By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: A post-hoc analysis of the ASPREE trial revealed that in presumably healthy elderly subjects, taking low-dose aspirin daily over three years was associated with a significant drop in hemoglobin and ferritin levels vs. placebo, even when patients with major bleeding events were excluded.
SOURCE: McQuilten ZK, Thao LTP, Pasricha SR, et al. Effect of low-dose aspirin versus placebo on incidence of anemia in the elderly. Ann Intern Med 2023;176:913-921.
Anemia is common in people older than age 75 years, which is detrimental to their health. Aspirin is common for secondary prevention of cardiac and cerebrovascular disease (less so for primary prevention). Although aspirin has been associated with major bleeding, usually gastrointestinal (GI), little is known about its potential contribution to chronic anemia of the elderly.
McQuilten et al performed a post-hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, which was a double-blind, randomized, placebo-controlled primary prevention study. During ASPREE, the researchers assessed whether taking 100 mg of aspirin per day vs. placebo would extend the duration of disability-free life in healthy individuals age 70 years and older (age 65 years and older for Black and Hispanic participants from the United States). All participants underwent annual hemoglobin concentration measurements, along with a more extensive biochemical analysis at entry and at three years.
The primary outcome of this post-hoc analysis was the incidence of anemia according to World Health Organization criteria (hemoglobin [Hgb] level lower than 130 g/dL for men and lower than 120 g/dL for women). Secondary outcomes included ferritin levels to assess iron deficiency and major hemorrhage.
ASPREE included 18,153 presumably healthy community-dwelling subjects living in Australia and the United States. The authors excluded patients with Hgb levels lower than 12 g/dL for men and lower than 11 g/dL for women; patients living with current or recurrent bleeding conditions; those currently using aspirin for secondary prevention; those using antiplatelet or anticoagulant drugs; and those with a history of a cardiovascular event, atrial fibrillation, or dementia. Subjects were allowed to take other nonsteroidal anti-inflammatory drugs.
The previously reported primary results of ASPREE indicated there was a higher risk of death from cancer in the aspirin group vs. placebo.1 Accordingly, investigators performed a sensitivity analysis to assess whether the effect of aspirin on anemia risk was independent of cancer events. The median follow-up was 4.7 years in both groups, and 78% underwent at least a three-year follow-up.
Fewer than 6% died, and fewer than 3% were lost to follow-up. The estimated probability of developing anemia within five years was 24% for the aspirin group and 20% for the placebo group (HR, 1.20; 95% CI, 1.12-1.30). By three years, ferritin levels had declined by 16% in the aspirin group vs. 3% in the placebo group.
More patients in the aspirin group recorded ferritin levels that were lower than 45 μg/L (13% vs. 10%) and experienced a greater overall decline in ferritin levels by 12% vs. placebo. Sensitivity analyses, such as excluding those with major bleeding or cancer, did not affect the results.
The authors concluded that among apparently healthy older adults, low-dose aspirin increased the incidence of anemia and decline in ferritin levels independent of major bleeding. They recommended periodic monitoring of hemoglobin in older patients taking aspirin.
COMMENTARY
This analysis of the ASPREE study suggests this aspirin-associated anemia likely is caused by occult (presumably GI) bleeding, since those with major bleeding were excluded. Aspirin inhibits the COX-1 enzyme, which reduces gastric prostaglandins, weakens the protective barrier of the gut wall, and slows platelet aggregation. All this would promote occult GI bleeding. Since this phenomenon likely results in progressive anemia with time, McQuilten et al recommended periodic monitoring of hemoglobin levels in older patients who are taking aspirin. Once a year would be a reasonable frequency, but probably should be shorter for those with predisposing conditions, such as renal dysfunction and systemic inflammatory diseases. Also, the authors suggested confining prophylactic aspirin use in older patients to evidence-based indications.
The large study population; the randomized, double-blind design; the two country-based patient population; and the exclusion of subjects with anemia or conditions predisposing to it at baseline all were strengths. Thus, the results should be widely applicable.
However, there were some weaknesses. For example, major bleeding episodes had to result in hospitalization to be detected, so bleeding (e.g., epistaxis that could be treated at home) was not included. The authors did not explore the causes of anemia; any iron supplementation after the entry visit might not have been reported. Finally, there was no functional or quality of life assessment. Still, for older patients on aspirin therapy, detecting anemia and treating it seems like a reasonable thing to do.
REFERENCE
1. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018;379:1519-1528.
A post-hoc analysis of the ASPREE trial revealed that in presumably healthy elderly subjects, taking low-dose aspirin daily over three years was associated with a significant drop in hemoglobin and ferritin levels vs. placebo, even when patients with major bleeding events were excluded.
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