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RESEARCH ARTICLE Association of Antithrombotic Drug Use With Incident Intracerebral Hemorrhage Location Nils Jensen Boe, MD, Stine Munk Hald, PhD, Alexandra Redzkina Kristensen, MD, Soren M ¨ oller, PhD, ¨ Jonas A. Bojsen, MD, Mohammad Talal Elhakim, MD, €7,61
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RESEARCH ARTICLE Association of Antithrombotic Drug Use With Incident Intracerebral Hemorrhage Location Nils Jensen Boe, MD, Stine Munk Hald, PhD, Alexandra Redzkina Kristensen, MD, Soren M ¨ oller, PhD, ¨ Jonas A. Bojsen, MD, Mohammad Talal Elhakim, MD,
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RESEARCH ARTICLE
Association of Antithrombotic Drug Use With Incident
Intracerebral Hemorrhage Location
Nils Jensen Boe, MD, Stine Munk Hald, PhD, Alexandra Redzkina Kristensen, MD, Soren M ¨ oller, PhD, ¨
Jonas A. Bojsen, MD, Mohammad Talal Elhakim, MD, Mark A. Rodrigues, PhD, FRCR, MBChB, B...
research article association of antithrombotic dru
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RESEARCH ARTICLE
Association of Antithrombotic Drug Use With Incident
Intracerebral Hemorrhage Location
Nils Jensen Boe, MD, Stine Munk Hald, PhD, Alexandra Redzkina Kristensen, MD, Sören Möller, PhD, Correspondence
Jonas A. Bojsen, MD, Mohammad Talal Elhakim, MD, Mark A. Rodrigues, PhD, FRCR, MBChB, BSc, Dr. Gaist
Rustam Al-Shahi Salman, PhD, Jesper Hallas, DrMedSci, Luis A. Garcı́a Rodrı́guez, MD, Magdy Selim, MD, PhD, dgaist@health.sdu.dk
Larry B. Goldstein, MD, and David Gaist, PhD
Abstract
Background and Objectives
Few population-based studies have assessed associations between the use of antithrombotic
(platelet antiaggregant or anticoagulant) drugs and location-specific risks of spontaneous in-
tracerebral hemorrhage (s-ICH). In this study, we estimated associations between antith-
rombotic drug use and the risk of lobar vs nonlobar incident s-ICH.
Methods
Using Danish nationwide registries, we identified cases in the Southern Denmark Region of first-
ever s-ICH in patients aged 50 years or older between 2009 and 2018. Each verified case was
classified as lobar or nonlobar s-ICH and matched to controls in the general population by age,
sex, and calendar year. Prior antithrombotic use was ascertained from a nationwide prescription
registry. We calculated odds ratios (aORs) for associations between the use of clopidogrel, aspirin,
direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA), and lobar and nonlobar
ICH in conditional logistic regression analyses that were adjusted for potential confounders.
Results
A total of 1,040 cases of lobar (47.9% men, mean age [SD] 75.2 [10.7] years) and 1,263 cases of
nonlobar s-ICH (54.2% men, mean age 73.6 [11.4] years) were matched to 41,651 and 50,574
controls, respectively. A stronger association with lobar s-ICH was found for clopidogrel (cases:
7.6%, controls: 3.5%; aOR 3.46 [95% CI 2.45–4.89]) vs aspirin (cases: 22.9%, controls: 20.4%;
aOR 2.14 [1.74–2.63; p = 0.019). Corresponding estimates for nonlobar s-ICH were not
different between clopidogrel (cases: 5.4%, controls: 3.4%; aOR 2.44 [1.71–3.49]) and aspirin
(cases: 20.7%, controls: 19.2%; aOR 1.77 [1.47–2.15]; p = 0.12). VKA use was associated with
higher odds of both lobar (cases: 14.3%, controls: 6.1%; aOR 3.66 [2.78–4.80]) and nonlobar
(cases: 15.4%, controls: 5.5%; aOR 4.62 [3.67–5.82]) s-ICH. The association of DOAC use
with lobar s-ICH (cases: 3.5%, controls: 2.7%; aOR 1.66 [1.02–2.70]) was weaker than that of
VKA use (p = 0.006). Corresponding estimates for nonlobar s-ICH were not different between
DOACs (cases: 5.1%, controls: 2.4%; aOR 3.44 [2.33–5.08]) and VKAs (p = 0.20).
Discussion
Antithrombotics were associated with higher risks of s-ICH, but the strength of the associations
varied by s-ICH location and drug, which may reflect differences in the cerebral micro-
angiopathies associated with lobar vs nonlobar hemorrhages and the mechanisms of drug action.
From the Neurology Research Unit (N.J.B., S.M.H., A.R.K., D.G.), Odense University Hospital; University of Southern Denmark; Open Patient Data Explorative Network (S.M.), Odense
University Hospital; Department Clinical Research (S.M.), University of Southern Denmark; Department of Radiology (J.A.B., M.T.E.), Odense University Hospital, Denmark; Centre for
Clinical Brain Sciences (M.A.R., R.A.-S.S.), University of Edinburgh, United Kingdom; Department of Clinical Pharmacology, Pharmacy and Environmental Medicine (J.H.), University of
Southern Denmark, Odense; Centro Español Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Beth Israel Deaconess Medical Center (M.S.), Harvard Medical School,
Boston, MA; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
, Glossary
CAA = cerebral amyloid angiopathy; DOACs = direct oral anticoagulants; ICH = intracerebral hemorrhage; IVH = isolated
intraventricular hemorrhages; OR = odds ratio; RSD = Region of Southern Denmark; s-ICH = spontaneous intracerebral
hemorrhage; SVD = small vessel disease; VKA = vitamin K antagonists.
Introduction Standard Protocol Approvals, Registration, and
Patient Consents
Antithrombotic drugs are effective in preventing thromboembolic Authorities in the RSD approved this study. Data were
events but carry a risk of intracerebral hemorrhage (ICH).1-4 pseudonymized,19 and informed consent was waived.
Differences in the pathology underlying ICH based on location
may affect the association between antithrombotic use and in- Data Availability
cident ICH. Supratentorial deep (nonlobar) ICH is commonly Danish law prohibits the sharing of or the authors granting
due to perforator vessel arteriolosclerosis, often attributed to hy- access to the data used for this study.
pertension.5 Although moderate-severe arteriolosclerosis can also
underlie lobar ICH,6,7 in 42% of cases, it coexists with cerebral Source Population
amyloid angiopathy (CAA), which is the only underlying For this study, the source population was all residents of the
microangiopathy in 15% of lobar ICH cases.6 A meta-analysis of RSD aged 50 years or older in 2009–2018. We chose this age
neuroimaging findings in patients with oral anticoagulant (OAC)- threshold because it is a component of the Boston criteria for
associated ICH vs non–OAC-associated ICH reported pooled CAA20 and due to the higher likelihood of secondary causes of
risk ratios of 1.02 [95% confidence interval (CI) 0.89–1.17] for ICH in younger populations (i.e., trauma, hemorrhagic trans-
lobar ICH vs 0.94 [95% CI 0.88–1.00] for deep hemorrhage.8 formation of an ischemic stroke, intracranial venous sinus
Subsequent studies not included in the meta-analysis reported thrombosis, aneurysmal subarachnoid hemorrhage-related
higher odds of incident ICH with use of anticoagulants for both ICH, vascular malformations, or neoplasms).
lobar and nonlobar locations.9,10 No population-based study has
yet reported risk estimates for the association between direct oral Cases
anticoagulant (DOAC) use and incident ICH by location. Studies Cases were identified as described previously.21-23 We used
investigating an association between platelet antiaggregant use both the Danish Stroke Registry and the National Danish
and risk of lobar vs nonlobar ICH have reported neutral results,10- Patient Registry to identify all individuals with first-ever
12
or a higher risk of lobar ICH,13 and none have provided risk spontaneous ICH (s-ICH) in the RSD during the study pe-
estimates for clopidogrel. We performed this population-based riod.21 We excluded patients with secondary causes for ICH.
study to further explore the association of OAC and platelet The physicians who classified the hemorrhage location veri-
antiaggregant use with the risk of incident ICH by location. fied the diagnosis of s-ICH based on both brain imaging re-
ports and discharge summaries using a validated method
described elsewhere.24 The index date was the date of
Methods symptom onset of s-ICH according to medical records, or if
Design unavailable, the date of hospital admission. Data that were
This population-based case-control study was nested within collected for this project on the patients with s-ICH were
the Region of Southern Denmark (RSD) using data from linked with information collected prospectively on all RSD
nationwide registries (see eMethods).14-17 We used the residents from 4 nationwide registries14-17 using the 10-digit
unique 10-digit personal identifier assigned to all Danish personal identifier assigned to all Danish residents at birth or
residents at birth or on immigration to link data across reg- on immigration.17
istries. The Strengthening and Reporting of Observational
Studies in Epidemiology reporting guidelines were followed. Based on criteria modified from a previous population-based
study,25 s-ICH location was classified as nonlobar if a single
Setting supratentorial deep ICH (i.e., located in the basal ganglia, internal
Health care is paid by taxes and free of charge at the time of or external capsule, or thalamus), single infratentorial ICH
use for all residents in Denmark. When stroke is suspected, (i.e., located in the brain stem or cerebellum), or multiple non-
patients are evaluated using established pathways with rapid lobar ICHs (supratentorial deep or infratentorial) were present;
access to neuroimaging. Patients are also subsequently lobar classification included all other ICHs. The nonlobar hem-
transferred or admitted to stroke units for specialized care. orrhages were subclassified as either “deep” (i.e., subcortical or
One of the 5 regions in Denmark, the RSD has a population of pontine) or “cerebellar” (a location occasionally associated with
1.2 million and in regard to sociodemographic and health CAA26). Isolated intraventricular hemorrhages (IVH) were in-
related characteristics, is representative of the population in cluded in overall analyses of ICH but excluded from location-
Denmark.18 The RSD has 5 stroke units and a single neuro- specific analyses. IVH can be related to small vessel disease
surgical department at a university hospital. (SVD).27 Patients with ICH with mortality within 30 days of the
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