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Older man taking aspirin

NIHR Signal Aspirin did not prevent deaths or disability in healthy older adults

Published on 18 December 2018

doi: 10.3310/signal-000696

In the ASPREE trial, older adults with no apparent cardiovascular disease who took daily aspirin saw no benefit in terms of reducing the chance of dying or having dementia or disability. Instead, it slightly increased their mortality and bleeding risk - aspirin was associated with an excess of 1.6 deaths per 1,000 people per year. Half of these deaths were due to cancer.

Aspirin is an established ‘secondary’ preventative treatment for people who have known cardiovascular disease. However, the risk-benefit balance of aspirin for ‘primary’ prevention in people without known cardiovascular disease is debated. This large trial enrolled over 19,000 community-dwelling adults aged over 70 years and assigned them to aspirin – at the dose of 100mg – or matching placebo.

The cancer association is unexpected and is at odds with most other research suggesting aspirin might decrease cancer risk, or be neutral. So, with only five years follow-up, this finding needs cautious interpretation at this stage.

Nevertheless, this research supports guideline recommendations which do not include aspirin as part of primary prevention in older people.

Share your views on the research.

Why was this study needed?

Cardiovascular disease is the leading cause of death in the UK. The British Heart Foundation reported that it accounted for 152,465 deaths in 2016, of which 66,076 deaths were from coronary heart disease and 37,771 from stroke. Latest available data shows that cardiovascular disease cost NHS England almost £4.3 billion in 2013/14.

Some studies have suggested that aspirin for primary prevention may give small cardiovascular benefits at the cost of an increased bleeding risk. Meanwhile, a 2010 study pooling the findings of four trials of primary and secondary prevention suggested that daily aspirin may reduce colorectal cancer risk over 20 years.

The current ASPREE study is one of three trials investigating the effects of aspirin for primary prevention each in people with risk factors. This study looks at use among healthy older adults, where age increases the risk. The ASCEND study looks at those with diabetes and the ARRIVE study, adults free of diabetes but with other cardiovascular risk factors.

What did this study do?

The ASPREE trial included 19,114 community-dwelling adults aged 70 years or older (65 years or older in those of black or Hispanic origin) from Australia and the US. Exclusion criteria included known coronary heart disease, atrial fibrillation, prior stroke, high blood pressure, dementia, physical disability, shortened life expectancy (<5 years), bleeding risk or contraindications to aspirin.

Participants were assigned to 100mg daily aspirin or placebo, with randomisation balanced by age and centre. Neither participants nor researchers were aware of allocation and adherence was equivalent in both groups.

The main trial outcome was disability-free survival – a composite of survival free from dementia or disability. This was reported in one publication, with two others reporting all-cause mortality and secondary outcomes of cardiovascular disease and bleeding.

Average follow-up was 4.7 years. This relatively short duration may give an incomplete look at effects on cancer development; it can take many years for the risk to change.

What did it find?

  • Aspirin did not affect disability-free survival. The event-rate for the composite of death, dementia or disability was 21 per 1,000 per year in both groups (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92 to 1.11).
  • However, looking at mortality specifically, there were slightly more deaths in the aspirin group at 12.7 per 1,000 per year compared with 11.1 deaths per year in the placebo group (HR 1.14, 95% CI 1.01 to 1.29). This gave an excess of 1.6 deaths per 1,000 per year due to aspirin.
  • Half of all deaths that occurred (522/1,052) were attributed to cancer, with again a slightly higher rate in the aspirin than placebo group: 6.7 vs 5.1 per 1,000 per year (HR 1.31, 95% CI 1.10 to 1.56). By cancer type, the only significant result was an increase for colorectal cancer (0.8 vs 0.5 per 1,000 related-deaths; HR 1.77, 95% CI 1.02 to 3.06).
  • However, there was a higher rate of major bleeding in the aspirin group at 8.6 events per 1,000 per year compared with 6.2 per 1,000 in the placebo group (HR 1.38, 95% CI 1.18 to 1.62). There was no difference in the rate of death from major bleeding, with less than 1 case per 1,000 per year in each group.
  • There was no difference in cardiovascular disease events, which was defined as fatal or non-fatal heart attack or stroke, or hospitalisation for heart failure, with 11 such events per 1,000 in each group (HR 0.95, 95% CI 0.83 to 1.08). Neither was there a difference in deaths from cardiovascular disease.

What does current guidance say on this issue?

The NICE guideline on cardiovascular disease risk assessment and reduction, recommends that GPs use a systematic approach to identify people at risk of cardiovascular disease, with use of the QRISK2 assessment tool. A score of 10% or more would indicate the need for primary prevention. This includes lifestyle modifications (diet, physical activity, smoking and alcohol), weight management and use of statins. The guideline does not give a recommendation on use of aspirin. Neither is aspirin mentioned in population-wide approaches to tackle cardiovascular disease.

Daily aspirin is recommended indefinitely as secondary prevention among people who have had an acute coronary event.

What are the implications?

This study seems to confirm that aspirin gives no benefit for healthy older adults who do not have established cardiovascular risk.

Subgroup analysis by population characteristics revealed that mortality was only increased among adults aged over 73 years (who accounted for half the study population). This seems in-line with the known bleeding risk in older adults.

However, the mortality risk was largely attributed to cancer, which is perhaps unexpected. Longer-term follow-up of this and other trials may better establish whether this is a true association.

The overall mortality in this trial was lower than a comparable group of people outside the trial. This could have been due to better lifestyles or other treatments such as statins. Aspirin might have different effects in the absence of these.

This trial result does not negate the established place of aspirin as secondary prevention in people with cardiovascular disease, or for other indications.

Citation and Funding

McNeil JJ, Nelson MR, Woods RL et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018;379:1519-28.

McNeil JJ, Wolfe R, Woods RL et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509-18.

McNeil JJ, Nelson MR, Woods RL et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379:1499-1508.

This project was funded by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (grant U01AG029824), the National Health and Medical Research Council of Australia (grants 334047 and 1127060) and by Monash University and the Victorian Cancer Agency.

Bibliography

Asano TK and McLeod RS. Non steroidal anti‐inflammatory drugs (NSAID) and aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev. 2004;(1):CD004079.

British Heart Foundation. Heart and circulatory diseases statistics 2018. London: British Heart Foundation; 2018.

British Heart Foundation. Heart and circulatory diseases statistics 2017: Chapter 4 - costs. London: British Heart Foundation; 2017.

McNeil JJ, Wolfe R, Woods RL et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509-18.

McNeil JJ, Nelson MR, Woods RL et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379:1499-1508.

NICE. Cardiovascular disease: risk assessment and reduction. CG181. London: National Institute for Health and Care Excellence; 2014, updated Sept 2016.

NICE. Cardiovascular disease prevention. PH25. London: National Institute for Health and Care Excellence; 2010.

NICE. Cardiovascular disease: identifying and supporting people most at risk of dying early. PH15. London: National Institute for Health and Care Excellence; 2008.

NICE. Myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease. CG172. London: National Institute for Health and Care Excellence; 2013.

NICE. Unstable angina and NSTEMI: early management. CG94. London: National Institute for Health and Care Excellence; 2010, updated Sept 2013.

Ridker PM. Should aspirin be used for primary prevention in the post-statin era? N Engl J Med. 2018;379:1572-74.

Rothwell PM, Wilson M, Elwin CE et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376: 1741-50.

Rothwell PM, Cook NR, Gaziano JM et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018;392:387-99.

Why was this study needed?

Cardiovascular disease is the leading cause of death in the UK. The British Heart Foundation reported that it accounted for 152,465 deaths in 2016, of which 66,076 deaths were from coronary heart disease and 37,771 from stroke. Latest available data shows that cardiovascular disease cost NHS England almost £4.3 billion in 2013/14.

Some studies have suggested that aspirin for primary prevention may give small cardiovascular benefits at the cost of an increased bleeding risk. Meanwhile, a 2010 study pooling the findings of four trials of primary and secondary prevention suggested that daily aspirin may reduce colorectal cancer risk over 20 years.

The current ASPREE study is one of three trials investigating the effects of aspirin for primary prevention each in people with risk factors. This study looks at use among healthy older adults, where age increases the risk. The ASCEND study looks at those with diabetes and the ARRIVE study, adults free of diabetes but with other cardiovascular risk factors.

What did this study do?

The ASPREE trial included 19,114 community-dwelling adults aged 70 years or older (65 years or older in those of black or Hispanic origin) from Australia and the US. Exclusion criteria included known coronary heart disease, atrial fibrillation, prior stroke, high blood pressure, dementia, physical disability, shortened life expectancy (<5 years), bleeding risk or contraindications to aspirin.

Participants were assigned to 100mg daily aspirin or placebo, with randomisation balanced by age and centre. Neither participants nor researchers were aware of allocation and adherence was equivalent in both groups.

The main trial outcome was disability-free survival – a composite of survival free from dementia or disability. This was reported in one publication, with two others reporting all-cause mortality and secondary outcomes of cardiovascular disease and bleeding.

Average follow-up was 4.7 years. This relatively short duration may give an incomplete look at effects on cancer development; it can take many years for the risk to change.

What did it find?

  • Aspirin did not affect disability-free survival. The event-rate for the composite of death, dementia or disability was 21 per 1,000 per year in both groups (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92 to 1.11).
  • However, looking at mortality specifically, there were slightly more deaths in the aspirin group at 12.7 per 1,000 per year compared with 11.1 deaths per year in the placebo group (HR 1.14, 95% CI 1.01 to 1.29). This gave an excess of 1.6 deaths per 1,000 per year due to aspirin.
  • Half of all deaths that occurred (522/1,052) were attributed to cancer, with again a slightly higher rate in the aspirin than placebo group: 6.7 vs 5.1 per 1,000 per year (HR 1.31, 95% CI 1.10 to 1.56). By cancer type, the only significant result was an increase for colorectal cancer (0.8 vs 0.5 per 1,000 related-deaths; HR 1.77, 95% CI 1.02 to 3.06).
  • However, there was a higher rate of major bleeding in the aspirin group at 8.6 events per 1,000 per year compared with 6.2 per 1,000 in the placebo group (HR 1.38, 95% CI 1.18 to 1.62). There was no difference in the rate of death from major bleeding, with less than 1 case per 1,000 per year in each group.
  • There was no difference in cardiovascular disease events, which was defined as fatal or non-fatal heart attack or stroke, or hospitalisation for heart failure, with 11 such events per 1,000 in each group (HR 0.95, 95% CI 0.83 to 1.08). Neither was there a difference in deaths from cardiovascular disease.

What does current guidance say on this issue?

The NICE guideline on cardiovascular disease risk assessment and reduction, recommends that GPs use a systematic approach to identify people at risk of cardiovascular disease, with use of the QRISK2 assessment tool. A score of 10% or more would indicate the need for primary prevention. This includes lifestyle modifications (diet, physical activity, smoking and alcohol), weight management and use of statins. The guideline does not give a recommendation on use of aspirin. Neither is aspirin mentioned in population-wide approaches to tackle cardiovascular disease.

Daily aspirin is recommended indefinitely as secondary prevention among people who have had an acute coronary event.

What are the implications?

This study seems to confirm that aspirin gives no benefit for healthy older adults who do not have established cardiovascular risk.

Subgroup analysis by population characteristics revealed that mortality was only increased among adults aged over 73 years (who accounted for half the study population). This seems in-line with the known bleeding risk in older adults.

However, the mortality risk was largely attributed to cancer, which is perhaps unexpected. Longer-term follow-up of this and other trials may better establish whether this is a true association.

The overall mortality in this trial was lower than a comparable group of people outside the trial. This could have been due to better lifestyles or other treatments such as statins. Aspirin might have different effects in the absence of these.

This trial result does not negate the established place of aspirin as secondary prevention in people with cardiovascular disease, or for other indications.

Citation and Funding

McNeil JJ, Nelson MR, Woods RL et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018;379:1519-28.

McNeil JJ, Wolfe R, Woods RL et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509-18.

McNeil JJ, Nelson MR, Woods RL et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379:1499-1508.

This project was funded by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (grant U01AG029824), the National Health and Medical Research Council of Australia (grants 334047 and 1127060) and by Monash University and the Victorian Cancer Agency.

Bibliography

Asano TK and McLeod RS. Non steroidal anti‐inflammatory drugs (NSAID) and aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev. 2004;(1):CD004079.

British Heart Foundation. Heart and circulatory diseases statistics 2018. London: British Heart Foundation; 2018.

British Heart Foundation. Heart and circulatory diseases statistics 2017: Chapter 4 - costs. London: British Heart Foundation; 2017.

McNeil JJ, Wolfe R, Woods RL et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509-18.

McNeil JJ, Nelson MR, Woods RL et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379:1499-1508.

NICE. Cardiovascular disease: risk assessment and reduction. CG181. London: National Institute for Health and Care Excellence; 2014, updated Sept 2016.

NICE. Cardiovascular disease prevention. PH25. London: National Institute for Health and Care Excellence; 2010.

NICE. Cardiovascular disease: identifying and supporting people most at risk of dying early. PH15. London: National Institute for Health and Care Excellence; 2008.

NICE. Myocardial infarction: cardiac rehabilitation and prevention of further cardiovascular disease. CG172. London: National Institute for Health and Care Excellence; 2013.

NICE. Unstable angina and NSTEMI: early management. CG94. London: National Institute for Health and Care Excellence; 2010, updated Sept 2013.

Ridker PM. Should aspirin be used for primary prevention in the post-statin era? N Engl J Med. 2018;379:1572-74.

Rothwell PM, Wilson M, Elwin CE et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376: 1741-50.

Rothwell PM, Cook NR, Gaziano JM et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018;392:387-99.

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly

Published on 18 September 2018

McNeil, J. J.,Nelson, M. R.,Woods, R. L.,Lockery, J. E.,Wolfe, R.,Reid, C. M.,Kirpach, B.,Shah, R. C.,Ives, D. G.,Storey, E.,Ryan, J.,Tonkin, A. M.,Newman, A. B.,Williamson, J. D.,Margolis, K. L.,Ernst, M. E.,Abhayaratna, W. P.,Stocks, N.,Fitzgerald, S. M.,Orchard, S. G.,Trevaks, R. E.,Beilin, L. J.,Donnan, G. A.,Gibbs, P.,Johnston, C. I.,Radziszewska, B.,Grimm, R.,Murray, A. M.

N Engl J Med , 2018

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. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Expert commentary

The finding that aspirin use led to an increased mortality in older people, together with the absence of any benefit in terms of prevention of dementia, disability or even cardiovascular disease, and the demonstration of definite harm (major bleeding) in parallel publications of the ASPREE trial gives a strong signal that aspirin should not be used for primary prevention in older people.

Other trials published this year (ASSERT and ARRIVE) have also failed to demonstrate net benefit of aspirin for primary prevention. The negative findings of these trials compared to earlier trials perhaps in part reflect better control of cardiovascular risk factors in the modern era, including the use of statins and blood pressure lowering medication.

However, before the door is completely shut on aspirin use for primary prevention, the possible impact of body weight on the optimal dose of aspirin needs to be considered – all the contemporary studies used 100mg aspirin, which Rothwell et al. (2018) suggest may be too low for many participants.

Jonathan Mant, Professor of Primary Care Research and Head of the Primary Care Unit, University of Cambridge

The commentator declares no conflicting interests