Among 19,114 healthy elderly patients without cardiovascular disease who were randomized to low-dose aspirin or placebo, aspirin did not reduce the primary composite outcome of death, dementia or persistent physical disability compared to placebo after a median follow-up of 4.7 years. Aspirin was associated with a higher risk of major hemorrhage. Similar recent trials found no benefit of aspirin for primary prevention in diabetic patients or those at moderate cardiovascular risk without increasing bleeding risk. Guidelines do not recommend routine aspirin use for primary prevention in adults over 70 years old due to lack of benefit and risk of bleeding.

1. Effect of Aspirin on Disability-free
Survival in the Healthy Elderly
Aspirin in Reducing Events in the Elderly (ASPREE)
Kerolus Shehata, MD

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

3. 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.

4. Study 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

6. Inclusion Criteria
• Age ≥70 years
• Age ≥65 if in the US and black or Hispanic

7. 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 M or <11 in F)
• Other condition with likely death within 5 years.
• Current use of antiplatelet or anticoagulant
• Aspirin use for secondary prevention
• Uncontrolled HTN
• Not willing to stop aspirin use, if currently taking for primary
prevention
• Compliance <80% during 4 week run-in
• Other trial participation

8. • 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
Baseline Characteristics

9. • For all variables, odds ratios
were between 0.67 and 1.50
(with an odds ratio of 1.50 as
the pre-specified limit for
performing an adjusted
analysis of end points) and
there were no significant
(P>0.05) differences between
the two trial groups.

10. Intervention
• Patients were randomized to either 100 mg 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.

11. Results

12. Cumulative Incidence
• The percentage of individuals who experience
the event in a defined time period.

13. Hazard Ratio
• The chance of an event occurring in the intervention
arm divided by the chance of the event occurring in
the control arm.
• Hazard ratios do not reflect a time unit of the study.

14. Cumulative Incidence of the Primary
Composite End Point
• First events that counted
toward the primary end
point during the trial
included 911 deaths, 549
cases of dementia, and
375 cases of persistent
physical disability.
• The graph stops at year 6
because only a small
number of participants
(44 in the aspirin group
and 43 in the placebo
group) reached year 7
21.5 vs 21.2 events per 1,000 Persons-years (HR = 1.01; 95% CI, 0.92-1.11, P=0.79)

15. Cumulative Incidence of Death
12.7 vs 11.1 events (HR 1.14; 95% confidence interval [CI], 1.01 to 1.29)
5.9% in the aspirin group vs. 5.2% in the placebo group (p < 0.05)

16. Cumulative Incidence of Dementia
6.7 vs. 6.9 events (HR 0.98; 95% CI, 0.83-1.15)

17. Cumulative Incidence of Persistent
physical disability
4.9 vs. 5.8 events per 1000 persons (HR 0.85, 95% CI 0.70-1.03)

18. Cumulative Incidence of CV events
10.7 events per 1,000 person-years
in the aspirin group vs. 11.3 events
per 1,000 person-years in the
placebo group (p = not significant)

19. Incidence of Major hemorrhage
8.6 events per 1,000 person-years in the aspirin group
vs. 6.2 events per 1,000 person-years in the placebo
group (p < 0.001)

20. Recap
• ASPREE 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 was published alongside two other primary prevention trials ASCEND
(2018) and ARRIVE (2018) 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).

21. Criticism
• Lack of generalizability to non-white
population (91.3% of participants are white)
• Like the other 2018 trials, low adherence to
aspirin (60 to 70% in all trials) and high
crossover.

22. 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.

23. Can we trust the study results?
• Internal validity: Can we attribute the
observed results on the study intervention or
is it confounded/biased through the study
design?
• External validity: Can we generalize the study
results on the general population:

24. Similar Trials
• The ARRIVE trial “Aspirin to Reduce Risk of Initial Vascular Events” showed
that among younger individuals with moderate risk of coronary heart
disease, the use of aspirin was not beneficial.
• The ASCEND trial “A Study of Cardiovascular Events In Diabetes” showed
that among diabetic patients, aspirin reduced the incidence of major
adverse cardiovascular events; however, this was somewhat
counterbalanced by an increase in major bleeding.

25. 2019 AHA/ACC Recommendations
for Aspirin Use
COR LOE Recommendations
IIb A
1. Low-dose aspirin (75-100 mg orally daily) might be
considered for the primary prevention of ASCVD
among select adults 40 to 70 years of age who are at
higher ASCVD risk but not at increased bleeding risk.
III:
Harm
B-R
2. Low-dose aspirin (75-100 mg orally daily) should not
be administered on a routine basis for the primary
prevention of ASCVD among adults >70 years of age.
III:
Harm
C-LD
3. Low-dose aspirin (75-100 mg orally daily) should not
be administered for the primary prevention of ASCVD
among adults of any age who are at increased risk of
bleeding.

26. USPSTF Recommendations

27. References
• McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free
survival in the healthy elderly. 2018;379:1499-1508.
• 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(16):1509–1518.
doi:10.1056/NEJMoa1805819
• 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. doi:10.1016/j.cct.2013.09.014
• Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of
randomized trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86.
• Zheng SL, Roddick AJ. Association of Aspirin Use for Primary Prevention With
Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-
analysis [published correction appears in JAMA. 2019 Jun 11;321(22):2245].
JAMA. 2019;321(3):277–287. doi:10.1001/jama.2018.20578

28. Thank You