The Role of Aspirin in Reducing ASCVD Mortality Among Adults with High Lp(a) Concentrations

Atherosclerotic cardiovascular disease (ASCVD) burden in young individuals is a major health concern, particularly in less developed nations where optimal primary preventive measures are insufficient(1). Primary prevention of cardiovascular disease (CVD still involves consideration of aspirin as the preferred antithrombotic medication, when appropriately indicated(2). In the context of primary ASCVD prevention, this article discusses the evidence supporting the benefits of aspirin among those with higher lipoprotein(a) [Lp(a)] genotypes.

Premature ASCVD Burden—Report from Global Burden of Disease Study: The Global Burden Disease Study (GBD) published in 2024 estimated that ischaemic heart disease will be the leading cause of death through 2050 affecting 186.5 million at the global level, followed by stroke (3).

The 20–54 age group had a greater mortality/DALY burden from ischemic heart disease (IHD) and ischemic stroke (IS) compared to > 55-year-old age group. Among the 20–54 age group, Asia experienced the fastest increases in mortality, disability-adjusted life years (DALY) rates for IHD, and adverse outcomes for PAD. (1) To lessen the burden of ASCVD, risk factor management remains the main focus of the therapeutic strategy.

The LEADD (Learnings with Experts to Advance Diabetic Dyslipidemia Management) study conducted across 226 sites comprising 4002 T2DM patients revealed that more than 80% of the participants with ASCVD/ASCVD risk factors did not receive recommended statins(4).

Elevated Lp(a)- Silent Causal & Independent CV Risk:

Through processes linked to enhanced atherogenesis, inflammation, and thrombosis, high levels of Lp(a), a lipoprotein that contains apoB100, are an independent and causal risk factor for ASCVD. (5)

A 2022 consensus statement from the European Atherosclerosis Society (EAS) highlighted that epidemiologic and genetic studies "strongly support a causal and continuous association between Lp(a) concentrations and cardiovascular outcomes," even at very low LDL cholesterol levels. (6)

Elevated Lp(a) is a major risk factor for early coronary artery disease (CAD) and acute myocardial infarction (AMI); increasing the risk of CAD by 2-3 times. Approximately 25% of Indians and other South Asians have higher Lp(a) levels (≥50 mg/dl), and high Lp(a) levels are common in Indians with CAD (7).

Improving Outcomes with Elevated Lp(a) – The Potential Role for Aspirin

An increasing quantum of research evidence suggests that people with elevated Lp (a) may benefit from taking aspirin for primary prevention. Aspirin therapy may have this benefit because Lp(a) has pro-thrombotic characteristics. (8) Moreover, the anti-fibrinolytic properties of Lp(a) may mitigate the risk of bleeding.(9)

In an investigation by Lacaze, Paul et al., 12,815 genotyped European ancestors aged 70 or older who had not experienced a cardiovascular event before and were enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial of 100 mg/d aspirin were examined to determine whether low-dose aspirin is beneficial in the context of primary prevention. According to the findings, there was a significant correlation between high LPA-GRS [lipoprotein(a) genomic risk score] and a higher risk of major adverse cardiovascular events (MACE) in the placebo group (HR: 1.70; 95% CI: 1.14-2.55), whereas the aspirin group had a lower risk (HR: 1.41; 95% CI: 0.90-2.23). Aspirin decreased MACE by 1.7 events per 1,000 person-years in all groups. Aspirin decreased MACE by 11.4 and 3.3 events per 1,000 person-years in the rs3798220-C and high LPA-GRS categories, respectively, without significantly raising the risk of bleeding. For primary prevention, people with increased lipoprotein(a) genotypes benefit from aspirin.(10)

Figure: Aspirin, Lipoprotein(a) Genotypes, and Primary Prevention of Cardiovascular Events. Adapted from Lacaze, Paul et al,. 80,14 (2022): 1287-1298. doi:10.1016/j.jacc.2022.07.027

Current Guidelines on the Consideration of Aspirin in CVD Prevention

The American Heart Association (AHA) Task Force on Clinical Practice Guidelines (11), the United States Preventive Services Task Force (12), and the American Diabetes Association (13) have all released guidelines in recent years regarding the recommendations for considering low-dose aspirin use in the primary prevention of CVD when appropriately indicated. The recommendations of these guidelines are tabulated here.

Guideline	Risk Level	Age Range (years)	Recommendation	COR**/ Suggestion for Practice Grade*	LOE*/Level of Certainty (net benefit)**
AHA Guideline on the Primary Prevention of Cardiovascular Disease**	“Elevated risk” per PCE or based on the presence of specific ASCVD risk factors	40-70	Low-dose aspirin (75-100 mg orally daily) might be considered for the primary prevention of ASCVD among select adults 40 to 70 years of age who are at higher ASCVD risk but not at increased bleeding risk.	IIb**	A**
2022 Aspirin Use to Prevent Cardiovascular Disease - US Preventive Services Task Force Recommendation Statement*	≥ 10% 10-year CVD Risk	40-59	The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit.	C*	Moderate*
American Diabetes Association (ADA)	Diabetes with a history of ASCVD	≥ 50	Aspirin therapy (75–162 mg/day) may be considered a primary prevention strategy in those with diabetes who are at increased cardiovascular risk after a comprehensive discussion with the individual on the benefits versus the comparable increased risk of bleeding.	A	NA
*Evidence rating system for USPSTF (Grade Definitions. U.S. Preventive Services Task Force. October 2018). ** Evidence rating system for ACC/AHA (https://cpr.heart.org/en/resuscitation-science/cpr-and-ecc-guidelines/tables/applying-class-of-recommendation-and-level-of-evidence). COR=Class of Recommendation; LOE = Level of Certainty; COR IIb/LOE A = high-quality evidence showing treatment may be reasonable, but effectiveness is not well established; COR III/LOE B-R = moderate-quality evidence showed no benefit and potential harm; COR III/LOE C-LD = week/limited data., PCE=Pooled Cohort Equation.

Aspirin+Atorvastatin in Treating ASCVD Events: Zhang et al. assessed the efficacy of atorvastatin and aspirin combination in treating ASCVD events in the form of ischemic stroke. About 127 individuals with ischemic strokes were recruited for the trial, and they were then randomized into two groups: the observation group (n = 66; aspirin plus atorvastatin) and the control group (n = 61; aspirin alone). Both the incidence of cerebrovascular disease (9.09% vs. 22.95%) and the recurrence rate of ischemic stroke (4.55% vs. 24.59%) were considerably reduced in the observation group compared to the control group (both P<0.05). In the observation group, a significant reduction in serum total cholesterol (4.99±0.21 before treatment vs 4.10±0.13 6 months after treatment, P= 0.045), triglycerides (2.07±0.06 before treatment vs 1.67±0.04 6 months after treatment, P=0.001), LDL-C (2.45±0.13 before treatment vs 1.86±0.11 6 months after treatment, P<0.001), and HDL-C (1.26±0.07 before treatment vs 1.52±0.08 6 months after treatment, P<0.001) levels were observed. The study concluded that aspirin and atorvastatin can effectively treat ischemic stroke, regulate cholesterol, and lipids, and improve atherosclerotic plaque and quality of life. (14)

Key Takeaways:

Premature ASCVD is a growing global health concern with the prevalence projected to rise in coming years. High lipoprotein(a) level is one strong risk factor for ASCVD. Although patient outcomes and prognoses have improved due to advances in primary and secondary prevention of cardiovascular disease (CVD), early risk factor screening and preventive management of modifiable risk factors for CVD remain essential for both the patient and healthcare community. Aspirin has long been used as a preventive measure for CVD, and it has been shown that aspirin benefits individuals with increased Lp (a). Aspirin combined with statin use also considerably improves lipid regulation and is superior to aspirin taken alone.

References:

1. Li, Z., Yang, Y., Wang, X. et al. Comparative analysis of atherosclerotic cardiovascular disease burden between ages 20–54 and over 55 years: insights from the Global Burden of Disease Study 2019. BMC Med 22, 303 (2024). https://doi.org/10.1186/s12916-024-03527-4

2. Santilli, Francesca et al. “Needs-based considerations for the role of low-dose aspirin along the CV risk continuum.” American journal of preventive cardiology vol. 18 100675. 15 Apr. 2024, doi:10.1016/j.ajpc.2024.100675

3. GBD 2021 Forecasting Collaborators. “Burden of disease scenarios for 204 countries and territories, 2022-2050: a forecasting analysis for the Global Burden of Disease Study 2021.” Lancet (London, England) vol. 403,10440 (2024): 2204-2256. doi:10.1016/S0140-6736(24)00685-8

4. AMBIKA GOPALAKRISHNAN UNNIKRISHNAN, ASHOK KUMAR DAS, BANSHI D. SABOO, SANJAY KALRA; 2213-PUB: Management Practices in Indian Type 2 Diabetes Mellitus (T2DM) Participants With or Without Comorbidities in Real-World LEADD (Learnings with Experts to Advance Diabetic Dyslipidemia Management) Study. Diabetes 1 June 2019; 68 (Supplement_1): 2213–PUB. https://doi.org/10.2337/db19-2213-PUB

5. Reyes-Soffer, Gissette et al. “Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association.” Arteriosclerosis, thrombosis, and vascular biology vol. 42,1 (2022): e48-e60. doi:10.1161/ATV.0000000000000147

6. Kronenberg, Florian et al. “Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.” European heart journal vol. 43,39 (2022): 3925-3946. doi:10.1093/eurheartj/ehac361

7. Enas, Enas A et al. “Lipoprotein(a): An underrecognized genetic risk factor for malignant coronary artery disease in young Indians.” Indian heart journal vol. 71,3 (2019): 184-198. doi:10.1016/j.ihj.2019.04.007

8. Bhatia HS, Becker RC, Leibundgut G, et al. Lipoprotein(a), platelet function and cardiovascular disease. Nat Rev Cardiol 2024;21:299-311.

9. Tsimikas, Sotirios. “A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies.” Journal of the American College of Cardiology vol. 69,6 (2017): 692-711. doi:10.1016/j.jacc.2016.11.042

10. Lacaze, Paul et al. “Aspirin for Primary Prevention of Cardiovascular Events in Relation to Lipoprotein(a) Genotypes.” Journal of the American College of Cardiology vol. 80,14 (2022): 1287-1298. doi:10.1016/j.jacc.2022.07.027

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12. USPSTF. Aspirin Use to Prevent Cardiovascular Disease: Preventive Medication. 2022. Retreived on 18th June 2024 from https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/aspirin-to-prevent-cardiovascular-disease-preventive-medication

13. American Diabetes Association Professional Practice Committee; 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2024. Diabetes Care 1 January 2024; 47 (Supplement_1): S179–S218. https://doi.org/10.2337/dc24-S010

14. Zhongbo Zhang, Xinzhe Yao, Minghua Wang, Yudiao Huang, Tong Shen, Weinan Zhang, Yingying Liu. Therapeutic effects of aspirin combined with atorvastatin on ischemic strokes.2018.Int J Clin Exp Med 2018;11(10):11104-11111