The 2019 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease (CVD) has softened prior recommendations regarding aspirin use for primary prevention, as the net cardiovascular (CV) benefit is small compared to the bleeding risk. The current class IIb recommendation is to consider aspirin in those 40 to 70 years of age who are at elevated atherosclerotic cardiovascular disease (ASCVD) risk without increased bleeding risk.¹ However, recent studies have raised the possibility of a particular benefit to aspirin in individuals with elevated Lipoprotein(a) (Lp[a]). Lp(a) has purported pro-thrombotic properties which may contribute to the risk of CVD; in particular, Lp(a) has been shown to interact with platelet receptors, potentially leading to increased platelet activation and aggregation.² Aspirin irreversibly inactivates cyclooxygenase 1 and limits thromboxane A2 production, reducing platelet activation, which may explain the potential benefit of aspirin in those with elevated Lp(a).² In light of this new evidence, reviewed below, the recent focused update to the 2019 National Lipid Association scientific statement on Lp(a) suggests consideration of aspirin using a patient centered approach in those with elevated Lp(a) (≥ 50mg/dL or 125nmol).³

Initial studies of Lp(a) and aspirin utilized genetic instruments in secondary analyses of two randomized controlled trials of aspirin in primary prevention: the Women's Health Study (WHS) and Aspirin in Reducing Events in the Elderly (ASPREE). Both analyses focused on carriers of rs3798220-C LPA single-nucleotide polymorphisms (SNP), which are associated with increased plasma Lp(a) levels and CV risk.^4,5 In WHS, carriers randomized to aspirin had a greater than 50% reduction in major CV events compared to those randomized to placebo (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.20-0.94). However, non-carriers randomized to aspirin did not exhibit a significant risk reduction (HR 0.91, 95% CI 0.77-1.08).⁴ In the secondary analysis of ASPREE, participants were evaluated based on both rs3798220 genotype and an LPA genomic risk score (GRS). In both carriers of the SNP and those with the highest levels of the GRS, aspirin was associated with a significant reduction in major adverse cardiovascular events (MACE), without increasing bleeding risk. Among SNP carriers, aspirin use was associated with a net benefit (balancing MACE reduction with risk of bleeding) of 8.1 events; among the highest quintile of the GRS, aspirin use was associated with a net benefit of 1.7 events.⁵ While both studies shed light on the potential benefit of aspirin in those with elevated Lp(a) in primary prevention, there are limitations that affect the generalizability of these results. Both studies included only participants of European ancestry. The WHS included only women, while ASPREE included participants with an average age of 75 years.^4,5 Additionally, only a minority of participants (3.2-3.7%) were SNP carriers,^4,5 and plasma Lp(a) levels, which are more widely available and clinically applicable, were not evaluated in relation to aspirin use.

Recently, however, these results were extended to plasma Lp(a) levels and broader populations in observational studies. In a study from the Multi-Ethnic Study of Atherosclerosis (MESA) published this year, Bhatia et al. investigated the association of self-reported aspirin use (at least 3 days a week) and coronary heart disease (CHD) outcomes, defined as CHD mortality or nonfatal myocardial infarction, in those with and without elevated Lp(a). A propensity matched cohort of 2,183 participants was evaluated, including 1,760 (81%) with Lp(a) ≤50mg/dL and 423 (19%) with Lp(a) >50mg/dL. The average age was 66 years, 45% were women, and approximately 50% were non-White with a median Lp(a) level of approximately 16 mg/dL. Over a median follow-up of 15.7 years, there was no benefit observed with aspirin therapy in those with Lp(a) ≤50mg/dL (HR 0.80, 95% CI 0.58-1.10). However, in those with Lp(a) >50mg/dL, aspirin use was associated with a 46% lower risk of CHD (HR 0.54, 95% CI 0.31-0.93). No difference in bleeding events among aspirin users by Lp(a) level was noted, though this analysis was limited.⁶ These results build on prior studies of LPA genetics as the first study to observe an association between aspirin use and a reduction in CV events by plasma Lp(a) levels. In particular, the study was conducted in a diverse, multi-ethnic United States (US)-based cohort which enhances generalizability.

Building on these results, Razavi et al. evaluated the association between aspirin use and ASCVD mortality in another study published this year. Using the third National Health and Nutrition Examination Survey (NHANES III, 1988-94), a representative cohort of the US population, a sample of 2,990 individuals, representing approximately 73 million adults in the US, was evaluated. Individuals 40 to 70 years of age without a prior history of ASCVD, with regular aspirin use, defined as ≥30 times in the past month, were included in the study. The median age was 60 years, 86.3% were non-Hispanic White, 9.4% non-Hispanic Black, and 4.3% Mexican American, and 7% of individuals reported regular aspirin use. The median Lp(a) in the population was 14 mg/dL and the percentage of individuals with Lp(a) ≥50mg/dL in those with and without regular aspirin use was similar. Over a median follow-up of 26 years, aspirin use was not associated with a reduction in ASCVD mortality in participants with Lp(a) <50mg/dL (HR 1.01, 95% CI 0.81-1.25). Conversely, in those with Lp(a) ≥50mg/dL, aspirin use was associated with a 52% reduction in ASCVD mortality (HR 0.48, 95% CI 0.28-0.83) and a statistically significant multiplicative interaction between Lp(a) and aspirin use for ASCVD mortality was found (p=0.001).⁷ These results validate the prior work in MESA and extend the results to ASCVD mortality. Both studies have limitations due to their observational nature, and in particular are subject to confounding by indication and residual confounding.

Taken together, there is a growing evidence base supporting a potential benefit for aspirin use in primary prevention in those with elevated Lp(a), starting with secondary analyses of clinical trials using genetic instruments and now including observational studies using plasma Lp(a) levels and more diverse populations (Table 1).^4-7 The benefit seen from aspirin therapy may be due to Lp(a)'s pro-thrombotic properties.² Additionally, bleeding risk may be offset by Lp(a)'s anti-fibrinolytic properties.⁸ Given Lp(a)'s high prevalence and lack of currently available targeted therapies, there is a need for strategies to lower ASCVD risk in this population, particularly in primary prevention. These studies suggest that aspirin may play a key role. Future randomized studies are needed to better understand the utility of aspirin in primary prevention in those with elevated Lp(a), and the balance of this benefit with potential safety concerns including bleeding.

Table 1: Summary of Studies of Aspirin and Lp(a)

References

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2. Bhatia HS, Becker RC, Leibundgut G, et al. Lipoprotein(a), platelet function and cardiovascular disease. Nat Rev Cardiol 2024;21:299-311.
3. Koschinsky ML, Bajaj A, Boffa MB, et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol 2024;18:e308-e319.
4. Chasman DI, Shiffman D, Zee RY, et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 2009;203:371-6.
5. Lacaze P, Bakshi A, Riaz M, et al. Aspirin for primary prevention of cardiovascular events in relation to lipoprotein(a) genotypes. J Am Coll Cardiol 2022;80:1287-
6. Bhatia HS, Trainor P, Carlisle S et al. Aspirin and cardiovascular risk in individuals with elevated lipoprotein(a): the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc 2024;13:e033562.
7. Razavi AC, Richardson LC, Coronado F, et al. Aspirin use for primary prevention among US adults with and without elevated lipoprotein(a). Am J Prev Cardiol 2024;18:100674.
8. Tsimikas S. A  test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol 2017;69:692-711.