Aspirin in Primary Prevention: Can Lipoprotein(a) Identify the Right Patient?

The Need for Precision Patient Stratification

Conventional risk prediction models include age, diabetes, hypertension, smoking, and cholesterol levels; however, they may not fully represent genetically induced residual cardiovascular risk. Lipoprotein(a) [Lp(a)], a genetically driven and mostly lifestyle-independent lipoprotein, has been identified as an independent risk factor for Athero-Sclerotic Cardiovascular Disease (ASCVD). ⁷ Reflecting this growing evidence, recent international guidelines & consensus statements recommend measuring Lp(a) at least once during adulthood to refine cardiovascular risk assessment and support more personalized preventive strategies. ^{7, 8}

Lipoprotein(a): How is it an Independent Driver of Atherosclerosis and Thrombosis?

• Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle composed of an LDL particle coupled to apolipoprotein(a) [apo(a)] via a covalent disulfide bond. ^{7, 9} Plasma Lp(a) concentrations are primarily governed by the LPA gene, remain relatively stable throughout life, and are hardly affected by lifestyle or conventional lipid-lowering medications. ^{7, 9}
• Robust epidemiological, genetic, and Mendelian randomization studies have shown increased Lp(a) as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. ^{7, 9} Unlike other lipid indicators, lipoprotein(a) [Lp(a)] has both atherogenic and prothrombotic characteristics, which contribute to cardiovascular risk via numerous complementary mechanisms.
• As an LDL-like particle, it promotes cholesterol deposition in the arterial wall, while its preferential transport of oxidized phospholipids exacerbates vascular inflammation, endothelial dysfunction, and plaque formation. In addition, the structural similarity between apolipoprotein(a) and plasminogen may interfere with fibrinolysis, resulting in a prothrombotic milieu. ^{8, 9}

These different biological characteristics not only affirm Lp(a) as an independent causal risk factor for ASCVD, but also suggest a convincing mechanistic basis for investigating whether people with increased Lp(a) benefit more from antiplatelet treatments like aspirin.

Can Aspirin Mitigate Cardiovascular Risk in Lp(a) Carriers?

The evidence supporting Lp(a)-guided aspirin therapy has evolved over the past decade through analyses of several landmark clinical trials.

• Women's Health Study (WHS): Carriers of the LPA rs3798220 variant assigned to placebo had a 2.2-fold greater risk of major cardiovascular events than non-carriers (HR 2.21; 95% CI, 1.39–3.52). Aspirin therapy was associated with a 56% relative risk reduction in major cardiovascular events among these genetically susceptible individuals (HR 0.44; 95% CI, 0.20-0.94), but there was no significant effect reported among non-carriers (P = 0.048). ¹⁰
• ARIC Study: The ARIC study further supported the role of Lp(a)-guided aspirin therapy. Among carriers of the LPA rs3798220 variant, the hazard ratio for coronary heart disease was 1.57 (95% CI, 0.92–2.69) in non-users of aspirin but decreased to 0.86 (95% CI, 0.38–1.95) among regular aspirin users, indicating attenuation of the increased cardiovascular risk associated with the variant. ¹¹
• ASPREE Trial: In a pharmacogenetic analysis involving 12,815 adults aged ≥70 years without prior cardiovascular disease, carriers of the LPA rs3798220-C variant had a significantly higher risk of Major Adverse Cardiovascular Events (MACE) 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). Aspirin decreased risk of MACE by 11.4 occurrences per 1,000 person-years in variant carriers without a substantial increase in clinically severe bleeding, indicating a favorable benefit-risk ratio in genetically vulnerable individuals at cardiovascular risk. ¹²
• Number Needed to Treat (NNT) Evidence: Stratifying aspirin therapy by LPA genotype substantially improves treatment efficiency and protective benefit. The estimated NNT to prevent one major cardiovascular event decreases from 250–833 in the general primary prevention population to 33.8–38 among carriers of high-risk LPA variants, highlighting the potential clinical value of a precision approach for considering aspirin in primary prevention. ¹³
• ASCEND Trial: The ASCEND trial randomized 15,480 adults with diabetes but no established cardiovascular disease to receive aspirin 100 mg daily or placebo. Over a mean follow-up of 7.4 years, aspirin reduced the risk of serious vascular events (8.5% vs. 9.6%; rate ratio, 0.88; 95% CI, 0.79–0.97) but increased major bleeding (4.1% vs. 3.2%; rate ratio, 1.29; 95% CI, 1.09–1.52). Although the trial did not stratify outcomes by Lp(a), it highlighted the importance of identifying high-risk subgroups in whom the cardiovascular benefits of aspirin may outweigh the bleeding risk. ³
• Aspirin- Primary Prevention Meta-analysis: A pooled meta-analysis of primary prevention trials demonstrated that aspirin reduced the risk of overall cardiovascular events by 15% and myocardial infarction by 30%, confirming its antithrombotic efficacy in preventing first cardiovascular events. However, the modest absolute benefit observed in unselected populations, together with the risk of bleeding, underscored the need for improved patient selection. Subsequent Lp(a)-guided analyses have identified genetically susceptible individuals as a subgroup in whom the cardiovascular benefits of aspirin may be substantially greater. In the Women's Health Study, carriers of the rs3798220 LPA variant had a >50% lower risk of major cardiovascular events (HR 0.44; 95% CI 0.20–0.94), while in MESA, aspirin was associated with a 46% lower relative risk of coronary heart disease among individuals with Lp(a) >50 mg/dL (HR 0.54; 95% CI 0.31–0.93), reinforcing the concept of precision prevention. ¹³

Key Takeaways

• The role of aspirin in primary prevention is moving from one-size-fits-all to precision-based management.
• Accumulating evidence suggests that people with elevated Lp(a) levels or high-risk LPA genotypes may benefit more from aspirin than the general population.
• Incorporating Lp(a) into cardiovascular risk assessment should enhance patient selection, optimize net clinical benefit, and help redefine primary prevention, while future research will further guide treatment decisions.

Abbreviations:

CVD- Cardiovascular Disease; Lp(a)- Lipoprotein(a); ASCVD- Athero-Sclerotic Cardiovascular Disease; WHS- Women's Health Study; ARIC- Atherosclerosis Risk in Communities; ASPREE - ASPirin in Reducing Events in the Elderly; HR- Hazard Ratio; MACE - Major Adverse Cardiovascular Events; NNT- Number Needed to Treat; ASCEND - A Study of Cardiovascular Events in Diabetes; MESA - Multi-Ethnic Study of Atherosclerosis