Anticoagulation Resumption After Intracerebral Hemorrhage
Current Atherosclerosis Reports
Anticoagulation Resumption After Intracerebral Hemorrhage
Yan-guang Li 0 1 2 3
Gregory Y. H. Lip 0 1 2 3
0 Department of Cardiology, Chinese PLA Medical School , Beijing , China
1 Institute of Cardiovascular Sciences, University of Birmingham , Birmingham, England , UK
2 Gregory Y. H. Lip
3 Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University , Aalborg , Denmark
Purpose of review Decision-making on resuming oral anticoagulant (OAC) after intracerebral hemorrhage (ICH) evokes significant debate among clinicians. Such patients have been excluded from randomized clinical trials. This review article provides a comprehensive summary of the evidence on anticoagulation resumption after ICH. Recent findings OAC resumption does not increase the risk of recurrent ICH and can also reduce the risk of all-cause mortality. OAC cessation exposes patients to a significantly higher risk of thromboembolism, which could be reduced by resumption. The optimal timing of anticoagulation resumption after ICH is still unknown. Both early (< 2 weeks) and late (> 4 weeks) resumption should be reached only after very careful assessment of risks for ICH recurrence and thromboembolism. The introduction of new oral anticoagulants and other interventions, such as left atrial appendage closure, has provided some patients with more alternatives. Summary Given the lack of high-quality evidence to guide clinical decision-making, clinicians must carefully balance the risks of thromboembolism and recurrent ICH in individual patients. We propose a management approach which would facilitate the decision-making process on whether anticoagulation is appropriate, as well as when and how to restart anticoagulation after ICH.
Intracerebral hemorrhage (ICH) is associated with a high risk of
mortality and stroke, as well as recurrent ICH [
]. Of note, ICH
is also the most devastating adverse event in patients receiving
oral anticoagulants (OAC) [
]. Among patients on
anticoagulation, the annual incidence of ICH varies between
0.6 and 1.0% [
]. Indeed, anticoagulation-related ICH is more
severe and associated with more extensive hemorrhage and
higher mortality rate, compared with spontaneous ICH [
Anticoagulation is supported by Class I guidelines for
patients with atrial fibrillation (AF) and high risk of ischemic
stroke (IS) and systemic embolism (SE), mechanical
prosthetic valves, or those at high risk of deep venous thrombosis
(DVT) and pulmonary embolism (PE). Decision-making on
resuming anticoagulation after ICH evokes significant debate
among clinicians. Such patients have been excluded from
randomized clinical trials of stroke prevention in AF. As with
decision-making with anticoagulation therapy in any patient,
carefully balancing the risks of thromboembolism and
bleeding, especially the risk of recurrent ICH, is the primary
concern when making this decision in patients who have
experienced a recent ICH [
]. The lack of high-quality evidence,
however, makes the decision-making challenging for
clinicians and quite variable in practice [
At a simplistic level, we propose three steps to make such a
decision (Fig. 1): first, evaluate the individual’s risk of
thromboembolism and hemorrhage [
]; second, choose the optimal
a n t i c oa g u l a n t a n d a p p r o p r i a t e t i m i n g t o r e i n i t i a t e
]; and third, reduce the risk of recurrent
hemorrhage through controlling modifiable risk factors, such
as uncontrolled hypertension, anemia, renal dysfunction,
diabetes, and heart failure (HF) [
Evaluate the risk of TE
Mechanical valve DVT/P E
Evaluate the risk of recurrent ICH
Assess bleeding risk eg. HAS-BLED score No-OAC OAC
Timing of resumption
Early resumption (2 weeks) for high TE risk patients CT guided
Late resumption (4 weeks) for high ICH risk patients
Address modifiable bleeding
risk factors* at every patient contact ;
Schedule high bleeding risk patients** for more regular review and follow-up
labile international normalized ratio (INR), elderly, drugs/alcohol
concomitantly; ICH, intracerebral hemorrhage; OAC, oral
anticoagulant; PE = pulmonary embolism; TE = thromboembolism. A
single asterisk indicates modifiable bleeding risk factors that include
uncontrolled blood pressure, labile INRs (if on warfarin), concomitant
aspirin/NSAID use, alcohol excess. Double asterisks indicate high risk
patients can be defined as HAS-BLED score ≥ 3
Nevertheless, this approach towards decision-making
could also be difficult in clinical practice, because of the lack
of risk evaluation tools for complicated clinical conditions, the
insufficient evidence from the randomized clinical trials, and
the existence of shared risk factors for both thromboembolism
This review article aims to provide an up-to-date overview
regarding the pros and cons of restarting anticoagulation after
ICH. We also propose a management approach which would
f a c i l it a t e t h e de c i s io n - m a k i n g pr o c e s s o n w h e t h e r
anticoagulation is appropriate, as well as when and how to
restart anticoagulation after ICH.
The Risks of Recurrent ICH,
Thromboembolism, and Mortality
Current guidelines recommended that the decision on
restarting OAC should be taken by a multidisciplinary team
of stroke physicians, neurologists, cardiologists,
neuroradiologists, and neurosurgeons [
]. This decision mainly depends
on an individual’s risk of recurrent ICH versus risk of
thromboembolism. The relative risk of mortality is also a
Risk of Recurrent ICH After OAC Resumption
In non-anticoagulated patients with a history of ICH, the
1year risk of recurrent ICH ranges from 0 to 8.6% [
patients resuming OAC, this number ranges from 2.5 to 8%
]. For example, in one multicenter study (n = 267),
warfarin resumption was associated with an annual ICH recurrence
rate of 2.56% [
]. Whether OAC resumption per se truly
increases the risk of recurrent ICH is still debatable, given
the many associated comorbidities related to ICH recurrence.
The majority of studies demonstrate that OAC resumption
did not increase the risk of recurrent ICH [
14, 15 , 16–19
(see Table 1). In one retrospective cohort study (n = 160),
recurrent ICH occurred with higher frequency after OAC
resumption, but this was statistically nonsignificant compared
with patients who did not resume OAC (7.6 vs. 3.7%, p =
0.48) . Also, OAC resumption did not increase the risk
of ICH in a Danish nationwide cohort study [
]. In another
large observational cohort (n = 2415), warfarin resumption
after incident ICH was associated with similar risk of recurrent
ICH to non-resumption of warfarin [
]. These results were
confirmed by a recent systematic review and meta-analysis,
including eight studies and 5306 ICH patients, in which
reinstatement of OAC had a similar risk of recurrent ICH to
nonOAC restarters [
Nevertheless, some contradictory results exist. For
example, a retrospective study (n = 428) showed that OAC
restarting increased the risk of major bleeding (5.5 vs. 3.1
per 100 patient-years, p = 0.024), and recurrent ICH was
observed only in patients with OAC use [
]. Different study
designs and selection biases may explain the contradictory
results. In many studies, only the patients with “less severe”
ICH, that is ICH with smaller volume of hemorrhage and mild
functional changes, could have received OAC resumption,
hence leading to a lower recurrent ICH risk [
For clinical practice, different patient profiles may lead to a
varying risk of ICH recurrence, and therefore, individualized
evaluation is critical [
]. We suggest that risk factors for
recurrent ICH should be considered before deciding OAC
resumption [24, 25]. Currently, there are some
wellidentified risk factors for recurrent ICH (Table 2). For
example, the location of ICH is a significant risk factor. Lobar
hemorrhage has a higher ICH recurrent rate compared with
hemorrhage in a deep cortical location (22 vs. 4% for
cumulative 2-year rate, p = 0.007) .
In postoperative (neurosurgery for ICH) patients with
spontaneous ICH, diabetes mellitus (odds ratio [OR], 2.72;
95% CI, 1.01–7.35) has been related to recurrent ICH .
In other studies, patients with hepatic C virus infection had
increased risk of ICH (HR, 1.60; 95% CI, 1.24–2.06) , as
has severe hypertension (systolic blood pressure ≥ 160 mmHg
or diastolic blood pressure ≥ 110 mmHg), which was
associated with a sixfold increased risk of ICH . In addition,
patients with recent intracranial microbleeds had substantial
risk of incident ICH . Leukoaraiosis was also related with
high risk of significant ICH (relative risk [RR], 1.65; 95% CI,
1.26–2.16) . For these two risk factors, brain imaging
evidence provided by computed tomography (CT) or
magnetic resonance imaging (MRI) is required.
Ethnicity is also a major risk factor for ICH. Asian
populations had higher risk of ICH in the major trials of the
nonVKA oral anticoagulants (NOACs) [32–35]. For example, in
the R E-LY (Randomized Evaluation of Long-term
Anticoagulant Therapy) trial, Asian populations had higher
risk of ICH in both of the warfarin (1.10 vs. 0.71%/year)
and dabigatran (0.45 vs. 0.29%/year) arms compared with
non-Asian populations . Further, the East Asian
population had over twofold risk of ICH compared with non-East
Asian ones in the ARISTOTLE (Apixaban for Reduction in
Stroke and Other Thromboembolic Events in Atrial
Fibrillation) trial (warfarin, 1.88 vs. 0.67%/year; apixaban,
0.67 vs. 0.30%/year) .
Modifiable bleeding risk factors should be addressed at
every opportunity: for example, uncontrolled blood pressure
and concomitant use of aspirin or non-steroidal
anti-inflammatory drugs. An approach based on modifiable bleeding risk
factors alone, however, is an inferior strategy to using a formal
bleeding risk score to assess bleeding risk [
9, 10, 36
Several bleeding risk scores have been proposed (Tables 3
and 4), including the mOBRI score (modified Outpatient
Bleeding Risk Index) , the HEMORR2HAGES score
(Hepatic or Renal Disease, Ethanol Abuse, Malignancy,
Older Age, Reduced Platelet Count or Function,
ReBleeding Risk, Hypertension, Anemia, Genetic Factors,
Excessive Fall Risk, Stroke) , the Shireman score ,
the HAS-BLED score (Hypertension, Abnormal Renal/Liver
Function, Stroke, Bleeding History or Predisposition, Labile
INR, Elderly, Drugs/Alcohol Concomitantly) , the ATRIA
score (Anticoagulation and Risk Factors In Atrial Fibrillation)
, and the ORBIT score (national Outcomes Registry for
Better Informed Treatment of Atrial Fibrillation) . Of the
various bleeding risk scores, the HAS-BLED score has been
validated to predict ICH and recurrent ICH after first
spontaneous ICH [
10, 47, 48
]. For example, in patients with
spontaneous ICH, the risk of ICH recurrence increased with the
HAS-BLED score, ranging from 1.37% per patient-year for
a score of 1 to 2.90% per patient-year for a score of 4 .
Although some patients have significant risk factors or a
high bleeding risk score, these need not be considered
absolute contraindications. Indeed, a high bleeding risk score
should be used to identify the patients at risk for more careful
review and early follow-up after OAC resumption, and not
used as an excuse to withhold OAC , because during
OAC cessation the patients face a higher risk of
thromboembolism, which can increase mortality .
Risk of Thromboembolism During OAC Cessation
OAC resumption is important for the patients at high risk of
thromboembolism, such as those with prosthetic mechanical
valve, high risk of PE, and AF patients with a high
CHA2DS2VASc score (congestive HF, hypertension, age ≥ 75 years,
type 2 diabetes, previous stroke/TIA/thromboembolism,
vascular disease, age 65~74 years, and gender category), i.e.,
CHA2DS2-VASc score ≥ 4. In a recent systematic review
and meta-analysis of restarting OAC after ICH, AF is the most
common reason for anticoagulation (34.7–77.8%), followed
by prosthetic heart valve (2.6–27.8%), venous
thromboembolism (7.9–20.8%), and previous IS (3.7–71.8%) [
]. In other
studies, the most common reason for OAC resumption after
ICH was mechanical heart valve (39–68%) [
Undoubtedly, the prolonged cessation of OAC after ICH
would expose these high-risk patients to a greater risk of
For example, the risk of major thromboembolism among
patients (n = 13,000) with prosthetic heart valves and not on
OAC was 4.0 per 100 patient-years (95% CI, 2.9–5.2) .
Mitral valve prosthesis is associated with a fivefold higher
incidence of valve thrombosis and 1.5 times greater incidence
of thromboembolism . The combination of double
mechanical prosthesis was related to an even higher risk of
thromboembolism (91%) [
]. Also, the risk of DVT was 2
to 15% in patients with recent ICH . PE occurs in 1 to 5%
of recent ICH patients in which anticoagulation was stopped
]. Given the high risk of recurrent venous
thromboembolism, these patients may require antithrombotic therapy
despite the risk of recurrent ICH.
OAC resumption can reduce the risk of thromboembolism.
For example, a retrospective study demonstrated that OAC in
AF patients after ICH was associated with a significantly
reduced incidence of thromboembolism (RR, 0.19; 95% CI,
]. In a nationwide cohort (n = 2415), warfarin
resumption had a lower rate of IS and SE in AF patients with
hemorrhagic stroke (HR, 0.49; 95% CI, 0.24–1.02) [
]. In a
Danish cohort (n = 1725), the patients with OAC resumption
were associated with 41 to 54% lower risk of IS/SE and
allcause mortality, compared with no OAC treatment [
These results were also confirmed in the Danish nationwide
registries (n = 6369) (HR, 0.58; 95% CI, 0.35–0.97) [
another Danish study (HR, 0.55; 95%, 0.39–0.78) [
] and in a
German cohort (5.2 vs. 15% per 100 patient-years, p < 0.001)
]. In a recent meta-analysis about OAC resumption after
ICH, reinitiation of OAC resulted in a significantly lower risk
of thromboembolic complications (HR, 0.34; 95% CI, 0.25–
]. Also, the MUCH-Italy study (Multicentre Study on
Cerebral Hemorrhage in Italy) showed an 81% reduced risk of
thromboembolism among patients restarted OAC after ICH
Despite the high risk of thromboembolism and the
efficiency of anticoagulation, a large proportion of ICH survivors
often do not resume OAC [
1 , 15 , 54, 55
]. Although some
prior studies suggest that OAC could be discontinued safely
for a certain period without significant high risk of
thromboembolism, the duration of this period is less certain . For
example, in the REVERSE-AD study (Reversal Effects of
Idarucizumab on Active Dabigatran), the majority of the
thrombotic events occurred in patients who had not resumed
OAC in the first 30 days after ICH . Thus, although
immediate OAC resumption is not appropriate for most patients,
the duration of withholding OAC should be carefully
conside r e d a n d b a l a n c e d a g a i n s t t h e r i s k o f r e c u r r e n t
There are some well-identified risk factors for
thromboembolism (see Table 2), and several risk scoring systems have
been proposed to evaluate the individual’s risk of
thromboembolism, such as the CHADS2  and CHA2DS2-VASc
scores in AF , and the modified Wells score  and the
revised Geneva score in venous thromboembolism 
(Table 4). Identifying these risk factors and risk score would
be useful to predict the individuals’ risk of thromboembolism.
OAC Resumption and Risk of Mortality
The 1-year risk of mortality in patients with ICH who restarted
OAC ranges from 2.5 to 48% (Table 1). Previous studies
demonstrated that OAC resumption after ICH had significantly
lower risk of death [
1 , 16
]. In a large Danish observational
study, warfarin resumption reduced the rate of mortality in
patients with hemorrhagic stroke (Table 1) [17 ]. More
recently, the MUCH study showed a reduced mortality rate in
patients with warfarin resumption compared with those not on
]. While OAC resumption in patients with lobar ICH
is associated with higher risk of recurrent ICH, it is also
associated with decreased mortality (HR, 0.29; 95% CI, 0.17–
Timing of Restarting OAC
In patients who require OAC after the acute period of ICH, it
is important to choose the right timing for restarting OAC. The
opinion about the timing of reinitiating OAC (warfarin) ranges
from 3 days to 30 weeks . In a Japanese survey, for
example, 28% patients restarted OAC within the first week, 25%
during the second week, 28% between 3 or 4 weeks, and 18%
after 4 weeks .
In the Danish nationwide cohort (n = 1725), OAC was
restarted at 2–10 weeks after ICH [
]. Other evidence
supports that OAC can be restarted 4–8 weeks after ICH if the
cause of ICH has been treated . Also, restarting OAC at
4 weeks after ICH was associated with 42 to 59% lower risk of
recurrent ICH [
]. In a multicenter retrospective study in
Germany (n = 719), anticoagulation was restarted at median of
31 days, and these patients had fewer ischemic complications
(5.2 vs. 15.0%, p < 0.001), decreased risk of unfavorable
functional outcome (RR, 0.55; 95% CI, 0.39–0.78), and similar
hemorrhagic complications (8.1 vs. 6.6%, p = 0.48),
compared with no OAC resumption [
]. Another study also
demonstrated that OAC resumption at 2 weeks after ICH seemed
reasonable, resulting in less clinical events including
thromboembolism event [
Although heparin or OAC may probably be safe to be
restarted after day 7 post-ICH, without increasing the risk of
ICH , any early OAC resumption (<2 weeks) should be
cautiously considered. An observational study demonstrated
that early OAC resumption (<2 weeks) could not improve the
composite outcome (i.e., thromboembolic events, major
bleeding events, and all-cause mortality), particularly because
of an increased risk of major bleeding events [
]. Given these
risks, some researchers have suggested that OAC should be
avoided in the first 2 weeks after OAC-associated
parenchymal ICH and resumption at 4 weeks if the cause of ICH has
been amended or in patients with small ICH and high
thromboembolic risk .
Hence, the timing of OAC restarting depends on individual
clinical condition (i.e., the risks of thromboembolism and
likelihood of recurrent ICH). For example, in patients with
brainstem or cerebellar ICH, the timing should be delayed at
least 8–10 weeks after the event . On the other hand, in
patients with prosthetic mechanical valves, who have a (very)
high risk of thromboembolism, OAC is suggested to be
resumed at 2 weeks after the onset of ICH or sooner if the
hemorrhage burden is small and causative mechanism treated
When considering the timing of restarting anticoagulation,
a brain CT scan and MRI can help to confirm the resolution of
ICH . Restarting OAC without the confirmation of ICH
resolution has been related to increased composite outcome
(i.e., thromboembolic events, major bleeding events, and
allcause mortality) in a retrospective study (RR, 4.40; 95% CI,
]. Nevertheless, selection bias such that
subjects with less severe ICH often restart OAC earlier than
severe ones, may have led to these findings of better outcomes.
The Choice of Anticoagulant
Currently, we have a number of anticoagulants that are
approved for use for atrial fibrillation and PE/DVT. The vitamin
K antagonists (VKAs) are widely used in patients with AF,
mechanical/prosthesis heart valve, and DVT. In patients with
prosthetic mechanical valves, the VKAs are the only choice
for anticoagulation . For AF patients, VKAs have been
associated with a 64% reduced risk of stroke and 26%
reduction in all-cause mortality, compared to control or placebo;
however, VKAs use is also associated with a higher risk of
With the introduction of NOACs, which are associated
with a significantly lower risk of ICH, the risk of
anticoagulation-related ICH is perhaps decreasing compared
to the VKA era . The NOACs could be an optimal choice
when considering anticoagulation resumption in patients with
AF and incident ICH. Also, NOAC-related ICH seems to be
less severe than that of warfarin, with smaller hematoma
volumes, less hematoma expansion, and lower risk of poor
functional outcome or death [
The availability of reversal agents for the NOACs also is a
consideration when using these drugs, given the possibility of
rapid anticoagulation reversal in patients with incident ICH.
However, the evidence of NOACs in patients with AF and
recent ICH remains limited. Given the significantly lower risk
of ICH in AF patients , the role of NOACs in these
patients could be promising. In patients at high risk of DVT and
PE, NOACs may also be an alternative to warfarin [
Heparin is also widely used as a temporary parenteral
anticoagulant. One previous study demonstrated that low-dose
heparin treatment after 48 h of onset in ICH patients was not
associated with an increased hematoma growth and should be
used for DVT and PE prophylaxis [
Reducing the Risk of Recurrent ICH After
After restarting OAC, the risk of ICH recurrence can be
reduced through controlling those modifiable bleeding risk
factors (Table 2) [
]. In patients in whom OAC resumption
is not an option, left atrial appendage occlusion in patients
with AF and the intra-venous filter in patients with DVT
and PE are reasonable alternatives to reduce
thromboembolic risk [
In patients treated with warfarin, well-controlled
international normalized range (INR) was related to less major
bleeding and thromboembolism compared with those without OAC
(p < 0.01, respectively) [
]. Thus, in patients with
mechanical prosthetic valves, for which only warfarin could be used,
time in therapeutic range (ideally > 70%) is important. A
lower target INR should not be encouraged, which is related to
higher risk of thromboembolism in comparison to the
guideline-recommended INR ranges [
Given the observational nature of the studies regarding OAC
resumption after ICH, there is uncertainty regarding
resumption of OAC therapy and its timing. The limited high-quality
evidence regarding this issue leads to limited evidence-based
guidelines and inconsistency in clinical practice. There are
randomized clinical trials ongoing, which may provide more
information in the future [
]. For example, the APACHE-AF
(Apixaban versus Antiplatelet drugs or no antithrombotic
drugs after anticoagulation-associated intraCerebral
HaEmorrhage in patient with Atrial Fibrillation) trial is a
phase II, multicenter, randomized clinical trial, aiming to
evaluate the risk of IS and recurrent ICH for patients restarted with
]. This plans to include 100 AF patients
with a history of recent ICH randomly assigned in a 1:1 ratio
to apixaban or control [
]. The SoSTART (Start or Stop
Anticoagulants Randomised Trial) trial is a multicenter,
randomized, open, interventional trial, aiming to recruit 800
participants. This trial aims to test whether restarting full
treatment dose OAC would result in a beneficial net reduction of
all serious vascular events compared with not starting OAC
Compliance with Ethical Standards
Conflict of Interest Yan-guang Li and Gregory Y.H. Lip declare no
conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
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