Research Summary

Aspirin and Cardiovascular Risk in Older Adults: Long-term Data from the ASPREE Trial

Edited by:
Ashton L. Stahl

Key Highlights

  • In older adults without prior cardiovascular disease, randomization to low-dose aspirin did not provide a long-term reduction in major adverse cardiovascular events (MACE) over a median of 8.3 years.
  • After the randomized trial ended, participants initially assigned to aspirin experienced higher post-trial MACE rates than those assigned to placebo.
  • Across the entire in-trial and post-trial period, aspirin was associated with a higher rate of major haemorrhage compared with placebo.
  • As-treated analyses of ongoing aspirin use showed no long-term MACE benefit but confirmed elevated bleeding risk.

In the ASPirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial and its extended observational follow-up (ASPREE-XT), investigators examined whether daily low-dose aspirin (100 mg) improves cardiovascular outcomes and overall safety in community-dwelling older adults without prior cardiovascular events, dementia, or significant physical disability in Australia and the United States (US). In this extended report from the European Heart Journal, investigators focused on long-term and post-trial effects on major adverse cardiovascular events (MACE) and major hemorrhage.

Participants were aged ≥ 70 years (≥ 65 years for US minorities) at enrollment between 2010 and 2014 and were randomized to aspirin or placebo for a median in-trial period of 4.7 years. The trial ended early in June 2017, and the study medication was discontinued. From June 2017 onward, consenting participants entered ASPREE-XT, an observational extension with continued event adjudication using the same standardized definitions and masked expert committees. The present analysis includes follow-up to the fourth ASPREE-XT annual visit (2021–2022).

Study Findings

The primary outcomes were incident MACE, defined as a composite of non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, and coronary heart disease death, and major hemorrhage, defined as hemorrhagic stroke, symptomatic intracranial bleeding, or clinically significant extracranial bleeding leading to transfusion, hospitalization, prolonged hospitalization, surgery, or death. All-cause mortality was also evaluated.

Among 19,114 randomized participants (9,525 aspirin; 9,589 placebo), 15,668 who remained free of in-trial MACE consented to ASPREE-XT. Median follow-up for MACE and major hemorrhage in the post-trial period was 4.3 years, yielding a total median follow-up of 8.3 years across in-trial and post-trial phases.

Over the entire period, there was no long-term MACE benefit of aspirin: the hazard ratio (HR) for MACE comparing aspirin with placebo was 1.04 (95% CI 0.94-1.15). However, the effect of aspirin changed over time. During the randomized trial, aspirin showed a non-significant trend toward lower MACE (HR 0.89, 95% CI 0.77–1.03). In contrast, during the post-trial period, participants initially randomized to aspirin had higher MACE rates than those randomized to placebo (HR 1.18, 95% CI 1.02-1.37). Similar patterns were observed for myocardial infarction (post-trial HR 1.25, 95% CI 1.01-1.54).

For bleeding, aspirin was consistently associated with harm over the long term. Across in-trial and post-trial follow-up, aspirin increased the rate of major hemorrhage (HR 1.24, 95% CI 1.10–1.39), with higher rates of upper gastrointestinal bleeding (HR 1.43, 95% CI 1.13–1.81) and bleeding at other sites (HR 1.25, 95% CI 1.01–1.54). During the post-trial period alone, major hemorrhage rates were similar between groups (HR 1.08, 95% CI 0.91–1.29).

As-treated analyses using inverse probability of censoring weighting, which estimated the effect of ongoing aspirin use over the whole in-trial and post-trial period, yielded HRs for MACE close to unity (eg, HR 0.97, 95% CI 0.84–1.12) and confirmed higher bleeding risk with continued aspirin use.

Clinical Implications

According to the study authors, these extended ASPREE data indicate that, in older adults without prior cardiovascular events, multi-year low-dose aspirin for primary prevention does not translate into a net long-term reduction in MACE and is associated with increased major bleeding over the combined trial and post-trial periods. The observation of higher post-trial MACE rates in those initially randomized to aspirin, together with the sustained bleeding signal, underscores the need to weigh potential benefits against bleeding risks when considering low-dose aspirin in this population.

The authors note that these findings should inform clinical decision-making in older adults, particularly given persistently high rates of low-dose aspirin use for primary prevention despite guideline recommendations against routine initiation in this age group.

Expert Commentary

“The present study provides novel evidence concerning long-term MACE and hemorrhage following aspirin use in initially healthy older adults,” the researchers concluded. “The finding of no long-term MACE benefit needs to be considered in clinical decision-making if aspirin is being considered for use in this context.”

Reference

Wolfe R, Broder JC, Zhou Z, et al. Aspirin, cardiovascular events, and major bleeding in older adults: extended follow-up of the ASPREE trial. European Heart Journal. Published online. PMCID: PMC12596486.