Abstract
Importance: Spontaneous (nontraumatic) intracerebral hemorrhage (ICH) is the most severe complication of antithrombotic drug use. Objectives: To estimate the strength of association between use of antithrombotic drugs and risk of ICH and to examine major changes in the incidence of ICH in the general population. Design, Setting, and Participants: This case-control study of patients with a first-ever ICH from January 1, 2005, to December 31, 2018, matched by age, sex, and calendar year with general population controls (1:40 ratio), assessed case and control patients 20 to 99 years of age in population-based nationwide registries in Denmark (population of 5.8 million). Exposures: Use of low-dose aspirin, clopidogrel, a vitamin K antagonist (VKA), or a direct oral anticoagulant (DOAC). Main Outcomes and Measures: Association of ICH with antithrombotic drug use, annual age- and sex-standardized incidence rate of ICH, and prevalence of treatment with antithrombotic drugs. Conditional logistic regression models estimated adjusted odds ratios (aORs) (95% CIs) for the association of antithrombotic drugs with ICH. Results: Among 16765 cases with ICH (mean [SD] age, 72.8 [13.1] years; 8761 [52.3%] male), 7473 (44.6%) were exposed to antithrombotic medications at the time of ICH onset. The association with ICH was weakest for current use of low-dose aspirin (cases: 28.7%, controls: 22.6%; aOR, 1.51; 95% CI, 1.44-1.59) and clopidogrel (cases: 6.2%, controls: 3.4%; aOR, 1.65; 95% CI, 1.47-1.84) and strongest with current use of a VKA (cases: 12.0%, controls: 5.0%; aOR, 2.76; 95% CI, 2.58-2.96). The association with ICH was weaker for DOACs (cases: 3.0%, controls: 1.8%; aOR, 1.83; 95% CI, 1.61-2.07) than for VKAs. Compared with 2005, the prevalence of use of oral anticoagulants among general population controls in 2018 was higher (3.8% vs 11.1%), predominantly because of increased use of DOACs (DOACs: 0% vs 7.0%; VKA: 3.8% vs 4.2%). Antiplatelet drugs were used less frequently (24.7% vs 21.4%) because of decreased use of low-dose aspirin (24.3% vs 15.3%), whereas clopidogrel use increased (1.0% vs 6.8%). The age- and sex-standardized incidence rate of ICH decreased from 33 per 100000 person-years in 2005 to 24 per 100000 person-years in 2018 (P <.001 for trend). Conclusions and Relevance: In Denmark from 2005 to 2018, use of antithrombotic drugs, especially VKAs, was associated with ICH. Although use of oral anticoagulation increased substantially during the study period, the incidence rate of ICH decreased..
Original language | English |
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Article number | e218380 |
Journal | JAMA network open |
Volume | 4 |
Issue number | 5 |
Number of pages | 14 |
ISSN | 2574-3805 |
DOIs | |
Publication status | Published - 6 May 2021 |
Bibliographical note
Funding Information:Author Contributions: Drs Möller and Gaist had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Hald, García Rodríguez, Al-Shahi Salman, Pottegård, Gaist. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Hald, Gaist. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Hald, Möller, Gaist. Supervision: Christensen, Pottegård, Hallas, Gaist. Conflict of Interest Disclosures: Dr García Rodríguez reported receiving personal fees from Bayer AG outside the submitted work. Dr Al-Shahi Salman reported receiving special project grants from the British Heart Foundation for RESTART (Restart or Stop Antithrombotics Randomised Trial) and SoSTART (Start or Stop Anticoagulants Randomised Trial) paid to the University of Edinburgh and grants from GE Healthcare paid to the University of Edinburgh outside the submitted work. Dr Sharma reported receiving grants from Bayer, BMS, and Portola and personal fees from Pfizer and Bayer outside the submitted work. Dr Christensen reported serving as a steering committee member and national lead in the TICH-2 (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) and ANNEXA-I (Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor) trials. Dr Pottegård reported receiving grants from Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Novo Nordisk, Servier, and LEO Pharma outside the submitted work. Dr Gaist reported receiving speak honoraria from Bristol-Myers Squibb outside the submitted work. No other disclosures were reported.
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