Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2022 Oct 4;80(14):1287-1298.
doi: 10.1016/j.jacc.2022.07.027.

Aspirin for Primary Prevention of Cardiovascular Events in Relation to Lipoprotein(a) Genotypes

Paul Lacaze  1 , Andrew Bakshi  2 , Moeen Riaz  2 , Galina Polekhina  2 , Alice Owen  2 , Harpreet S Bhatia  3 , Pradeep Natarajan  4 , Rory Wolfe  2 , Lawrence Beilin  5 , Stephen J Nicholls  6 , Gerald F Watts  7 , John J McNeil  2 , Andrew M Tonkin  2 , Sotirios Tsimikas  3
Affiliations
Randomized Controlled Trial

Aspirin for Primary Prevention of Cardiovascular Events in Relation to Lipoprotein(a) Genotypes

Paul Lacaze et al. J Am Coll Cardiol. .

Erratum in

  • Correction.
    [No authors listed] [No authors listed] J Am Coll Cardiol. 2022 Nov 15;80(20):1963. doi: 10.1016/j.jacc.2022.10.002. J Am Coll Cardiol. 2022. PMID: 36357094 No abstract available.

Abstract

Background: The role of aspirin in reducing lipoprotein(a)-mediated atherothrombotic events in primary prevention is not established.

Objectives: This study sought to assess whether low-dose aspirin benefits individuals with elevated plasma lipoprotein(a)-associated genotypes in the setting of primary prevention.

Methods: The study analyzed 12,815 genotyped individuals ≥70 years of age of European ancestry and without prior cardiovascular disease events enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial of 100 mg/d aspirin. We defined lipoprotein(a)-associated genotypes using rs3798220-C carrier status and quintiles of a lipoprotein(a) genomic risk score (LPA-GRS). We tested for interaction between genotypes and aspirin allocation in Cox proportional hazards models for incidence of major adverse cardiovascular events (MACE) and clinically significant bleeding. We also examined associations in the aspirin and placebo arms of the trial separately.

Results: During a median 4.7 years (IQR: 3.6-5.7 years) of follow-up, 435 MACE occurred, with an interaction observed between rs3798220-C and aspirin allocation (P = 0.049). rs3798220-C carrier status was associated with increased MACE risk in the placebo group (HR: 1.90; 95% CI: 1.11-3.24) but not in the aspirin group (HR: 0.54; 95% CI: 0.17-1.70). High LPA-GRS (vs low) was associated with increased MACE risk in the placebo group (HR: 1.70; 95% CI: 1.14-2.55), with risk attenuated in the aspirin group (HR: 1.41; 95% CI: 0.90-2.23), but the interaction was not statistically significant. In all participants, aspirin reduced MACE 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 LPA-GRS subgroups, aspirin reduced MACE by 11.4 and 3.3 events per 1,000 person-years respectively, without significantly increased bleeding risk.

Conclusions: Aspirin may benefit older individuals with elevated lipoprotein(a) genotypes in primary prevention.

Keywords: aspirin; cardiovascular disease; genetics; lipoprotein(a); primary prevention.

PubMed Disclaimer

Conflict of interest statement

Funding Support and Author Disclosures The ASPREE Biobank is supported by a Flagship cluster grant (including the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne), grants U01AG029824 and U19AG062682 from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants 334047 and 1127060 from the National Health and Medical Research Council of Australia, and Monash University and the Victorian Cancer Agency. Dr Lacaze is supported by a National Heart Foundation Future Leader Fellowship (102604). Dr McNeil is supported by a National Health and Medical Research Council Leadership Fellowship (IG1173690). Dr Bhatia is partially supported by National Institutes of Health grant 5T32HL079891, as part of the University of California San Diego Integrated Cardiovascular Epidemiology Fellowship. Dr Natarajan is supported by grants from the National Heart, Lung, and Blood Institute/National Institutes of Health (R01HL142711, R01HL127564). Bayer AG provided low-dose aspirin and placebo tablets for the clinical trial but had no other relationship with the work. Dr Riaz is a paid employee of Regeneron Genetics Center, a Subsidiary of Regeneron Pharmaceuticals Inc. Dr Natarajan has received investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; has received personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, and Roche/Genentech; is a co-founder of TenSixteen Bio; is a shareholder of geneXwell and TenSixteen Bio; and has a spouse who is an employee of Vertex, all unrelated to the present work. Dr Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi-Regeneron; and has served as a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, and Novo Nordisk. Dr Tonkin has received research support from Bayer for materials in ASPREE; and has received honoraria for Advisory Board participation or lectures from Amgen, AstraZeneca, Boehringer Ingelheim, and Pfizer. Dr Tsimikas is a co-inventor and has received royalties from patents owned by the University of California-San Diego; is a co-founder of and has an equity interest in Oxitope, LLC and its affiliates (Kleanthi Diagnostics, LLC and Covicept Therapeutics, Inc); and has a dual appointment at the University of California San Diego and Ionis Pharmaceuticals; although these relationships have been identified for conflict-of-interest management based on the overall scope of the project, the research findings included in this particular publication may not necessarily relate to the interests of the previous companies; the terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

FIGURE 1
FIGURE 1. Study Flow Chart Indicating the Selection of the Final Data Set
The ASPREE (ASPirin in Reducing Events in the Elderly) trial enrolled 19,114 individuals ≥70 years (≥65 years for U.S. minorities) with no prior history of cardiovascular disease events. DNA samples were provided by 14,052 ASPREE Biobank participants at enrollment. Genotyped samples were excluded for failed quality control (n = 142) and ancestry stratification (n = 959). The final data set (n = 12,815) included only genotyped participants with European descent ≥70 years of age.
FIGURE 2
FIGURE 2. Cumulative Incidence of MACE Stratified by rs3798220-C Carrier Status
Among 12,815 genotyped participants, 406 (3.2%) were carriers of the rs3798220-C allele (404 heterozygotes, 2 homozygotes, considered as a single carrier group). For rs3798220-C carriers (red line) vs noncarriers (blue line), we estimated the cumulative incidence of major adverse cardiovascular events (MACE) in the aspirin and placebo groups. (A) A higher cumulative incidence of MACE was observed in rs3798220-C carriers in the placebo arm of the trial. (B) However, this risk was attenuated in the aspirin arm, with a lower cumulative incidence of MACE observed in rs3798220-C carriers than noncarriers.
FIGURE 3
FIGURE 3. Subgroup Analyses of MACE and Bleeding Events in the ASPREE Trial
Among 12,815 genotyped participants of the ASPREE (ASPirin in Reducing Events in the Elderly) trial, we used Cox proportional hazards regression to model relationships between genotype groups of interest [rs3798220-C carriers and noncarriers, and high vs low quintile of a lipoprotein(a) genomic risk score (LPA-GRS)] with incidence of major adverse cardiovascular events (MACE) and clinically significant bleeding events, adjusting for covariates. We tested for interaction between aspirin allocation and rs3798220-C carrier status, and high vs low LPA-GRS quintile (quintile 5 [Q5]), in the overall genotyped cohort. Interaction between rs3798220-C carrier status and aspirin allocation was significant for MACE (P = 0.049) but not for bleeding in the overall cohort. No interaction between the highest vs lowest LPA-GRS quintile and aspirin allocation was observed for MACE (P = 0.55) or clinically significant bleeding (P = 0.94).
FIGURE 4
FIGURE 4. Cumulative Incidence of MACE in Highest vs Lowest LPA-GRS Quintiles
We calculated an LPA-GRS using variants listed in Supplemental Table 1. We estimated the cumulative incidence of MACE between participants in the highest (red line) vs lowest (blue line) quintiles of the LPA-GRS distribution. (A) In the placebo arm, a higher cumulative incidence of MACE was observed in the high vs low LPA-GRS quintile. (B) However, in the aspirin arm, a lower cumulative incidence of MACE was observed in the highest vs lowest LPA-GRS quintile. Lp(a) = lipoprotein(a); other abbreviations as in Figure 3.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Aspirin, Lipoprotein(a) Genotypes, and Primary Prevention of Cardiovascular Disease Events
Our study provides evidence that aspirin specifically benefits older individuals with elevated lipoprotein(a) [Lp(a)] genotypes in the setting of primary prevention of cardiovascular disease (CVD). In 12,815 genotyped participants in the ASPREE (ASPirin in Reducing Events in the Elderly) trial, aspirin reduced major adverse cardiovascular events (MACE) by 1.7 events per 1,000 person-years and increased clinically significant bleeding (BLEEDS) by 1.7 events per 1,000 person-years (indicating no net benefit of aspirin). However, in the rs3798220-C carrier group and the highest quintile of a lipoprotein(a) genomic risk score (LPA-GRS) distribution, aspirin reduced MACE by 11.4 and 3.3 events, respectively, without significantly increased bleeding risk, indicating a shift toward the net benefit of aspirin.
See this image and copyright information in PMC

Comment in

References

    1. Tsimikas S. Lp (a) as a new target for reduction of risk of cardiovascular disease and emergence of novel therapies to lower Lp (a). Curr Opin Endocrinol Diabetes Obes. 2016;23:157–164. - PMC - PubMed
    1. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382:244–255. - PubMed
    1. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–423. - PMC - PubMed
    1. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–2853. - PMC - PubMed
    1. Varvel S, McConnell JP, Tsimikas S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol. 2016;36:2239–2245. - PubMed

Publication types