Aspirin ‘benefit may outweigh harm’ in some elevated Lp(a) genotypes
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Low-dose aspirin for primary prevention of CV events may benefit older adults with elevated lipoprotein(a)-associated genotypes, according to a new analysis of the ASPREE trial.
Elevated plasma Lp(a) levels confer up to a fourfold increased risk for CVD, with an estimated 20% to 30% of the general population affected, 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 measurements are indicated in primary prevention in the setting of elevated Lp(a); there are currently no approved pharmacological therapies for targeted treatment.
In the ASPREE trial, a study of 100 mg aspirin once daily in healthy older adults with no CVD history, researchers found that low-dose aspirin did not reduce CVD risk vs. placebo and conferred an increase in risk for major hemorrhage.
“The overall results of the ASPREE trial failed to demonstrate a significant reduction in CVD events with aspirin, but this was associated with a significant increase in major bleeding,” Lacaze and colleagues wrote. “We sought to examine whether a subgroup of ASPREE participants benefited, specifically those who carry genotypes associated with elevated Lp(a) levels. We examined whether individuals enrolled into the ASPREE trial carrying these genotypes benefited specifically from aspirin.”
Assessing carrier status, CV risk
Lacaze and colleagues analyzed data from 12,815 genotyped adults aged 70 years or older without prior CVD enrolled in the ASPREE trial. Researchers defined Lp(a)-associated genotypes using rs3798220-C carrier status and quintiles of a Lp(a) genomic risk score. Researchers than assessed interaction between genotypes and aspirin allocation for incidence of major adverse CV events and clinically significant bleeding.
During a median follow-up of 4.7 years, 435 major adverse CV events occurred, with an interaction observed between rs3798220-C and aspirin allocation (P for interaction = .049). Researchers found that rs3798220-C carrier status was associated with increased risk for major adverse CV events in the placebo group (HR = 1.9; 95% CI, 1.11-3.24; P = .018) but not in the aspirin group (HR = 0.54; 95% CI, 0.17- 1.7; P = .294).
A high Lp(a) genomic risk score was associated with increased risk for major adverse CV events in the placebo group (HR = 1.7; 95% CI, 1.14-2.55) compared with a low genomic risk score; however, risk was attenuated in the aspirin group (HR = 1.41; 95% CI, 0.9-2.23), though the interaction was not statistically significant.
Aspirin reduced major adverse CV 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 CV events 11.4 and 3.3 events per 1,000 person-years, respectively, without significantly increasing bleeding risk.
“Our study provides evidence that aspirin may specifically benefit older individuals with genotypes associated with elevated plasma Lp(a) in the setting of high-risk primary prevention of CVD events and that overall benefit may outweigh harm related to major bleeding,” the researchers wrote. “Aspirin is a widely available, well-tolerated and low-cost therapeutic option and could play an important role in reducing Lp(a)-mediated CVD risk.”
Genetic variant ‘implies 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 findings indicate that platelet inhibition by aspirin produces a significant reduction of events in people with an elevated Lp(a) genotype, supporting the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation rather than by loss of fibrinolytic activity.
“Interestingly, [the authors] showed that in the aspirin group, carriers of the LPA gene variant had a lower risk of events than noncarriers,” Devesa and colleagues wrote. “They also calculated a lipoprotein(a) genetic risk score and showed that high quintiles of Lp(a) genetic risk score had a lower risk of events than low quintiles. This suggests that these events are mainly led by some prothrombotic mechanism that is attenuated by low-dose aspirin.
“On the other hand, the authors found a significant interaction with aspirin when comparing carriers with noncarriers,” Devesa and colleagues wrote. “However, this interaction was not significant when comparing high Lp(a) genetic risk score quintiles to low quintiles. This could suggest that the presence of the genetic variant implies a specific risk that does not fully overlap with that conferred by the elevated circulating Lp(a) levels.”
Reference:
- Devesa A, et al. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.08.722.
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