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ASPREE randomized clinical trial showed a higher risk of intracranial hemorrhage in healthy older people treated with daily low-dose aspirin

Jul 27, 2023 | Neuroscience

The authors from Australia and the United States conducted a prospective, randomized, double-blind, placebo-controlled trial (The Aspirin in Reducing Events in the Elderly- ASPREE), that evaluated the risk of ischemic stroke and intracranial hemorrhage in a cohort of nearly 20,000 older people who were free of overt cardiovascular disease and were treated with long-term, daily, low-dose aspirin. The results showed no statistically significant difference in the incidence of ischemic stroke between the aspirin and placebo groups. However, the totals of intracranial hemorrhage, resulting from a combination of hemorrhagic stroke and other causes of intracerebral hemorrhage, such as subdural, extradural, and subarachnoid bleeding, were significantly higher among individuals treated with aspirin than in individuals assigned to placebo.

Aspirin is an antiplatelet agent used in low doses (75-100 mg/d) to prevent cardiovascular events. It is still widely used for primary and secondary prevention of stroke, despite some recent unfavorable findings. An increased bleeding tendency is its major adverse effect.

About the study

The Aspirin in Reducing Events in the Elderly (ASPREE) trial was a prospective, randomized, double-blind, placebo-controlled trial that evaluated the administration of daily low-dose aspirin in older adults free of overt cardiovascular disease. The study was conducted among older people living in Australia or the United States. The researchers provided a comprehensive report on the incidence of first stroke and bleeding events during the study’s follow-up (median follow-up was 4.7 years, ranging from 3.6 to 5.7 years.).

Individuals who were 70 years of age or older and who did not have a history of atrial fibrillation, stroke, transient ischemic attack, or myocardial infarction were included. Members of racial or ethnic minority groups aged 65 to 70 years were also included, due to their higher risk of cardiovascular disease. At enrollment, there were no participants diagnosed with dementia or physical disability. Participants were randomized and assigned to receive daily 100-mg enteric-coated aspirin or a matching placebo. 

Four subgroups of ischemic stroke were identified: cardioembolic (a clear cardiac cause, typically atrial fibrillation), large-vessel atherosclerosis (ipsilateral ischemic stroke with ≥50% of extracranial or intracranial stenosis), small-vessel occlusion (clinical lacunar stroke syndrome and evidence of a lacunar infarction), and undetermined etiology (when ≥2 causes were identified, the evaluation was complete, but no cause was identified or etiological investigations were incomplete).

Intracranial hemorrhage was diagnosed based on the location identified on neuroimaging (basal ganglionic, lobar, brainstem, or other) or as subarachnoid, subdural, or extradural.

Results

The secondary analysis of a randomized clinical trial included 19 114 older adults. Out of 19 114 participants, 56.4% were females, and the median age was 74.  9525 individuals were treated with aspirin and 9589 received a placebo.

The first stroke experienced 203 participants (4.7%) who received a placebo and 195 individuals (4.6%) who were treated with aspirin. In total, 21.6% of all strokes (86 cases) were hemorrhagic strokes. Treatment with aspirin did not result in a statistically significant reduction in the risk of ischemic stroke. The ischemic stroke experienced 146 (1.5%) participants treated with aspirin, and 166 individuals (1.7%) assigned to placebo. The subgroup analysis showed no evidence of a differential effect of aspirin across subgroups regarding age, sex, smoking, diabetes, dyslipidemia, hypertension, or country (Australia or the USA).

The rate of hemorrhagic stroke observed in participants treated with low-dose aspirin (49 individuals, 0.5%) was not significantly higher than in participants who received a placebo (37 individuals, 0.4%). The biggest difference in the location of hemorrhagic strokes between individuals who received aspirin or placebo was within the territory of deep perforator arteries of the basal ganglia. However, this difference was not statistically significant.

There were more other intracranial bleeding events than hemorrhagic stroke episodes, but there were no significant differences in rates of other intracranial bleedings between participants assigned to aspirin or placebo. The frequency of subdural hematoma and subarachnoid hemorrhage was higher among individuals treated with aspirin, but, this difference was not significant. 

The principal finding of this secondary analysis of a randomized clinical trial was that the totals of stroke and other categories of intracranial hemorrhage were significantly higher among individuals treated with aspirin than in those who received a placebo. This finding was attributed to an increase in a combination of subdural, extradural, and subarachnoid bleeding among individuals who received aspirin compared to the placebo group.

According to this study, an increase in intracerebral hemorrhagic events in absolute terms outweighed a smaller and nonsignificant decrease in ischemic strokes among individuals treated with aspirin. 

The authors suggested that clinicians should be aware of an increased risk of intracerebral bleeding among older individuals who are treated with aspirin and are prone to falls. Head injuries, usually from falls, are common among older people. They also stated that the findings of this study are cautionary regarding the inclusion of aspirin to prevent cardiovascular disease in healthy older adults. According to their findings, a low-dose aspirin may not have a role in the primary prevention of stroke and caution should be taken in the use of aspirin in older persons prone to head trauma. 

This article was published in JAMA Netw Open.

 

Journal Reference

Cloud GC, 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. (Open Access)  https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2807630

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