Aspirin Associated with Increased Risk for Incident Heart Failure in Large Patient-level Pooled Analysis

Blerim Mujaj, MD, PhD

Use of aspirin is associated with a 26% increased risk of heart failure (HF) in persons who have at least one risk factor for the condition, according to findings of a study published online Monday in the journal ESC Heart Failure. HF risk factors evaluated in the study included smoking, obesity, hypertension, elevated cholesterol, diabetes, and cardiovascular disease (CVD)

“This is the first study to report that among individuals with a least one risk factor for heart failure, those taking aspirin were more likely to subsequently develop the condition than those not using the medication,” said study lead author Blerim Mujaj, MD, PhD, of the University of Freiburg, Germany in a statement from the European Society of Cardiology. “While the findings require confirmation, they do indicate that the potential link between aspirin and heart failure needs to be clarified.”

Mujaj and colleagues cite results of previous randomized trials (WATCH, WARCEF) that found no beneficial effect of aspirin in patients with HF compared with other antithrombotic therapy. A third trial (WASH), while it did not include an antithrombotic arm, concluded there was no evidence that aspirin was "effective or safe," in HF patients. Still other studies have produced contradictory results, the investigators say, with the totality of data leaving uncertainty--and controversy--about the aspirin-HF association.

Their study aimed to evaluate incident HF among persons with and without CVD and to determine whether there is an association between aspirin use and new HF diagnosis in at-risk individuals.

Study population

For the study cohort, the researchers tapped the HOMAGE database which includes subject-level data from 21 studies of >46 000 participants from western Europe and the US. Study eligibility for inclusion in the current analysis required availability of information on aspirin use and the incidence of fatal and/or non-fatal HF, with at least 20 HF events.

The final population selected for analysis numbered 30 287 individuals at risk for developing HF where "at risk" was defined as presence of ≥1 of the following: smoking, obesity, high blood pressure, elevated cholesterol, diabetes, and CVD. Participants were aged ≥40 years and free of heart failure at baseline.

Aspirin use was recorded at enrolment and participants were classified as users or non-users. Among users, investigators recorded the main therapeutic indications (eg, hypertension, MI, CHD, AF, or history of cerebrovascular events). Participants were followed-up for the first incidence of fatal or non-fatal HF hospitalization.

Average age of participants in the final group was 67 years, 33.9% were women. At baseline, a total of 7698 (24.9%) participants were treated with aspirin.

Findings

During a median follow-up period of 5.3 years, 1330 participants experienced fatal or non-fatal HF with an incident rate of 14.5 (95% CI 13.4–15.7) per 1000 person-years in the aspirin group versus 5.9 (95% CI 5.5–6.4) per 1000 person-years in the non-aspirin group.

The authors then describe 4 levels of adjustment for aspirin use using multivariable regression:

1. Age and sex
2. BMI, smoking, alcohol, systolic/diastolic BP, heart rate, total cholesterol/HDL ratio, creatinine
3. Treatment with RAAS inhibitors, CCBs, diuretics, beta-blockers, lipid-lowering treatment
4. History of hypertension, diabetes, history of CVD

They found that, regardless of adjustment model used, the risk of HF was consistently and positively associated with aspirin use.

A follow-up analysis to evaluate consistency of the results matched aspirin users and nonusers for HF risk factors and, according to the study, aspirin remained associated with a 26% increased risk of a new HF diagnosis. Further, on repeated analysis after exclusion of persons with a CVD history, among the nearly 23 000 participants (64%) free of CVD, aspirin use was associated with a 27% increased risk of incident heart failure.

Finally, in stratified analyses to assess differences in risk between categories of age, sex, and body eight, Mujaj and colleagues report an association of increased risk for incident HF in men (HR 1.37, 95% CI 1.17–1.59; P_interaction=.04) and an association of increased risk for incident HF among the participants aged >69 years (P_interaction=.03)

“This was the first large study to investigate the relationship between aspirin use and incident heart failure in individuals with and without heart disease and at least one risk factor,” said Mujaj in the statement. “Aspirin is commonly used – in our study one in four participants were taking the medication. In this population, aspirin use was associated with incident heart failure, independent of other risk factors.”

“Aspirin is commonly used – in our study one in four participants were taking the medication. In this population, aspirin use was associated with incident heart failure, independent of other risk factors.”

The authors write in the study conclusion that current clinical guidelines on the use of aspirin reflect ongoing uncertainty about risk vs benefit, noting that “aspirin use for primary prevention has been controversial even when compared with aspirin use in patients with established atherosclerotic CVD.” Their findings support the need for additional clarity on any benefit of aspirin use on HF events.

“Large multinational randomized trials in adults at risk for heart failure are needed to verify these results,” stated Mujaj. “Until then, our observations suggest that aspirin should be prescribed with caution in those with heart failure or with risk factors for the condition.”

Reference: Mujaj B, Zhang ZY, Yan WY, et al. Aspirin use is associated with increased risk for incident heart failure: a patient-level pooled analysis. ESC Heart Failure. Published online November 22, 2021. DOI: 10.1002/ehf2.13688