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Frequency of Intracranial Hemorrhage With Low-Dose Aspirin in Individuals Without Symptomatic Cardiovascular DiseaseA Systematic Review and Meta-analysis

Educational Objective
To determine whether use of low-dose aspirin is associated with an overall increased risk of intracranial hemorrhage among people without symptomatic cardiovascular disease.
1 Credit CME
Key Points

Question  Does preventive, low-dose aspirin increase the frequency of intracranial hemorrhage in the general population?

Findings  In this systematic review and meta-analysis that included 13 randomized clinical trials, low-dose aspirin was associated with an increased risk of any intracranial bleeding.

Meaning  Use of low-dose aspirin was associated with an overall increased risk of intracranial hemorrhage among people without symptomatic cardiovascular disease.

Abstract

Importance  Use of low-dose aspirin for the primary prevention of cardiovascular events remains controversial because increased risk of bleeding may offset the overall benefit. Among major bleeding events, intracranial hemorrhage is associated with high mortality rates and functional dependency.

Objective  To assess the risk of intracranial hemorrhage associated with low-dose aspirin among individuals without symptomatic cardiovascular disease.

Data Sources  PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1966 to October 30, 2018.

Study Selection  Randomized clinical trials that compared low-dose aspirin (daily dose ≤100 mg) vs control and recorded the end points of intracranial hemorrhage separately for active treatment and control groups were included.

Data Extraction and Synthesis  A random-effect estimate was computed based on the Mantel-Haenszel method. Relative risk with 95% CI was used as a measure of aspirin vs control on risk of intracranial hemorrhage.

Main Outcomes and Measures  The main outcomes were any intracranial hemorrhage, intracerebral hemorrhage, subdural or extradural hemorrhage, and subarachnoid hemorrhage, for aspirin vs control.

Results  The search identified 13 randomized clinical trials of low-dose aspirin use for primary prevention, enrolling 134 446 patients. Pooling the results from the random-effects model showed that low-dose aspirin, compared with control, was associated with an increased risk of any intracranial bleeding (8 trials; relative risk, 1.37; 95% CI, 1.13-1.66; 2 additional intracranial hemorrhages in 1000 people), with potentially the greatest relative risk increase for subdural or extradural hemorrhage (4 trials; relative risk, 1.53; 95% CI, 1.08-2.18) and less for intracerebral hemorrhage and subarachnoid hemorrhage. Patient baseline features associated with heightened risk of intracerebral hemorrhage with low-dose aspirin, compared with control, were Asian race/ethnicity and low body mass index.

Conclusions and Relevance  Among people without symptomatic cardiovascular disease, use of low-dose aspirin was associated with an overall increased risk of intracranial hemorrhage, and heightened risk of intracerebral hemorrhage for those of Asian race/ethnicity or people with a low body mass index.

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Article Information

Accepted for Publication: March 15, 2019.

Corresponding Author: Meng Lee, MD, Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Chiayi Branch, 6 W Section, Chiapu Road, Puzi, Taiwan 613 (menglee5126@gmail.com).

Published Online: May 13, 2019. doi:10.1001/jamaneurol.2019.1120

Author Contributions: Drs Huang and Lee 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: Huang, Lee.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Huang, Lee.

Critical revision of the manuscript for important intellectual content: Saver, Wu, Lin, Ovbiagele.

Statistical analysis: Huang, Wu, Lee.

Administrative, technical, or material support: Huang.

Supervision: Saver, Ovbiagele.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grant MOST105-2628-B-182-008-MY2 from the Ministry of Science and Technology, Taiwan, and grants CORPG6D0101, CORPG6D0102, and CORPG6D0103 from Chang Gung Memorial Hospital, Taiwan.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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