, 95% CI 0.48 to 2.31). More participants allocated Based on the currently available evidence, restarting antiplatelets
to apixaban than allocated to avoid anticoagulation had a recur- in patients who have had an intracranial haemorrhage appears
rent ICH (aHR 4.08, 95% CI 0.45 to 39.91), but there was no safe, and there is currently no clear preference for starting or
difference between the treatment groups in the rate of ischaemic avoiding OAC in patients with AF and previous ICH or intra-
stroke (aHR 0.96, 95% CI 0.31 to 2.97). Before the results of cranial haemorrhage. If starting OAC is considered, an NOAC
these trials, observational studies had suggested that survivors of is generally preferred over VKAs, although data remain limited
intracranial haemorrhage recommencing OAC had a lower risk in patients with ICH. Information on the timing of initiation
of ischaemic stroke (RR 0.46, 95% CI 0.29 to 0.72), whereas of OACs after ICH is scare, but 7–8 weeks appears a sensible
the risk of recurrent ICH was comparable (RR 1.23, 95% CI optimum for avoiding early haemorrhagic events and preven-
0.80 to 1.87) to those who did not,24 and that OAC resumption tion of ischaemic complications. The place of LAAO is yet to be
was associated with a decreased risk of death and of ischaemic determined. We encourage randomisation into ongoing clinical
stroke and comparable risk of ICH recurrence, both in non- trial of OAC and LAAO in patients with ICH and AF.
lobar and in lobar haemorrhage.25 OAC resumption was asso-
ciated with decreased risk of death (aHR 0.27, 95% CI 0.08 to ANTITHROMBOTIC MEDICATION IN PATIENTS WITH
0.86 for possible CAA (n=136); aHR 0.30, 95% CI 0.10 to 0.92 CEREBRAL MICROBLEEDS
for probable CAA (n=54)).26 The results of these observational Cerebral microbleeds are small, black, rounded lesions seen on
studies could have been confounded by indication, and most MRI scans sensitive to paramagnetic material; scans of this type
patients on anticoagulation were treated with vitamin K antago- include T2*-weighted gradient recalled echo and susceptibility-
nists (VKAs). The neutral results of SoSTART and APACHE-AF weighted imaging.31 Histological correlation studies indicate that
940 Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249
Table 1 Ongoing trials of anticoagulation in patients with AF and previous ICH
Study Setting Eligibility criteria Intervention Control Primary outcome(s)
NASPAF Canada Previous ICH Any NOAC Aspirin 81 mg/day ICH and ischaemic stroke
NCT02998905 AF, CHADS2 2+ Mean follow-up 1 year
ASPIRE United States Previous ICH within 14–180 Apixaban Aspirin 81 mg/day All-cause stroke and death of
NCT03907046 days any cause within 3 years
AF or atrial flutter, CHA2DS2-
VASc 2+
ENRICH-AF North America, Europe, Previous symptomatic Edoxaban Single antiplatelet or no (1) All-cause stroke, (2) Major
NCT03950076 Asia intracranial haemorrhage antithrombotic haemorrhage, median follow-
AF, CHA2DS2-VASc 2+ up 2 years
PRESTIGE-A
F Europe Previous ICH within 6 months Any NOAC Antiplatelet or no (1) Time to first ischaemic
NCT03996772 AF, CHA2DS2-VASc 2+ (men), antithrombotic stroke, (2) Time to first ICH,
3+ (women) within 3 years
STATICH Europe Previous ICH AF: Any anticoagulant AF: No anticoagulant ICH within 2 years
NCT03186729 AF or vascular disease No AF: Any antiplatelet No AF: No antiplatelet
with antiplatelet treatment
indicated
A3ICH France Previous ICH 1. Apixaban Antiplatelet or no All-cause stroke, major
NCT03243175 AF, CHA2DS2-VASc 2+ 2. LAAO antithrombotic, no LAAO cardiovascular events, and
major bleeding, within 2
years
AF, atrial fibrillation; ICH, intracerebral haemorrhage; LAAO, left atrial appendage occlusion; NOAC, non-vitamin K oral anticoagulant.
most radiological microbleeds correspond, as hypothesised, to

small areas of bleeding related to cerebral small vessels.32 Cere-
bral microbleeds have found clinical application as a biomarker
of the presence and type of cerebral small vessel disease. In
particular, a strictly lobar location has good diagnostic accu-
racy for CAA, at least in hospital-based cohorts of patients with
symptomatic ICH (figure 1).33
For the last two decades or so, microbleeds have generated
substantial research interest as well as clinical anxiety regarding
their potential role in predicting the future risk of intracranial
haemorrhage. It is hypothesised that as a marker of fragile,
bleeding-prone small vessels, microbleeds will be associated
with increased intracranial bleeding risk, particularly in patients
treated with antithrombotic drugs.
Current evidence
Multiple prospective cohort studies have now confirmed a
clear association between increasing microbleed burden and
intracranial haemorrhage risk.34 35 A recent large-scale interna-
tional collaborative study has also demonstrated that cerebral
microbleeds improve the prediction of intracranial haemorrhage
in patients with previous ischaemic stroke or TIA, and that a
cerebral microbleed-based risk score (the Microbleeds Interna-
tional Collaborative Network - Intracranial Haemorrhage score,
MICON- ICH) has improved discrimination for intracranial
haemorrhage compared with widely used clinical prediction
instruments like the HAS-BLED (Hypertension, Abnormal renal/
liver function, Stroke history, Bleeding, Labile international
normalised ratio, Elderly, Drugs), ATRIA (Anticoagulation and
Risk factors in Atrial Fibrilllation) or ORBIT (Outcomes Registry
for Better Informed Treatment of Atrial Fibrillation) scores.36
However, the same data indicate that microbleeds are also asso- Figure 1 Microbleeds in sporadic small vessel disease. Top, left,
ciated with an increased risk of ischaemic stroke, although they Susceptibility-weighted MRI sequences showing deep CMBs suggesting
do not appear to improve discrimination for ischaemic stroke deep perforator arteriopathy, and right: strictly lobar CMBs with
risk over clinical variables alone.36 In a pooled analysis of indi- disseminated siderosis and evidence of previous lobar ICH, suggesting
vidual patient data from 38 studies, the absolute risk of isch- cerebral amyloid angiopathy respectively. Bottom: T2 sequences show
aemic stroke exceeded that of intracranial haemorrhage even in compatible patterns of white matter hyperintensity and enlarged
patients with 10 or more microbleeds (annual rates: intracranial perivascular spaces. CMBs: cerebral microbleeds; ICH, intracerebral
haemorrhage: 2.7%; ischaemic stroke: 6.4%), or microbleeds in haemorrhage.
a strictly lobar distribution suggesting CAA (annual rates: intra- presentation which requires antiplatelet therapy; minimising the
cranial haemorrhage: 1.3%; ischaemic stroke: 4.8%).35 risk of stent thrombosis after a percutaneous coronary interven-
Microbleeds have also been investigated in several RCTs of tion; and the risk of bleeding posed by combining OAC and anti-
antithrombotic agents. Secondary analyses of the PERFORM platelet therapy.43
and NAVIGATE-ESUS trials did not show any interaction of
microbleeds at baseline with allocated treatment effects.37 38 This
suggests that microbleeds do not modify the net benefit or harm Current evidence
of antithrombotic therapy. However, in the PICASSO (Preven- Avoiding long-term combination therapy in AF patients with
tion of Cardiovascular Events in Asian Patients with Ischaemic coronary artery disease without a recent acute coronary
Stroke at High Risk of Cerebral Haemorrhage) trial, which syndrome is supported by a systematic review and meta-analysis
enrolled participants with previous ischaemic stroke and high of observational data,44 which showed similar rates of throm-
intracranial bleeding risk (evidenced by a history of symptom- botic and ischaemic events in patients treated with single anti-
atic intracranial haemorrhage, radiological evidence of previous platelet therapy and OAC compared with oral anticoagulation
ICH, or the presence of two or more cerebral microbleeds), alone (HR 1.09, 95% CI 0.92 to 1.29), but higher rates of major
a substudy found that in those with microbleeds only at base- bleeding with the former (HR 1.61, 95% CI 1.38 to 1.87). The
line, cilostazol was associated with a lower risk of intracranial AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban
bleeding than aspirin (HR 0.08, 95% CI 0.01 to 0.61).39 in Patients with Stable Coronary Artery Disease) trial compared
single antiplatelet therapy and rivaroxaban to rivaroxaban alone
Research priorities in patients with AF and stable coronary artery disease. Although
By using microbleeds to identify patients at highest risk, it may it was stopped early for increased mortality in the combined
be possible to test new interventions that may have a lower treatment group, the trial demonstrated non- inferiority of
intracranial bleeding risk. For example, in those with AF, the rivaroxaban alone for a composite primary outcome of stroke,
assessment of cerebral microbleeds could help prevent intracra- systemic embolism, myocardial infarction, coronary revascular-
nial haemorrhage by identifying patients in whom LAAO should isation and death (HR 0.72, 95% CI 0.55 to 0.95), and supe-
be considered.40 In those with non- cardioembolic ischaemic riority for major bleeding (HR 0.59, 95% CI, 0.39 to 0.89).45
stroke or TIA, microbleeds could identify patients for trials of This observation was evident irrespective of CHA2DS2VASc or
antithrombotic agents with lower expected bleeding risk, for HAS-BLED scores.46
example, cilostazol. In a systematic review and meta-analysis, the pooled prev-
Cortical superficial siderosis (cSS) is associated with CAA, alence of carotid stenosis in AF patients was 12.4% (95% CI
and a very high risk of future ICH in patients meeting modi- 8.7% to 16.0%), with reported prevalence ranging from 4.4%
fied Boston criteria, which might exceed that of ischaemic stroke to 24.3%.47 The pooled prevalence of carotid plaque was 48.4%
(26.9% /year in patients with extensive bilateral cSS included in and the prevalence of AF in patients with carotid stenosis was
a single centre prospective cohort study).41 Whether antithrom- 9.3% (range 3.6–10.0). Thus, about 1 in 10 patients with AF
botic treatment should be modified or withheld in patients with have carotid stenosis, and vice versa. Also, non-stenotic carotid
cSS not meeting modified Boston criteria or without previous disease is present in about half of AF patients. Despite this, few
ICH should be investigated, though very large studies would be data exist to guide the management of patients with AF and
needed due to its rarity in such patients.42 carotid or peripheral arterial disease, but the increased bleeding
risk with combination therapy observed in patients with coro-
nary artery disease might reasonably be expected in these
Recommendations patients.48 In the absence of evidence that concomitant anti-
Based on the available data, the presence or burden of platelet therapy reduces the risk of stroke or major cardiovas-
microbleeds should not preclude the use of antithrombotic cular events, European guidelines recommend against its use in
therapy (antiplatelet drugs or OAC) for secondary prevention of patients with peripheral arterial disease without vascular events
ischaemic stroke or TIA. Accurate predictions regarding future in the last twelve months.49
intracranial haemorrhage risk (eg, using the MICON-ICH score) In high- risk stable atherosclerotic vascular disease patients
can nevertheless inform discussions about prognosis and high- without AF, the COMPASS trial randomised 27 395 participants
light patients in whom measures to mitigate bleeding risk (such to receive rivaroxaban 2.5 mg two times per day plus aspirin
as intensive blood pressure control, avoiding alcohol and careful 100 mg one time per day, rivaroxaban 5 mg two times per day
review of concomitant medication) should be prioritised and or aspirin 100 mg one time per day.50 The incidence of the
monitored particularly closely. primary outcome, a composite of cardiovascular death, stroke or
myocardial infarction, was lower in the rivaroxaban-plus-aspirin
ANTITHROMBOTIC STRATEGIES IN PATIENTS WITH group compared with the aspirin-alone group (4.1% vs 5.4%;
INDICATIONS FOR BOTH ANTICOAGULANT AND HR 0.76, 95% CI 0.66 to 0.86). Although more major bleeding
ANTITHROMBOTIC TREATMENT events occurred in the combination group (3.1% vs 1.9%; HR
Many patients with AF have vascular disease, whether coronary, 1.70, 95% CI 1.40 to 2.05), mortality was also lower (HR 0.82,
carotid or peripheral artery disease. In such patients, there is both 95% CI 0.71 to 0.96), without an increase in intracranial or fatal
a need to prevent stroke due to AF, which requires OAC, and bleeds. Of the secondary outcomes, ischaemic stroke was signifi-
to prevent stroke due to vascular disease, which in the non-AF cantly lower with combination therapy compared with aspirin
setting usually requires antiplatelet therapy. In AF patients with (HR 0.51, 95% CI 0.38 to 0.68), and with rivaroxaban alone
associated coronary artery disease, antithrombotic manage- vs aspirin (HR 0.69, 95% CI 0.53 to 0.90). In the subgroup of
ment varies between acute and stable clinical scenarios. In those patients with stable peripheral or carotid artery disease, combi-
presenting with an acute coronary syndrome, a balance must nation therapy also significantly reduced major adverse cardio-
be found between AF-related stroke prevention which requires vascular and peripheral arterial events as well as stroke, when
OAC; reducing cardiac ischaemia in an acute coronary syndrome compared with aspirin monotherapy, but again with more major
has been shown to reduce adverse outcomes in patients with AF,
in various independent cohorts.56–60
ANTICOAGULANT INITIATION AFTER ACUTE AF-ASSOCIATED

ISCHAEMIC STROKE
Around two- thirds of patients with cardioembolic ischaemic
stroke are already known to have AF at presentation or will be
diagnosed with AF during their initial hospitalisation.61 While
Figure 2 Suggested antithrombotic management for patients with atrial the long-term benefit of OAC for stroke prevention in AF is well
fibrillation undergoing PCI for an acute coronary syndrome (ACS). AF, atrial established,62 63 these patients pose the additional challenge of
fibrillation; NOAC, non-vitamin K oral anticoagulants; PCI, percutaneous deciding when anticoagulation should be initiated or resumed.64
coronary intervention. In the first 2 to 4 weeks after AF-associated ischaemic stroke, the
daily risk of recurrence is around 0.5% if untreated.65–67 This
must be balanced against the risk of clinically significant haem-
bleeding.51 Rivaroxaban alone did not significantly reduce major orrhagic transformation, roughly 0.4% per day in the first week
adverse cardiovascular events or stroke compared with aspirin after stroke,68 which might be increased by early anticoagula-
alone, but did reduce major adverse limb events and increased tion. RCTs of anticoagulation with heparin or VKAs suggest that
major bleeding. initiation within 48 hours of onset is not of net benefit compared
with more delayed initiation, with weak evidence of a reduction
Research priorities in recurrent ischaemic stroke outweighed by clear evidence of
Whether a similar combination therapy strategy as in the an increased risk of symptomatic intracranial haemorrhage.69
COMPASS trial would be beneficial in patients with AF and Consistent with this, current guidelines suggest delaying antico-
vascular disease is uncertain. More clinical trials are needed to agulation by up to 2 weeks (table 2),11 48 49 70–73 a period based
establish the best antithrombotic strategy for ischaemic stroke largely on expert opinion and small historical studies describing
prevention in AF patients with evidence of large arterial disease, the time course of haemorrhagic transformation.74 75 The
such as complex aortic plaque or symptomatic (and severe) increasing use of NOACs suggests a need to review this prac-
carotid disease. In addition, emerging technologies have been tice, as NOACs pose half the risk of intracranial haemorrhage
proposed, such as use of the percutaneous permanent carotid of VKAs, at least in the long term,63 and might therefore offer
filter which is investigated in the CAPTURE (Carotid Artery favourable risk-benefit balance in the acute phase.
Implant for Trapping Upstream Emboli for Preventing Stroke in
Atrial Fibrillatio Patients) trial.52 Current evidence
The initial results of the TIMING study were presented at the
Recommendations European Stroke Organisation Conference in September 2021.76
The current recommended management approach after an To date, these are the only RCT data on when to initiate antico-
acute coronary syndrome in a patient with AF is to have an agulation with an NOAC after AF-associated ischaemic stroke.
initial 1-month period of triple therapy with OAC, aspirin and In 888 participants randomised to anticoagulation initiation
a P2Y12 inhibitor (usually clopidogrel), after which the patient at 0–5 or 5–10 days from stroke and followed up for 90 days,
is managed with OAC plus a single antiplatelet (usually clopido- early anticoagulation was statistically non- inferior (based on
grel) (figure 2). In patients with a relatively low risk of thrombo- a prespecified margin of 3%) to delayed anticoagulation. The
embolism and a particularly high risk of bleeding (eg, HASBLED absolute risk of the composite primary outcome of ischaemic
score of 3 or higher; previous ICH with high recurrence risk, stroke, symptomatic ICH and mortality was lower in the early
for example, lobar location or probable CAA), the initial triple anticoagulation group, but superiority was not demonstrated.
therapy period may be omitted.43 Once ‘stable’ (arbitrarily Most included patients had mild ischaemic stroke (defined clin-
defined as 12 months onwards) the patient is managed with ically), and no ICH occurred in either study arm. These results
OAC monotherapy, either an NOAC or well- managed VKA provide some reassurance regarding the safety of early antico-
with a time in therapeutic range ≥70%, with a preference for an agulation, but further RCTs are needed to establish the optimal
NOAC given their better safety profile in clinical trials.53 timing of anticoagulation, both in patients with mild stroke, and
When combination therapy is used, efforts to mitigate bleeding those with moderate or severe stroke. Three RCTs are currently
risk are particularly important, and should aim to address modi- recruiting (OPTIMAS, ELAN and START) (table 3).
fiable bleeding risk factors (including hypertension, alcohol Several observational studies have also reported outcomes
excess and pharmacokinetic and pharmacodynamic drug inter- according to anticoagulation timing (online supplemental table
actions), and identify the patients with the highest bleeding risk 1). Collectively, these studies suggest that early anticoagulation
for early review and follow-up. Such a strategy has been tested with an NOAC is not associated with a high risk of intracranial
in a prospective cluster RCT of AF patients (with or without haemorrhage, and that this risk is low compared with that of
comorbid vascular disease), resulting in a reduction in major recurrent ischaemic stroke.77–83 Unexpectedly, several studies of
bleeding at 1 year and an increase in OAC use.54 We should also these studies found numerically higher intracranial haemorrhage
not forget that stroke prevention is only one aspect of the inte- rates with more delayed anticoagulation, or similar or higher
grated approach to AF care, as reflected in the Atrial fibrilla- rates of recurrent ischaemia in early treatment groups.80–83 Given
tion Better Care pathway recommended in the 2020 European substantial imbalances in stroke severity, size and the presence of
Society of Cardiology guidelines.49 ‘A’ refers to Avoid stroke/ haemorrhagic transformation between groups, these results are
Anticoagulation; ‘B’ Better symptom management with patient- likely to be confounded by treatment bias. For instance, while
centred decisions on rate or rhythm control’ and ‘C’ Cardiovas- unadjusted event rates from the RAF-NOACs study suggested
cular risk factor and comorbidity optimisation.55 This pathway the optimal timing of anticoagulation might lie between 4 and
Table 2 Current guidelines on anticoagulation initiation timing after ischaemic stroke
Guideline Date Summary of recommendations Reference
70
Royal College of Physicians, UK 2016 Defer anticoagulation for at least 14 days in disabling stroke; defer by no more than 14 days in non-disabling
stroke.
71
Canadian Stroke Best Practice 2017 Optimal timing to start anticoagulant therapy after stroke not defined by clinical trials; consider age, infarct
Recommendations size, imaging appearances, comorbidities and recurrence risk; suggests use of ESC 2016 ‘1-3-6-12’ guideline.
72
European Heart Rhythm Association 2018 Substantial study data regarding timing of initiation are missing. Present recommendations based on
consensus opinion. Suggests use of ESC 2016 ‘1-3-6-12’ guideline.
48
CHEST 2018 Oral anticoagulation should usually be started within 2 weeks. The optimal timing within this period is not
known. Infarct size is predictive of early recurrence, haemorrhagic transformation, and poor outcome, so
might not be helpful in determining the net benefit of early treatment.
73
American Heart Association/American 2019 Reasonable to initiate anticoagulation between 4 and 14 days after onset in most patients with an AIS in the
Stroke Association setting of AF.
11
European Stroke Organisation 2019 No recommendation based on randomised trials possible. Inclusion of patients in ongoing randomised trials
of early anticoagulation encouraged.
49
European Society of Cardiology/ 2020 Robust data to inform optimal timing are lacking. Initiate as soon as considered possible from neurological
EACTS perspective. Whereas infarct size/stroke severity is used clinically to guide timing of OAC initiation, the
usefulness of such an approach in estimating the net benefit of early treatment may be limited.
AF, atrial fibrillation; AIS, Acute ischaemic stroke; ESC, European Society of Cardiology; OAC, oral anticoagulants.
14 days after onset, a finding that has influenced current guide- in a thalamocapsular infarct causing a severe sensorimotor
lines,73 a multivariable analysis correcting for confounding syndrome, or in a large posterior cerebral artery infarct causing
factors found no significant association between initiation period hemianopia alone. Increasing infarct size is also associated with
and the study composite outcome.78 an increased risk of recurrent ischaemic stroke in patients with
AF,86 suggesting it may not reliably discriminate between patients
Research priorities who should be anticoagulated soon after stroke, and those in
Once robust data from clinical trials are available, subgroup whom anticoagulation should be delayed. Accordingly, this rule
analyses might allow the development of a personalised has been removed from the updated 2020 guideline.49
approach to anticoagulation initiation, based on an individu- Haemorrhagic transformation on initial imaging also gener-
alised assessment of the risks of haemorrhagic transformation ally delays anticoagulation.87 However, minor haemorrhagic
and recurrent ischaemic stroke. Currently, stroke severity and transformation (haemorrhagic infarction by ECASS classifica-
the presence of haemorrhagic transformation on initial imaging tion) is common after cardioembolic stroke,88 is not clearly asso-
are major determinants of anticoagulation timing, influenced by ciated with worse clinical outcome,89 and has not been shown to
the European Society of Cardiology’s 2016 ‘1-3-6-12’ rule.84 85 affect the risk–benefit balance of early anticoagulation. Haem-
However, clinically assessed stroke severity is an imperfect proxy orrhagic infarction might indicate diffuse low-pressure bleeding
for the volume of infarcted tissue, which is likely to be a more from necrotic brain tissue, rather than the focal, higher-pressure
direct determinant of the risk of haemorrhagic transforma- bleeding, possibly triggered by reperfusion90 that forms a paren-
tion.86 A considerable mismatch is not uncommon, for example chymal haematoma associated with poor clinical outcomes
Table 3 Completed and ongoing trials of anticoagulation timing after AF-associated ischaemic stroke
Infarct size or severity
Study Setting and status criteria Intervention Control Primary outcome
TIMING Sweden Any severity/size Any NOAC Any NOAC Recurrent ischaemic stroke,
NCT02961348 (completed, 888 participants) No specific exclusion for HT 0–4 days 5–10 days sICH and all-cause mortality
at 90 days
OPTIMAS United Kingdom Any severity/size Any NOAC Any NOAC All-cause stroke and
NCT03759938 (ongoing, recruitment PH2 HT excluded 0–4 days 7–14 days systemic embolism at 90
target=3478) days
ELAN Europe, Israel, Japan Infarct size determines Any NOAC Any NOAC Recurrent ischaemic stroke,
NCT03148457 (ongoing, recruitment intervention timing* Minor-moderate stroke: <48 Minor-moderate stroke: 6–7 major intracranial and
target=2000) PH1 and PH2 HT excluded hours days extracranial bleeding,
Major stroke: 6–7 days Major stroke: 12–14 days systemic embolism and
vascular death at 30 days
START United States If infarct size assessable on Any NOAC Recurrent ischaemic stroke,
NCT03021928 (ongoing, recruitment target imaging: infarcts <1.5 cm Adaptive design with four study arms: 48–72 hours, 120–144 sICH, systemic embolism
n=1000) diameter or >1/2 size of hours, 216–240 hours, 312–336 hours, and all-cause mortality at
MCA territory excluded 30 days
If not: NIHSS <5 or >23
excluded
*Infarct size classified as minor (<1.5 cm diameter), moderate (cortical superficial branch of ACA, MCA or PCA, deep MCA branch, internal borderzone territory or multiple minor
lesions) or major (complete ACA, MCA, or PCA, or multiple branches of ACA, MCA or PCA, or multiple arterial territories, or posterior circulation lesion ≥1.5 cm diameter).
ACA, anterior cerebral artery; AF, atrial fibrillation; HT, Haemorrhagic transformation; ICH, intracerebral haemorrhage; MCA, middle cerebral artery; NIHSS, National Institutes of
Health Stroke Scale; NOACs, non-vitamin K oral anticoagulants; PCA, posterior cerebral artery.

ANTITHROMBOTIC ‘FAILURE’
As antithrombotic medication is the mainstay of stroke preven-
tion in cardiovascular medicine, many patients with ischaemic
stroke are on antithrombotic therapy prior to stroke onset.
Management of these break-through strokes (‘treatment failure’
describes this scenario insufficiently) is a frequent and major
challenge in cerebrovascular medicine.
Current evidence
Figure 3 Reported predictors of ICH and recurrent stroke in patients Antiplatelet therapy using aspirin provides a modest risk-
with recent AF-related ischaemic stroke. AF, atrial fibrillation; HT, reduction for recurrent stroke not related to AF.115 However,
haemorrhagic transformation; ICH, intracerebral haemorrhage; NIHSS, ischaemic stroke despite antiplatelet therapy is frequent, with
National Institutes of Health Stroke Scale recent data suggesting 20%–35% of patients with stroke were
on antiplatelet therapy at stroke onset.116 117 Prior antiplatelet
therapy has been found to be associated with reduced stroke
(ECASS parenchymal haematoma type 2). Early anticoagulation severity.116 117 Reasons for stroke despite antiplatelet therapy
may include insufficient reduction of platelet aggregation by
initiation might therefore be insufficient to convert haemor-
aspirin and other antiplatelet agents or underlying stroke aetiol-
rhagic infarction to a parenchymal haematoma. In 96 patients
ogies, where antiplatelet therapy is less effective (eg, AF, ipsilat-
with baseline haemorrhagic transformation included in nine
eral high-grade carotid stenosis).
observational studies of early anticoagulation,91–99 none expe-
Although in vivo platelet function testing118 and testing for
rienced symptomatic intracranial haemorrhage. However, it has
genetic polymorphisms predisposing for reduced efficacy of
also not been proven that delaying anticoagulation increases the
different antiplatelet agents are available, their role to guide
risk of recurrent stroke: in a pooled analysis of the RAF and
treatment decisions is currently debated not only in neurology
RAF-NOAC studies, delaying initiation by a mean of 12 days
but also in cardiology.119 120 A recent meta-analysis121 identified
in patients with haemorrhagic transformation did not lead to
addition of or switch to a different antiplatelet agent to be asso-
additional recurrent ischaemic strokes compared with patients
ciated with fewer vascular events but no RCT has yet investi-
without haemorrhagic transformation.87 Secondary analyses
gated optimal treatment strategies.
including functional outcome measures, considering the higher
Dual-antiplatelet therapy combining aspirin and clopido-
morbidity and mortality of ICH than ischaemic stroke, would
grel has been shown to be an effective therapy in patients with
also be informative.
minor stroke or high risk TIA used for a limited period after
Observational studies in patients with AF and recent stroke the event.122 Recurrent stroke despite dual antiplatelet therapy
have identified numerous other risk factors for early recurrent was found to be associated with CYP2C19 loss-of-function allele
ischaemic and haemorrhagic events (figure 3).87 95 100–105 There status in a subanalysis of patients enrolled in the CHANCE trial
is a need to synthesise these into risk models suitable for clinical (from China)123 while there was no association between loss-
application, as existing prediction models intended for use in of-
function allele status and recurrent stroke among patients
AF, such as CHA2DS2-VASc and HAS-BLED, are validated for enrolled in the POINT trial (mostly from Europe and the
long-term use. Even more risk factors have been identified in USA). However, genetic testing to guide clinical decisions is not
patients with recent ischaemic stroke of any aetiology, including currently standard of care and there are limited data to recom-
diabetes and hyperglycaemia, renal function, the hyperin- mend its use.
tense middle cerebral artery sign, leukocytosis, hypertension, Anticoagulation using NOACs or VKAs is highly effective in
obesity, smoking and alcohol habits, and elevated C reactive preventing ischaemic stroke and systemic embolism in patients
protein.106–109 These have been included in scoring systems with AF.62 63 However, patients with AF may have stroke despite
which predict early recurrence110 111 or haemorrhagic transfor- taking NOAC or VKA, with a rate of 1.0%–1.5% per year in
mation (mainly postthrombolysis)112–114 in all-cause ischaemic RCTs.124–127 Recent data from the USA (2012–2015)128 and
stroke with reasonable accuracy. In the absence of AF-specific Switzerland (2015–2019)129 found that among patients with AF
models for early recurrence or bleeding, these scores might be (known before or newly diagnosed after stroke onset) who had
investigated for use in risk stratification, although some compo- a stroke, 30% (USA) and 38% (Switzerland) were taking any
nents of these scores might be significant mainly as surrogate OAC at the time of stroke onset. 8.8% of participants in the
markers for AF. USA and 20% in Switzerland were taking an NOAC at onset.
Thus, with more than one out of three patients with AF taking
anticoagulants at the time of stroke onset, this represents a major
Recommendations challenge not only for acute recanalisation therapies130 131 but
In light of the limitations of current evidence, offering enrolment also for secondary prevention.
in an RCT, if available, is likely to represent the best clinical care Reasons for having a stroke despite anticoagulant therapy
for most patients. In centres not participating in a relevant RCT, are heterogeneous and poorly understood. Three different clus-
early anticoagulation within 5 days of onset might be appro- ters should be distinguished (figure 4): (1) competing stroke
priate in most patients with minor stroke, with later initiation aetiology (eg, stroke due to large artery arteriosclerosis, small
in patients with moderate or severe stroke.64 In the absence of vessel disease, cervical artery dissection, endocarditis, active
severe symptomatic intracranial haemorrhage, we recommend malignancy or other determined origins); (2) medication error
anticoagulation initiation within 14 days in all patients. We (eg, lack of compliance, use of non-label NOAC dosage, phar-
prefer NOAC use in the absence of a definite indication for VKA macokinetic drug interactions reducing anticoagulant efficacy)
treatment. and (3) cardioembolism despite anticoagulation (no evidence
Figure 4 Suggested approach to patients with ischaemic stroke despite oral anticoagulation. AF, atrial fibrillation; DOAC, direct OAC; LAAO, left atrial
appendage occlusion; NOAC, non-vitamin K OAC; OAC, oral anticoagulant.
for competing stroke aetiology or medication error). Using the 0.53 to 0.85), although in patients undergoing cardiac surgery
ASCOD132 classification (a multicause aetiological classification for a separate indication.137
system of stroke causes), in 95% of patients at least one poten-
tial additional non- cardiac cause of stroke was identified.133 Recommendations
However, in the same study, medication error (eg, VKA therapy In the absence of evidence from RCTs, figure 4 includes sugges-
with INR <2.0 at stroke onset, non- label NOAC dosage or tions for work-up and secondary prevention therapy with respect
low NOAC plasma levels) was observed in 55% of patients. A to the most probable underlying cause of ischaemic stroke despite
multicentre study of patients with stroke despite NOAC therapy OAC. In patients with recurrence despite antiplatelet therapy,
found comparable results with non-cardioembolic stroke aeti- the possibility of a previously unrecognised and treatable cause
ology and NOAC dosing error being frequent.134 A thorough should be considered. Short-term dual antiplatelet therapy is
aetiological work-up including investigation of additional stroke generally indicated. There is insufficient evidence to recommend
aetiologies (eg, vessel imaging, MRI) and anticoagulation dosing platelet function or genetic testing as standard of care, but this
and adherence should be a standard of care for patients with approach might help to provide personalised treatment options
AF who have a stroke despite anticoagulant therapy. Review of in selected patients.
concomitant medication is particularly important in patients
prescribed NOACs, as monitoring of anticoagulant effect is not
routine. Drugs expected to reduce NOAC plasma levels include SILENT STROKE AND ASYMPTOMATIC SMALL VESSEL
rifampicin, carbamazepine, phenytoin, phenobarbitone, primi- DISEASE
done and St Johns’ wort (P-glycoprotein or CYP3A4 inducers). Whether aspirin or other antithrombotics should be used to
Whether NOAC monitoring leads to clinical benefit in patients prevent first-
ever stroke or myocardial infarction in patients
who cannot stop interacting medication is uncertain.135 with incidentally discovered silent stroke, high white matter
An international, multicentre study found that patients with hyperintensity (WMH) burden or microbleeds is controversial,
AF who had a stroke despite anticoagulant therapy (88.8% VKA) without evidence from high-quality RCTs. This clinical scenario
are at increased risk of having another stroke (HR 1.6, 95% CI arises frequently, as the prevalence of silent cerebrovascular
1.2 to 2.3) with an annualised rate of 8.9% per year.136 In this disease is high in older patients undergoing neuroimaging for
study, anticoagulation was changed (eg, switching between VKA indications unrelated to stroke. Population-based studies show
and NOAC therapy, or changing the type of NOAC) in 31% that more than 20% of persons older than 80 have either one or
of patients, but most patients continued the same anticoagu- more brain infarcts, high WMH burden or one or more cerebral
lant therapy as before the stroke. Neither treatment—change of microbleeds.138 139
anticoagulation or continuing the same anticoagulant as before
stroke—was associated with decreased hazard of recurrent Current evidence
stroke. Observational evidence shows that the presence of brain infarcts,
high WMH and microbleeds are associated with higher risk for
Research priorities future stroke, even after accounting for the higher risk factor
The optimal secondary prevention therapy after stroke despite burden in patients with these lesions. In a systematic review and
anticoagulant therapy in patients with AF remains unclear. meta-analysis,140 stroke risk was substantially elevated in persons
Future studies should focus on potential mechanisms of stroke with silent brain infarcts (HR 2.38, 95% CI 1.87 to 3.04), high
(eg, additional aetiology and medication error) and new treat- WMH (HR 2.45, 95% CI 1.93 to 2.12) and microbleeds (HR
ment options for those with cardioembolism despite antico- 1.89, 95% CI 1.55 to 2.53), independent of hypertension and
agulation. Such treatments might include LAAO, as the recent other vascular risk factors.
LAAOS- III (Left Atrial Appendage Occlusion Study III) trial Thus, these signs of clinically unrecognised cerebrovascular
found that LAAO with anticoagulation reduced ischaemic stroke disease mark patients at higher risk of stroke who might benefit
risk compared with anticoagulation alone (HR 0.67; 95% CI from the application of vascular risk reduction strategies. Some
guidelines recommend a risk-based approach for primary preven- recommends against use of aspirin in patients with silent cere-
tion; for example, by recommending statins based on the esti- bral small vessel disease, based on inconclusive evidence from
mated 10-year probability of having a stroke or MI.141 From that one small trial.154 We recommend that aspirin should generally
perspective, the presence of silent cerebrovascular disease might not be used in patients with silent cerebrovascular disease, unless
favour applying additional management strategies for patients there is another indication such as a clinical history of TIA, isch-
at high risk. However, the commonly used validated prediction aemic stroke or myocardial infarction. However, in patients with
models for stroke and MI risk are based on demographics, risk non-lacunar brain infarction, the use of aspirin can be consid-
factors and simple physiological and laboratory measurements, ered, particularly if there is an embolic pattern of infarction or
without incorporating MRI information. MRI information prob- there is evidence that atherosclerosis or atheroembolism is the
ably improves the classification of risk,142 but prediction models likely cause.
using MRI have not yet been derived and externally validated for
widespread use in patients without previous clinically diagnosed
CONCLUSION
ischaemic stroke or TIA.
Table 4 summarises recommendations based on the available
The potential downsides of aspirin therapy must also be
evidence for each antithrombotic dilemma. Although recent
considered. The pathophysiology of silent cerebrovascular
evidence from large-scale observational studies and a limited
disease is less certain than for symptomatic stroke. In the elderly,
number of RCTs has provided reassurance about the use of
most silent brain infarcts are lacunes. Silent lacunes may have a
antithrombotic therapy in high- risk populations—specifically
different pathophysiology than symptomatic lacunar infarctions
antiplatelets in those with previous ICH, and antiplatelets and
caused by occlusion of lenticulostriate and basilar arteries, and
anticoagulants in those with high microbleed burdens (but not
may not be related to thrombosis.143 One study failed to find
necessarily CAA)—many uncertainties remain. Ongoing RCTs
evidence that genetic predisposition to thrombosis was associ-
should soon establish the optimal time to start anticoagulants
ated with lacunes even though it was associated with cardioem-
after ischaemic stroke in patients with AF, and whether antico-
bolic and large artery stroke.144 The pathophysiology of WMH
agulants can be used safely in those with previous ICH (and the
is even less certain, with increasing evidence that elevated blood-
role of LAAO after ICH). Other clinical dilemmas are further
brain permeability is a key step.145 Two trials, of warfarin146 and
from resolution, notably the role of combination antithrombotic
aspirin,147 found that antithrombotic treatment increased the
therapy in patients with AF and peripheral or coronary artery
risk of ICH in patients with high WMH burden. Some patients
disease, the best approach to stroke prevention when antithrom-
with high WMH have underlying CAA, a vasculopathy that
botic treatment appears to have failed, and the use of antithrom-
predisposes to ICH.148 Microbleeds are associated with higher
botics in patients with cerebrovascular disease without clinical
risk of first ever ICH in the general population, but are also
stroke or TIA. New data have not only resolved some old chal-
associated with higher risk of future ischaemic stroke such that
lenges, but highlighted new ones: more well-designed RCTs are,
in persons with microbleeds the overall absolute number of new
as always, needed.
ischaemic strokes exceeds the number of new ICHs.149
The applicability of aspirin for patients with silent cerebro- Contributors DJW had the idea for the article, and developed the outline with JB.
vascular disease must also be considered in light of recent trials All authors drafted sections of the manuscript, critically reviewed and revised the
(without neuroimaging) that either failed to find a beneficial manuscript for intellectual content and approved the final submission.
effect of aspirin or found a small effect similar in size to the Funding The authors have not declared a specific grant for this research from any
increased harm from major bleeding.150 Contemporary guide- funding agency in the public, commercial or not-for-profit sectors.
lines either do not recommend aspirin use for primary preven- Competing interests DJW reports personal fees from Bayer, Alnylam and Portola
tion151 or only recommend that it be considered in higher risk outside the submitted work. EES reports personal fees from Alnylam Pharmaceuticals,
patients (based on cardiovascular risk factor profile or predicted Bayer and Portola, outside the submitted work. GL reports consultancy and speaker
risk from validated models) but not in the elderly older than fees from Bayer, Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim,
Microlife, Roche and Daiichi-Sankyo outside the submitted work. DJS reports funding
70.152 from Bayer and Pfizer, outside the submitted work.
Patient consent for publication Not applicable.
Research priorities Provenance and peer review Commissioned; externally peer reviewed.
To address current gaps in knowledge, studies are needed to Supplemental material This content has been supplied by the author(s). It
develop and validate models to stratify the risks of stroke and has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
cardiovascular disease in persons with and without silent cere- been peer-reviewed. Any opinions or recommendations discussed are solely those
brovascular disease, and to test antithrombotic strategies. The of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
relevance of different forms of cerebrovascular disease (eg, responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
lacunes vs WMHs) requires further investigation. of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Recommendations
Given current uncertainties, care should be individualised. ORCID iDs
A Scientific Statement from the American Heart Associa- Catharina J M Klijn http://orcid.org/0000-0002-8495-4578
David J Seiffge http://orcid.org/0000-0003-3890-3849
tion recommends that patients with silent brain infarcts or
David J Werring http://orcid.org/0000-0003-2074-1861
high WMH should be considered at high risk for stroke, but
without specific recommendations on aspirin.139 A Canadian
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Table 4 Summary of recommendations
Dilemma Recommendations
Antithrombotic use after intracerebral ► Use antiplatelets if there is a strong indication (eg, related to ischaemic hear disease, ischaemic stroke or TIA).
haemorrhage ► Whether to start or avoid OAC after ICH in patients with AF remains uncertain.
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Cerebrovascular disease

Antithrombotic dilemmas in stroke medicine: new

most radiological microbleeds correspond, as hypothesised, to

ANTICOAGULANT INITIATION AFTER ACUTE AF-ASSOCIATED

944 Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249

Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249 947

948 Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249

Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249 949

950 Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249

Best JG, et al. J Neurol Neurosurg Psychiatry 2022;93:939–951. doi:10.1136/jnnp-2020-325249 951

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