The New England Journal of Medicine OCTOBER 18, 2018

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

John J. McNeil, Robyn L. Woods, Mark R. Nelson, et al. for the ASPREE Investigator Group

Bottom Line

In healthy elderly adults, daily low-dose aspirin did not increase the duration of disability-free survival but was associated with a significantly higher risk of major hemorrhage.

Key Findings

1. The primary composite endpoint of disability-free survival (all-cause mortality, dementia, or persistent physical disability) occurred at a rate of 21.5 events per 1,000 person-years in the aspirin group compared to 21.2 events per 1,000 person-years in the placebo group (hazard ratio, 1.01; 95% CI, 0.92 to 1.11; P=0.79).

2. Aspirin was associated with a significantly higher rate of major hemorrhage (8.6 vs. 6.2 events per 1,000 person-years; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001).

3. All-cause mortality was higher in the aspirin group compared to the placebo group (5.9% vs. 5.2%; hazard ratio, 1.14; 95% CI, 1.01 to 1.29), largely driven by an increase in cancer-related deaths.

4. Aspirin did not provide a significant reduction in cardiovascular events, including myocardial infarction, stroke, or cardiovascular death.

Study Design

Design

RCT

Double-Blind

Sample

19,114

Patients

Duration

4.7 yr

Median

Setting

Multicenter, US and Australia

Population Community-dwelling adults aged 70 years and older (or 65 years and older for US minorities) without prior cardiovascular disease, dementia, or persistent physical disability.

Intervention 100 mg enteric-coated aspirin daily

Comparator Matching placebo daily

Outcome Composite of death, dementia, or persistent physical disability

Study Limitations

• The observed increase in all-cause mortality, particularly cancer mortality, was an unexpected secondary finding that warrants cautious interpretation and further investigation.

• The study population was restricted to healthy older adults without pre-existing cardiovascular disease, limiting the generalizability of these findings to higher-risk populations.

• The follow-up period of 4.7 years may be insufficient to fully observe the long-term oncologic effects of aspirin, as cancer latency often spans longer durations.

Clinical Significance

The ASPREE trial suggests that low-dose aspirin is not beneficial for primary prevention in healthy adults aged 70 or older and carries an unfavorable benefit-risk profile due to increased major bleeding risk. These findings have led to updated clinical guidelines recommending against the routine initiation of aspirin for primary prevention in the elderly.

Historical Context

For decades, low-dose aspirin was widely recommended for cardiovascular primary prevention. However, the benefits in non-elderly populations were increasingly questioned, and there was a complete absence of high-quality data regarding its safety and efficacy in the rapidly growing elderly population, leading to the initiation of the ASPREE trial.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of aspirin's inhibition of cyclooxygenase-1 (COX-1) explain both its intended cardioprotective effect and the specific side effect of major gastrointestinal hemorrhage observed in the ASPREE trial?

Key Response

Aspirin irreversibly inhibits COX-1, which prevents the formation of Thromboxane A2 in platelets, reducing aggregation. However, COX-1 is also responsible for synthesizing cytoprotective prostaglandins in the gastric mucosa. In healthy elderly patients without established vascular disease, the benefit of reduced platelet aggregation is statistically outweighed by the loss of gastric protection, leading to the increased bleeding risk noted in the study.

Resident

A 74-year-old patient with no history of atherosclerotic cardiovascular disease (ASCVD), diabetes, or smoking presents for a wellness visit. They have been taking aspirin 81mg daily for primary prevention for ten years without side effects. Based on the ASPREE findings, what is the most appropriate management of their aspirin therapy?

Key Response

The ASPREE trial demonstrated that in adults ≥70 years, aspirin did not provide a disability-free survival benefit but significantly increased major hemorrhage. Clinicians should discuss deprescribing aspirin for primary prevention in this age group, as the lack of benefit persists even in patients who have previously tolerated the drug, and the risk of bleeding increases significantly with age.

Fellow

The ASPREE trial reported a surprising increase in all-cause mortality, primarily driven by cancer-related deaths in the aspirin group. How does this finding reconcile with—or contradict—previous meta-analyses (such as those by Rothwell et al.) that suggested a long-term chemopreventive effect of aspirin against colorectal cancer?

Key Response

Previous studies suggesting a chemopreventive effect often involved younger cohorts and longer follow-up periods (10-20 years). The ASPREE cohort was older (median 74), and the follow-up was shorter (4.7 years). The 'cancer signal' in ASPREE may suggest that in the elderly, aspirin could potentially accelerate the progression of established late-stage occult malignancies, highlighting that the biological effect of aspirin on carcinogenesis may be age- or stage-dependent.

Attending

How should the use of 'disability-free survival' as a primary composite endpoint in the ASPREE trial change our approach to evaluating preventive therapies in the 'old-old' population compared to traditional MACE (Major Adverse Cardiovascular Events) endpoints?

Key Response

Traditional MACE endpoints focus on vascular events, but for the elderly, quality of life and functional independence are often more relevant. ASPREE's use of disability-free survival (incorporating dementia and physical disability) acknowledges that a 'prevented' MI is of limited value if the patient suffers a life-altering hemorrhage or cognitive decline. This shifts the focus from organ-specific outcomes to global geriatric vitality.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

ASPREE utilized a 'healthy volunteer' cohort, excluding those with a high risk of cardiovascular disease or significant comorbidities. How does this selection bias impact the hazard ratios for bleeding, and what statistical methods could be used to estimate the effect size in a more frail, real-world geriatric population?

Key Response

Healthy volunteer bias likely underestimates the absolute risk of bleeding compared to the general elderly population. To estimate real-world effects, researchers could use targeted maximum likelihood estimation (TMLE) or G-computation to transport the trial's findings to a representative electronic health record (EHR) dataset, adjusting for the baseline covariate distributions of frailty and comorbidity.

Journal Editor

The ASPREE trial was terminated early based on the recommendation of the data and safety monitoring board (DSMB). As a reviewer, what concerns would you raise regarding the robustness of the secondary 'cancer mortality' finding given the shortened follow-up period and the potential for informative censoring?

Key Response

Early termination for futility or harm regarding the primary endpoint can lead to 'random highs' in secondary outcomes. A reviewer would flag that the cancer mortality increase lacked a clear biological mechanism and could be an artifact of baseline imbalances in occult malignancy or insufficient follow-up to see the long-term protective effects, necessitating a cautious editorial tone regarding that specific finding.

Guideline Committee

Following the publication of ASPREE, the USPSTF updated its recommendations on aspirin for primary prevention. How does this trial's evidence specifically justify the transition from a 'C' to a 'D' recommendation for adults aged 60 and older?

Key Response

Prior to ASPREE, there was insufficient evidence for the ≥70 age group. The 2022 USPSTF update now recommends against (Grade D) initiating aspirin for primary prevention in adults aged 60 years or older. The ASPREE trial provided the definitive high-level evidence that the 'net benefit' is negative in this cohort, as the certain risk of major hemorrhage (HR 1.38) consistently offsets any potential, statistically non-significant reduction in cardiovascular events.

Clinical Landscape

Noteworthy Related Trials

1998

HOT Trial

n = 18,790 · Lancet

Tested

Low-dose aspirin 75mg daily

Population

Patients with hypertension

Comparator

Placebo

Endpoint

Major cardiovascular events

Key result: Aspirin significantly reduced the risk of major cardiovascular events, specifically myocardial infarction, in hypertensive patients.

2018

ARRIVE Trial

n = 12,546 · Lancet

Tested

Aspirin 100mg daily

Population

Patients at moderate risk for cardiovascular disease

Comparator

Placebo

Endpoint

Time to first occurrence of composite cardiovascular outcome

Key result: Aspirin use did not result in a lower rate of cardiovascular events compared to placebo in patients at moderate cardiovascular risk.

2018

ASCEND Trial

n = 15,480 · NEJM

Tested

Aspirin 100mg daily

Population

Patients with diabetes and no evident cardiovascular disease

Comparator

Placebo

Endpoint

Composite of serious vascular events

Key result: Aspirin prevented serious vascular events in diabetic patients but also significantly increased the risk of major bleeding.

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