ASPREE

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McNeil JJ, et al. "Effect of aspirin on disability-free survival in the healthy elderly". The New England Journal of Medicine. 2018. 379(16):1-10.
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Clinical Question

Among healthy, community-dwelling seniors, does low-dose aspirin reduce death, dementia, or persistent physical disability when compared with placebo?

Bottom Line

Among healthy, community-dwelling seniors, does low-dose aspirin did not reduce incident death, dementia, or persistent physical disability when compared with placebo. Aspirin was associated with increased risk of major hemorrhage.

Major Points

Trials like ISIS-2 (1988) solidified the role of aspirin in secondary prevention of CVD. The role of aspirin in primary prevention is less clear, especially among low-risk elderly adults. In this population, the bleeding risk from aspirin may outweigh the benefit from CVD risk reduction. As a reflection of the uncertain benefit of aspirin in seniors, the 2016 USPSTF guidelines were unable to give a recommendation on the use of aspirin among adults age ≥70 years.[1]

The Aspirin in Reducing Events in the Elderly (ASPREE; 2018) trial enrolled 19,114 healthy elderly patients (≥70 years old, ≥65 years old in Hispanic or Black patients) without a history of CVD, cerebrovascular disease, dementia, or any other chronic condition that would likely limit survival to less than 5 years. Patients were randomized to either aspirin 100mg daily or placebo and followed prospectively for all-cause death, dementia, or physical disability. With a median follow-up of 4.7 years, rates of disability-free survival were similar between aspirin and placebo groups (21.5 and 21.2 events per 1000 person-years, respectively). Aspirin was associated with higher incidence of major hemorrhage (8.6 vs. 6.2 events per 1000 person years; HR 1.38; 95% CI 1.18-1.62; P<0.001).

The trial highlights the growing shift toward patient centered outcomes measuring disability free survival as recognition of the importance of quality as well as quantity of life. It was published alongside two other primary prevention trials ASCEND (2018)[2] and ARRIVE (2018)[3], which also found no benefit of aspirin in diabetic patients and high risk patients without diabetes, respectively. Despite the results of these 3 recent trials, a 2019 meta-analysis of 13 primary prevention trials still found a benefit for aspirin use in primary prevention (HR 0.89, 95% credible interval 0.84, 0.95; NNT=265) at a cost of increased bleeding (HR 1.43; 95% credible interval 1.30, 1.56; NNH=210).[4]

Guidelines

ACC/AHA primary prevention of CVD (2019, adapted)

  • Aspirin 75-200 mg po qday for primary prevention of ASCVD:
    • Consider use in select adults 40-70 years old at elevated risk of ASCVD but not at elevated risk of bleeding (COR IIb, LOE A)
    • Avoid use among adults age >70 years old (COR III/harm, LOE B-R)
    • Avoid use among adults of any age at increased risk of bleeding (COR III/harm, LOE C-LD)

Design

  • Multicenter, randomized, double-blind, placebo-controlled
  • N=19,114
    • Aspirin (n=9,525)
    • Placebo (n=9,589)
  • Setting: 34 sites in the United States and 16 sites in Australia
  • Enrollment: 2010-2014
  • Median follow-up: 4.7 years
  • Analysis: Intention-to-treat
  • Primary outcome: Disability-free survival

Population

Inclusion Criteria

  • Age ≥70 years; age ≥65 if in the US and black or Hispanic

Exclusion Criteria

  • Prior CVD including MI, HF, angina, CVA/TIA, carotid stenosis >50% or prior CEA/stent, prior PCI/angioplasty/CABG, or AAA
  • Atrial fibrillation
  • Dementia or modified MMSE score <78/100
  • Severe physical disability (e.g., unable to perform ADLs)
  • High risk of bleeding or anemia (hgb <12 in males or <11 g/dL in females)
  • Other condition with likely death within 5 years.
  • Current use of antiplatelet or anticoagulant
  • Aspirin use for secondary prevention
  • Uncontrolled hypertension
  • Not willing to stop aspirin use, if currently taking for primary prevention
  • Compliance <80% during 4 week run-in
  • Other trial participation

Baseline Characteristics

Values are means unless otherwise stated

  • Median age 74 years, 56% Female
  • BMI: 28.1
  • Hemoglobin: 14.2
  • Fasting glucose: 98.9
  • HDL 61.5, total cholesterol 202.7
  • Creatinine 0.9, eGFR 73
  • SBP 139 ± 17 mmHg, DBP 77 ± 10 mmHg

Interventions

  • Patients were randomized to either aspirin 100mg of enteric coated aspirin daily or placebo.
  • All underwent 4-week placebo run-in phase, patients with 80% adherence as measured by pill count were randomized 1:1
  • Patients had in person visits yearly and 3 monthly phone call to encourage retention

Outcomes

Presented as aspirin vs. placebo. Values are events per 1000 patient-years

Primary Outcome

Disability-free survival (Defined as all-cause mortality, dementia, or persistent physical disability.)
21.5 vs 21.2 events (HR = 1.01; 95% CI, 0.92-1.11, P=0.79)

Secondary Outcomes

All-cause mortality
12.7 vs 11.1 events (HR 1.14; 95% confidence interval [CI], 1.01 to 1.29)
Dementia
6.7 vs. 6.9 events (HR 0.98; 95% CI, 0.83-1.15)
Persistent physical disability
4.9 vs. 5.8 events (HR 0.85, 95% CI 0.70-1.03)
Major hemorrhagic event
8.6 vs. 6.2 events (HR 1.38 95% CI 1.18-1.62, P <0.001)
Clinically significant bleeding including hemorrhagic stroke.

Subgroup Analysis

For the primary outcome the lack of effect was consistent across all subgroups, with exception of frailty. This effect however was inconsistent; there was no benefit in the non frail and fail group but favoured aspirin in the pre-frail group.

Criticisms

  • Lack of generalisability to non-white population (91.3% of participants white)
  • Like the other 2018 trials, low adherence to aspirin (60 to 70% in all trials) and high crossover[5]

Funding

Grants received from the National Institute on Ageing, National Cancer Institute at the National Institutes of Health, National Health and Medical Research Council of Australia, Monash University and the Victorian Cancer Agency.

Further Reading

  1. Bibbins-Domingo K & U.S. Preventive Services Task Force Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann. Intern. Med. 2016. 164:836-45.
  2. Bowman L et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N. Engl. J. Med. 2018. 379:1529-1539.
  3. Gaziano JM 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. 392:1036-1046.
  4. Zheng SL & Roddick AJ Association of Aspirin Use for Primary Prevention With Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis. JAMA 2019. 321:277-287.
  5. Fernandes A et al. "Doctor, Should I Keep Taking an Aspirin a Day?". N. Engl. J. Med. 2019. 380:1967-1970.