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March 07, 2023; 100 (10) Research Article

Association Between Statin Use and Intracerebral Hemorrhage Location

A Nested Case-Control Registry Study

Nils Jensen Boe, View ORCID ProfileStine Munk Hald, View ORCID ProfileMie Micheelsen Jensen, View ORCID ProfileJonas Asgaard Bojsen, View ORCID ProfileMohammad Talal Elhakim, Sandra Florisson, Alisa Saleh, Anne Clausen, Sören Möller, View ORCID ProfileFrederik Severin Gråe Harbo, Ole Graumann, Jesper Hallas, View ORCID ProfileLuis Alberto García Rodríguez, View ORCID ProfileRustam Al-Shahi Salman, View ORCID ProfileLarry B. Goldstein, View ORCID ProfileDavid Gaist
First published December 7, 2022, DOI: https://doi.org/10.1212/WNL.0000000000201664
Nils Jensen Boe
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Stine Munk Hald
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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  • ORCID record for Stine Munk Hald
Mie Micheelsen Jensen
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Jonas Asgaard Bojsen
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Mohammad Talal Elhakim
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Sandra Florisson
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Alisa Saleh
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Anne Clausen
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Sören Möller
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Frederik Severin Gråe Harbo
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Ole Graumann
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Jesper Hallas
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Luis Alberto García Rodríguez
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Rustam Al-Shahi Salman
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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Larry B. Goldstein
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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David Gaist
From the Research Unit for Neurology (N.J.B., S.M.H., M.M.J., S.F., A.S., D.G.), Departments of Radiology (J.A.B., M.T.E., F.S.G.H., O.G.) and Clinical Research (S.M.), and the Open Patient Data Explorative Network (OPEN) (A.C., S.M.), Odense University Hospital, University of Southern Denmark; Department of Clinical Pharmacology (D.M.), Pharmacy and Environmental Medicine, University of Southern Denmark; Centro Espanõl Investigación Farmacoepidemiológica (L.A.G.R.), Madrid, Spain; Centre for Clinical Brain Sciences (R.A.-S.S.), University of Edinburgh, United Kingdom; and Department of Neurology and Kentucky Neuroscience Institute (L.B.G.), University of Kentucky, Lexington.
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  • ORCID record for David Gaist
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Citation
Association Between Statin Use and Intracerebral Hemorrhage Location
A Nested Case-Control Registry Study
Nils Jensen Boe, Stine Munk Hald, Mie Micheelsen Jensen, Jonas Asgaard Bojsen, Mohammad Talal Elhakim, Sandra Florisson, Alisa Saleh, Anne Clausen, Sören Möller, Frederik Severin Gråe Harbo, Ole Graumann, Jesper Hallas, Luis Alberto García Rodríguez, Rustam Al-Shahi Salman, Larry B. Goldstein, David Gaist
Neurology Mar 2023, 100 (10) e1048-e1061; DOI: 10.1212/WNL.0000000000201664

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Abstract

Background and Objectives A causal relationship between statin use and intracerebral hemorrhage (ICH) is uncertain. We hypothesized that an association between long-term statin exposure and ICH risk might vary for different ICH locations.

Methods We conducted this analysis using linked Danish nationwide registries. Within the Southern Denmark Region (population 1.2 million), we identified all first-ever cases of ICH between 2009 and 2018 in persons aged ≥55 years. Patients with medical record–verified diagnoses were classified as having a lobar or nonlobar ICH and matched for age, sex, and calendar year to general population controls. We used a nationwide prescription registry to ascertain prior statin and other medication use that we classified for recency, duration, and intensity. Using conditional logistic regression adjusted for potential confounders, we calculated adjusted ORs (aORs) and corresponding 95% CIs for the risk of lobar and nonlobar ICH.

Results We identified 989 patients with lobar ICH (52.2% women, mean age 76.3 years) who we matched to 39,500 controls and 1,175 patients with nonlobar ICH (46.5% women, mean age 75.1 years) who we matched to 46,755 controls. Current statin use was associated with a lower risk of lobar (aOR 0.83; 95% CI, 0.70–0.98) and nonlobar ICH (aOR 0.84; 95% CI, 0.72–0.98). Longer duration of statin use was also associated with a lower risk of lobar (<1 year: aOR 0.89; 95% CI, 0.69–1.14; ≥1 year to <5 years aOR 0.89; 95% CI 0.73–1.09; ≥5 years aOR 0.67; 95% CI, 0.51–0.87; p for trend 0.040) and nonlobar ICH (<1 year: aOR 1.00; 95% CI, 0.80–1.25; ≥1 year to <5 years aOR 0.88; 95% CI 0.73–1.06; ≥5 years aOR 0.62; 95% CI, 0.48–0.80; p for trend <0.001). Estimates stratified by statin intensity were similar to the main estimates for low-medium intensity therapy (lobar aOR 0.82; nonlobar aOR 0.84); the association with high-intensity therapy was neutral.

Discussion We found that statin use was associated with a lower risk of ICH, particularly with longer treatment duration. This association did not vary by hematoma location.

Glossary

aOR=
adjusted OR;
CAA=
cerebral amyloid angiopathy;
ICH=
intracerebral hemorrhage;
IVH=
intraventricular hemorrhage;
RSD=
Region of Southern Denmark;
SVD=
small vessel disease

Footnotes

  • 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.

  • Submitted and externally peer reviewed. The handling editor was José Merino, MD, MPhil, FAAN.

  • CME Course: NPub.org/cmelist

  • Received August 29, 2022.
  • Accepted in final form October 24, 2022.
  • © 2022 American Academy of Neurology
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  • Reader Response: Association Between Statin Use and Intracerebral Hemorrhage Location: A Nested Case-Control Registry Study
    • Tomoyuki Kawada, Professor, Nippon Medical School
    Submitted December 21, 2022
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