Aspirin ‘benefit may outweigh harm’ in some elevated Lp(a) genotypes

September 26, 2022

3 min read


Lacaze and Devesa do not report relevant financial information. The relevant financial information of all other authors can be found in the study and in the editorial.

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Older adults with elevated lipoprotein(a)-associated genotypes may benefit from low-dose aspirin for primary prevention of cardiovascular events, according to a new analysis from the ASPREE study.

Elevated plasma Lp(a) levels lead to an up to four-fold increased risk of cardiovascular disease, affecting an estimated 20% to 30% of the general population. Paul Lacaze, PhD, Associate Professor in the Department of Epidemiology and Preventive Medicine at Monash University School of Public Health and Preventive Medicine in Melbourne, Australia, and colleagues wrote in the Journal of the American College of Cardiology. However, no specific measures are indicated in primary prevention with elevated Lp(a); There are currently no approved pharmacological therapies for targeted treatment.

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In the ASPREE study, a study of aspirin 100 mg once daily in healthy older adults with no cardiovascular history, researchers found that low-dose aspirin did not reduce cardiovascular risk compared to placebo and increased the risk of major bleeding.

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“The overall results of the ASPREE study did not show a significant reduction in CVD events with aspirin, but this was associated with a significant increase in major bleeding,” Lacaze and colleagues wrote. “We wanted to investigate whether a subset of ASPREE participants benefited, specifically those carrying genotypes associated with elevated Lp(a) levels. We examined whether individuals enrolled in the ASPREE study who carried these genotypes benefited specifically from aspirin.”

Assessment of carrier status, CV risk

Lacaze and colleagues analyzed data from 12,815 genotyped adults aged 70 years or older without prior CVD who were enrolled in the ASPREE study. Researchers defined Lp(a)-associated genotypes using rs3798220C carrier status and quintiles of a genomic Lp(a) risk score. Researchers then assessed the interaction between genotypes and aspirin allocation for the occurrence of major adverse cardiovascular events and clinically significant bleeding.

During a median follow-up of 4.7 years, 435 serious adverse cardiovascular events occurred where an interaction between rs3798220-C and aspirin allocation was observed (P for interaction = .049). The researchers found that rs3798220-C carrier status was associated with an increased risk of serious adverse cardiovascular events in the placebo group (HR=1.9; 95% CI, 1.11-3.24; P = 0.018), but not in the aspirin group (HR = 0.54; 95% CI, 0.17-1.7; P = 0.294).

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A high Lp(a) genomic risk score was associated with an increased risk of serious adverse cardiovascular events in the placebo group (HR=1.7; 95% CI, 1.14-2.55) compared to one low genomic risk score; however, the risk was attenuated in the aspirin group (HR = 1.41; 95% CI, 0.9-2.23), although the interaction was not statistically significant.

Aspirin reduced major adverse cardiovascular events by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years. However, in the rs3798220-C and high Lp(a) genomic risk score subgroups, aspirin reduced major adverse cardiovascular events by 11.4 and 3.3 events per 1,000 person-years, respectively, without significantly increasing the risk of bleeding.

“Our study provides evidence that aspirin may specifically benefit elderly individuals with genotypes associated with elevated plasma Lp(a) levels in the context of high-risk primary prevention of cardiovascular events, and that the overall benefit outweighs the harm associated with severe bleeding may predominate,” the researchers wrote. “Aspirin is a widely used, well-tolerated, and inexpensive therapeutic option and may play an important role in reducing Lp(a)-mediated cardiovascular risk.”

Genetic variant “carries a specific risk”

In a related editorial Ana Devesa, MD, PhD, a research and Cardiovascular Imaging Fellow at Mount Sinai Hospital and colleagues wrote that the results suggest that platelet inhibition by aspirin causes a significant reduction in events in people with an elevated Lp(a) genotype, supporting the hypothesis that the prothrombotic mechanism of Lp(a) is more likely to be mediated Platelet aggregation is considered mediated by loss of fibrinolytic activity.

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“Interesting, [the authors] showed that in the aspirin group carriers of the LPA Gene variant had a lower event risk than non-carriers,” Devesa and colleagues wrote. “They also calculated a lipoprotein(a) genetic risk score and showed that high quintiles of the Lp(a) genetic risk score had a lower event risk than low quintiles. This suggests that these events are primarily caused by a prothrombotic mechanism that is attenuated by low-dose aspirin.

“On the other hand, when comparing carriers with non-carriers, the authors found a significant interaction with aspirin,” Devesa and colleagues wrote. “However, this interaction was not significant when comparing quintiles with high Lp(a) gene risk with low quintiles. This may indicate that the presence of the genetic variant implies a specific risk that does not fully overlap with that presented by the elevated circulating Lp(a) levels.”


  • Devesa A et al. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.08.722.