REVIEW

Systematic Review of Observational Research Studying the

Long-Term use of Antithrombotic Medicines Following
Intracerebral Hemorrhage
Robert W.V. Flynn,1 Thomas M. MacDonald,1 Gordon D. Murray2 & Alexander S.F. Doney1
1 Medicines Monitoring Unit (MEMO), Division of Medical Sciences, University of Dundee, Dundee, Scotland, UK
2 Public Health Sciences Section, Division of Community Health Sciences, University of Edinburgh, Edinburgh, Scotland, UK

Keywords
Anticoagulants; cerebral hemorrhage; platelet
aggregation inhibitors; systematic review.
Correspondence
Alexander Doney, Medicines Monitoring Unit,
Ninewells Hospital and Medical School, Dundee
DD1 9SY, Scotland, UK.
Tel.: +44 1382 633883;
Fax: +44 1382 632682;
E-mail: a.doney@chs.dundee.ac.uk

doi: 10.1111/j.1755-5922.2009.00118.x

Patients with intracerebral hemorrhage frequently have indications for antithrombotic therapy. This represents a therapeutic dilemma as intracerebral
hemorrhage is considered a contraindication to antithrombotic medication.
Previous systematic reviews have revealed no long-term randomised studies
addressing this issue. Our objective was to review observational studies describing the long-term follow-up of patients receiving antithrombotic therapy
following intracerebral hemorrhage. Searches were conducted in MEDLINE
and EMBASE from 1984 to 2008 for any observational studies detailing use of
antithrombotic treatments in patients with intracerebral hemorrhage. Included
studies must have had follow-up extending beyond discharge. The primary
endpoint was recurrent intracerebral hemorrhage. Secondary endpoints were
ischemic events and serious vascular events. 1,301 articles were reviewed: two
epidemiological studies and six case series met the inclusion criteria. These described a total of 46 subjects receiving antiplatelet agents (from one study) and
42 patients receiving oral anticoagulants (from one study and six case-series).
For patients receiving subsequent aspirin there were seven recurrent intracerebral hemorrhages and four subsequent thrombo-occulsive events. Amongst
patents restarting oral anticoagulation there were four recurrent intracerebral bleeds and nine subsequent thrombo-occulsive events. There is a marked
paucity of evidence to guide clinicians when planning the long-term management of patients with intracerebral hemorrhage and cogent indications for antithrombotic therapy. Published guidance addressing this issue is not evidence
based. In the continued absence of randomised studies addressing antithrombotic use following intracerebral hemorrhage, there is a clear requirement for
further high quality observational data on the clinical impact of antithrombotic
therapy in this important patient group.

Introduction
The use of antiplatelet medication is well established as
reducing risk of death, myocardial infarction and occlusive stroke [1]. Similarly anticoagulant medications are
proven as effective in the primary and secondary prevention of venous thromboembolism, myocardial infarction and thromboembolic stroke [2]. However it has also
been shown that use of both antiplatelet and anticoagulant medicines increases rates of intracerebral hemor-

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Cardiovascular Therapeutics 28 (2010) 177184 

rhage [13]. The consensus view is that having an intracerebral hemorrhage infers increased risk of a recurrent
hemorrhagic event amongst surviving patients [4], and
for this reason intracerebral hemorrhage is generally considered a contraindication to the use of these antithrombotic medicines.
A common dilemma in clinical practice arises when
patients present with intracerebral hemorrhage whilst
taking antiplatelet or anticoagulant therapies, or when
patients with a history of intracerebral hemorrhage

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Systematic Review of Antithrombotic Medicine Use Following Intracerebral Hemorrhage

subsequently develop conditions for which such

medicines are indicated [5]. This issue of antithrombotic
use following intracerebral hemorrhage has previously
been addressed in a systematic review of randomised
studies [6]. However this review found only studies of
short-term treatment with most patients randomised
to receive antiplatelet medicines following presumed
ischemic stroke, and with therapy stopped following
diagnosis of intracerebral hemorrhage. For antiplatelet
drugs the relative risk of death was 0.96 (95% CI 0.62
to 1.50) and for recurrent intracranial hemorrhage was
1.02 (95% CI 0.58 to 1.80). These wide confidence
intervals ruled out neither modest harm nor moderate
benefit. No studies were found that addressed the safety
of antithrombotic prescribing following intracerebral
hemorrhage in the longer term.
Observational studies can often provide the only means
of investigating the safety or otherwise of medicines
where patients have both indications and contraindications to therapy, a situation which would make a randomised controlled trial ethically difficult to justify. The
objective of this study therefore was to undertake an
inclusive systematic review of published observational
studies of antithrombotic prescribing following intracerebral hemorrhage where such a prescribing dilemma
exists.

R.W.V. Flynn et al.

Types of Outcome Measure

The primary endpoint was recurrent intracerebral hemorrhage. The secondary endpoints were serious thromboocclusive events (thromboocclusive stroke, myocardial
infarction).

Search Strategy for Identication of Studies

Only papers from 01-Jan-1984 onwards were reviewed
as before this time CT scanning was not widely available
[6]. Searches of English language publications were conducted in both MEDLINE (Ovid) and EMBASE (Ovid).
The search used previously developed strategies combining inclusive terms for intracranial hemorrhage [7],
anticoagulants & antiplatelet medicines [8], and observational studies [9]. A hand search of the bibliographies of
the retrieved articles was conducted to identify further
publications of interest.

Methods of the Review

The abstracts identified in the search were screened to exclude irrelevant papers. The text of retrieved papers was
screened to assess: (i) whether the research question had
been addressed, (ii) methodological quality, (iii) whether
bibliography contained any useful references. Single case
reports were excluded.

Methods
Criteria for Considering Studies for This Review
This review was limited to observational studies with
follow-up extending beyond discharge.

Types of Study
Any observational outcome study that included details of
the antithrombotic treatment of patients with intracerebral hemorrhage.

Types of Participant
Study subjects must have suffered a radiologicallyconfirmed intracerebral hemorrhage. Only studies in
adults were considered.

Types of Intervention
Any use of antiplatelet or anticoagulant medicines following an intracerebral hemorrhage was considered regardless of dosage.

178

Assessment of Methodological Quality

The selection, comparability and outcomes of the studies
were assessed using the scoring system of the NewcastleOttawa Scale (NOS) group for case-control and cohort
studies [10]. The criteria by which the quality of the
studies was assessed were based on the selection (representativeness of exposed cohort, selection of nonexposed
cohort, description of exposure), comparability (controlling for potential confounders) and outcome (assessment
of outcome, duration of follow-up, level of follow-up).
As most of the relevant studies retrieved were case series
for which no standards of quality exist, these were assessed based on the ascertainment of exposure, outcome
and duration of follow-up.

Data Extraction
Data were extracted onto a prespecified form under the following headings: type of intracerebral hemorrhage, duration of follow-up, number of patients
receiving subsequent antithrombotic medicines, type
of antithrombotic medication used, indication for antithrombotic medicines, number of patients suffering

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Cardiovascular Therapeutics 28 (2010) 177184 

R.W.V. Flynn et al.

Systematic Review of Antithrombotic Medicine Use Following Intracerebral Hemorrhage

secondary intracranial hemorrhages and number of patients suffering subsequent thromboocclusive events.

Data Synthesis & Analysis

A summary of the eligible cohort studies is contained in
the text and in tables. A summary of relevant case series
publications has been tabulated.

Results
The databases of both MEDLINE and EMBASE were last
searched on 26 December 2008. In total the database and
hand search of reference lists resulted in 1,301 abstracts
being screened with the full text of 366 papers being retrieved (Figure 1). Abstracts were mostly excluded because they did not address the principal research question
or because they had an inappropriate population. There
were eight qualifying studies (two epidemiological studies
and six case series) with sufficient duration of follow-up.

Epidemiological Studies
Two studies were found that contained adequate numbers of patients together with a meaningful control group
(Table 1) [11,12]. The study by Viswanathan et al. addressed only the issue of antiplatelet use postintracerebral hemorrhage with patients receiving subsequent anticoagulants excluded [11]. This study achieved a 7 star
rating (out of a possible 8) for the NOS criteria. Two hundred and seven survivors of intracerebral hemorrhage
were followed up for a median of 19.5 months of which
46 (22%) subsequently received antiplatelet medication.
There were a total of 39 recurrent intracerebral hemorrhages, of which 7 were amongst antiplatelet users. There
were 11 subsequent ischemic cardiovascular events 4 of
which were in antiplatelet receiving patients. The risk for
recurrent lobar intracerebral hemorrhage in antiplatelet
users was 1.2 (95% CI 0.4 to 3.3) and for deep intracerebral hemorrhage was 1.2 (95% CI 0.1 to 14.3). The risk of
subsequent ischemic events was also not significant (HR
1.2; 95% CI 0.34.8).
The study by Claassen et al. addressed the continuation
of anticoagulation in patients following warfarin associated intracerebral hemorrhage [12]. This study achieved
a 3 star rating according to the NOS criteria. Forty eight
patients with ICH survived to discharge and were followed up for a median of 36 months. Twenty three of
these were restarted on oral anticoagulation. Of those
who restarted warfarin there were three subsequent
intracerebral hemorrhages (2 traumatic, 1 nontraumatic), 2 subsequent ischemic strokes and 4 subsequent

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Cardiovascular Therapeutics 28 (2010) 177184 

Figure 1 Systematic review owchart showing number of papers considered.

myocardial infarctions. Of those who were not restarted

on warfarin there were no subsequent intracranial hemorrhages, 5 ischemic strokes, 6 myocardial infarctions
and 2 nonstroke thromboembolisms. The low number of
events during follow-up meant that a meaningful multivariate analysis adjusting for potential confounders could
not be done and relative risk estimates for the separate
endpoints of thromboembolic events and secondary intracerebral hemorrhage were not calculated. The unadjusted risk for the combined endpoint of thromboembolic
events and recurrent intracerebral hemorrhage was 1.4
(95% CI 0.44.9). Although there was a high level of
completeness, all four of the original 52 patients lost to
follow-up came from the nonrestarted group, a fact that

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Systematic Review of Antithrombotic Medicine Use Following Intracerebral Hemorrhage

R.W.V. Flynn et al.

Table 1 Epidemiological studies with long-term follow-up of patients with/without antithrombotic therapy following intracerebral hemorrhage

Author, year

n patients

Age

Viswanathan et al., 2006 [11]

Patients Rx APs
46
72.1

Patients Rx oAC
23
70.8

Subsequent
intracerebral
hemorrhages

Subsequent
T/O events

Sex (M:F)

AT indication

114:93

23 IHD, 7 AF,
7 PHV, 5 IS/TIA,
4 unknown

median 19.5 months

n/s

n/s

32

9 AF, 10 PHV, 3 VT,

1 other

mean 49.8 months

14 AF, 2 PHV, 7 VT,

2 other

mean 36.1 months

13

Patients not receiving APs

161
n/s
n/s
Claassen et al., 2008 [12]

Duration of
follow-up

13:10

Patients not receiving oAC

25
75.8
14:11

n/s not statebaseline characteristics of exposed and unexposed cohorts were not described
AT, antithrombotic; T/O thromboocclusive; Rx, prescribed; AP, antiplatelet; oAC, oral anticoagulation; IHD, ischemic heart disease; AF, atrial brillation;
PHV, prosthetic heart valve; IS, ischemic stroke; TIA, transient ischemic attack; VT, venous thromboembolism.

could have an important effect on the conclusions if all

suffered the same outcome.

Case Series
Case series were small in scale, consisted of patients
observed in clinical practice and addressed the issue
of anticoagulant medicines following hospitalisation for
intracerebral hemorrhage. Whilst there were no meaningful comparators and potential confounders were not
controlled for, cases were well defined (radiologicallyconfirmed), had their drug exposure adequately described and had high level of follow-up. Some of these
studies consisted of series of consecutive cases which
could be considered representative of the patient popu-

lation, although this distinction was not always clear. Six

of these case series addressed the principal issue of the
use of antithrombotic medicines postintracerebral bleed
[1320], and these are summarised in Table 2. In total
these studies describe the follow-up of 20 patients with
intracerebral hemorrhage who received anticoagulation
of durations of 6 months or more. Amongst these patients
there were 2 subsequent intracerebral hemorrhages and
3 subsequent major thromboocclusive events.

Excluded Studies
Thirteen other studies addressed the use of both oral
and parenteral anticoagulants following different types
of intracranial hemorrhage, however the follow-up times

Table 2 Case series with long-term follow-up

Author, year
Butler & Tait, 1998 [1315]
Nakagawa, 1995 [16]
Nagano, 1991 [17]
Lau, 1991 [18]
Babikian et al., 1988 [19]
Punthakee et al., 2002 [20]

Total
patients
in study

ICH
patients
Rx AT

35
4
2
4
6
20

5
1
2
2
3
7

Age
4470
11
17, 60
4065
3577
4682

Sex
(M:F)
NS
1:0
2:0
1:3
2:1
3:8

AT indication
PHV
PHV
PHV
PHV
PHV
5 PHV, 2 PE, 1MI,
1PVD, 1
arrythmias, 1
unstable angina

Duration of
follow-up

AT
type

Subsequent
hemorrhagic
strokes

T/O
events

23 months
36 month
6 months min
Up to 3 years
6 months
2.8 years mean

oAC
oAC
oAC
oAC
oAC
oAC

0
0
1
0
0
0

3
0
0
0
0
???

Deaths not
related to
AT therapy
1

1
1

Rx, prescribed; NS, not stated; ICH, intracerebral hemorrhage; AT, antithrombotic; PHV, prosthetic heart valve; PE, pulmonary embolism; MI, myocardial
infarction; PVD, peripheral vascular disease; oAC, oral anticoagulation.

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Systematic Review of Antithrombotic Medicine Use Following Intracerebral Hemorrhage

were short (i.e., followed-up to discharge or up to

28 days) or had no statement of the duration of followup [2135]. Other studies predated the study period [36],
had index events, exposures or outcomes that were not
clearly defined [3740], considered only subarachnoid
hemorrhage [41] or were not in English [42].

Discussion
We have conducted a systematic review of published English language observational studies that addressed the
issue of patients with intracerebral hemorrhage and subsequent antithrombotic medication. Previous reviews of
randomised control trials in this area revealed only a few
studies that only addressed the short-term use of antithrombotic drugs in patients in the acute setting only
and therefore provide little evidence to guide clinicians
when faced with the dilemma of antithrombotic use in
the longer-term management of patients with intracerebral hemorrhage [6]. This lack of evidence from randomised controlled trials probably reflects the ethical
challenges of prescribing subjects a medication to which
they have an apparent contraindication, and the practical issue of recruiting patients with a disabling condition
[43]. Our review has therefore concentrated on observational studies and has revealed there is also a marked
paucity of observational data on which to assess the risks
and benefits attributable to antithrombotic medicines following intracerebral hemorrhage. The available literature
describing the long-term follow-up of such patients consists of 8 publications including a total of only 46 patients
receiving aspirin and 42 patients receiving oral anticoagulation.

Antiplatelet Use
In the case of antiplatelet medicines the current available
evidence we found comes from a single observational
study by Viswanathan et al. [11] The risk estimates associated with postintracerebral hemorrhage antiplatelet
use in this small but high quality study had large confidence interval limits. The authors concluded that antiplatelet use was not associated with a large increased
risk of recurrent intracerebral hemorrhage. Some commentators have taken a more cautious interpretation of
the results, suggesting that antiplatelet medicines should
only be used following intracerebral hemorrhage in high
risk patients and that further data is required [44,45].
Others however take the view that this study shows there
is no increased risk with antiplatelet medicines following
intracerebral hemorrhage and even seem anxious at the
low numbers of patients receiving them [46].

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Cardiovascular Therapeutics 28 (2010) 177184 

Oral Anticoagulants
In the case of anticoagulant drug use following intracerebral hemorrhage the published evidence comes from
1 epidemiological study and 6 case series and consists of
42 patients followed-up for 6 months or more. Amongst
these there were 4 recurrent intracerebral bleeds and
9 subsequent thrombocculsive events. Again this represents insufficient evidence to judge the safety of anticoagulant use following intracerebral hemorrhage.
In spite this paucity of evidence there is a variety of
opinion and guidance available to prescribers faced with
this therapeutic dilemma. As in the case of antiplatelet
agents these views frequently display a dichotomy of
opinion [4,43,47]. Treatment guidelines typically make
little mention of whether antithrombotic medicines when
indicated can or should be continued following an intracerebral hemorrhage [48]. Where guidance does exist it
is based on expert opinion, as is common with such
guidelines [49]. Balancing the competing risks of recurrent intracerebral hemorrhage and subsequent ischemia,
as has been suggested [50], is impossible as our review
has shown the risk of recurrent intracerebral bleeding
whilst on oral anticoagulation is not known.
The occurrence of this therapeutic dilemma, already
becoming more frequent, can be expected to increase
further still [51]. Established risk factors for intracerebral hemorrhage are increasing age, hypertension and
hypocholesterolemia, with male sex, high alcohol intake and ethnicity also implicated [52,53]. Many of these
factors, in particular age and, hypertension, are shared
with ischemic disease for which antithrombotic drugs are
commonly indicated [54]. This implies that a substantial
proportion of patients presenting with intracerebral hemorrhage will also be at risk of ischemic events from which
protection would normally be indicated. In addition the
use of anticoagulant therapy for prophylaxis in patients
with mechanical prosthetic heart valves and atrial fibrillation has markedly increased in recent years.
This systematic review used an inclusive and comprehensive search strategy and we are confident that
we have collected all published English language observational studies addressing the question of antithrombotic use following intracerebral hemorrhage. The review has also encompassed case series and case reports
which, in the absence of more robust evidence, have
been acknowledged as being useful in hypothesis generation [55]. There are however well known problems with
such case reports. They are anecdotal in nature, and cases
may be cherry picked and therefore unrepresentative
of the population of interest. Additionally their typically
low numbers and lack of comparison group means that
they cannot be used to test for valid statistical associations

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Systematic Review of Antithrombotic Medicine Use Following Intracerebral Hemorrhage

[55]. It is acknowledged that they represent the lowest

level of clinical evidence [56]. Even if sufficient observational studies had been found there would be concerns
with issues of confounding and bias, particularly confounding by indication. In such nonrandomised studies,
patients perceived as either being at low risk of recurrent intracerebral hemorrhage or at high risk of ischemic
events may be more likely to be prescribed antithrombotic medicines. This could lead to an underestimate of
the risk of recurrent intracerebral hemorrhage and overestimate of the risk of subsequent ischemic events in
those receiving treatment. Attempting to control for such
biases will be a major challenge for future studies.

Conclusion
Patients with intracerebral hemorrhage frequently have
indications for antithrombotic therapy; however such
medicines are commonly perceived as contraindicated
in this context. In addition to the lack of randomised
controlled trial data addressing this issue, our review
has revealed there is also a marked paucity of observational data on which to judge the safety of
anticoagulant and antiplatelet medicines following intracerebral hemorrhage. As it is unlikely that randomised
controlled trials will be performed in this area in the near
future, the need for more high quality observational data
in this area is crucial [50,57]. Clearly, however, if these
studies indicate no harm, the question of whether patients with intracerebral hemorrhage should receive the
well established benefits of antithrombotic medications
will ultimately require testing in a formal randomised
study.

Acknowledgments
Robert Flynn is funded on an unrestricted grant by Chief
Scientist Office, Scottish Executive Health Department
(Fellowship grant CZF/1/41). All authors contributed to
the securing of the funding and the concept of this review. In addition, each authors contributions were as follows: RF Collection & review of reference materials, drafting of the manuscript, interpretation of findings, revision
of article. TM Interpretation of findings and critical revision of manuscript. GM Critical revision of manuscript.
AD Assisted with review of reference material, drafting article, interpretation of findings, critical revision of
article.

Conict of Interest
None.
182

R.W.V. Flynn et al.

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