Daily low-dose aspirin in healthy older adults without previous cardiovascular events did not prolong healthy, independent living (life free of dementia or persistent physical disability), according to the large ASPREE clinical trial. Risk of dying from a range of causes, including cancer and heart disease, varied and will require further analysis and additional follow-up.
In a large clinical trial to determine the risks and benefits of daily low-dose aspirin in healthy older adults without previous cardiovascular events, aspirin did not prolong healthy, independent living (life free of dementia or persistent physical disability). Risk of dying from a range of causes, including cancer and heart disease, varied and will require further analysis and additional follow-up of study participants. These are the initial findings from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, partially supported by the National Institutes of Health.
ASPREE is an international, randomised, double-blind, placebo-controlled trial that enrolled 19,114 older people (16,703 in Australia and 2,411 in the US). The study began in 2010 and enrolled participants aged 70 and older; 65 was the minimum age of entry for African-American and Hispanic individuals in the US because of their higher risk for dementia and cardiovascular disease.
At study enrolment, ASPREE participants could not have dementia or a physical disability and had to be free of medical conditions requiring aspirin use. They were followed for an average of 4.7 years to determine outcomes.
“Clinical guidelines note the benefits of aspirin for preventing heart attacks and strokes in persons with vascular conditions such as coronary artery disease,” said NIA director Dr Richard J Hodes. “The concern has been uncertainty about whether aspirin is beneficial for otherwise healthy older people without those conditions. This study shows why it is so important to conduct this type of research, so that we can gain a fuller picture of aspirin’s benefits and risks among healthy older persons.”
The team of scientists was led by Dr John J McNeil, head of the department of epidemiology and preventive health at Monash University, Melbourne, Australia, and Dr Anne M Murray, director of the Berman Centre for Outcomes and Clinical Research at Hennepin Healthcare in Minneapolis. The research was supported in part by the National Institute on Aging (NIA) and the National Cancer Institute (NCI), both parts of the NIH.
The Australian component of the study also received funding from the Australian National Health and Medical Research Council and Monash University. Aspirin and placebo were supplied by Bayer, which had no other involvement with the study.
In the total study population, treatment with 100 mg of low-dose aspirin per day did not affect survival free of dementia or disability. Among the people randomly assigned to take aspirin, 90.3% remained alive at the end of the treatment without persistent physical disability or dementia, compared with 90.5% of those taking a placebo. Rates of physical disability were similar, and rates of dementia were almost identical in both groups.
The group taking aspirin had an increased risk of death compared to the placebo group: 5.9% of participants taking aspirin and 5.2% taking placebo died during the study. This effect of aspirin has not been noted in previous studies; and caution is needed in interpreting this finding. The higher death rate in the aspirin-treated group was due primarily to a higher rate of cancer deaths. A small increase in new cancer cases was reported in the group taking aspirin but the difference could have been due to chance.
The researchers also analysed the ASPREE results to determine whether cardiovascular events took place. They found that the rates for major cardiovascular events – including coronary heart disease, non-fatal heart attacks, and fatal and nonfatal ischemic stroke – were similar in the aspirin and the placebo groups. In the aspirin group, 448 people experienced cardiovascular events, compared with 474 people in the placebo group.
Significant bleeding – a known risk of regular aspirin use – was also measured. The investigators noted that aspirin was associated with a significantly increased risk of bleeding, primarily in the gastrointestinal tract and brain. Clinically significant bleeding – haemorrhagic stroke, bleeding in the brain, gastrointestinal haemorrhages or haemorrhages at other sites that required transfusion or hospitalisation – occurred in 361 people (3.8%) on aspirin and in 265 (2.7%) taking the placebo.
As would be expected in an older adult population, cancer was a common cause of death, and 50% of the people who died in the trial had some type of cancer. Heart disease and stroke accounted for 19% of the deaths and major bleeding for 5%.
“The increase in cancer deaths in study participants in the aspirin group was surprising, given prior studies suggesting aspirin use improved cancer outcomes,” said Dr Leslie Ford, associate director for clinical research, NCI division of cancer prevention. “Analysis of all the cancer-related data from the trial is under way and until we have additional data, these findings should be interpreted with caution.”
“Continuing follow-up of the ASPREE participants is crucial, particularly since longer term effects on risks for outcomes such as cancer and dementia may differ from those during the study to date,” said Dr Evan Hadley, director of NIA’s division of geriatrics and clinical gerontology. “These initial findings will help to clarify the role of aspirin in disease prevention for older adults, but much more needs to be learned. The ASPREE team is continuing to analyse the results of this study and has implemented plans for monitoring participants.”
As these efforts continue, Hadley emphasised that older adults should follow the advice from their own physicians about daily aspirin use. It is important to note that the new findings do not apply to people with a proven indication for aspirin such as stroke, heart attack or other cardiovascular disease.
In addition, the study did not address aspirin’s effects in people younger than age 65. Also, since only 11% of participants had regularly taken low-dose aspirin prior to entering the study, the implications of ASPREE’s findings need further investigation to determine whether healthy older people who have been regularly using aspirin for disease prevention should continue or discontinue use.
Abstract 1
Background: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk.
Methods: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure).
Results: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001).
Conclusions: The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (
Authors
John J McNeil, Rory Wolfe, Robyn L Woods, Andrew M Tonkin, Geoffrey A Donnan, Mark R Nelson, Christopher M Reid, Jessica E Lockery, Brenda Kirpach, Elsdon Storey, Raj C Shah, Jeff D Williamson, Karen L Margolis, Michael E Ernst, Walter P Abhayaratna, Nigel Stocks, Sharyn M Fitzgerald, Suzanne G. Orchard, Ruth E Trevaks, Lawrence J Beilin, Colin I Johnston, Joanne Ryan, Barbara Radziszewska, Michael Jelinek, Mobin Malik, Charles B Eaton, Donna Brauer, Geoff Cloud, Erica M Wood, Suzanne E. Mahady, Suzanne Satterfield, Richard Grimm, Anne M Murray
Abstract 2
Background: Information on the use of aspirin to increase healthy independent life span in older persons is limited. Whether 5 years of daily low-dose aspirin therapy would extend disability-free life in healthy seniors is unclear.
Methods: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or physical disability. Participants were randomly assigned to receive 100 mg per day of enteric-coated aspirin or placebo orally. The primary end point was a composite of death, dementia, or persistent physical disability. Secondary end points reported in this article included the individual components of the primary end point and major hemorrhage.
Results: A total of 19,114 persons with a median age of 74 years were enrolled, of whom 9525 were randomly assigned to receive aspirin and 9589 to receive placebo. A total of 56.4% of the participants were women, 8.7% were nonwhite, and 11.0% reported previous regular aspirin use. The trial was terminated at a median of 4.7 years of follow-up after a determination was made that there would be no benefit with continued aspirin use with regard to the primary end point. The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person-years in the aspirin group and 21.2 per 1000 person-years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). The rate of adherence to the assigned intervention was 62.1% in the aspirin group and 64.1% in the placebo group in the final year of trial participation. Differences between the aspirin group and the placebo group were not substantial with regard to the secondary individual end points of death from any cause (12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group), dementia, or persistent physical disability. The rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001).
Conclusions: Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo.
Authors
John J McNeil, Robyn L Woods, Mark R Nelson, Christopher M Reid, Brenda Kirpach, Rory Wolfe, Elsdon Storey, Raj C Shah, Jessica E Lockery, Andrew M Tonkin, Anne B Newman, Jeff D Williamson, Karen L Margolis, Michael E Ernst, Walter P Abhayaratna, Nigel Stocks, Sharyn M Fitzgerald, Suzanne G Orchard, Ruth E Trevaks, Lawrence J Beilin, Geoffrey A Donnan, Peter Gibbs, Colin I Johnston, Joanne Ryan, Barbara Radziszewska, Richard Grimm, Anne M Murray
Abstract 3
Background: In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo.
Methods: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed.
Results: Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56).
Conclusions: Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution.
Authors
John J McNeil, Mark R Nelson, Robyn L Woods, Jessica E Lockery, Rory Wolfe, Christopher M Reid, Brenda Kirpach, Raj C Shah, Diane G Ives, Elsdon Storey, Joanne Ryan, Andrew M Tonkin, Anne B Newman, Jeff D Williamson, Karen L Margolis, Michael E Ernst, Walter P Abhayaratna, Nigel Stocks, Sharyn M Fitzgerald, Suzanne G Orchard, Ruth E Trevaks, Lawrence J Beilin, Geoffrey A Donnan, Peter Gibbs, Colin I Johnston, Barbara Radziszewska, Richard Grimm, Anne M Murray
[link url="https://www.nih.gov/news-events/news-releases/daily-low-dose-aspirin-found-have-no-effect-healthy-life-span-older-people"]NIH material[/link]
[link url="https://www.nejm.org/doi/10.1056/NEJMoa1805819"]New England Journal of Medicine abstract 1[/link]
[link url="https://www.nejm.org/doi/10.1056/NEJMoa1800722"]New England Journal of Medicine abstract 2[/link]
[link url="https://www.nejm.org/doi/10.1056/NEJMoa1803955"]New England Journal of Medicine abstract 3[/link]
[link url="https://www.medicalbrief.co.za/archives/studies-look-benefits-aspirin-patients-cvd/"]See also: Studies look at the benefits of aspirin for patients with CVD[/link]