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ASPREE

Effect of Aspirin on Disability-free Survival in the Healthy Elderly

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Year of Publication: 2018

Authors: McNeil JJ, Woods RL, Nelson MR, ..., for the ASPREE Investigator Group

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2018;379:1499-508.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1800722

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1800722

Clinical Question

Does daily low-dose aspirin (100 mg) prolong disability-free survival (survival free from dementia or persistent physical disability) compared with placebo in healthy community-dwelling older adults without cardiovascular disease?

Bottom Line

In 19,114 healthy elderly persons (median age 74) followed for a median of 4.7 years, daily 100 mg enteric-coated aspirin did not prolong disability-free survival compared with placebo (HR 1.01; 95% CI 0.92-1.11; P=0.79). Aspirin significantly increased major hemorrhage by 38% (3.8% vs 2.8%; HR 1.38; P<0.001), with an additional 2.4 serious bleeding events per 1000 person-years. All-cause mortality was numerically higher with aspirin (HR 1.14; 95% CI 1.01-1.29, unadjusted for multiple comparisons); the authors note this difference could be a chance finding and defer cause-specific analyses to companion articles.

        Major Points
        No benefit on disability-free survival: aspirin 100 mg daily vs placebo, HR 1.01 (95% CI 0.92-1.11; P=0.79), rates 21.5 vs 21.2 per 1000 person-years.
Significantly increased major hemorrhage: 3.8% vs 2.8% (HR 1.38; 95% CI 1.18-1.62; P<0.001), +2.4 serious bleeding events per 1000 person-years.
No reduction in dementia: 6.7 vs 6.9 per 1000 person-years (HR 0.98; 95% CI 0.83-1.15).
Numerically higher all-cause mortality with aspirin: 12.7 vs 11.1 per 1000 person-years (HR 1.14; 95% CI 1.01-1.29), unadjusted for multiple comparisons.
Deaths dominated the primary endpoint (50%), followed by dementia (30%) and persistent physical disability (20%).
Trend toward reduced persistent physical disability with aspirin: 4.9 vs 5.8 per 1000 person-years (HR 0.85; 95% CI 0.70-1.03) — not significant.
Consistent null result across nearly all subgroups: no effect modification by sex, age, country, race, BMI, smoking, diabetes, hypertension, dyslipidemia, cancer history, or prior aspirin use.
Trial stopped early for futility in June 2017 (median 4.7 years, IQR 3.6-5.7) after interim analysis showed similar primary endpoint rates.
19,114 participants aged ≥70 (≥65 for Black/Hispanic in US), median age 74, 56% female, from 50 centers in Australia and US. 4-week placebo run-in required ≥80% adherence.
Landmark trial that, along with ARRIVE and ASCEND (published simultaneously in 2018), led to revised ACC/AHA guidelines against routine aspirin for primary prevention in adults ≥70.

      

Design

Study Type: Randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind (participants, trial staff, investigators, GP associates all blinded). Block randomization stratified by trial center (US) or GP clinic (Australia) and age (65-79 or ≥80). 4-week placebo run-in with ≥80% adherence required.

Enrollment Period: March 2010 to December 2014

Follow-up Duration: Median 4.7 years (IQR 3.6-5.7). Stopped early June 2017 for futility.

Centers: 50

Countries: Australia, United States

Sample Size: 19114

Analysis: Intention-to-treat. Planned interim analysis at 1,893 primary events using Haybittle-Peto stopping rule.

Inclusion Criteria

Community-dwelling men and women.
Age ≥70 years (≥65 for Black and Hispanic individuals in the United States).
Free from cardiovascular or cerebrovascular disease.
Free from any chronic illness likely to limit survival to <5 years.
Modified Mini-Mental State Examination (3MS) score ≥78 (scale 0-100).
No substantial physical disability: no Katz ADL score of 4 or 5 on any of 6 basic activities.
Adherence ≥80% during 4-week placebo run-in (measured by pill count).

Exclusion Criteria

Clinical diagnosis of dementia.
Known high risk of bleeding.
Contraindication to aspirin.
3MS score <78.
Substantial physical disability (Katz ADL score 4 or 5 on any item).
History of cardiovascular or cerebrovascular disease.
Low hemoglobin level.
Uncontrolled high blood pressure.
Chronic illness likely to limit survival to <5 years.
Physician judgment that participant was ineligible.

Baseline Characteristics

Characteristic	Aspirin (N=9,525)	Placebo (N=9,589)
Age 65-73	4,719 (49.5%)	4,823 (50.3%)
Age ≥74	4,806 (50.5%)	4,766 (49.7%)
Median age	74 years	74 years
Female sex	5,373 (56.4%)	5,410 (56.4%)
Australia	8,322 (87.4%)	8,381 (87.4%)
United States	1,203 (12.6%)	1,208 (12.6%)
White	8,708 (91.4%)	8,742 (91.2%)
Black	451 (4.7%)	450 (4.7%)
Hispanic	240 (2.5%)	248 (2.6%)
BMI (mean±SD)	28.1±4.8	28.1±4.7
Current smoker	352 (3.7%)	383 (4.0%)
Diabetes mellitus	1,027 (10.8%)	1,030 (10.7%)
Hypertension	7,065 (74.2%)	7,148 (74.5%)
Dyslipidemia	6,159 (64.7%)	6,308 (65.8%)
Cancer history	1,827 (19.2%)	1,833 (19.1%)
Prior regular aspirin use	1,053 (11.1%)	1,041 (10.9%)
Not frail	5,603 (58.8%)	5,643 (58.8%)
Prefrail	3,707 (38.9%)	3,740 (39.0%)
Frail	215 (2.3%)	206 (2.1%)

Arms

Field	Aspirin	Control
Intervention	100 mg enteric-coated aspirin tablet once daily (supplied by Bayer Pharma, Germany).	Matching placebo tablet once daily (supplied by Bayer Pharma, Germany).
Duration	Median 4.7 years (IQR 3.6-5.7). Adherence in final 12 months: 62.1%.	Median 4.7 years (IQR 3.6-5.7). Adherence in final 12 months: 64.1%.

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of death from any cause, dementia, or persistent physical disability (first occurrence)	Primary	914 events; 21.2 per 1000 person-years	921 events; 21.5 per 1000 person-years	1.01	0.79
Death from any cause	Secondary	494; 11.1 per 1000 py	558; 12.7 per 1000 py	HR 1.14
Dementia	Secondary	292; 6.9 per 1000 py	283; 6.7 per 1000 py	HR 0.98
Persistent physical disability	Secondary	224; 5.8 per 1000 py	188; 4.9 per 1000 py	HR 0.85
Major hemorrhagic event	Secondary	265 (2.8%); 6.2 per 1000 py	361 (3.8%); 8.6 per 1000 py	HR 1.38	<0.001
Hemorrhagic stroke (incl SAH)	Secondary	40 (0.4%)	49 (0.5%)
Major hemorrhage	Adverse	265 (2.8%); 6.2 per 1000 py	361 (3.8%); 8.6 per 1000 py	HR 1.38	<0.001
Clinically significant bleeding	Adverse	225; 5.3 per 1000 py	312; 7.4 per 1000 py
Hemorrhagic stroke	Adverse	40 (0.4%)	49 (0.5%)
Additional bleeding attributable to aspirin	Adverse		2.4 per 1000 person-years exposure

Subgroup Analysis

Pre-specified subgroups: sex, age (<74 vs ≥74), country, race/ethnicity, BMI, prior aspirin use, frailty (not frail/prefrail/frail), cancer history, smoking, diabetes, hypertension, dyslipidemia. No significant interactions with the primary endpoint except for frailty (inconsistent directions across categories). Consistent null result across all other subgroups.

Criticisms

Relatively short duration (median 4.7 years) — may be too short for conditions with long latencies like Alzheimer's disease and cancer.
Does not address benefit of earlier initiation (younger age) or longer duration of aspirin.
Predominantly white population (91.3%) — limited applicability to Black, Hispanic, and other nonwhite groups.
Does not address whether healthy older persons already taking aspirin should discontinue.
Early termination for futility may have reduced power for secondary endpoints.
Declining adherence: only 62-64% still taking study medication in final 12 months.
Low prior aspirin use (11%) limits generalizability to that population.
Secondary endpoints not adjusted for multiple comparisons — mortality signal (HR 1.14) should be interpreted cautiously.

Funding

National Institute on Aging (U01AG029824), National Cancer Institute (NIH). National Health and Medical Research Council of Australia; Monash University; Victorian Cancer Agency. Bayer Pharma provided aspirin and placebo but had no other role.

Based on: ASPREE (The New England Journal of Medicine, 2018)