Journal of Stroke 2024;26(1):13-25

https://doi.org/10.5853/jos.2023.01578

Review

Update of Anticoagulation Use in Cardioembolic

Stroke With a Special Reference to Endovascular
Treatment
Apostolos Safouris,1,2,3 Klearchos Psychogios,1 Lina Palaiodimou,2 Peter Orosz,3 George Magoufis,4,5
Odysseas Kargiotis,1 Aikaterini Theodorou,2 Theodore Karapanayiotides,6 Stavros Spiliopoulos,5
Sándor Nardai,3 Amrou Sarraj,7 Thanh N. Nguyen,8 Shadi Yaghi,9 Silke Walter,10 Simona Sacco,11
Guillaume Turc,12,13,14,15 Georgios Tsivgoulis2,16
1
Stroke Unit, Metropolitan Hospital, Piraeus, Greece
2
Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
3
Department of Neurointerventions, National Institute of Mental Health, Neurology and Neurosurgery, Semmelweis University, Department of
Neurosurgery, Budapest, Hungary
4
Interventional Neuroradiology Unit, Metropolitan Hospital, Piraeus, Greece
5
Second Department of Radiology, Interventional Radiology Unit, “Attikon” University Hospital, Athens, Greece
6
Second Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki, Greece
7
Department of Neurology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
8
Department of Neurology and Radiology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
9
Department of Neurology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA
10
Department of Neurology, Saarland University Medical Centre, Homburg, Germany
11
Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy
12
Department of Neurology, GHU Paris Psychiatrie et Neurosciences, Paris, France
13
INSERM U1266, Paris, France
14
FHU Neurovasc, Paris, France
15
Université Paris Cité, Paris, France
16
Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

Cardioembolic stroke is a major cause of morbidity, with a high risk of recurrence, and anticoagulation Correspondence: Dr. Georgios Tsivgoulis
Second Department of Neurology,
represents the mainstay of secondary stroke prevention in most patients. The implementation of “Attikon” University Hospital, School of
endovascular treatment in routine clinical practice complicates the decision to initiate anticoagulation, Medicine, National and Kapodistrian
University of Athens, Rimini 1, Chaidari,
especially in patients with early hemorrhagic transformation who are considered at higher risk of Athens, Greece 12462
hematoma expansion. Late hemorrhagic transformation in the days and weeks following stroke Tel: +30-6937178635
Email: [email protected]
remains a potentially serious complication for which we still do not have any established clinical
https://orcid.org/0000-0002-0640-3797
or radiological prediction tools. The optimal time to initiate therapy is challenging to define since
delaying effective secondary prevention treatment exposes patients to the risk of recurrent Received: May 15, 2023
Revised: November 30, 2023
embolism. Consequently, there is clinical equipoise to define and individualize the optimal timepoint Accepted: December 4, 2023
to initiate anticoagulation combining the lowest risk of hemorrhagic transformation and ischemic
recurrence in cardioembolic stroke patients. In this narrative review, we will highlight and critically
outline recent observational and randomized relevant evidence in different subtypes of cardioembolic
stroke with a special focus on anticoagulation initiation following endovascular treatment. We will
refer mainly to the commonest cause of cardioembolism, non-valvular atrial fibrillation, and examine
the possible risk and benefit of anticoagulation before, during, and shortly after the acute phase of

Copyright © 2024 Korean Stroke Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which
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pISSN: 2287-6391 • eISSN: 2287-6405 https://j-stroke.org 13

 Safouris et al. Anticoagulation After EVT

stroke. Other indications of anticoagulation after ischemic stroke will be briefly discussed. We provide a
synthesis of available data to help clinicians individualize the timing of initiation of oral anticoagulation
based on the presence and extent of hemorrhagic transformation as well as stroke severity.

Keywords Ischemic stroke; Endovascular treatment; Anticoagulation; Symptomatic intracranial

hemorrhage; Hemorrhagic transformation

Introduction less than 30% of the infarcted area with mild space-occupying
effect, and PH-2 hemorrhage in more than 30% of the infarct-
Cardioembolism is a major cause of acute ischemic stroke (AIS) ed area with significant space-occupying effect.13 Both ECASS II
and anticoagulation (AC) is key to secondary prevention.1 Atrial and ECASS III defined sICH as any intracranial hemorrhage (ICH)
fibrillation (AF) is the most common cause of cardioembolic stroke on follow-up imaging associated with an increase of at least
and a risk factor for hemorrhagic transformation (HT) due to 4 points on the National Institutes of Health Stroke Scale (NI-
blood-brain barrier (BBB) disruption in AIS patients.2 However, HSS) from baseline, or with mortality; ECASS III emphasized on
a recent systematic review of endovascular treatment (EVT) in a causal relationship between ICH occurring in the first 7 days
patients with AF did not show an increased risk of symptomatic after treatment and clinical deterioration.14 The Safe Implemen-
intracranial hemorrhage (sICH) compared to patients without tation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST)
AF, documenting a rate of around 6.5% in both treatment arms.3 criteria define sICH as a PH-2 complicating AIS within 22–36
The risk of early recurrence of AIS related to AF may range be- hours, leading to an increase in the NIHSS of at least 4 points
tween 4% and 8% in the first 14 days of ictus without AC.4,5 Early from baseline or to death.15 The Heidelberg Bleeding Classifica-
initiation of AC may be effective in preventing early recurrence, tion provided more granularity in describing sICH, being more in-
but the potential benefit must be balanced against the risk of clusive for different types of ICH, and provided a formal approach
HT (1%–5% during the first 14 days), which is associated with a to investigate causal relation with neurological deterioration.16
2- to 3-fold increase in mortality and morbidity.6,7 sICHs primari-
ly occur in the first hours after EVT, and less frequently beyond Vitamin K antagonists versus
24 hours.8 Current international guidelines provide some expert non-vitamin K antagonist oral
opinions based mostly on observational data,9-11 without specific anticoagulants in the AIS setting
guidance for patients after EVT that has been widely implement-
ed in AIS treatment in recent years.12 Observational data indicate that non-vitamin K antagonist oral
Currently, there is clinical equipoise to define and individual- anticoagulants (NOACs) may be more effective in preventing
ize the optimal timepoint to initiate AC combining the lowest ischemic recurrences early after an ischemic stroke compared to
risk of HT and ischemic recurrence in cardioembolic stroke pa- vitamin K antagonists (VKAs).17 It has also been shown that the
tients. In this narrative review, we will highlight and critically risk of fatal ICH within 30 days might be greater with early VKA
outline recent observational and randomized relevant evidence treatment,18 and early NOAC initiation was associated with re-
in different subtypes of cardioembolic stroke with a special fo- duced risk of long-term poor clinical outcomes compared to VKAs,
cus on AC initiation following EVT. We will also provide guid- mainly due to lower ICH risk.19 The Initiation of Anticoagulation
ance to individualize the timing of initiation of oral AC based on after Cardioembolic stroke (IAC) study showed a benefit of NO-
the presence and extent of HT as well as stroke severity. ACs versus VKAs in early recurrence.20 The Acute Stroke With
Xarelto to Reduce Intracranial Hemorrhage, Recurrent Embolic
Definitions of HT & sICH Stroke, and Hospital Stay (Triple AXEL)21 failed to detect any dif-
ference between rivaroxaban or VKAs in new ischemic lesions
The European Cooperative Acute Stroke Study (ECASS) II radio- or new ICH on follow-up magnetic resonance imaging (MRI) at
logical criteria for grading HT distinguishes between hemorrhagic 4 weeks. It should be noted that the rivaroxaban arm received a
infarction (HI) 1 for small petechiae without space-occupying reduced and off-label daily dose of 10 mg/d for the first 5 days
effect, HI-2 for more confluent petechiae without space-occu- after randomization.
pying effect, parenchymal hematoma (PH) 1 for hemorrhage in A recent systematic review and meta-analysis comparing the

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Vol. 26 / No. 1 / January 2024

efficacy of NOACs versus VKAs within 1 week or within 2 weeks on transthoracic echocardiogram; higher scores are associated
following AIS showed that treatment with NOACs was associ- with high embolic risk and patients should receive earlier AC.27
ated with significantly improved survival and reduced odds of HT Concomitant stroke mechanisms such as cancer-related hyper-
and recurrent ischemic stroke compared to VKAs.22 Overall ben- coagulability, small vessel disease, and large artery atheroscle-
efit over VKAs seems to apply to both once-daily and twice- rosis predicted stroke recurrence in the IAC study.28 Therefore,
daily NOACs.23 it should be emphasized that an effective secondary prevention
strategy post-AIS in AF patients may extend beyond AC, espe-
The evolution of guidelines cially for those already on AC.29

The 2016 European Society of Cardiology guidelines for the man- Safety of earlier anticoagulation in
agement of AF introduced the “1-3-6-12” rule for AC initiation patients at high risk of recurrent
post-AIS: 1 day after transient ischemic attack (TIA), 3 days after embolism
mild AIS (NIHSS score <8 points), 6 days after moderate AIS (NI-
HSS score: 8–15 points), and 12 days after severe stroke (NIHSS An analysis of the Early Recurrence and Major Bleeding in Pa-
score >15 points) after exclusion of ICH on imaging.9 Additional tients With Acute Ischemic Stroke and Atrial Fibrillation Treated
clinical and imaging factors were listed to hasten or postpone With Non–Vitamin K Oral Anticoagulants (RAF-NOACs) study
initiation of treatment, but no specific guidance was provided revealed that 5% of the patients who had initiated NOACs within
in case of HT or PH detection. Despite its simplicity, a drawback 24–48 hours from index AIS developed HT, suggesting that the
of a purely clinical algorithm is that it does not account for the two days after AIS may be unsuited for AC initiation.17 In the
variation in brain infarct volumes in patients with the same NI- same analysis, the delay of 12 days to initiate AC in patients with
HSS score, that possibly influences HT risk. The 2016 European HT as compared to those without, was not associated with a sig-
Stroke Organisation (ESO)-Karolinska Stroke Update underlined nificant increase in the rate of recurrent ischemic stroke. Com-
the importance of infarct size and proposed the “4-7-14” day rule: bined data from 2 prospective, multicenter, Japanese registries
4 days after mild AIS and small infarct size (lesion ≤1.5 cm), 7 days on AF patients with AIS/TIA (Stroke Acute Management with
after moderate stroke and medium infarct size, and 14 days after Urgent Risk-factor Assessment and Improvement [SAMURAI]-
severe AIS and large infarct size.10 The same recommendation was NVAF and Recurrent Embolism Lessened by rivaroxaban, an Anti-
included as expert opinion statement in the ESO recommenda- Xa agent, of Early Dosing for acute ischemic stroke and transient
tions for secondary prevention of stroke and other thromboem- ischemic attack with atrial fibrillation [RELAXED]) were used to
bolic events in patients with stroke or TIA and AF, suggesting examine whether early NOAC initiation according to stroke se-
antiplatelet therapy in the first 48 hours after AF-associated verity was safe and effective.30 Indeed, NOAC initiation within
stroke.24 The American Heart Association and American Stroke 1 day after TIA, within 2 days after AIS with NIHSS <8, within
Association’s guidelines are quite broad and suggest initiating 3 days after AIS with NIHSS 8–15, and within 4 days after AIS
AC between 4–14 days after AIS, even in the context of HT after with NIHSS >15 (1-2-3-4-day rule) was associated with better
individual assessment of risks and benefits, considering anti- efficacy and similar safety compared with later initiation. Timing
platelet therapy until AC initiation.11 of Oral Anticoagulant Therapy in Acute Ischemic Stroke With
Atrial Fibrillation (TIMING) is a recently published prospective,
Treatment individualization and risk registry-based, multicenter, open-label, noninferiority, random-
stratification ized-controlled trial (RCT) performed in Swedish stroke units.31
Early NOAC initiation (≤4 days) was noninferior to late (5–10
In the absence of randomized evidence, experts suggest delay- days), as no AIS patient experienced sICH and rates of recur-
ing AC in patients with severe symptomatic HT, such as PH-2.25 rent AIS and death were numerically lower in the early initia-
Other experts prioritize imaging findings when facing this ther- tion group.
apeutic conundrum. They suggest initiating AC within 2 days
for infarct sizes <1.5 cm in diameter, 4–5 days for sizes 1.6–3 cm Anticoagulation after other
at, at day 7 for infarcts 3 cm or more, 7–10 days in HT HI-1 and Cardioembolic causes of stroke
HI-2 and for PH-2, subarachnoid or subdural hemorrhage post-
poning AC for a minimum of 2–4 weeks.26 The ALESSA score is AF due to moderate/severe mitral stenosis caused by rheumatic
based on patient age, lesion size, and severe atrial enlargement disease is considered valvular and NOACs are not formally indi-

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 Safouris et al. Anticoagulation After EVT

cated for stroke prophylaxis.32-34 Mechanical heart valves contin- ceived high risk of stroke recurrence, the most common anti-
uously activate the coagulation cascade, leading to very high thrombotic regimen is heparin (unfractionated heparin [UFH] or
local concentrations of thrombin, meaning that very high doses LMWH) at a therapeutic dose with or without aspirin.47,48 Figure 1
of NOACs may be necessary to achieve anti-thrombin activity shows an illustrative case of late sICH in an AIS patient with in-
comparable to VKA.35-37 As a result, VKAs are the mainstay for traluminal thrombus treated with AC following the detection of
secondary prevention of cardioembolic stroke in patients with paroxysmal AF.
mechanical heart valves with an international normalized ratio
(INR) goal of 3 for most stroke patients since they are consid- Recent developments
ered at high risk for thromboembolism.38 In the largest analysis
of patients with mechanical heart valves presenting with acute The first randomized trial on timing of NOAC anticoagulation
parenchymal ICH, early re-initiation of VKA was associated with was a study that excluded severe strokes or infarcts with ECASS
increased rates of hemorrhagic complications until 13 days af- grade I or II HT (NCT03433235). Patients were randomized to ei-
ter initial ICH and with respect to safety should not be routinely ther a standard dose of edoxaban on day 3 for mild stroke and on
restarted before 14 days; the earliest day of initiation resulted day 6 for moderate stroke or half-dose of edoxaban from symp-
day 6 reserved only for patients at high thromboembolic risk.39 tom onset until day 3 (for mild stroke) or day 6 (for moderate
These timepoints may be seen as the maximum possible delay stroke), and a standard dose of edoxaban thereafter. This was a
to initiate AC, since even AIS patients presenting with PH are small trial that failed to detect any difference in clinical outcomes
believed to have a lower risk of hematoma expansion than pri- or late HT; however, asymptomatic ischemic lesion on MRI were
mary ICH patients. numerically higher in the early initiation group, a finding that the
VKAs may also be the only AC indicated in patients with aor- authors attributed to the low dose of edoxaban used.49 Early Ver-
tic or mitral bioprosthetic valves who experienced ischemic stroke sus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic
under antiplatelet therapy.38 Non-valvular AF complicated with Stroke Patients With Atrial fibrillatioN (ELAN, NCT03148457)
left atrial thrombus may be seen in AIS patients; the role of NO- was recently published.50 ELAN is unique in distinguishing differ-
ACs is not well-established.40 Similarly, cardioembolic stroke ent AIS subgroups depending on infarct size.10 NOAC initiation
from left ventricular thrombus in patients with history of ante- within 2 days from mild or moderate infarct and within 1 week
rior myocardial infarction and reduced ejection fraction might for major infarct carried the same risk for sICH (0.2%) compared
necessitate VKAs for 3 months whereas the efficacy of NOACs with later start. There was no significant difference in recurrent
is uncertain.40-42 stroke or systemic embolism risk, despite lower numerically rates
in the early start group. These results are highly suggestive of the
Non-cardioembolic AC indications safety of early NOAC initiation post-stroke and are hypothesis-
post-stroke generating for future research regarding recurrent embolism
risk reduction.
Screening in patients with acute hemiplegic stroke has shown
an incidence of deep vein thrombosis (DVT) of 50% within 2 weeks Ongoing RCTs
in the absence of heparin prophylaxis; most affect the paretic
lower limb, are asymptomatic and are located below the knee.43 Three ongoing RCTs will further explore the optimal timing for
A recent study showed that 5% of AIS patients treated with EVT AC resumption after AIS: Optimal timing of anticoagulation af-
may develop DVT and 2% may develop pulmonary embolism (PE), ter acute ischemic stroke with atrial fibrillation (OPTIMAS, Eu-
especially in patients with metastatic cancer.44 The mainstay of draCT, 2018003859–38),51 Optimal Delay Time to Initiate Anti-
DVT/PE treatment is AC. Compared with low-molecular weight coagulation after Ischemic Stroke in Atrial Fibrillation (START,
heparin (LMWH) bridging with VKA, NOACs have been shown to NCT03021928),52 and Lixiana Acute Stroke Evaluation Registry
be noninferior for recurrent venous thromboembolism and are (LASER, NCT03494530).53 Only START will include patients with
associated with a lower risk of major bleeding, including intra- HT per investigator’s judgment; LASER will exclude any PH and
cranial bleeding.45 OPTIMAS will exclude PH-2 patients. Patients receiving systemic
Intraluminal thrombus is detected in 1.6%–3.2% of AIS pa- or endovascular reperfusion therapies will not be excluded from
tients on computed tomography angiography, mainly due to all three RCTs. Consequently, information to guide AC initiation
large artery atherosclerotic disease (82%), but also caused by in AIS patients receiving EVT that is complicated with PH is ex-
dissection, hypercoagulability, or cardioembolism.46 Due to a per- pected to remain limited in the near future.

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Vol. 26 / No. 1 / January 2024

A B

Figure 1. A 70-year-old woman, with a history of arterial hypertension and diabetes mellitus, presented with intermittent vertigo and diplopia for 48 hours.
The National Institutes of Health Stroke Scale (NIHSS) on admission was 4 and magnetic resonance imaging revealed multiple acute ischemic lesions on dif-
fusion-weighted imaging (A). Digital subtraction angiography revealed a sub-occlusive intraluminal thrombus of the right vertebral artery in the V4 segment
(B). The left posterior cerebral artery was occluded in the P1 segment but slow flow to the P2 segment was noted through a small posterior communicating
artery. Thrombectomy was undertaken but was unsuccessful to recanalize the right vertebral artery. The cause of intraluminal thrombus was believed to be an
underlying atherosclerotic plaque, since the patient was in sinus rhythm. The patient received clopidogrel and therapeutic dose of low-molecular weight hep-
arin (LMWH) and was discharged 4 days later with NIHSS score of 1. She presented 2 weeks after discharge with right hemianopia and aphasia (NIHSS-score:
10 points). Paroxysmal atrial fibrillation was detected on electrocardiogram. Repeat brain computed tomography revealed an extensive lobar intracranial
hemorrhage of the left occipital lobe (C). LMWH and clopidogrel were halted and the patient had a neurosurgical evacuation of the hematoma with good, but
partial, recovery (NIHSS score of 6 points). She was treated with apixaban 5 mg bid 12 days after surgical evacuation.

Anticoagulation with factor XI inhibitors temic Embolism in People With Irregular and Often Rapid Heart-
beat [Atrial Fibrillation], and at Risk for Stroke [OCEANIC-AF],
Factor XI (FXI) inhibitors (asundexian and milvexian) represent NCT05643573; A multicenter, randomized, placebo-controlled,
the next potential generation of AC.54 In the Program of Anti- double-blind, parallel group and event driven phase 3 study of
coagulation via Inhibition of FXIa by the Oral Compound BAY the oral FXIa inhibitor asundexian [BAY 2433334] at a dose of
2433334-NonCardioembolic Stroke (PACIFIC-STROKE) study, 50 mg od for the secondary prevention of ischemic stroke in adult
there was no increase in the risk of HT or ICH after early inter- patients with an acute non-cardioembolic ischemic stroke [OCE-
vention and inclusion of mild and moderate stroke (NIHSS <16) ANIC-Stroke]; NCT05686070). OCEANIC-AF was stopped early
and in post-intravenous thrombolysis (IVT) and/or EVT partici- due to inferior efficacy of asundexian versus apixaban.57 Another
pants.55 MRI data after study intervention showed similar inci- multicenter, randomized, placebo-controlled, double-blind, par-
dence of HT between milvexian and placebo. Similar results were allel group and event driven phase 3 study of the oral FXIa in-
obtained in the Antithrombotic treatment with factor XIa inhibi- hibitor milvexian (BMS-986177) at a dose of 25 mg bid for the
tor Milvexian to Optimize Management of Acute Thromboem- secondary prevention of ischemic stroke is conducted in adult
bolic events for Secondary Stroke Prevention (AXIOMATIC-SSP) patients with an acute non-cardioembolic ischemic stroke (LI-
trial.56 Asundexian was undergoing two phase 3 RCTs (A Study BREXIA-Stroke; NCT05702034).
to Learn How Well the Study Treatment Asundexian Works and
How Safe it is Compared to Apixaban to Prevent Stroke or Sys-

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 Safouris et al. Anticoagulation After EVT

Anticoagulation before EVT Bridging AC therapy

Pretreatment with therapeutic AC is a contraindication for IVT A post hoc analysis of the Early Recurrence and Cerebral Bleed-
but not for EVT. Major EVT registries have shown that pretreat- ing in Patients With Acute Ischemic Stroke and Atrial Fibrilla-
ment with NOACs is not associated with sICH, but data are con- tion (RAF) and RAF-NOACs studies examined the efficacy and
flicting regarding VKAs. In the Bernese-European Registry for safety of bridging AC therapy. Bridging therapy was defined as
Ischemic Stroke Patients Treated Outside Current Guidelines full-dose LMWH started before or concurrently with VKAs, until
With Neurothrombectomy Devices Using the Solitaire FR With INR reaches therapeutic range, or full-dose LMWH before initi-
the Intention for Thrombectomy (BEYOND-SWIFT), VKAs were ating NOAC treatment. Bridging therapy more than doubled the
associated with an increased risk of sICH and mortality, while the odds of either ischemic or hemorrhagic outcomes and this in-
risk was lower with NOACs.58 In the Spanish NORDICTUS registry, crease was statistically significant.66 These findings were inde-
VKAs, but not NOACs, were an independent predictor of sICH.59 pendently reproduced in the IAC observational study that was
In contrast, the German Stroke Registry-Endovascular Treatment conducted in the United States.20 Other RCTs also confirm that
(GSR-ET) failed to detect an association with AC pretreatment bridging therapy in AF patients without AIS is either deleteri-
and early HT.60 In conclusion, pretreatment with NOACs is con- ous or non-beneficial during the perioperative period.67,68
sistently found safe in observational EVT studies, but more data
may be needed for VKAs, since it remains possible that there Is there any remaining indication for
exists an INR threshold beyond which hemorrhagic risk is in- heparin during or after EVT?
creased. Nevertheless, current international recommendations
do not advocate against EVT in large vessel occlusion patients Periprocedural single dose UFH is still being used during EVT, es-
pretreated with VKAs.11,61 pecially in the context of extra- or intracranial atherosclerotic
disease where stenting may be performed during the emergent
Periprocedural anticoagulation procedure.69,70 UFH was used in more than a third of patients in
the Basilar Artery Occlusion Endovascular Intervention versus
Data from the Multicenter Randomized Clinical Trial of Endovas- Standard Medical Treatment (BEST) trial and its use could have
cular Treatment of Acute Ischemic Stroke (MR CLEAN) Registry been related to the increased risk of sICH associated with EVT
suggested that the use of IV UFH is safe during EVT.62 In a sys- compared to the medical treatment group (Figure 2).71 Intrave-
tematic review, heparin use during EVT increased the odds of nous glycoprotein IIb/IIIa inhibitors may be effective in prevent-
good functional outcome but carried an increased risk for sICH,63 ing intraprocedural re-occlusion even if low doses may be need-
a finding that was similar with the results of a systematic review ed to ensure safety, and clinical practice suggests that emergent
of RCTs comparing aspirin to AC in AIS of cardioembolic origin.64 use of UFH may not be necessary for stent patency but data on
The Multicenter Randomized Clinical Trial of Endovascular Treat- direct comparison with heparin are lacking.72
ment for Acute Ischemic Stroke in the Netherlands (MR CLEAN- A recent observational study compared ultra-early AC, de-
MED) was an RCT that compared the combination of moderate fined as the initiation of UFH or LMWH <24 hours, to early AC
(5,000 IU bolus followed by 1,250 IU/h for 6 h) or low-dose (5,000 defined as the initiation <3 days post-EVT in patients with AF.
IU bolus followed by 500 IU/h for 6 h) UFH with aspirin to aspi- The control group was anticoagulated with VKAs, NOACs, or
rin monotherapy.65 A significant shift towards worse functional LMWH on or after day 4.73 Patients received one of two heparin
outcomes was documented in the interim analysis for moderate- dosing schemes, both without aspirin: a low-dose (generally re-
dose UFH versus no UFH; a nonsignificant shift towards the ferred to as prophylactic dose) and intermediate (initial UFH dose
same direction has also been attested for low-dose UFH. sICH of 500 IU/h or maximum dose over 500 IU/h, or LMWH dose of
occurred more often in patients who received UFH (adjusted 4,000 or 4,250 IU two times per day). Patients receiving hepa-
odds ratio 1.98; 95% confidence interval: 1.14–3.46) and the rin showed significantly better functional outcomes in 90 days
RCT was discontinued due to safety concerns. Certain major lim- without increase of sICH in both ultra-early and early initiation
itations of this RCT need to be acknowledged. IVT pretreatment groups compared to the control group, especially in the context
was not a contraindication for AC, all patients received aspirin of ultra-early initiation which was also associated with a signif-
and many cases of sICH occurred in the subgroup of patients that icant decrease in the risk of asymptomatic ICH. Whether this ap-
had concurrent acute cervical carotid artery revascularization. proach of post-procedural use of intermediate-dose UFH/LMWH
is safe and effective remains to be seen in future studies.

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Vol. 26 / No. 1 / January 2024

A B C

D E F

Figure 2. A 63-year-old man with atrial fibrillation presented with acute left hemianopia and gait disturbance. Emergent magnetic resonance imaging re-
vealed an acute ischemic lesion in the distribution of the right posterior cerebral artery (PCA) (A). Digital subtraction angiography revealed a complete basilar
artery (BA) occlusion (B) that was recanalized with mechanical thrombectomy (C). Distal right PCA was left occluded given the extensive established infarc-
tion of the right occipital lobe (C). The patient was loaded with aspirin (500 mg) and clopidogrel (600 mg) and received a bolus of 5,000 units of unfractionat-
ed heparin and residual BA stenosis was treated with 2 intracranial stents (D). Computed tomography (CT) post-treatment showed extravasated contrast
within the right occipital lobe infarction (E). The patient had abrupt neurological deterioration 20 hours after recanalization. Emergent CT revealed an exten-
sive parenchymal hematoma type 2 originating from the right occipital lobe (F). The patient deceased hours later.

Anticoagulation initiation after EVT cantly higher risk of sICH was documented.78 A similar increase
in sICH has been described in isolated posterior cerebral artery
EVT does not appear to increase the risk of sICH in the Highly Ef- (PCA) EVT although an increase in sICH was not confirmed in an
fective Reperfusion evaluated in Multiple Endovascular Stroke isolated PCA occlusion meta-analysis comparing patients treat-
Trials (HERMES) meta-analysis of RCTs of the anterior circula- ed with EVT versus medical management.79,80 Early HT renders
tion.74 Presumably EVT does not increase overall rates of sICH early NOAC initiation problematic in patients with cardioem-
despite treatment-related hemorrhagic complications, since bolic stroke.
reducing infarct size reduces the risk of spontaneous (non-EVT- There is scarce data on AC initiation in patients with early HT
related) HT. However, in the late-time window MR CLEAN LATE post-EVT. A recent retrospective Japanese study examined 111
trial, the risk of sICH was significantly higher in the EVT group patients that received EVT for anterior circulation AIS. NOACs
(adjusted odds ratio 4.59).75 Numerically higher rates of sICH and were started at a median of 1 day in the no HT group, 3 days in
any ICH were also noted in the ANGEL-ASPECT and Rescue Ja- the HI group (interquartile range [IQR] 2–5 days), and 7 days in
pan LIMIT randomized EVT trials of large ischemic core.76,77 Pos- the PH group (5 patients with PH-1 and 6 patients with PH-2;
terior circulation EVT appears to increase sICH risk. A meta-anal- IQR 7–10 days).81 There were only 2 cases of sICH in the no HT
ysis of RCTs including the recently published positive trials of group and 2 cases of new asymptomatic ICH in AIS patients with
basilar artery occlusion EVT showed that EVT was associated with PH-1 occurring before initiation of NOACs; no cases of new sICH
better outcome and lower risk of death at 3 months, but a signifi- (late HT) following NOAC initiation in both HI and PH groups

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 Safouris et al. Anticoagulation After EVT

were documented. The study is limited by its retrospective char- ing cardioembolic stroke with or without acute reperfusion ther-
acter and its small size, with only 16 patients with HI and 13 apies, focus on early (24–48 first hours) HT. Much less is known
patients with PH, but provides evidence that the risk of late HT for late HT that is also discussed in the current narrative review.
under NOACs is low. In a study on bridging AC after cardioembolic stroke, HT has been
A prospective Chinese study suggests that very early AC initi- reported to occur in a bimodal distribution—an early benign and
ation might be harmful. One hundred twenty-five patients re- a late symptomatic PH-2—suggesting a different pathophysiolo-
quiring AC initiated treatment <5 days after EVT, 66 patients af- gy of late HT.83 Persistent disruption of the BBB appears within
ter 5–14 days and 43 patients 15 days or later after index event. 24 hours after infarction and may last for several weeks,84 but
sICH occurred only in the early initiation group and the differ- early BBB disruption may not predict delayed HT.85 Imaging data
ence was statistically significant, as was the increase in any ICH confirms BBB derangement weeks after stroke.86 Despite much
in the same group.82 Moreover, EVT to AC time was an indepen- research in developing imaging biomarkers for predicting early
dent risk factor of sICH, ICH, and systemic hemorrhage after HT87 and late HT,88,89 we have no reliable data on the prevalence
initiating AC. EVT for internal carotid artery occlusion was also of late intracranial bleeding (in the subacute phase of stroke)
associated with increased ICH risk after AC initiation. Embolic re- and whether AC therapy increases its risk. An elegant study us-
currences were similar in all treatment groups. This study pro- ing transcranial sonography to detect HT and Doppler to detect
vides no data on treatment strategy for patients with HT post- delayed recanalization indicated that time of HT development is
EVT but raises a red flag for initiating AC within the first 4 days associated with time of recanalization in patients with large
post-EVT, especially in the context of internal carotid artery re- vessel occlusion.90 Moreover, HT does not always occur imme-
canalization that could be related to greater infarct volume or diately after recanalization, but at a median delay of 40 hours.
periprocedural use of antithrombotics. A synthesis of available To our knowledge, this interesting observation has not been rep-
data with relevant expert-opinion based recommendations is licated. It is possible that if very late reperfusion occurs, it may
provided in Figure 3 and Table 1 and a simplified illustration of lead to late HT.91 Angiogenesis post-ischemic stroke may pro-
the proposed treatment algorithm is available in Figure 4. mote recovery but can also predispose to HT if it is premature,
due to enhanced vascular permeability of newly formed, im-
Future research mature vessels.92

Most of the research studies that evaluate the incidence and

prognostics factors of HT occurring during the first days follow-

Reference Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 12 Day 14
ESC 20169 TIA Mild AIS Moderate AIS Severe AIS
AHA/ASA 2019 11
All AIS
Guidelines
Moderate AIS and Severe AIS and
ESO 201940 Mild AIS and small infarct size
medium infarct size large infarct size
Moderate
Kimura46 TIA Mild AIS Severe AIS EVT 13%
AIS

Registries TIMING47 All AIS EVT 14%

Nishimoto 54
No HT HI PH EVT 100%
Ma 55
Increased sICH risk All AIS EVT 100%

Figure 3. Day rules proposed for initiating anticoagulation after cardioembolic stroke/TIA and registries including patients post-EVT. Days refer to days after
index event as the minimal delay for each stroke category to initiate anticoagulation. Mild AIS: NIHSS <8; Moderate AIS: NIHSS 8–15; Severe AIS: NIHSS
>15; Small infarct size: Ischemic lesion ≤1.5 cm; Medium infarct size: NIHSS <8 and lesion in a cortical superficial branch of middle cerebral artery (MCA), or
involving the MCA deep branch, or in internal border zone territories, or in a cortical superficial branch of posterior cerebral artery (PCA), or lesion involving
the PCA branch or lesion in a cortical superficial branch of anterior cerebral artery (ACA); large infarct size: anterior circulation: lesion involving complete ter-
ritory of MCA, PCA, or ACA or involving 2 cortical superficial branches of MCA or involving a cortical superficial branch of MCA associated to the MCA deep
branch, or involving more than 1 artery territory (eg, MCA associated to ACA territories); posterior circulation: lesion involving brain stem or cerebellum >1.5
cm. TIA, transient ischemic attack; EVT, endovascular treatment; ESC, European Society of Cardiology; AIS, acute ischemic stroke; AHA/ASA, American Heart
Association and American Stroke Association; ESO, European Stroke Organisation; HT, hemorrhagic transformation; HI, hemorrhagic infarction; PH, parenchy-
mal hemorrhage; NIHSS, National Institutes of Health Stroke Scale.

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Vol. 26 / No. 1 / January 2024

Table 1. Individualized treatment strategy for initiating anticoagulation in acute ischemic stroke patients with atrial fibrillation receiving EVT
Study Treatment strategy
van der Steen et al.65 Avoid unfractionated heparin during EVT
Altavilla et al.66 Do not bridge oral anticoagulation with full dose heparin
Palaiodimou et al.22 Prefer NOACs
Ma et al.82 Starting oral anticoagulation >4 days from symptom onset may reduce intracranial hemorrhage risk
27
Paciaroni et al. Consider earlier initiation of oral anticoagulation in patients with ALESSA* scores 3–4
Nishimoto et al.81 - Starting oral anticoagulation ≤14 days from symptom onset may reduce risk of recurrent ischemic stroke
- Hemorrhagic infarction: initiation <7 days from symptom onset appears safe (earliest time point of initiation: 5 days)
- Parenchymal hemorrhage: initiation ≤14 days from symptom onset appears safe (earliest time point of initiation: 7 days)
EVT, endovascular treatment; NOACs, non-vitamin K antagonist oral anticoagulants.
*ALESSA score (0–4 points): 1 point for patient age 70–79, 2 points for those 80 or older, 1 point for ischemic lesion on neuroimaging with diameter >1.5 cm,
and 1 point for severe atrial enlargement on transthoracic echocardiogram.

stroke, depending on the risk of recurrent embolism, predicted by

the ALESSA score, and the existence of early PH. More research
NOAC initiation
is required to understand and predict late HT, which—in contrast
Unsafe Safe
to early HT—has not received attention in recent years.

Antiplatelet PH

ALESSA 3–4
Funding statement
None
EVT D2 D5 Day 14

Figure 4. Synthesis of available data for initiating anticoagulation (AC) af-

Conflicts of interest
ter endovascular treatment (EVT). Starting non-vitamin K antagonist oral
anticoagulants (NOACs) without bridging is possible at day 2 but may be Apostolos Safouris has received a stipendium from the Hellenic
safer at day 5, even in the context of hemorrhagic infarction. Delaying ini- Neurological Society for training in Interventional Neurology
tiation at 7–14 days for patients with parenchymal hemorrhage may be
safe. Aspirin should be given until NOAC initiation. ALESSA scores 3–4
that is unrelated to the manuscript.
should prompt earlier AC initiation.

Author contribution
Conclusions
Conceptualization: AS, GT (Georgios Tsivgoulis). Study design:
Accumulating data provides valuable information on the bene- AS, GT (Georgios Tsivgoulis). Writing—original draft: AS, KP, LP,
fits and risks of early AC after AIS. The increasing familiarity of PO, GM, OK, GT (Georgios Tsivgoulis). Writing—review & edit-
clinicians with NOACs, which present a more favorable safety ing: AT, TK, SS, SN, AS, TNN, SY, SW, SS, GT (Guillaume Turc).
profile compared to full-dose heparin or VKAs in the subacute Approval of final manuscript: all authors.
phase of AIS, is reflected on recently published observational
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