Primary Prevention with Aspirin: Lowering ASCVD Mortality in Adults with Elevated Lipoprotein(a)

Quick Takeaways:

• Elevated Lp(a) (>=50 mg/dL) significantly raises ASCVD risk, affecting around 25% of Indians.
• One-time Lp(a) screening in adulthood is recommended, especially for those with a family history of early cardiovascular disease.
• Studies show aspirin use could lower major CV events and ASCVD mortality in individuals with elevated Lp(a).
• Combining aspirin with statin therapy further reduces ASCVD events, particularly in high-risk CV risk patient populations.
• Digital tools like the Aspirin-Guide app help clinicians assess the balance of CV benefits and bleeding risks, thus optimizing aspirin use in eligible patients for ASCVD prevention.

Lipoprotein(a) [Lp(a)] is a stable, genetically determined risk factor that markedly elevates atherosclerotic cardiovascular disease (ASCVD) risk through prothrombotic and proinflammatory mechanisms, particularly at levels ≥50 mg/dL [or ≥125 nmol/L] (1). It is estimated that approximately 25% of Indians have elevated Lp(a), highlighting the importance of targeted prevention (2). As specific treatments for Lp(a) are currently limited, primary prevention strategies, including aspirin and statin therapy, are gaining focus in this direction as essential tools for managing elevated cardiovascular (CV) risk in individuals with high Lp(a) (3).

Elevated Lipoprotein(a) [Lp(a)] and ASCVD Risk: How & How Much?

Due to its structural similarity to plasminogen, elevated Lp(a) contributes to a prothrombotic state that impairs clot breakdown and promotes inflammation.The rs3798220 variant in the Lp(a) gene is associated with elevated Lp(a) levels, significantly increasing cardiovascular disease risk due to enhanced atherothrombotic potential (4).

This places individuals with high Lp(a) levels at up to a four-fold higher ASCVD risk, necessitating the need for targeted primary prevention. The European Society of Cardiology (ESC) and the Canadian Cardiovascular Society (CCS) guidelines recommend that adults, especially those with a family history of premature ASCVD, measure Lp(a) at least once in their lifetime to help assess CV risk (1).

Evidence for Aspirin Use in Elevated Lipoprotein(a) [Lp(a)]: Revisiting Clinical Evidence

Landmark Women’s Health Study (WHS): In the WHS, women carrying the rs3798220 variant of Lp(a) who used low-dose aspirin saw a 56% relative risk reduction in major cardiovascular events compared to non-users. This suggests aspirin can offset ASCVD risk among those with elevated Lp(a) (1).

ASPREE Trial: The ASPREE trial showed a 76% relative risk reduction in major cardiovascular events among older adults with the rs3798220 variant who were treated with aspirin, underscoring aspirin’s potential for those genetically predisposed to high Lp(a) (1).

Multi-Ethnic Study of Atherosclerosis (MESA): In MESA, aspirin use in individuals with Lp(a) >50 mg/dL resulted in a 46% reduction in coronary heart disease (CHD) events, effectively reducing their ASCVD risk to levels comparable with those without elevated Lp(a) (1).

ASCVD Mortality Reduction with Aspirin in Elevated Lp(a)

The third National Health and Nutrition Examination Survey (NHANES III) data indicated a 52% reduction in ASCVD mortality among adults aged 40-70 years with elevated Lp(a) who used aspirin regularly. This risk reduction was unique to those with elevated Lp(a), highlighting aspirin’s mortality benefit for this subgroup (5)

Personalized Primary Prevention with Aspirin and Statin

Despite evolving guidelines that limit routine aspirin use, elevated Lp(a) provides a compelling case for personalized primary prevention. The United States Preventive Services Task Force (USPSTF) guidelines recommend aspirin for adults aged 40-59 years with a 10-year ASCVD risk of >10%, and elevated Lp(a) may serve as an additional marker to identify those most likely to benefit from aspirin combined with statin therapy (6). Lipid Association of India (LAI) recommends statins as a primary intervention to lower LDL-C in high ASCVD-risk individuals, including those with elevated Lp(a), and advises low-dose aspirin for those with additional risk factors, emphasizing shared decision-making to manage bleeding risk (7).

To further individualize and optimize aspirin use, the Aspirin-Guide app offers clinicians a tailored assessment of cardiovascular benefits versus bleeding risks of low-dose aspirin therapy, supporting informed decisions for high-risk patients. Evidence supports the use of aspirin in conjunction with statins as a primary prevention approach for high-risk individuals, especially given the lack of targeted therapies for Lp(a).

Figure 1: Aspirin in primary cardiovascular prevention: current evidence and guidelines recommendations. Abbreviations: Adapted from Della Bona, Roberta et al. “Aspirin in Primary Prevention: Looking for Those Who Enjoy It.” Journal of clinical medicine vol. 13,14 4148. 16 Jul. 2024, doi:10.3390/jcm13144148.

Abbreviation: ABI: ankle-brachial index; ACC/AHA: American College of Cardiology/American Heart Association; ADA: American Diabetes Association; ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CV: cardiovascular; CVD: cardiovascular disease ESC: European Society of Cardiology; PPI: proton pump inhibitors; USPSTF: United States Preventive Services Task Force; y.o.: years old.

Reference:

1. Sukkari, Mohamad Hekmat et al. “Is there a benefit of aspirin therapy for primary prevention to reduce the risk of atherosclerotic cardiovascular disease in patients with elevated Lipoprotein (a)-A review of the evidence.” American journal of preventive cardiology vol. 15 100579. 1 Sep. 2023, doi:10.1016/j.ajpc.2023.100579

2. 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

3. Bhatia, Harpreet S. “Aspirin and lipoprotein(a) in primary prevention.” Current opinion in lipidology vol. 34,5 (2023): 214-220. doi:10.1097/MOL.0000000000000891

4. 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

5. Razavi, Alexander C et al. “Aspirin use for primary prevention among US adults with and without elevated Lipoprotein(a).” American journal of preventive cardiology vol. 18 100674. 27 Apr. 2024, doi:10.1016/j.ajpc.2024.100674

6. Huang, Athena L et al. “US population qualifying for aspirin use for primary prevention of cardiovascular disease.” American journal of preventive cardiology vol. 18 100669. 16 Apr. 2024, doi:10.1016/j.ajpc.2024.100669

7. Puri, Raman et al. “Lipid Association of India 2023 update on cardiovascular risk assessment and lipid management in Indian patients: Consensus statement IV.” Journal of clinical lipidology vol. 18,3 (2024): e351-e373. doi:10.1016/j.jacl.2024.01.006