Thrombosis Research 191 (2020) 1–8

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Thrombosis Research
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Full Length Article

Incidence and prognostic factors for recurrence of intracerebral hemorrhage T

in patients with and without atrial fibrillation: A cohort study
⁎
Thure Filskov Overvada,b, , Søren Due Andersena,c, Torben Bjerregaard Larsena,d,
Gregory Y.H. Lipd,e, Mette Søgaarda,d, Flemming Skjøtha,f, Peter Brønnum Nielsena,d
a
Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
b
Department of Internal Medicine, North Denmark Regional Hospital, Hjørring, Denmark
c
Department of Neurology, Aalborg University Hospital, Aalborg, Denmark
d
Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark
e
Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
f
Unit for Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Intracerebral hemorrhage is a devastating vascular event. Clinical factors prognostic of recurrence
Intracerebral hemorrhage facilitating individualized post-bleeding patient management are sparsely described. We aimed to describe in-
Prognosis cidence of recurrence of intracerebral hemorrhage and explore the prognostic value of 25 clinical characteristics
Stroke prevention in patients with and without atrial fibrillation.
Recurrence
Methods: Cohort study of patients with incident intracerebral hemorrhage diagnosed from 2003 to 2016 iden-
Atrial fibrillation
tified using nationwide Danish administrative registries. Results reported as cumulative incidence of in-
Risk stratification
tracerebral recurrence accounting for competing risk of death. Univariate and multivariate prognostic factors for
recurrence estimated using Cox regression (hazard ratios [HRs], 95% confidence intervals [CI]).
Results: We identified 9255 patients with incident intracerebral hemorrhage (median age 73 years, 46.6% fe-
males, 16% with atrial fibrillation). Five-year risks of recurrence of intracerebral hemorrhage were approxi-
mately 10% in the study population, although slightly higher for patients without atrial fibrillation. Prognostic
factors for recurrence were broadly similar for patients with and without atrial fibrillation. Age in cate-
gories < 60 years (reference), age 60–70 years (HR 1.29, 95% CI 1.02–1.64), age 70–80 years (HR 1.59, 95% CI
1.26–2.00), age > 80 years (HR 1.19, 95% CI 0.91–1.55), nursing home residency (HR 1.48, 95% CI 1.02–2.13),
and Scandinavian Stroke Scale score (‘mild’ versus ‘moderate’ (HR 1.40, 95% CI 1.13–1.72) and ‘severe’ (HR
1.96, 95% CI 1.61–2.39)) were the strongest prognostic factors.
Conclusion: Risk of recurrence of intracerebral hemorrhage after five years was approximately 10%. Clinical
characteristics associated with recurrence were few and broadly similar for patients with and without atrial
fibrillation, with age and measure of incident bleeding severity, as reflected by Scandinavian Stroke Scale score,
being the most important.

1. Introduction 10 years [5].

Stroke remains a leading cause of death and disability. The vast
majority of strokes are of ischemic origin, but approximately 10% of
strokes occur due to intracerebral hemorrhage [1]. Spontaneous in-
tracerebral hemorrhage is a devastating vascular event with an in-
cidence rate of 25 per 100,000 person-years and a one-month mortality
of up to 40% [2–4]. The majority of intracerebral hemorrhage survivors
are left with permanent disability [4]. Adding to this, a substantial
proportion experience recurrence, with reports of up to 15% after
The etiology behind intracerebral hemorrhage is multifactorial,
with leading causes being hypertension, cerebral amyloid angiopathy,
or use of antithrombotic medication, particularly anticoagulant agents
[6,7]. An increasing number of patients are treated with antithrombotic
treatment, largely owing to a rise in prevalence of patients with atrial
fibrillation. Accordingly, the proportion of intracerebral hemorrhages
attributed to use of antithrombotic medication is rising [8]. Identifying
clinical characteristics associated with recurrence of intracerebral he-
morrhage would facilitate more individualized risk stratification that

⁎
Corresponding author at: Aalborg University Hospital Science and Innovation Centre, Søndre Skovvej 15, DK-9100 Aalborg, Denmark.
E-mail address: t.overvad@rn.dk (T.F. Overvad).

https://doi.org/10.1016/j.thromres.2020.03.024
Received 13 January 2020; Received in revised form 27 March 2020; Accepted 30 March 2020
Available online 21 April 2020
0049-3848/ © 2020 Elsevier Ltd. All rights reserved.
T.F. Overvad, et al.
could improve secondary prevention strategies, for example, the plan-
ning of the intensity of clinical follow-up or post-bleeding antith-
rombotic treatment decisions. Many patients, e.g., with atrial fibrilla-
tion, have a continued indication for antithrombotic treatment [9]. The
potential benefit of resuming antithrombotic treatment must be ba-
lanced against risk of bleeding recurrence, but there is a paucity of data
providing guidance for this delicate clinical decision [10]. Specifically,
there are no randomized trials of the net clinical benefit of resuming
antithrombotic treatment post intracerebral hemorrhage, and no formal
recommendation of use of risk stratification tools to guide such treat-
ment decisions [11–13].
In this nationwide cohort study, we sought to describe the incidence
of and prognostic factors for recurrence of intracerebral hemorrhage in
patients with and without atrial fibrillation.
2. Materials and methods
2.1. Study design and data variables
This was a register-based nationwide cohort study. Each person
living in Denmark has a unique identification number that allows for
individual-level linkage of information from nationwide registries [14].
For this study, we used data from four registries; 1) The Civil Regis-
tration system containing information about age, sex and vital status, 2)
the Danish National Patient Register, which includes information on all
discharge diagnoses from Danish hospitals since 1977 [15], 3) the
Danish Stroke Registry, which holds information about all recorded
stroke events in Denmark since 2003 [16], and 4) the Danish National
Prescription Registry storing information about all claimed prescrip-
tions from Danish pharmacies since 1995 [17].
2.2. Study population
The study population consisted of all Danish citizens aged
≥18 years with an incident diagnosis of spontaneous intracerebral
hemorrhage diagnosed from 2003 to 2016 (International Classification
of Diseases (ICD) code I61) in the Danish Stroke Registry [16,18].
Hospital departments regularly treating patients with acute stroke or
transient ischemic attack are required by law to report details on the
events to the Danish Stroke Registry, which was founded in 2003. Ac-
cordingly, the sensitivity of an intracerebral hemorrhage diagnosis in
this registry is high (> 90%) [19]. Patients with a previous ICD-10
intracerebral hemorrhage diagnosis from before the Danish Stroke
Registry was founded (n = 180), patients registered with a traumatic
intracranial bleeding at the date of discharge for the incident in-
tracerebral hemorrhage event (n = 81), and patients registered with
thrombolysis treatment during admission (n = 84) were excluded.
2.3. Predictor variables
Potential prognostic factors for recurrence of intracerebral hemor-
rhage were described at baseline, i.e., at time of diagnosis of the in-
cident intracerebral hemorrhage event, and identified from existing
literature and included age, sex, household status, atrial fibrillation,
diabetes mellitus, hypertension, heart failure, kidney disease, vascular
disease, myocardial infarction, chronic pulmonary disease, previous
ischemic stroke, previous major bleeding, migraine, depression, de-
mentia, Parkinson's disease, epilepsy, smoking, alcohol intake, statins,
selective serotonin reuptake inhibitors (SSRIs), antithrombotic treat-
ment status prior to the incident intracerebral hemorrhage,
Scandinavian Stroke Scale score, and surgical evacuation of the he-
matoma. The Scandinavian Stroke Scale is a score used to predict
outcomes after acute stroke based on various clinical observations [20].
Information about comorbidities was obtained using a combination of
data from the National Stroke Registry and the National Patient Reg-
ister. Information about use of prescription drugs was available from
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Thrombosis Research 191 (2020) 1–8
the National Prescription Registry. Information about definition of the
clinical characteristics and their data sources is available in Supple-
mentary Table S1.
2.4. Outcomes
Patients were followed through March 2016 for the primary out-
come of recurrence of intracerebral hemorrhage as recorded in the
Danish Stroke Registry [16]. A secondary outcome was the combined
outcome of intracerebral hemorrhage or death (recorded in the Civil
Registration System), since some instances of intracerebral hemorrhage
recurrence are immediately fatal and therefore may not be recorded in
a hospital discharge registry.
2.5. Statistical analysis
The index (baseline date) was defined as the date of discharge for
the incident intracerebral hemorrhage event. Baseline characteristics
were presented overall and for patients with and without atrial fi-
brillation as number of patients and with proportions for categorical
variables and with median, inter-quartile range, for continuous vari-
ables. The cumulative incidence of recurrence of intracerebral hemor-
rhage taking into account the competing risk of death and the cumu-
lative risk of the combined outcome intracerebral hemorrhage or death
were reported according to baseline status of atrial fibrillation [21].
Competing risk from death not related to the outcome of interest is a
potential problem in this study. Due to the register-based nature of our
dataset, we were unable to distinguish deaths due to bleeding recur-
rence and deaths due to other causes, particularly since many deaths
after intracerebral hemorrhage occur rapidly after the bleeding event
[22]. In our analytic strategy, we included two different approached to
address competing risk of death 1) by using a composite endpoint in-
cluding all-cause mortality. This approach does not allow for inference
about the direct association between exposure and outcome of interest
(not including death), but is the total association between the exposure
and (composite) outcome. 2) We used the Aalen-Johansen estimator to
estimate the cumulative incidence of intracerebral hemorrhage recur-
rence, which makes strong assumptions about the at-risk time of events
(stroke) after death [21]. For both approaches we estimated the in-
cidence of recurrence stratified by baseline status of atrial fibrillation.
We further applied a time-to-event analysis using a Cox proportional
hazards regression model with time since incident intracerebral he-
morrhage as the underlying time axis to estimate associations with
outcomes. For the main analysis, patients were censored when reaching
the primary outcome, initiating oral anticoagulation (warfarin, phen-
procoumon, dabigatran, rivaroxaban, or apixaban), dying, emigrating,
or at end-of-study. Patients were followed for a maximum of 5 years.
Univariate analyses were stratified according to the presence of base-
line atrial fibrillation. Due to too few events in the atrial fibrillation
subgroup, a post-hoc interaction analysis for a potential modification of
atrial fibrillation status on the prognostic factors was performed to test
whether it was reasonable to perform a multivariate analysis for the
entire study population as a whole. Results were presented using forest
plots. Missing variables were categorized as ‘missing’ and results are
presented. The associations between the continuous variables age and
Scandinavian Stroke Scale score and recurrence of intracerebral he-
morrhage were also investigated using a restricted cubic spline with
results presented graphically. In a sensitivity analysis, a landmark
analysis starting follow-up 30 days after discharge for the incident in-
tracerebral hemorrhage event was conducted, excluding patients who
experienced bleeding recurrence, death, or were otherwise censored
due to emigration or anticoagulation prescription claims within the first
30 days after discharge. Results are reported with 95% confidence in-
tervals. Stata v.15 was used for data analysis.
T.F. Overvad, et al. Thrombosis Research 191 (2020) 1–8

Table 1
Baseline characteristics for patients with incident intracerebral hemorrhage
overall and stratified by atrial fibrillation status.
No atrial Atrial Overall
fibrillation fibrillation

N (%) 7797 (84.2%) 1458 (15.8%) 9255 (100%)

Age, median, IQR 71.4 79.4 72.9
(60.7–80.0) (72.3–85.1) (62.5–81.3)
< 60 years 23.7 (1846) 4.6 (67) 20.7 (1913)
60–70 years 22.6 (1763) 14.9 (217) 21.4 (1980)
70–80 years 28.5 (2224) 33.0 (481) 29.2 (2705)
> 80 years 25.2 (1964) 47.5 (693) 28.7 (2657)
Female sex 46.8 (3647) 45.7 (667) 46.6 (4314)
Household status
Cohabitant 54.5 (4248) 47.4 (690) 53.4 (4938)
Living alone 36.6 (2850) 44.3 (644) 37.8 (3494)
Other, e.g. nursing home 3.8 (299) 4.3 (62) 3.9 (361)
Missing 5.1 (394) 4.1 (59) 4.9 (453)
Scandinavian Stroke Scale 40 (22–52) 40 (23–50) 40 (22–52)
score, median, IQR Fig. 1. Cumulative incidence function of intracerebral hemorrhage recurrence
Mild (> 42) 41.6 (3242) 40.4 (589) 41.4 (3831) in patients with and without atrial fibrillation.
Moderate (26–42) 23.5 (1834) 26.4 (385) 24.0 (2219)
Severe (< 26) 25.8 (2015) 25.4 (370) 25.8 (2385)
Missing 9.1 (706) 7.8 (114) 8.9 (820) chronic kidney disease, vascular disease, myocardial infarction, chronic
Surgical evacuation of 4.4 (346) 3.5 (51) 4.3 (397) pulmonary disease, and major bleeding (see Table 1). Moreover, former
intracerebral hemorrhage smoking was more prevalent and current smoking less so, among pa-
Lifestyle tients with atrial fibrillation. Statins and oral anticoagulants were more
Smoking
Never 31.4 (2451) 32.4 (472) 31.6 (2923)
frequently used among patients with atrial fibrillation whereas use of
Former 21.6 (1682) 26.1 (381) 22.3 (2063) antiplatelet therapy was highest among patients without atrial fi-
Current 22.8 (1774) 13.6 (199) 21.3 (1973) brillation. The Scandinavian Stroke Scale score was similarly dis-
Missing 24.2 (1890) 27.8 (406) 24.8 (2296) tributed among patients with and without atrial fibrillation.
Alcohol intakea
Risk development over time is shown in Fig. 1: the overall cumu-
Recommended 70.3 (5475) 72.1 (1046) 70.6 (6521)
Above recommended 10.0 (779) 5.9 (86) 9.4 (865) lative incidence of recurrence of intracerebral hemorrhage taking into
Missing 19.7 (1533) 21.9 (318) 20.0 (1851) account the competing risk of death was slightly higher among patients
Comorbidities without atrial fibrillation, with a cumulative incidence of just above
Diabetes mellitus 11.6 (901) 17.1 (249) 12.4 (1150) 10% after five years compared to approximately 9% in patients with
Hypertension 49.7 (3876) 61.7 (899) 51.6 (4775)
Heart failure 6.7 (523) 29.9 (436) 10.4 (959)
atrial fibrillation. Overall, 660 recurrent events were registered; 589 in
Chronic kidney disease 3.2 (250) 7.4 (108) 3.9 (358) patients without and 71 in patients with atrial fibrillation. In the main
Vascular disease 11.1 (863) 22.3 (325) 12.8 (1188) analysis, 431 (5.5%) patients without atrial fibrillation at baseline and
Previous myocardial 5.9 (462) 17.2 (251) 7.7 (713) 385 (26.4%) patients with atrial fibrillation at baseline were censored
infarction
during follow-up for claiming a prescription for an oral anticoagulant
Chronic obstructive 9.0 (699) 13.7 (200) 9.7 (899)
pulmonary disease drug. The risk of the combined outcome of intracerebral hemorrhage or
History of ischemic stroke 22.2 (1719) 31.3 (456) 23.5 (2175) death was markedly higher for patients with atrial fibrillation, see
History of major extracranial 7.8 (608) 15.2 (222) 9.0 (830) Supplementary Fig. S1.
bleeding
History of nontraumatic 5.7 (445) 5.3 (77) 5.6 (522)
intracranial bleeding
(subarachnoid, subdural, or 3.1. Prognostic factors for recurrence of intracerebral hemorrhage
epidural)
Migraine 4.7 (369) 4.0 (58) 4.6 (427) On univariate analysis, prognostic factors for intracerebral hemor-
Depression 27.9 (2175) 30.3 (442) 28.3 (2617) rhage were broadly similar between patients with and without atrial
Dementia 4.7 (369) 6.2 (90) 5.0 (459)
Parkinson's disease 0.9 (70) 1.2 (18) 1.0 (88)
fibrillation, with overlapping confidence intervals across all factors (see
Epilepsy 5.9 (460) 6.0 (88) 5.9 (548) Fig. 2). A statistical test for interaction between atrial fibrillation status
Medication and the prognostic factors revealed no statistically significant interac-
Statin 29.3 (2281) 44.5 (649) 31.7 (2930) tion, although previous major extracranial bleeding may carry different
Selective serotonin reuptake 24.6 (1918) 28.3 (412) 25.2 (2330)
prognostic information depending on atrial fibrillation status. Hence,
inhibitors
Oral anticoagulationb 2.8 (221) 56.6 (825) 11.3 (1046) for the purpose of a multivariate analysis, patients with and without
Antiplatelet therapyb 28.4 (2213) 23.1 (337) 27.6 (2550) atrial fibrillation were combined and the multivariate analysis per-
formed only for the entire population.
Figures are % (n) unless otherwise noted. Fig. 3 shows multivariate adjusted hazard rate ratios for recurrence
a
Recommended alcohol intake per week: ≤7 for women and ≤14 for men. of intracerebral hemorrhage at 5-year follow-up. Higher age was asso-
b
Patients with a claimed prescription within 180 days prior to the in-
ciated with higher rate of recurrence: Compared with patients aged <
tracerebral hemorrhage.
60 years, HRs were for age 60–70 years [HR 1.30 (1.03–1.65)], age
70–80 years [HR 1.60 (1.27–2.01)], and age > 80 years [HR 1.20
3. Results
(0.91–1.57)]. Household status ‘other’, e.g., nursing home patients (HR
1.48 (1.03–2.15)), and more severe bleeding as reflected by lower
We identified 9255 patients with incident intracerebral hemorrhage
Scandinavian Stroke Scale score category indicating more severe index
who met the eligibility criteria, of which 16% had a previous diagnosis
event (higher rates for ‘moderate’ [HR 1.40 (1.13–1.72)] and ‘severe’
of atrial fibrillation. Patients with atrial fibrillation were older and
[HR 1.94 (1.59–2.37)] versus ‘mild’) were also factors associated with
more often had a history of diabetes, hypertension, heart failure,
higher rates of recurrence of intracerebral hemorrhage. Non-significant

3
T.F. Overvad, et al. Thrombosis Research 191 (2020) 1–8

Fig. 2. Univariate hazard rate ratios (95% confidence interval) for intracerebral hemorrhage recurrence after 5 years of follow up in patients with and without atrial
fibrillation.
Footnote: Time since first intracerebral hemorrhage was used as the underlying time axis. P is for a statistical test for a modification by atrial fibrillation status on the
prognostic value of the predictors. Recommended alcohol intake per week: ≤7 for women and ≤14 for men.

trends for higher rates of recurrence were observed in patients with
history of epilepsy, previous use of oral anticoagulation and statins.
Conversely, rates of recurrence were lower in patients with co-
morbidities such as diabetes mellitus, history of non-traumatic in-
tracranial bleeding, and living alone vs. being cohabitant. Lower rates
with wide confidence intervals overlapping unity were observed for
dementia, heart failure, Parkinson's disease, and use of antiplatelet
therapy. The remaining investigated factors were not associated with
recurrence risk.
Figs. 4 and 5 depict adjusted hazard rate ratios for recurrence of

4
T.F. Overvad, et al.
Fig. 3. Predictors of 5-year intracerebral hemorrhage recurrence in a multi-
variate analysis.
Footnote: Time since first intracerebral hemorrhage was used as the underlying
time axis. Analysis adjusted for all predictors in the table. Recommended al-
cohol intake per week: ≤7 for women and ≤14 for men.
intracerebral hemorrhage for the continuous values of age and the
Scandinavian Stroke Scale score, respectively, showing that both age
and Scandinavian stroke score level correlate with rate of recurrence,
except for the very oldest patients.
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Thrombosis Research 191 (2020) 1–8
Fig. 4. Adjusted hazard rate ratios for recurrence of intracerebral hemorrhage
according to age.
Footnote: Age modelled using a restricted cubic spline and adjusted for factors
as listed in Fig. 3. Shaded area represents 95% confidence interval.
Fig. 5. Adjusted hazard rate ratios for Scandinavian Stroke Scale score and
recurrence of intracerebral hemorrhage.
Scandinavian Stroke Scale score modelled using a restricted cubic spline and
adjusted for factors as listed in Fig. 3. Shaded area represents 95% confidence
interval. Note that higher Scandinavian Stroke Scale score reflects less severe
bleeding.
3.2. Secondary analyses
Supplementary Figs. S2 and S3 show univariate and multivariate
hazard rate ratios for the composite endpoint of recurrence of in-
tracerebral hemorrhage or death stratified according to atrial fibrilla-
tion status. Some of the same factors found to be prognostic for in-
tracerebral hemorrhage alone were also associated with the combined
endpoint, including age, Scandinavian Stroke Scale score, epilepsy, and
household status ‘other’, e.g., nursing home residents. In addition,
traditional cardiovascular risk factors such as atrial fibrillation, dia-
betes mellitus, chronic kidney disease, chronic obstructive pulmonary
disease, history of ischemic stroke, dementia, current smoking, and
high alcohol intake were associated with higher rates of the combined
outcome of recurrence of intracerebral hemorrhage or death. Statin use
was associated with lower risk of the combined outcome.
An analysis of the 8050 patients who were alive, event-free and
otherwise uncensored 30 days after discharge for the incident in-
tracerebral hemorrhage event indicated a lower 5-year cumulative in-
cidence of intracerebral hemorrhage recurrence of approximately 8%
T.F. Overvad, et al.
than in the main analysis, see Supplementary Fig. S4. In general, pre-
dictors of bleeding recurrence were similar irrespective of excluding the
first 30-days of follow-up, see Supplementary Fig. S5.
4. Discussion
In this nationwide cohort study of patients with intracerebral he-
morrhage, risk of recurrence was high for patients with and without
atrial fibrillation, ≈10% after 5 years. We showed that risk profiles for
bleeding recurrence were broadly similar for patients with and without
atrial fibrillation. Of 25 investigated clinical factors, only few covariates
were robust prognostic factors for recurrence of intracerebral hemor-
rhage, including age, Scandinavian Stroke Scale score, and household
status.
The prevalence of atrial fibrillation in our population of patients
with intracerebral hemorrhage was in line with previous studies [23].
Conversely, the overall risk of recurrence of intracerebral hemorrhage
was lower compared with a recent Danish cohort study investigating
similar matters (≈10% vs ≈14% at 5-year follow-up) [24]. However,
the previous Danish study used only administrative discharge registry
codes from the National Patient Register to identify recurrence, which
very likely includes administrative diagnostic recoding in relation to
subsequent hospital admissions or control visits that contribute to an
overestimation of risk. In addition, our study extends these findings by
investigating prognostic factors in strata of atrial fibrillation, and by
including some important lifestyle factors (alcohol, smoking) and
measures of bleeding severity as reflected by the Scandinavian Stroke
Scale score.
In a smaller cohort study (only 68 recurrence of intracerebral he-
morrhages) of patients with primary intracerebral hemorrhage, clinical
characteristics associated with recurrence differed from our study, with
previous ischemic stroke, previous use of aspirin, and diabetes mellitus
being associated with higher risk of recurrence while treated hy-
pertension was associated with lower risk of recurrence [5].
Use of SSRI's has been associated with risk of intracerebral hemor-
rhage, but we found only a weak association with recurrence of in-
tracerebral hemorrhage or death in patients without atrial fibrillation
[25]. Although we found no clear association between migraine and
recurrence of intracerebral hemorrhage, migraine has been associated
with risk of hemorrhagic stroke independent of traditional cardiovas-
cular risk factors [26]. Statins have been associated with lower risk of
intracerebral hemorrhage in a cohort of stroke-free patients [27]. As
with the present study, the Scandinavian Stroke Scale score has been
shown to be associated with death and disability after acute stroke [28].
4.1. Clinical implications
Patients who experience intracerebral hemorrhage are considered a
very high-risk population, with a substantial risk of particularly death
but also of bleeding recurrence, which is confirmed by the present re-
sults. Also, patients who experience intracerebral hemorrhage are at
high risk of both recurrence as well as of ischemic events [29,30]. In the
present analysis, we aimed to provide data that could guide clinical
decision-making post intracerebral hemorrhage, including decisions on
intensity of follow-up and selection of suitable candidates for continued
antithrombotic treatment.
Importantly, this study did not aim to investigate causes of recur-
rence of intracerebral hemorrhage, but merely to identify clinical
characteristics associated with recurrence that can be used for risk
stratification purposes [31]. Therefore, the multivariate analyses served
not to isolate the effect of the variables through confounder adjustment,
but merely to identify the most robust prognostic factors. As such, the
presented associations do therefore not necessarily have a causal in-
terpretation, and one cannot infer that, e.g., diabetes mellitus has a
protective effect on recurrence risk despite the lower event rate found
in this subgroup.
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Thrombosis Research 191 (2020) 1–8
There are currently no randomized trials available to guide whether
patients stand to gain from resumed antithrombotic treatment post-in-
tracerebral hemorrhage or specifically about the timing of resumption
[32]. Accordingly, clinicians around the globe have widely different
preferences [33,34]. In the absence of randomized trials, decisions for
clinical management, including antithrombotic treatment, can be sup-
ported by knowledge about factors prognostic for recurrence of in-
tracerebral hemorrhage. We chose to censor patients in case they re-
sumed or initiated anticoagulation in order to derive prognostic data
from an untreated population. For example, although resumption of
oral anticoagulation is associated with reduced risk of ischemia in ob-
servational studies [35], patients at high risk of recurrence of in-
tracerebral hemorrhage even in the absence of anticoagulation should
perhaps be less aggressively treated with respect to resumption of oral
anticoagulation. Ongoing studies will ascertain the net clinical benefit
of resuming oral anticoagulation in this high-risk population.
The issue of ‘shared’ risk factors often complicates treatment deci-
sions regarding antithrombotic treatment, i.e., many factors prognostic
for ischemic events are also prognostic for bleeding. Many traditional
stroke risk factors including heart failure, diabetes mellitus, hyperten-
sion, vascular disease, smoking, and alcohol have been associated with
ischemic stroke in atrial fibrillation [36–38]. However, many of these
factors did not predict recurrence of intracerebral hemorrhage in this
study. Such differences in risk profiles for bleeding versus ischemic
event may be particularly useful when weighing the potential risks and
benefits of antithrombotic treatment.
Multiple scores for estimating a patient's prognosis following in-
tracerebral hemorrhage exist [39,40]. Most scores estimate either
functional disability or death, but when searching for evidence that
support decisions for resumption of antithrombotic treatment, knowl-
edge on the specific clinical prognosis of bleeding recurrence is needed.
In this regard, patients with atrial fibrillation are a specific clinical
category, since most patients have a strong indication for antic-
oagulation.
4.2. Strengths and limitations
The study cohort was sufficiently large to investigate a large number
of prognostic variables. Nonetheless, the number of outcomes among
patients with atrial fibrillation were limited, reducing the precision in
this subgroup. Information on both incident and recurrent recurrence of
intracerebral hemorrhage were based on data from a nationwide stroke
registry with mandatory registration. The positive predictive value of a
diagnosis of recurrence of intracerebral hemorrhage in the Danish re-
gistries is unknown, but likely to be highest in the dedicated Danish
Stroke Registry compared with the administrative National Patient
Register, since some codes in the National Patient Register likely re-
present carry-over diagnoses of the previous intracerebral hemorrhage
event registered in relation to subsequent control visits [24]. Such false
positive codes are not registered in the Stroke Registry. The positive
predictive value of a diagnosis of atrial fibrillation is also high (> 90%)
[41]. Ideally, studies with adjudicated outcomes including post-mortem
assessment of causes of death would provide more definitive data on
the incidence of and prognostic factors for recurrence of intracerebral
hemorrhage, since some deaths are likely to represent undiagnosed
bleeding recurrence.
We censored patients in case they claimed a prescription for oral
anticoagulation. Such patients are unlikely to be a random subset of the
study population, which may have impacted on the observed associa-
tions. We did not censor patients in case the claimed a prescription for
antiplatelet therapy, since such treatment has been reported to be safe
without an increase in associated bleeding risk following intracranial
bleeding [42,43].
We did no formal adjustment for multiple comparisons [44]. Due to
the large number of factors under investigation, we cannot rule out that
some of the observations are due to change, and we encourage future
T.F. Overvad, et al.
studies to validate our findings. We lacked data on some potentially
important and clinically relevant factors, including measures of an-
thropometry, biomarkers, amyloid angiopathy, and information on
imaging data including cerebral microbleeds, leukoaraiosis, and the
anatomical location and volume of the primary bleeding event [45–48].
Also, information about Glasgow Coma Score has proven valuable for
prediction of mortality in this population [39]. Information on blood
pressure levels were unavailable, which may have limited the prog-
nostic value of hypertension in this study.
5. Conclusion
Incidence of recurrence of intracerebral hemorrhage was frequent in
patients both with and without atrial fibrillation. Importantly, factors
prognostic for recurrence were broadly similar between patients with
and without atrial fibrillation and included age, household status, and
stroke severity as measured by Scandinavian Stroke Scale score. This
information may help tailor clinical decisions regarding intensity of
clinical follow-up and antithrombotic treatment decisions in the high-
risk population of patients with intracerebral hemorrhage.
Acknowledgements
The study was supported by “The BMS/Pfizer ERISTA Program
2016”. The sponsor had no role in the design; conduct of study; col-
lection, management, analysis, and interpretation data; preparation,
review, or approval of the manuscript; and decision to submit the
manuscript for publication.
Author contributions
T.F.O., P.B.N. and F.S. had full access to all of the data in the study
and take responsibility for the integrity of the data and the accuracy of
the data analysis. Study concept and design: All authors. Acquisition,
analysis, or interpretation of data: P.B.N., F.S., T.F.O., M.S., S.D.A.,
T.B.L, and G.Y.H.L. Drafting the manuscript: T.F.O. Critical revision of
the manuscript for important intellectual content: All authors.
Statistical analysis: T.F.O., P.B.N. and F.S. Obtained funding: P.B.N.
Study supervision: P.B.N., F.S., T.B.L., M.S. and G.Y.H.L. Approved the
submitted version: All authors.
Disclaimer
This study was based on data from the Danish National Stroke
Registry as provided by the Danish Clinical Registries (RKKP) on March
30, 2017.
Ethical standards
No ethical approval or written informed patient consent is required
for studies based on data from administrative Danish registries.
Permissions and data availability statement
Permissions to access data from the nationwide registries were ob-
tained through the Danish Health Data Agency. Because of the sensitive
nature of the data collected for this study, requests to access the data set
from qualified researchers trained in human subject confidentiality
protocols may be sent to The Danish Health Data Agency at
forskerservice@sundhedsdata.dk.
Declaration of competing interest
Dr. Lip has received consulting fees from Bayer/Janssen, BMS/
Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife and
Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer
7
Thrombosis Research 191 (2020) 1–8
Ingelheim, Microlife, Roche, and Daiichi-Sankyo. Dr. Larsen has served
as an investigator for Janssen Scientific Affairs, LLC, and Boehringer
Ingelheim and received speaking fees from Bayer, BMS/Pfizer,
Boehringer Ingelheim, MSD, and AstraZeneca. Mr. Nielsen has received
speaking fees from Boehringer Ingelheim and Bayer, consulting fees
from Bayer and Daiichi-Sankyo; and grant support from BMS/Pfizer.
Mr. Skjøth has received consulting fees from Bayer. Ms. Søgaard, Dr.
Overvad and Dr. Andersen report no disclosures.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.thromres.2020.03.024.
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