Risk of Ischemic Stroke after Intracranial Hemorrhage in Patients with Atrial Fibrillation
Risk of Ischemic Stroke after Intracranial Hemorrhage in Patients with Atrial Fibrillation
Michael P. Lerario 0 1 2
Gino Gialdini 0 1 2
Daniel M. Lapidus 0 1 2
Mesha M. Shaw 0 1 2
Babak B. Navi 0 1 2
Alexander E. Merkler 0 1 2
Gregory Y. H. Lip 0 1 2
Jeff S. Healey 0 1 2
Hooman Kamel 0 1 2
0 1 Department of Neurology, Weill Cornell Medical College , New York, NY , United States of America, 2 Feil Family Brain and Mind Research Institute, Weill Cornell Medical College , New York, NY , United States of America, 3 Centre for Cardiovascular Sciences, University of Birmingham , Birmingham , United Kingdom , 4 Thrombosis Research Unit, Aalborg University , Aalborg , Denmark , 5 Population Health Research Institute, McMaster University , Hamilton, ON , Canada
1 Competing Interests: Gregory Y.H. Lip has served as a consultant for Bayer , Merck, Sanofi, BMS/Pfizer
2 Editor: James M. Brophy, McGill University Health Center / Royal Victoria , CANADA
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: This work was supported by grant
K23NS082367 from the National Institute of
Neurological Disorders and Stroke and a grant from
the Michael Goldberg Stroke Research Fund (HK).
The sponsors had no role in the design of the study,
the collection and analysis of the data, the
preparation of the manuscript, or the decision to
We aimed to estimate the risk of ischemic stroke after intracranial hemorrhage in patients with atrial fibrillation.
Materials and Methods
Using discharge data from all nonfederal acute care hospitals and emergency departments
in California, Florida, and New York from 2005 to 2012, we identified patients at the time of
a first-recorded encounter with a diagnosis of atrial fibrillation. Ischemic stroke and
intracranial hemorrhage were identified using validated diagnosis codes. Kaplan-Meier survival
statistics and Cox proportional hazard analyses were used to evaluate cumulative rates of
ischemic stroke and the relationship between incident intracranial hemorrhage and
Among 2,084,735 patients with atrial fibrillation, 50,468 (2.4%) developed intracranial hem
orrhage and 89,594 (4.3%) developed ischemic stroke during a mean follow-up period of
3.2 years. The 1-year cumulative rate of stroke was 8.1% (95% CI, 7.5–8.7%) after intrace
rebral hemorrhage, 3.9% (95% CI, 3.5–4.3%) after subdural hemorrhage, and 2.0% (95%
CI, 2.0–2.1%) in those without intracranial hemorrhage. After adjustment for the CHA2DS2
VASc score, stroke risk was elevated after both intracerebral hemorrhage (hazard ratio
[HR], 2.8; 95% CI, 2.6–2.9) and subdural hemorrhage (HR, 1.6; 95% CI, 1.5–1.7).
Cumulative 1-year rates of stroke ranged from 0.9% in those with subdural hemorrhage and a
CHA2DS2-VASc score of 0, to 33.3% in those with intracerebral hemorrhage and a
CHA2DS2-VASc score of 9.
Daiichi-Sankyo, Biotronik, Medtronic, Portola, and
Boehringer Ingelheim and has been on the speakers
bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim,
Daiichi-Sankyo, and Medtronic. Jeff S. Healey has
received research grants from Medtronic, St. Jude
Medical, Boston Scientific, Boehringer-Ingelheim, and
Bristol-Meiers Squibb, and has served on advisory
boards for Boehringer-Ingelheim and Bayer. Hooman
Kamel has served on the speakers bureau for
Genentech. All other authors report that no
competing interests exist.
In a large, heterogeneous cohort, patients with atrial fibrillation faced a substantially height
ened risk of ischemic stroke after intracranial hemorrhage. The risk was most marked in
those with intracerebral hemorrhage and high CHA2DS2-VASc scores.
Atrial fibrillation (AF) increases the risk of ischemic stroke by 3- to 5-fold.[
] Many patients
with AF are treated with anticoagulant drugs because of their proven efficacy in preventing
] However, anticoagulation with vitamin-K antagonists doubles the
risk of intracranial hemorrhage compared to aspirin. Non-vitamin K antagonist oral
anticoagulant drugs such as apixaban may not significantly increase the risk of intracranial
hemorrhage compared with aspirin,[
] but the use of any antithrombotic therapy in patients with AF
is associated with a 0.4% annual risk of intracranial hemorrhage,[
] which is substantial given
the high rates of permanent disability and mortality after anticoagulant-associated intracranial
After the development of intracranial hemorrhage, antithrombotic therapy is almost always
stopped for some period of time,[
] if not indefinitely. Given the proven benefit of
anticoagulant drugs in reducing stroke, it is likely that the withdrawal of anticoagulation increases
the risk of subsequent stroke.[
] However, the magnitude of ischemic stroke risk after
intracranial hemorrhage in patients with AF remains uncertain because reported rates of
AFrelated thromboembolism after intracranial hemorrhage vary widely from 2% to 40%.[
7, 9, 11
Also, some studies have reported no association between the occurrence of intracranial
hemorrhage and an increased risk of subsequent ischemic stroke. No systemic review of the
literature has been performed previously in this population. Understanding the risk of ischemic
stroke after intracranial hemorrhage is necessary to assess the risks and benefits of resuming
] or pursuing other therapies such as left atrial appendage closure.[
Therefore, we evaluated the risk of ischemic stroke after intracranial hemorrhage in a large,
heterogeneous cohort of patients with AF.
Materials and Methods
We performed a retrospective cohort study using administrative discharge data from
California, Florida, and New York. Designated agencies in each state collect standardized data on all
discharges from nonfederal emergency departments (ED) and acute care hospitals, and report
these data in a de-identified format to the Agency for Healthcare Research and Quality for its
Healthcare Cost and Utilization Project.[
] A unique linkage number allows patients to be
followed across ED visits and hospitalizations over multiple years.[
] Our study was approved
by the Weill Cornell Medical College institutional review board.
Using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM)
codes 427.3x in any discharge diagnosis position, we included patients at the time of a
firstever recorded ED visit or hospitalization with an AF diagnosis between 2005–2010 in
California, 2005–2011 in Florida, and 2006–2010 in New York. These observation periods were
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chosen to ensure at least 1 year of follow-up data for all study patients. To focus on incident
cases, we excluded patients with a diagnosis of ischemic stroke prior to or during the index
visit for AF or a diagnosis of intracranial hemorrhage prior to the index visit for AF. Lastly, to
maximize follow-up, we excluded patients who were not residents of California, Florida, or
Our exposure variable was a time-varying covariate for intracranial hemorrhage, defined as
either intracerebral or subdural hemorrhage. We excluded cases of subarachnoid hemorrhage
because this type of hemorrhage has a negligible recurrence rate in this population[
] and thus
does not present the same long-term management challenge as other types of intracranial
hemorrhage. Intracerebral hemorrhage was defined by ICD-9-CM code 431 in any hospital
discharge diagnosis code position in the absence of a primary discharge code for rehabilitation
(V57) or any discharge code for subarachnoid hemorrhage (430) or trauma (800–804 or 850–
854). This algorithm has been validated to have a sensitivity of 85% and a specificity of 96% for
] To our knowledge, ICD-9-CM diagnosis codes for subdural
hemorrhage have not been previously validated, so we performed an assessment of the
reliability of these codes at New York-Presbyterian Hospital/Weill Cornell Medical Center. A
boardcertified neurologist (A.E.M.) reviewed the medical records of 50 randomly-selected patients
with any hospital discharge diagnosis code for subdural hemorrhage (ICD-9-CM codes 432.1,
852.2x, or 852.3x) and the records of a random sample of 50 patients with a cerebrovascular
diagnosis other than subdural hemorrhage (ICD-9-CM codes 430–438 except for 432.1), and
adjudicated the presence or absence of subdural hemorrhage while blinded to the diagnosis
code. Using this adjudication as the gold standard, we determined that the diagnosis codes for
subdural hemorrhage have a sensitivity of 96% (95% confidence interval [CI], 85–99%) and a
specificity of 90% (95% CI, 79–97%).
Our outcome was ischemic stroke, defined as ICD-9-CM codes 433.x1, 434.x1, or 436 in any
hospital discharge diagnosis code position without a concurrent primary discharge code for
rehabilitation (V57) or any codes for trauma (800–804 or 850–854), intracerebral hemorrhage
(430), or subarachnoid hemorrhage (431). This algorithm has been previously validated to be
86% sensitive and 95% specific for the diagnosis of ischemic stroke.[
We similarly used ICD-9-CM codes from hospital claims to collect information on the
following demographic variables and vascular risk factors that may confound the relationship
between intracranial hemorrhage and ischemic stroke: age, sex, race, insurance status,
hypertension, diabetes, coronary artery disease, congestive heart failure, peripheral vascular disease,
chronic kidney disease, history of transient ischemic attack, and chronic obstructive pulmonary
disease. We used this information to calculate each patient’s CHA2DS2-VASc score, a validated
measure of thromboembolic risk in AF.[
Descriptive statistics with exact CIs were used to calculate crude rates of intracranial
hemorrhage and ischemic stroke. Kaplan-Meier survival statistics were used to calculate the
cumulative incidence of ischemic stroke, stratified by intracranial hemorrhage status (none versus
intracerebral versus subdural). Intracranial hemorrhage status was modeled using a
time-varying covariate. Patients entered observation at the time of the index encounter with AF and
were followed for return visits for ischemic stroke, with the last date of available follow-up
being December 31, 2011 in California or New York, and December 31, 2012 in Florida. This
resulted in up to 5 years of total follow-up for patients in New York, 6 years in California, and
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7 years in Florida. Cox proportional hazards analysis was used to examine the association
between intracranial hemorrhage and subsequent ischemic stroke while adjusting for the
CHA2DS2-VASc score. In a sensitivity analysis, we adjusted for all the demographic
characteristics and vascular risk factors listed above instead of the CHA2DS2-VASc score. We visually
inspected log-log plots to verify the proportional hazards assumption. Among patients with
intracranial hemorrhage, we calculated cumulative rates of stroke stratified by the
CHA2DS2VASc score. The threshold for statistical significance was set at α = 0.05. Stata/MP version 13
(College Station, TX) was used for all analyses.
We identified 2,084,735 patients at the time of their first-recorded AF diagnosis. Mean
followup was 3.2 (±2.1) years for those without intracranial hemorrhage, 2.6 (±2.2) years for those
with intracerebral hemorrhage, and 3.2 (±2.1) for those with subdural hematoma. During this
time, 50,468 patients (2.4%) developed intracranial hemorrhage. Of these intracranial
hemorrhages, 24,330 (48.2%) were intracerebral and 26,138 (51.8%) were subdural. Compared to
patients without hemorrhage, those with intracranial hemorrhage were somewhat older and
had a slightly higher burden of vascular comorbidities as measured by the CHA2DS2-VASc
score (Table 1).
During the observation period, 89,594 patients (4.3%) developed ischemic stroke. The
1-year cumulative rate of stroke was 8.1% (95% CI, 7.5–8.7%) after intracerebral hemorrhage,
3.9% (95% CI, 3.5–4.3%) after subdural hemorrhage, and 2.0% (95% CI, 2.0–2.1) in those
without intracranial hemorrhage (P < 0.001 for test of trend; Fig 1). After adjustment for the
CHA2DS2-VASc score, stroke risk was elevated after both intracerebral hemorrhage (hazard
ratio [HR], 2.8; 95% CI, 2.6–2.9) and subdural hemorrhage (HR, 1.6; 95% CI, 1.5–1.7). These
associations were essentially unchanged in sensitivity analyses adjusting for the individual
components of the CHA2DS2-VASc score, as well as the additional vascular comorbidities and
demographic characteristics, including insurance status, listed in Table 1.
Cumulative rates of ischemic stroke after intracranial hemorrhage varied from 0.9% (95%
CI, 0.1–6.0%) in those with subdural hemorrhage and a CHA2DS2-VASc score of 0, to 33.3%
(95% CI, 5.5–94.6%) in those with intracerebral hemorrhage and a CHA2DS2-VASc score of 9
(Table 2, Figs 2 and 3).
In a large, heterogeneous sample of patients with AF, we found a heightened risk of ischemic
stroke after intracranial hemorrhage. Intracranial hemorrhage was associated with subsequent
stroke risk even after adjustment for demographic characteristics and shared vascular risk
factors. Cumulative rates of stroke were higher after intracerebral as opposed to subdural
hemorrhage and in those with higher CHA2DS2-VASc scores.
Several prior studies have evaluated ischemic stroke rates after intracranial hemorrhage.
These studies reported a wide range of risk for subsequent stroke—ranging from 2–40%—and
conflicting findings on whether intracranial hemorrhage was associated with an increased risk
7, 9, 11, 12
] Our findings in a large, heterogeneous cohort with several years of
follow-up indicate that AF patients face a very high absolute risk of ischemic stroke after
intracranial hemorrhage, especially intracerebral hemorrhage. These results are confirmed by recent
data from Danish registries which demonstrated an increased risk of ischemic stroke following
intracranial hemorrhage, particularly if oral anticoagulation was not resumed.[
However, these analyses were performed in an ethnically homogenous cohort and did not stratify
stroke risk based on compartment of hemorrhage (e.g., intraparenchymal versus subdural).
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Abbreviations: COPD, chronic obstructive pulmonary disease; IQR, interquartile range; SD, standard deviation.
*Data are presented as number (%) unless otherwise specified.
†Self-reported by patients or their surrogates. Numbers do not sum to group totals because of missing race/ethnicity data in 1.9% of patients.
‡Numbers do not sum to group totals because of missing payment-source data in <0.01% of patients.
§The CHA2DS2VASc score assigns 2 points each for age 375 years or prior stroke or transient ischemic attack, and 1 point each for hypertension,
diabetes, peripheral vascular disease, age 65–74 years, or female sex. It has been shown to have moderate predictive value for thromboembolism in atrial
||Data represent the number of Elixhauser comorbid conditions, which comprise a comprehensive set of 28 comorbidity measures for use with large
Currently, the vast majority of patients do not resume anticoagulation after intracerebral
] so our findings may be explained by low rates of proven anticoagulant therapy
in this population.
Our study has several noteworthy limitations. Most importantly, we lacked data on
antithrombotic drug therapy, and therefore could not assess the risk of ischemic stroke after
intracranial hemorrhage in relation to the status of antithrombotic drug use. The use of deidentified
data precluded linking of these patient records to Medicare prescription data, which would
have allowed adjustment for antithrombotic therapy. However, this would be expected to
introduce a conservative bias, because it is likely that at least some proportion of patients
resumed anticoagulant therapy after a period of time,[
] and therefore the risk of ischemic
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Fig 1. Cumulative ischemic stroke rates in atrial fibrillation patients, stratified by intracranial hemorrhage status. Differences between groups were
significant (P < 0.001 for test of trend).
stroke after intracranial hemorrhage in patients who are not receiving anticoagulant therapy is
likely to be even higher than we found. Future use of registries which do include prescription
data could prove helpful in linking stroke rates to the selection and timing of antithrombotic
reintroduction following intracranial hemorrhage. Second, we relied on administrative data
*The CHA2DS2-VASc score assigns 2 points each for age 75 years or prior stroke or transient ischemic attack, and 1 point each for hypertension,
diabetes, peripheral vascular disease, age 65–74 years, or female gender. It has been validated as a clinical prediction rule for thromboembolism in atrial
†The rate in this stratum could not be estimated due to insufficient numbers of patients and events.
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Fig 2. Cumulative ischemic stroke rates after intracerebral hemorrhage in atrial fibrillation patients,
stratified by CHA2DS2-VASc scores. Differences between groups were significant (P < 0.001 for test of
and may have misclassified patient characteristics and outcomes. We attempted to maximize
the reliability of our classifications by using validated codes. Furthermore, misclassifications of
intracranial hemorrhage and ischemic stroke would mostly have served to attenuate
associations and bias our study towards finding no association between intracranial hemorrhage and
ischemic stroke. Nevertheless, we were unable to assess the risk of stroke in relation to certain
Fig 3. Cumulative ischemic stroke rates after subdural hemorrhage in atrial fibrillation patients,
stratified by CHA2DS2-VASc scores. Differences between groups were significant (P < 0.001 for test of
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clinical characteristics, such as the size and precise etiology of intracranial hemorrhage. Lobar
intracranial hemorrhages are associated with a higher risk of recurrence than hemorrhages
affecting the deeper structures of the brain,[
] and patients with lobar hemorrhages may have
been less likely to resume anticoagulant therapy[
] and thus may have faced a higher risk of
subsequent stroke. Furthermore, it is possible that some comorbidities were not recorded or
coded during the inpatient admissions, and therefore not included in our analysis. However,
this would likely underestimate the risk of future ischemic stroke as our patients would have
even more vascular comorbidities in actuality than we reported. Third, we lacked outpatient
data and therefore likely sampled a sicker cohort than the general population of patients with
AF. However, this bias would mostly apply to the control group without intracranial
hemorrhage, because intracranial hemorrhage almost always results in hospitalization.[
when compared to the overall population of patients with AF, patients with AF and intracranial
hemorrhage may face an even higher relative risk of ischemic stroke than we found.
AF patients with intracranial hemorrhage faced a heightened risk of subsequent ischemic
stroke, and the absolute risks were notably high for those with intracerebral hemorrhage and/
or high CHA2DS2-VASc scores. Our findings may have important clinical implications for this
vulnerable group of patients who face a particularly high risk of thromboembolism when
anticoagulation is withdrawn after hemorrhage.[
] Although recent observational data
suggests that timely resumption of anticoagulation may improve outcomes,[
of anticoagulation following intracranial hemorrhage has been uncommon in practice during
the same time period.[
] Given the fact that the newer, non-vitamin K antagonist oral
anticoagulant drugs cause substantially less intracranial hemorrhage than vitamin K
antagonists, further study correlating rates of stroke with antithrombotic usage patterns is needed
to better evaluate the risks and benefits of anticoagulant resumption and the implementation
of therapeutic alternatives to anticoagulation, such as left atrial appendage closure devices,[
in patients with high risk of recurrent hemorrhage.
S1 Checklist. Strobe Statement. Checklist of items that should be included in reports of
Conceived and designed the experiments: MPL GG DL MMS AEM GYHL JSH BBN HK.
Performed the experiments: HK. Analyzed the data: MPL GG AEM GYHL JSH BBN HK.
Contributed reagents/materials/analysis tools: HK. Wrote the paper: MPL GG DL MMS AEM GYHL
JSH BBN HK.
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