Low-dose aspirin increases risk of anemia in older people
Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly: A Secondary Analysis of the Aspirin in Reducing Events in the Elderly TrialLiterature - McQuilten ZK, Thao LTP, Pasricha SR, et al. - Ann Intern Med. 2023 Jul;176(7):913-921. doi: 10.7326/M23-0675
Introduction and methods
The risk of major bleeding during aspirin therapy is highest in older age groups . At the same time, approximately 30% of people aged ≥75 years are anemic , but very few studies have measured the effect of aspirin on anemia, particularly in the elderly.
Aim of the study
The study aim of this analysis was to investigate the effect of daily low-dose aspirin on the incidence of anemia in a generally healthy older population. The secondary aims were to explore the effect of aspirin on changes in hemoglobin and ferritin (as indicator of iron deficiency) levels.
This was a post-hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) trial, a double-blind, placebo-controlled, primary prevention RCT designed to assess whether daily aspirin treatment extends the duration of disability-free life compared with placebo in healthy older people [3-7]. In total, 19,114 community-dwelling persons aged ≥70 years (≥65 years for US participants of Black or Hispanic heritage) in Australia and the USA were randomized to enteric-coated aspirin 100 mg daily or placebo.
Key exclusion criteria were, among others, anemia (defined as hemoglobin<120 g/L for men and <110 g/L for women), current or recurrent condition with a high bleeding risk, current use of aspirin for secondary prevention, use of other antiplatelet drugs or anticoagulants, and history of diagnosed CV event. Hemoglobin levels were measured annually, whereas ferritin levels were assessed at baseline and 3 years after randomization.
In the post-hoc analysis, participants who met the WHO definition of anemia (hemoglobin<130 g/L for men and <120 g/L for women) or with no baseline hemoglobin measurements were excluded, leaving 18,153 participants for the analysis (of whom 9407 were treated with aspirin and 9106 received placebo). Median follow-up duration was 4.7 years (IQR: 3.6–5.7).
The primary endpoint was incident anemia, defined according to the WHO definition. A prespecified secondary endpoint of the trial was major bleeding, which was a composite of hemorrhagic stroke, symptomatic intracranial bleeding, or clinically significant extracranial bleeding (defined as bleeding leading to transfusion, hospitalization, prolongation of hospitalization, surgery, or death).
Effect of aspirin on anemia incidence
- The incidence of anemia was 51 events per 1000 person-years in the aspirin group and 43 events per 1000 person-years in the placebo group (HR: 1.20; 95%CI: 1.12–1.29).
- The estimated probability of experiencing anemia within 5 years was 23.5% (95%CI: 22.4%–24.6%) in the aspirin group and 20.3% (95%CI: 19.3%–21.4%) in the placebo group.
- A sensitivity analysis that accounted for cancer incidence showed the same treatment effect for aspirin (HR: 1.20; 95%CI: 1.11–1.30). After adjustment for characteristics associated with increased anemia risk, the treatment effect also remained (adjusted HR: 1.19; 95%CI: 1.11–1.28).
- The effect of aspirin on incident anemia was consistent across several subgroups, such as after stratification by age, sex, CKD, diabetes, smoking status, alcohol use, prior aspirin use, and NSAID or proton pump inhibitor use.
Effect of aspirin on hemoglobin level
- The mean decline in hemoglobin level was 3.6 g/L per 5 years in the placebo group. The aspirin group had an estimated lower mean hemoglobin level at baseline of 0.4 g/L (95%CI: 0.1–0.7) and experienced a steeper decline by 0.6 g/L per 5 years (95%CI: 0.3–1.0) compared with placebo.
Effect of aspirin on ferritin level
- Among 7139 participants with ferritin measurements at baseline and 3 years, the number of individuals with ferritin<45 µg/L at 3 years was greater in the aspirin group compared with the placebo group (13% vs. 9.8%), as was the prevalence of ferritin <100 mg/L at 3 years (39% vs. 31%).
- After adjustment for baseline ferritin levels, the mean decrease in ferritin level at 3 years in the aspirin group was 11.5% (95%CI: 9.3%–13.7%) greater compared with the placebo group.
- During the study, 273 participants (3.0%) in the aspirin group experienced ≥1 major bleeding event versus 192 (2.1%) in the placebo group.
- The total number of major bleeding events was 303 in the aspirin group and 215 in the placebo group.
- A sensitivity analysis in which major bleeding events were treated as a competing risk, in addition to all-cause death, showed that the effect of aspirin on anemia incidence, hemoglobin trajectory, and ferritin levels remained largely unchanged.
This post-hoc analysis of the ASPREE trial among community-dwelling elderly persons, with a median follow-up time of 5 years, showed that daily low-dose aspirin increased the risk of incident anemia by approximately 20% and induced a small but steeper decline in hemoglobin levels over time and a greater decrease in ferritin levels compared with placebo.
Although the authors did not collect data on the causes of anemia, they believe their findings together indicate the anemia was most likely related to lesser-grade or occult bleeding induced by aspirin use. “Because aspirin is typically a long-term intervention, it is likely that anemia will become progressively more frequent as treatment continues and thus indicates the need for regular measurement of hemoglobin levels among older aspirin-treated patients.”