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. 2019 May 13;76(8):906-914.
doi: 10.1001/jamaneurol.2019.1120. Online ahead of print.

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

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Free PMC article

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

Wen-Yi Huang et al. JAMA Neurol. .
Free PMC article

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.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.
Figure 1.. Relative Risk (RR) for Intracranial Hemorrhage (Aspirin vs Placebo or No Aspirin)
The sizes of the data markers indicate the weight of each trial. AAA indicates the Aspirin for Asymptomatic Atherosclerosis trial; APLASA, the Antiphospholipid Antibody Acetylsalicylic Acid study; ARRIVE, the Aspirin to Reduce Risk of Initial Vascular Events study; ASCEND, A Study of Cardiovascular Events in Diabetes; ASPREE, the Aspirin in Reducing Events in the Elderly trial; ECLAP, the European Collaboration on Low-Dose Aspirin in Polycythemia Vera; HOT, the Hypertension Optimal Treatment Study; JPAD, the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes Trial; JPPP, the Japanese Primary Prevention Project; POPADAD, the Prevention of Progression of Arterial Disease and Diabetes trial; PPP, the Primary Prevention Project; and WHS, the Women’s Health Study.
Figure 2.
Figure 2.. Subgroup Analysis of Intracerebral Hemorrhage (Aspirin vs Placebo or No Aspirin)
The sizes of the data markers indicate the weight of each trial. AAA indicates the Aspirin for Asymptomatic Atherosclerosis trial; APLASA, the Antiphospholipid Antibody Acetylsalicylic Acid study; ARRIVE, the Aspirin to Reduce Risk of Initial Vascular Events study; ASCEND, A Study of Cardiovascular Events in Diabetes; ASPREE, the Aspirin in Reducing Events in the Elderly trial; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); JPAD, the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes Trial; JPPP, the Japanese Primary Prevention Project; POPADAD, the Prevention of Progression of Arterial Disease and Diabetes trial; RR, relative risk; and WHS, the Women’s Health Study.

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