Aspirin Primary Prevention Benefit in Those With Raised Lp(a)?

September 28, 2022

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 September 26 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, Australia, 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."

Lacaze and colleagues explain that elevated plasma Lp(a) levels confer up to fourfold increased risk of cardiovascular disease, with around 20% to 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 1000 person-years and increased clinically significant bleeding events by 1.7 events per 1000 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 1000 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 1000 person-years, the researchers report.

"Hence in rs3798220-C carriers, aspirin appeared to have a net benefit of 8.1 events per 1000 person-years," they state.

In the highest LPA-GRS quintile, aspirin reduced major adverse cardiovascular events by 3.3 events per 1000 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 1000 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 1000 person-years.

Similar Findings in the Women's Health Study

Lacaze and colleagues point out that similar results have also been seen in another large aspirin primary prevention study — the Women's Health Study (WHS).

The WHS compared aspirin 100 mg every other day with placebo in initially healthy younger women. Previously reported results showed that women carrying the rs3798220-C variant, associated with highly elevated Lp(a) levels, had a twofold higher risk of cardiovascular events than noncarrier women in the placebo group, but this risk was reduced in the aspirin group. And there was no increased risk of bleeding in women with elevated Lp(a).

"These results, in the absence of any other randomized controlled trial evidence or approved therapy for treating Lp(a)-associated risk, have been used by some physicians as justification for prescribing aspirin in patients with elevated Lp(a)," Lacaze and colleagues note.

"In the present study of the ASPREE trial population, our results were consistent with the WHS analysis, despite randomizing older individuals (both men and women)," they add.

They say this validation of the WHS result provides evidence that a very high-risk subgroup of individuals with highly elevated Lp(a) — those carrying the rs3798220-C allele — may benefit from low-dose aspirin for the primary prevention of cardiovascular events. Further, the benefits in this subgroup specifically may outweigh any bleeding risk.

But they point out that rs3798220-C carriers comprise only a small portion of all individuals with elevated Lp(a) in the general population, while the polygenic LPA-GRS explains about 60% of the variation in directly measured plasma Lp(a) levels and has the potential advantage of being able to identify a larger group of individuals at increased risk.

The researchers note, however, that it is not clear to what extent the LPA-GRS results add further evidence to suggest that individuals with elevated Lp(a), beyond rs3798220-C carriers, may be more likely to benefit from aspirin.

"If the benefit of aspirin extends beyond very high-risk rs3798220-C carriers alone, to the broader 20% to 30% of individuals with elevated Lp(a), the potential utility of aspirin for the primary prevention of cardiovascular events would increase substantially," they say.

"Very High Clinical Relevance"

In an accompanying editorial, Ana Devesa, MD, Borja Ibanez, MD, PhD, and Valentin Fuster, MD, PhD, The National Center for Cardiovascular Research, Madrid, Spain, say that: "Lacaze et al are to be congratulated for a study of very high clinical relevance that represents a first indication for primary prevention for patients at high cardiovascular risk."

They explain that the pathogenic mechanism of Lp(a) is believed to be a combination of prothrombotic and proatherogenic effects, and the current findings support the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation. 

This would explain the occurrence of thrombotic events in the presence of atherosclerosis in that elevated Lp(a) levels may induce platelet adhesion and aggregation to the activated atherosclerotic plaque, thus enhancing the atherothrombotic process. Moreover, activated platelets release several mediators that result in cell adhesion and attraction of chemokines and proinflammatory cytokines, driving an inflammatory response and mediating atherosclerosis progression, they add.

The editorialists highlight the limitations of the study already acknowledged by the authors: the analysis used genotypes rather than elevated Lp(a) levels and included only those of European ancestry, meaning the results are difficult to extrapolate to other populations.

"The next steps in clinical practice should be defined, and there are still questions to be answered," they conclude. "Will every patient benefit from antithrombotic therapies? Should all patients who have elevated Lp(a) levels be treated with aspirin?"

The ASPREE Biobank is supported by grants from the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne, National Institutes of Health, National Health and Medical Research Council of Australia, and the Victorian Cancer Agency. Lacaze is supported by a National Heart Foundation Future Leader Fellowship.

J Am Coll Cardiol. Published online September 26, 2022. Abstract, Editorial

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