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McNeil JJ, Nelson MR, Woods RL, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med. 2018 Sep 16. doi: 10.1056/NEJMoa1803955.
Area Score
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Geriatrics
Public Health
Internal Medicine
Abstract

Background In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo. Methods From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or =65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed. Results Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). Conclusions Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Comments from MORE raters

General Internal Medicine-Primary Care(US) rater

The recently published ASPREE study of the effects of low-dose aspirin on disability-free survival in older adults demonstrated a borderline statistically significant increased risk for death in the aspirin group. The number-needed-to-treat to cause harm was quite high though at 143. Cancer deaths accounted for most of this increase. No particular cancer predominated. The authors rightly note that other aspirin studies have not demonstrated this result. The number of clinical endpoints that occurred was much less than the general population rate. This reduced the power of the study overall for a number of the measured endpoints. It does seem, though, that a takeaway message from the recent aspirin studies is that aspirin does not add much in primary prevention for most patients with controlled blood pressure and with good lipid control on statins who are otherwise fairly healthy.

Geriatrics rater

This is a thought-provking article that raises questions about the efficacy and safety of low-dose ASA in relatively healthy older persons at a time when low-dose ASA has been recommended for nearly all healthy elderly. As pointed out by the authors, the article's strength compared with previous studies is that it is based on an exclusively older population. The finding by McNeil et al that ASA appears to increase the risk for both all-cause mortality and cancer-related mortality irrespective of site appears to contradict previous meta-analyses, and may reflect a different biology in an older population that was poorly represented in previous studies. The authors acknowledge that the principal limitation is they did not statistically take into account their multiple comparisons, so the association of ASA with a small but statistically significant increased risk for cancer after ~3 years cannot be taken as definitive. Interestingly, in their supplementary analyses (Forest plot S2), being a white Australian but not being a white American was associated with a significantly increased risk for cancer-related mortality. This suggests that there may be an environment-ASA interaction that requires further exploration.

Internal Medicine rater

Even if one doesn`t believe the cancer-related excess mortality is causal, some of my primary care colleagues would do well to recognize that, at a minimum, there was no benefit of low-dose aspirin therapy in otherwise healthy older adults. There is the pervasive faith that something shown to be beneficial in patients with disease should also be beneficial in patients without disease - ergo the widespread belief that a baby aspirin "can`t hurt and might help" healthy adults, even not-so-old adults. Studies like this ought to help restrain that kind of thinking.

Public Health rater

The majority of participants were overweight or obese, which is a serious risk factor for developing cancer. Also, in different categories (diabetes, history of smoking, former cancer history), there were small differences between groups that might have influenced the result.

Public Health rater

This is definitely an important paper that could change a well entrenched paradigm for a hospitalist.