Low dose aspirin and risk of brain bleeding in the elderly

I am sure the above caption will come as a surprise to you.

It is a paper by Cloud et al. on “Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People: Secondary Analysis of a Randomised Clinical Trial JAMA Network Open. 2023;6(7): e2325803. doi:10.1001/jamanetworkopen.2023.25803”. I will be using lots of materials from this paper.

A stroke happens when blood is blocked from entering the brain — known as an ischaemic stroke, or when there is sudden bleeding in the brain — known as a haemorrhagic stroke.

Stroke is the leading cause of disability worldwide and the second leading cause of death. The Global Stroke Factsheet released in 2022 reveals that the lifetime risk of developing a stroke has increased by 50% over the last 17 years and now one in four people is estimated to have a stroke in their lifetime.

 From 1990 to 2019, there has been a 70% increase in stroke incidence, a 43% increase in deaths due to stroke, a 102% increase in stroke prevalence and a 143% increase in Disability Adjusted Life Years (DALY).

The most striking feature is that the bulk of the global stroke burden (86% of deaths due to stroke and 89% of DALYs) occurs in lower and lower-middle-income countries. This disproportionate burden experienced by lower and lower-middle-income countries has posed an unprecedented problem to families with fewer resources.

Top risk factors

The top ten risk factors for stroke are elevated systolic blood, high body mass index (BMI), high fasting blood glucose, air pollution, smoking, poor diet, high LDL cholesterol, kidney dysfunction, alcohol use, and low physical activity.

Aspirin is an antiplatelet agent that has been used in low doses (75-100 mg/d) for the prevention of cardiovascular events. Despite some recent unfavourable findings, it continues to be widely used for the primary and secondary prevention of stroke. Its major adverse effect is an increased bleeding tendency.

Information about the efficacy of low-dose aspirin in the primary prevention of stroke is derived from meta-analyses and results of recent major trials, most of which have been conducted in populations with mean ages younger than 70 years.

Increased fragility

Clinical characteristics of older individuals include an increased inherent susceptibility to haemorrhage, which may be associated with increased fragility of small blood vessels.

 In addition, older individuals experience an increased susceptibility to major and minor trauma as a result of falls and other accidents. Together, these outcomes may alter the balance of risks and benefits of antiplatelet drugs, especially if given to individuals at low risk in a primary prevention setting.

This concern is relevant given the high stroke risk in older individuals, worldwide increases in populations of older individuals and the importance of evaluating preventive strategies in this age group.

The Aspirin in Reducing Events in the Elderly (ASPREE) trial is the largest randomised controlled trial of low-dose aspirin focused on investigating the balance of risks and benefits of this therapy in an older age group.

In addition to its large size, the ASPREE study design included independent adjudication of stroke and haemorrhagic events by independent expert panels. It was, therefore, ideally positioned to evaluate the balance of risks and benefits of low-dose aspirin in a primary prevention setting.

Participants were randomised to daily 100-mg enteric-coated aspirin or a matching placebo. The primary outcome of ASPREE was disability-free survival (defined as survival free of physical disability and dementia), and this was not different between aspirin and placebo groups.

Preventive strategies for stroke are essential for reducing the incidence. Low-dose aspirin (75-100mg) is currently widely used to prevent the condition. While meta-analyses show that low-dose aspirin may reduce the risk of stroke, trials also show that it may increase the risk of intracranial and intracerebral haemorrhages — or bleeding in the skull and brain (Annie Lennon. MedicalNewsToday August 2, 2023).

Older individuals are particularly at risk of haemorrhage due to the fragility of their small blood vessels and their increased risk for trauma from falling and other accidents. These factors may alter the balance of risks and benefits of using aspirin. The aforementioned study indicated that in the elderly, low-dose aspirin did not reduce stroke risk, but it increased intracranial bleeding risk by 38%.

Data analysis

For the study, the researchers analysed data from 19,114 adults with an average age of 74 years old. Around 56% of participants were female, and none had a history of cardiovascular conditions such as stroke, or atrial fibrillation (AFib, heart attack).

 The participants were randomly assigned one of two groups and given either a daily 100 mg dose of aspirin (enteric-coated) or a placebo. They were tracked for an average of 4.7 years.

The researchers found that low-dose aspirin was linked to slight — but clinically insignificant — reductions in ischemic stroke incidence in the age group under reference. 
Aspirin did not lead to statistically significant reductions in hemorrhagic strokes either.

The researchers also noted that the elderly individuals taking aspirin were significantly more likely to develop intracranial bleeding than those on a placebo. Blood platelets — a type of blood cell that allows clotting — can form small clumps inside blood vessels in patients at risk of cardiovascular conditions.

Aspirin prevents the clumping of platelets inside blood vessels, leading to its blood thinning effect, to reduce the risk of a heart attack or stroke. In the same way that aspirin decreases the chance of blood clots forming and being sent to the brain, it also may increase the risk of bleeding in the brain.

 Forming blood clots is also one of the ways that the body stops bleeding. As a result, aspirin also hinders the body’s ability to control bleeding once it occurs. Aspirin is of benefit to people who have had an ischaemic stroke — when blood supply to the brain is interrupted or reduced — as it prevents clots from forming that could induce another stroke-secondary prevention.

First-time stroke prevention

The trial, however, looked at the use of aspirin to prevent first-time ischaemic stroke, which is ‘primary stroke prevention’, specifically in healthy older adults free of overt cardiovascular disease.

 [It thereby excludes] those who were most likely to benefit from low-dose aspirin. In healthy elderly patients with no cardiovascular risk factors, these findings suggest that recommending aspirin use can cause more harm than good.

 Such patients may opt for more conservative lifestyle modifications such as a healthy diet and regular exercise. The community needs to understand that there is certainly a beneficial role for aspirin in certain cases, but consultation with your healthcare provider is very important before its routine use in the healthy elderly.

The writer is a Chief Pharmacist
Cocoa Clinic