Debunking the Headlines on Aspirin Study (ASPREE)

by Sara Gottfried, MD and Lewis Chang, PhD

Media headlines have claimed that aspirin has no benefit for older adults. What’s the truth? Should we, as one major news website suggests, toss our aspirin?

Aspirin is derived from the bark of several species of willow trees. It has been used for centuries for pain and inflammation. As a low-dose therapy, aspirin has been prescribed to reduce the risk of heart disease, cancer, and stroke based on the results of multiple meta-analyses (see below). Earlier this week in the New England Journal of Medicine (NEJM), three research articles based on the findings of the ASPREE trial were simultaneously published.^1-3 These publications are attracting widespread media attention as the study results raised concerns regarding the harmful effects of low-dose aspirin—one of the most versatile drugs and natural ingredients in the world.

Amid the over-sensationalized but often over-simplified news headlines, this article aims to summarize objectively the ASPREE study findings and help you determine whether this new information is relevant to you, particularly if you regularly take low-dose aspirin or are considering taking it; and as a clinician, whether these findings should change your practice.

What did the ASPREE trial investigate?

The Aspirin in Reducing Events in the Elderly (ASPREE) trial is a double-blind, randomized, placebo-controlled trial (RCT) that investigated whether the potential primary prevention benefits of low-dose aspirin outweighed the risks in healthy older adults.⁴ (“Primary prevention” is defined as intervention to prevent the onset of a disease, as opposed to “secondary prevention” which aims to identify an established disease in a pre-symptomatic disease stage and then to prevent its progression. As described below, the primary prevention endpoint of the ASPREE trial was disability-free survival.)

Participants were randomized to two groups; one group received daily aspirin (100 mg per day) and the other received daily matching placebo that contained no active ingredient.

• The main research question was whether daily use of aspirin for 5 years would prolong disability-free life, including free from dementia and persistent physical disability, in healthy older adults.
• The secondary research question was to evaluate the effect of daily use of aspirin for 5 years on mortality, cardiovascular events, cancer (excluding non-melanoma skin cancer), dementia, mild cognitive impairment, depression, physical disability, and clinically significant bleeding in healthy older adults.

The main hypothesis of the study was that daily low-dose aspirin would extend disability-free and dementia-free life in these healthy elder adults.

Who were eligible to be in the ASPREE trial?

The ASPREE participants were healthier than the average general public of similar ages. Eligible participants were community-dwelling men and women from Australia and the U.S. who were ≥70 years of age, or ≥65 years of age among blacks and Hispanics in the U.S. They were required to be:⁵

• free of any significant chronic disease that would likely limit their survival to <5 years
• free of cardiovascular or cerebrovascular disease
• free of dementia and major physical disability

A total of 19,114 participants were recruited, including 16,703 from Australia and 2,411 from the U.S. The population was predominantly Caucasian (91%). By country, 98% of the Australian participants and 45% of the U.S. participants were non-Hispanic white. The median age of the group was 74 (ranging from 65 to 98 years of age), and 56.4% of the participants were women.

What did the ASPREE trial find?

An independent data and safety monitoring board reviewed the accumulating study data every 6 months. The trial was stopped ahead of schedule, at approximately 4.7 years, as data monitoring revealed no benefits with the aspirin treatment.

The first NEJM report described the main findings. Compared with placebo:¹

• Daily low-dose aspirin had no beneficial effects on the primary endpoint, i.e., occurrence of dementia, physical disability, and death from any cause.
• In contrast, the rate of major hemorrhage—including clinically significant bleeding and hemorrhagic stroke—was 3.8% in the aspirin group vs. 2.8% in the placebo group.

The second and third NEJM reports described findings from analyses of secondary endpoints. Compared with placebo:^2,3

• Daily low-dose aspirin did not reduce the risk of major cardiovascular events, such as hospitalization for heart failure, fatal and nonfatal myocardial infarction, and fatal and nonfatal ischemic stroke.
• Daily low-dose aspirin did not reduce the risk of death (from any cause).
• The rate of cancer-related death was statistically significantly higher in the aspirin group, at 3.1%, vs. 2.3% in the placebo group.

Together, these data demonstrate that low-dose aspirin is ineffective as a primary prevention agent in the predominantly white, healthy older adults. Conversely, it increases the risk of major hemorrhage.

Does that mean the risks of low-dose aspirin outweigh the benefits?

It depends on the purpose of the aspirin treatment and also on the age and health status of the users.

For primary prevention, accumulating clinical evidence from RCTs is against its use, as the benefits do not always outweigh the risks. For example:

• The ASPREE trial (described above) found significant, increased bleeding risks while there was no effect on prolonging disability-free survival among healthy old adults over 70 years of age.^1-3
• The ARRIVE trial (Aspirin to Reduce Risk of Initial Vascular Events) involved 12,546 patients (aged 55 years for men or 60 years for women or older) who had an average cardiovascular risk. Low-dose aspirin (100 mg daily) for 60 months did not reduce the risk of initial cardiovascular events. The rate of gastrointestinal bleeding events was 0.97% in the aspirin group vs. 0.46% in the placebo group.⁶
• The ASCEND trial (A Study of Cardiovascular Events in Diabetes) involved 15,480 participants with diabetes but without cardiovascular disease (aged 40 years or older). Low-dose aspirin (100 mg daily) for 7.4 years reduced the risk of serious vascular events by 12% but increased the risk of major bleeding by 29% compared with placebo.⁷
• A meta-analysis of 3 RCTs providing data for 10,037 participants without dementia found that 5 years of low-dose aspirin did not improve global cognition compared with placebo, but led to higher incidence of adverse events.⁸

For secondary prevention of cardiovascular disease, several meta-analyses of RCTs have demonstrated that the benefits of low-dose aspirin significantly outweigh the risks in various patient populations. For example:

• The Antiplatelet Trialists’ Collaboration’s analysis in 1994 and again in 2002 concluded that low-dose aspirin was definitely protective among most types of patients at high risk of occlusive vascular disease (such as those with acute myocardial infarction or unstable angina, and those with a history of myocardial infarction, stroke or transient ischemic attack). The reductions in vascular events were significantly in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and non-diabetic patients.^9,10
• The Antithrombotic Trialists’ Collaboration concluded in its 2009 analysis that, among patients who already had occlusive vascular disease, low-dose aspirin yielded a greater absolute reduction in serious vascular events, total stroke and coronary events, with a non-significant increase in hemorrhagic stroke.¹¹

For secondary prevention of cancer, accumulating evidence from RCTs demonstrates that low-dose aspirin is beneficial in reducing some cancer or cancer-related death. For example:

• In patients with a previous history of colorectal cancer or adenomas, 2-4 years of low-dose aspirin significantly reduced the risk of recurrent colorectal adenomas compared with placebo.¹²
• A meta-analysis of RCTs conducted in UK found that daily low-dose aspirin significantly reduced the risk of distant metastasis of adenocarcinoma (but not other solid cancers) and the risk of fatal adenocarcinoma.¹³
• A meta-analysis of RCTs found that low-dose aspirin reduced the risk of cancer deaths; the significant effects were observed after approximately 4 years of follow-up.¹⁴

How generalizable are the results of the ASPREE trial?

The information generated from the ASPREE trial is particularly relevant for those who are white, 70 years or order, and free of significant chronic disease and disability. The information is less applicable to older adults who are non-white (such as blacks and Hispanics) because there weren’t enough data to provide solid conclusion.

For individuals with existing chronic disease (such as cardiovascular disease and cancer) or with a history of significant chronic disease and are taking low-dose aspirin for secondary prevention, findings from the ASPREE trial is less applicable.

What are the key limitations of the ASPREE trial?

• There weren’t enough non-white participants in the study.
• The treatment duration of the ASPREE trial may not be long enough to detect an effect of low-dose aspirin on diseases that develop slowly, such as cancer and Alzheimer’s disease.
• The trial was not designed to investigate whether low-dose aspirin might be a beneficial primary prevention drug if individuals begin the treatment at a younger age.

Clinical Scenarios

• I am a healthy 70-year-old. May I take low-dose aspirin daily to prevent future disease?

If you have not been taking low-dose aspirin, do not start taking it. The risks of bleeding likely outweigh potential benefits.

If you have been taking low-dose aspirin for a while, you may want to discontinue it, but please consult with your doctor for a better risk-benefit assessment before making any decision.

• I am a healthy 60-year-old. May I take low-dose aspirin daily to prevent future disease?

Currently there are insufficient data on whether aspirin is an effective primary prevention agent for this age group. Please consult with your doctor for a more thorough assessment prior to taking aspirin.

• I am a healthy 50-year-old. May I take low-dose aspirin daily to prevent future disease?

Low-dose aspirin may be beneficial if you have increased underlying cardiovascular risks. However, this is a good time to consult with your doctor for a more thorough assessment so that you can make better informed decision.

• I have been taking low-dose aspirin for secondary prevention. Should I stop taking it?

There is strong clinical evidence that the benefits of low-dose aspirin significantly outweigh the risks, particularly for reductions in cardiovascular events and some cancer. Nevertheless, when in doubt, call your doctor.

Summary

Aspirin is not a panacea. Accumulating evidence, including data from the ASPREE trial, indicates that low-dose aspirin lacks benefits as a primary prevention agent. As a result, there is no reason for healthy older adults over the age of 70 to start low-dose aspirin to prevent future disease. However, for younger adults, and for older with pre-clinical conditions or chronic disease, the benefits may still outweigh the risks.

There are reasons why low-dose aspirin has such widespread use. It is an inexpensive yet powerful drug with many benefits, including for secondary prevention. Further, not only is aspirin anti-inflammatory, recent ground breaking research indicates that it also promotes resolution of inflammation by triggering productions of pro-resolving mediators.^15,16 Nevertheless, any drug—even a natural ingredient—also comes with attendant risks. Therefore, it is important that benefit-risk assessments are conducted based on an individual’s age, sex, current health condition, and needs, prior to committing to a regular low-dose aspirin regimen.

References

1. McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018. DOI: 10.1056/NEJMoa1800722.
2. 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. DOI: 10.1056/NEJMoa1805819.
3. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018. DOI: 10.1056/NEJMoa1803955.
4. ASPREE Investigator Group. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials. 2013;36(2):555-564.
5. McNeil JJ, Woods RL, Nelson MR, et al. Baseline characteristics of participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci. 2017;72(11):1586-1593.
6. Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018. pii: S0140-6736(18)31924-X. DOI: 10.1016/S0140-6736(18)31924-X.
7. ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018. DOI: 10.1056/NEJMoa1804988.
8. Veronese N, Stubbs B, Maggi S, et al. Low-dose aspirin use and cognitive function in older age: a systematic review and meta-analysis. J Am Geriatr Soc. 2017;65(8):1763-1768.
9. Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6921):81-106.
10. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86.
11. Antithrombotic Trialists Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860.
12. Veettil SK, Lim KG, Ching SM, Saokaew S, Phisalprapa P, Chaiyakunapruk N. Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMC Cancer. 2017;17(1):763.
13. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379(9826):1591-1601.
14. Mills EJ, Wu P, Alberton M, Kanters S, Lanas A, Lester R. Low-dose aspirin and cancer mortality: a meta-analysis of randomized trials. Am J Med. 2012;125(6):560-567.
15. Morris T, Stables M, Hobbs A, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol. 2009;183(3):2089-2096.
16. Chiang N, Bermudez EA, Ridker PM, Hurwitz S, Serhan CN. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci U S A. 2004;101(42):15178-15183.

Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.

Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.

Lewis Chang, PhD is Scientific Editorial Manager of R&D at Metagenics. Dr. Chang received his PhD in Nutritional Sciences at University of Washington, along with his MS in Nutrition and Public Health from Teachers College, Columbia University and BS in Pharmacy from National Taiwan University. Prior to joining Metagenics, he conducted dissertation research and completed a research assistantship and postdoctoral fellowship at the Fred Hutchinson Cancer Research Center in Seattle, WA. Dr. Chang has authored or co-authored and managed the publication of over 30 peer-reviewed journal articles and numerous scientific abstracts and posters. He has quite a green thumb, enjoys opera, theater and jazz, and loves cooking, collecting art, and learning to play gypsy jazz guitar.