Low-Dose Aspirin Linked With Increased Intracranial Bleeding Risk in Older Adults

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In comparison with placebo, older adults on low-dose aspirin had an increase in a combination of subdural, extradural, and subarachnoid bleeding.

Geoffrey Cloud, BSc, FRCP, FRACP, director of stroke services at Alfred Hospital, University of Melbourne

Geoffrey Cloud, BSc, FRCP, FRACP

Among a cohort of older, healthy adults, findings from a secondary analysis of the ASPREE randomized, double-blind, placebo-controlled study showed no statistically significant benefit in preventing stroke with low-dose aspirin; however, aspirin significantly increased the overall risk of intracranial bleeding. Above all, these data support recommendations from the US Preventive Services Task Force (USPSTF) that low-dose aspirin should not be prescribed for primary prevention in healthy older adults.

The trial featured 19114 older adults free of symptomatic cardiovascular disease who were randomly assigned to either daily 100-mg enteric-coated aspirin (n = 9525) or matching placebo (n = 9589). Recruitment took place between 2010 and 2014, and participants were followed up for a median of 4.7 (IQR, 3.6-5.7) years. The study’s primary outcome, disability-free survival, was previously reported, showing no difference between aspirin and placebo groups.

Led by Geoffrey Cloud, BSc, FRCP, FRACP, director of stroke services at Alfred Hospital, University of Melbourne, first stroke was experienced by 398 individuals, including 203 (4.7%) receiving placebo and 195 (4.6%) on aspirin (HR, 0.97; 95% CI, 0.79-1.18). For comparison, cardiovascular disease accounted for 91 deaths in the aspirin group and 112 deaths for those assigned to placebo.

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First ischemic stroke, occurring in 312 participants (78.4% of all strokes), was not significantly different by group. The corresponding event rate was 3.9 events per 1000 person-years (PY) with placebo and 3.4 events per 1000 PY with aspirin, indicating a nonsignificant risk reduction with aspirin (HR, 0.89; 95% CI, 0.71-1.11). Aspirin failed to show a different treatment effect across subgroups of age, sex, smoking, diabetes, dyslipidemia, frailty category, hypertension, or country (Australia or US).

Hemorrhagic Stroke and Intracranial Bleeding

  • Hemorrhagic strokes were less common than ischemic strokes, with 21.6% of all strokes being hemorrhagic.
  • The rate of hemorrhagic stroke recorded with aspirin (0.5%) was not statistically significantly greater than that with placebo (0.4%).
  • Overall, there was no statistically significant difference in rates of other intracranial bleeding events between individuals assigned to aspirin or placebo (0.6% vs. 0.4%).
  • However, the total number of intracranial bleeding events, including hemorrhagic strokes and other bleeding types, was significantly greater among individuals treated with aspirin compared to those receiving placebo (1.1% vs. 0.8%).

In total, 59 and 41 individuals from the aspirin and placebo groups, respectively, had intracranial bleeding (HR, 1.45; 95% CI, 0.98-2.16; P = .07). Although not statistically significant, the aspirin group showed a higher rate of patients with subdural hematoma and subarachnoid hemorrhage, whether occurring spontaneously or as a result of trauma. Between the groups, investigators observed significantly higher totals of stroke and other categories of intracranial bleeding (108 vs 79 individuals; HR, 1.38; 95% CI, 1.03-1.84; P = .03). In absolute terms, this resulted from an excess of 29 first intracranial bleeding events among individuals assigned to aspirin, which exceeded the decrease of 20 fewer ischemic strokes.

"Head injury, typically resulting from falls, is common in older individuals, and additional cases of bleeding after such occurrences are an important component of the risk-benefit equation of any antiplatelet agent in older adults," the study authors wrote. "Most additional cases of intracerebral hemorrhage (8/12 events) occurred in the basal ganglia, where hypertensive arteriopathy is considered to be the dominant pathology. Surprisingly, fewer additional cases occurred in the lobar regions, where cerebral amyloid angiopathy is thought to be the predominant underlying pathology and is common in this age group."

In an unadjusted model of overall stroke prevention, there were recorded HRs of 0.89 (95% CI, 0.71-1.11) and 1.38 (95% CI, 1.03-1.84) for the aspirin treatment effect on ischemic stroke and intracranial bleeding, respectively. Furthermore, there was a suggestion of divergence as the follow-up continued, largely because of other nonstroke categories of intracranial bleeding (HR, 1.45; 95% CI, 0.98-2.16). Among 1000 individuals taking 100 mg/d of low-dose aspirin over 5 years, there were 2.5 fewer ischemic strokes at the expense of 3.5 cases of intracranial hemorrhage, a finding that did not meet the threshold for statistical significance.

REFERENCE
1. Cloud GC, Williamson JD, Thao LTP, et al. Low-dose aspirin and the risk of stroke and intracerebral bleeding in healthy older people: secondary analysis of a randomized clinical trial. JAMA Netw Open. 2023;6(7):e2325803. doi:10.1001/jamanetworkopen.2023.25803.
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