Significant increase in intracranial bleeding with low-dose aspirin

A secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial found a significant increase in intracranial bleeding in those who take daily low-dose aspirin with no significant reduction of ischemic stroke, according to a new publication in the Journal of the American Medical Association.

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The ASPREE trial was the largest randomized, controlled trial of low-dose aspirin that focused on examining the balance of risks and benefits of the therapy in an older age group. The analysis authors aimed to investigate the incidence of first stroke and bleeding events occurring during a median 4.7 years of follow-up in the trial.

Participants in the study were aged 70 years or older with no history of atrial fibrillation, stroke, transient ischemic attack, or myocardial infarction. The participants were randomized to either daily 100 mg enteric-coated aspirin or a matching placebo. The primary outcome of ASPREE was disability-free survival and predetermined secondary endpoints were stroke and hemorrhagic events.

There were 19,114 participants from the United States and Australia who were recruited between 2010 and 2014 in the ASPREE trial. A total of 9525 participants were randomized to the aspirin group and 9589 were in the placebo group.

At the follow-up point, the rate of intracranial events, including stroke, was 5.8 per 1000 person-years. A first stroke was experienced by 398 individuals (4.7%), which included 203 (4.7%) receiving placebo and 195 (4.6%) receiving aspirin (hazard ratio [HR], 0.97; 95% CI, 0.79-1.18).

Among the participants, 312 experienced an ischemic stroke (78.4% of all strokes), of which 24 were fatal (10 individuals with placebo and 14 with aspirin). In those individuals who received aspirin, 146 (1.5%) experienced an ischemic stroke compared with 166 (1.7%) individuals assigned to placebo. Overall, the study investigators indicated that aspirin did not result in a statistically significant reduction in the risk of ischemic stroke (HR, 0.89; 95% CI, 0.71-1.11).

Moving on to the analysis of hemorrhagic stroke, there were 86 incidents observed in the study population (21.6% of all strokes). The rate of hemorrhagic stroke recorded with aspirin (49 individuals [0.5%]) was not statistically significantly greater than that with placebo (37 individuals [0.4%]; HR, 1.33; 95% CI, 0.87-2.04; P = .19), the authors found.

Although the difference in rates of other intracranial bleeding between those assigned to aspirin or placebo was not statistically significant (59 individuals [0.6%] versus 41 individuals [0.4]; HR, 1.45; 95% CI, 0.98-2.16; P = .07), the totals of stroke and other categories of intracranial bleeding were significantly greater among participants treated with aspirin (108 individuals [1.1%]) in comparison to those receiving placebo (79 individuals [0.8%]; HR, 1.38; 95% CI, 1.03-1.84; P = .03).

The authors of the secondary analysis discussed their principal finding, which was an increase in intracerebral hemorrhagic events which, in absolute terms, outweighed a smaller and nonsignificant reduction in ischemic strokes. This was notable, according to the investigators, because of the higher age-related risk in the studied population—older adults—and the previously reported efficacy of aspirin in secondary stroke prevention.

Additionally, the investigators noted that head injury, which typically results from falls and are common in older adults, are an important factor to consider when deciding the risks and benefit of any antiplatelet agent. This is especially important given the additional cases of intracerebral, subdural, and extradural hemorrhage observed in the aspirin group.

“These data support the recommendation of the USPSTF that low-dose aspirin should not be prescribed for primary prevention in healthy older adults,” the authors of the analysis concluded.

Reference

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