From the Journals

Aspirin primary prevention benefit in those with raised Lp(a)?


Aspirin may be of specific benefit for the primary prevention of cardiovascular disease in individuals with raised Lp(a) levels, a new study has suggested.

The study analyzed data from the ASPREE (ASPirin in Reducing Events in the Elderly) trial, which randomized 19,000 individuals aged 70 years or older without a history of cardiovascular disease to aspirin (100 mg/day) or placebo. While the main results, reported previously, showed no net benefit of aspirin in the overall population, the current analysis suggests there may be a benefit in individuals with raised Lp(a) levels.


The current analysis was published online in the Journal of the American College of Cardiology.

“Our study provides evidence that aspirin may specifically benefit older individuals with genotypes for elevated plasma Lp(a) in the setting of high-risk primary prevention of cardiovascular events and that overall benefit may outweigh harm related to major bleeding,” the authors, led by Paul Lacaze, PhD, Monash University, Melbourne, conclude.

They also point out that similar observations have been previously seen in another large aspirin primary prevention study conducted in younger women, the Women’s Health Study, and the current analysis provides validation of those findings.

“Our results provide new evidence to support the potential use of aspirin to target individuals with elevated Lp(a) for the primary prevention of cardiovascular events,” the researchers say.

They acknowledge that these results would be strengthened by the use of directly measured plasma Lp(a) levels, in addition to Lp(a) genotypes.

But they add: “Nonetheless, given the lack of any currently approved therapies for targeting elevated Lp(a), our findings may have widespread clinical implications, adding evidence to the rationale that aspirin may be a viable option for reducing Lp(a)-mediated cardiovascular risk.”

Dr. Lacaze and colleagues explain that elevated plasma Lp(a) levels confer up to fourfold increased risk of cardiovascular disease, with around 20%-30% of the general population affected. Despite the high burden and prevalence of elevated plasma Lp(a), there are currently no approved pharmacologic therapies targeting this lipoprotein. Although promising candidates are in development for the secondary prevention of Lp(a)-mediated cardiovascular disease, it will be many years before these candidates are assessed for primary prevention.

For the current study, researchers analyzed data from 12,815 ASPREE participants who had undergone genotyping and compared outcomes with aspirin versus placebo in those with and without genotypes associated with elevated Lp(a) levels.

Results showed that individuals with elevated Lp(a)-associated genotypes, defined in two different ways, showed a reduction in ischemic events with aspirin versus placebo, and this benefit was not outweighed by an increased bleeding risk.

Specifically, in the placebo group, individuals who carried the rs3798220-C allele, which is known to be associated with raised Lp(a) levels, making up 3.2% of the genotyped population in the study, had an almost twofold increased risk of major adverse cardiovascular events than those not carrying this genotype. However, the risk was attenuated in the aspirin group, with carriers of the rs3798220-C allele actually having a lower rate of cardiovascular events than noncarriers.

In addition, rs3798220-C carrier status was not significantly associated with increased risk of clinically significant bleeding events in the aspirin group.

Similar results were seen with the second way of identifying patients with a high risk of elevated Lp(a) levels using a 43-variant genetic risk score (LPA-GRS).

In the whole study population, aspirin reduced major adverse cardiovascular events by 1.7 events per 1,000 person-years and increased clinically significant bleeding events by 1.7 events per 1,000 person-years, suggesting parity between overall benefit versus harm.

However, in the rs3798220-C subgroup, aspirin reduced major adverse cardiovascular events by 11.4 events per 1,000 person-years (a more than sixfold higher magnitude of cardiovascular disease risk reduction than in the overall cohort), with a bleeding risk of 3.3 events per 1,000 person-years, the researchers report.

“Hence in rs3798220-C carriers, aspirin appeared to have a net benefit of 8.1 events per 1,000 person-years,” they state.

In the highest LPA-GRS quintile, aspirin reduced major adverse cardiovascular events by 3.3 events per 1,000 person-years (approximately twofold higher magnitude of risk reduction, compared with the overall cohort), with an increase in bleeding risk of 1.6 events per 1,000 person-years (almost identical bleeding risk to the overall cohort). This shifted the benefit versus harm balance in the highest LPA-GRS quintile to a net benefit of 1.7 events per 1,000 person-years.


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