Abstract
Spontaneous (nontraumatic) intracerebral hemorrhage (ICH) is the most severe complication of antithrombotic drug use. 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. 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). Use of low-dose aspirin, clopidogrel, a vitamin K antagonist (VKA), or a direct oral anticoagulant (DOAC). 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. Among 16 765 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 100 000 person-years in 2005 to 24 per 100 000 person-years in 2018 (P < .001 for trend). 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.
Highlights
Anticoagulant and antiplatelet drugs offer clear clinical benefits in the treatment and prevention of thrombosis, but their use is associated with an increased risk of intracerebral hemorrhage (ICH).[1,2,3] less common than gastrointestinal hemorrhage, ICH is a severe complication with high case fatality in the setting of antithrombotic therapy.[3,4] the advent of direct oral anticoagulants (DOACs) that were reported to be associated with reduced risk of ICH compared with warfarin in clinical trials in patients with atrial fibrillation[3] represented a major advance in oral anticoagulant (OAC) therapy
The association with ICH was weakest for current use of low-dose aspirin and clopidogrel and strongest with current use of a vitamin K antagonist (VKA)
The association with ICH was weaker for DOACs than for VKAs
Summary
Anticoagulant and antiplatelet drugs offer clear clinical benefits in the treatment and prevention of thrombosis, but their use is associated with an increased risk of intracerebral hemorrhage (ICH).[1,2,3] less common than gastrointestinal hemorrhage, ICH is a severe complication with high case fatality in the setting of antithrombotic therapy.[3,4] the advent of direct oral anticoagulants (DOACs) that were reported to be associated with reduced risk of ICH compared with warfarin in clinical trials in patients with atrial fibrillation[3] represented a major advance in oral anticoagulant (OAC) therapy. Observational studies can provide insights regarding the association of ICH with antithrombotic drug use in the wider population, including vulnerable populations, such as older people and patients with coexisting conditions, who are often less well represented in clinical trials
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