Benefit of Aspirin Could Depend on Lipoprotein(a) Levels, Study Finds


An analysis of NHANES found aspirin's benefits in primary prevention may hinge on lipoprotein(a) (Lp(a)) levels, halving ASCVD mortality risk with Lp(a) ≥50 mg/dL.

Alexander Razavi, MD, PhD, MPH | Credit: American College of Cardiology

Alexander Razavi, MD, PhD, MPH
Credit: American College of Cardiology

A new study suggests the benefits of aspirin in primary prevention could depend on a person’s lipoprotein(a) [Lp(a)] levels.

An analysis of more than 2900 people with a median follow-up of 26 years, results of the study suggest regular aspirin use in those aged 40 to 70 years cut the risk of atherosclerotic cardiovascular disease (ASCVD) mortality in half among those with Lp(a) levels of 50 mg/dL or more but had no benefit among those with reduced Lp(a).

“This is the first study to observe an ASCVD mortality benefit associated with aspirin therapy for primary prevention for individuals with elevated Lp(a),” wrote investigators. “Given the high prevalence of elevated Lp(a) (approximately 20% across populations), which is predominantly genetically determined, these findings may have substantial public health implications for the utilization of aspirin for primary prevention.”

In recent years, the role of aspirin in primary prevention has been placed in the crosshairs of guideline updates and recommendation statement from numerous major organizations. As recently as 2009, nearly 40% of US adults reported aspirin use, but revelations questioning the benefits and risk of use have come forth as the result of new data.

In 2019, the American College of Cardiology and American Heart Association recommended aspirin be used infrequently in routine primary prevention of ASCVD because of a lack of net benefit. In 2022, the US Preventive Services Task Force issued no recommendations indicating their stance that low-dose aspirin should not be initiated for primary prevention in individuals ages 60 years or older and initiation of low-dose aspirin should be considered on an individualized basis in adults aged 40 to 59 years with a 10-year cardiovascular risk of 10% or greater.

However, as this shift occurred, improved assays and movement in the therapeutic pipeline have reignited conversations around Lp(a). Building on a report from a propensity-matched analysis of the MESA study showing a 46% lower risk of coronary heart disease events with regular aspirin use in those with elevated Lp(a), investigators launched the current study with the intent of further exploring this relationship using a nationally representative sample of US adults.

Led by Alexander Razavi, MD, PhD, MPH, of Emory Clinical Cardiovascular Research Institute, investigators designed the research endeavor as an analysis of the third NHANES, which collected baseline data between 1988 and 1994 and was the only cycle of this cohort to measure Lp(a). To be considered eligible for inclusion, participants were required to be 40 to 70 years of age, have available measures of Lp(a), reported on aspirin use, have no history of myocardial infarction or stroke, and have available information on covariables and follow-up through National Death Index records.

The primary outcome of interest for the study was the association between regular aspirin use and ASCVD mortality in those with and without elevated Lp(a). Investigators established 50 mg/dL and greater as the threshold d for elevated Lp(a) in the study. As part of NHANES, aspirin use was assessed by asking “In the past month have you taken any aspirin?” and “How often did you use aspirin during the past month?”. For the purpose of analysis, regular aspirin use was defined as taking aspirin 30 or more times in the month before the interview.

A total of 2990 participants meeting inclusion criteria were identified by study investigators. Representative of 73 million US adults, this cohort had a mean age of 50 years, 53% were female, 9% were non-Hispanic Black people, and 7% reported regular aspirin use. Compared to their counterparts without regular aspirin use, those reporting regular aspirin use were older, more likely to be male, and more likely to be of non-Hispanic White race and ethnicity.

In multivariable-adjusted analyses, regular aspirin use was associated with a statistically significant 52% reduction in relative risk of ASCVD mortality among individuals with elevated Lp(a) (Hazard Ratio [HR], 0.48; 95% Confidence Interval [CI], 0.28 to 0.83). However, this association was not observed for those without elevated Lp(a) (HR, 1.01; 95% Ci, 0.81 to 1.25; P for interaction = .001). Investigators pointed out further analysis demonstrated these results were consistent when using an alternate day dosing definition for regular aspirin use.

Investigators noted multiple limitations to consider when interpreting results of their research. These included inherent limitations associated with use of NHANES survey data, use of mass-based assay for quantifying Lp(a), only collecting aspirin use data at baseline, and lack of information on aspirin safety, including major bleeding events.

“Future net clinical benefit (benefit-harm) analyses involving the interaction of aspirin and Lp(a) with incident ASCVD and major bleeding events are needed,” investigators wrote.1


Razavi AC, Richardson LC, Coronado F, et al. Aspirin use for primary prevention among US adults with and without elevated lipoprotein(a). American Journal of Preventive Cardiology. Published online April 2024:100674. doi:10.1016/j.ajpc.2024.100674

Boakye E, Uddin SMI, Obisesan OH, et al. Aspirin for cardiovascular disease prevention among adults in the United States: Trends, prevalence, and participant characteristics associated with use. Am J Prev Cardiol. 2021;8:100256. Published 2021 Sep 22. doi:10.1016/j.ajpc.2021.100256

Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in J Am Coll Cardiol. 2019 Sep 10;74(10):1429-1430] [published correction appears in J Am Coll Cardiol. 2020 Feb 25;75(7):840]. J Am Coll Cardiol. 2019;74(10):e177-e232. doi:10.1016/j.jacc.2019.03.010

US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577–1584. doi:10.1001/jama.2022.4983

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