Lipoprotein(a), ASCVD risk, and Aspirin- What is the Latest Evidence Saying?

Lipoprotein (a) [Lp(a)] is considered pro-atherosclerotic, pro-inflammatory, pro-thrombotic, and anti-fibrinolytic. Lipoprotein(a) levels >50 mg/dL are associated with an increased risk of cardiovascular diseases (1), with an estimated 1 in 5 individuals having elevated Lp(a). (2)

Role of Lipoprotein(a) in ASCVD:

Lp(a) increases the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, thereby promoting the adhesion of monocytes to the endothelium and initiating atherosclerotic plaque formation. Lp(a) exhibits a higher affinity for the vascular wall, proteoglycans, and fibronectin on the endothelial cell surface , and this leads to the accumulation of Lp(a) in the arterial intima, contributing to the development of atherosclerotic lesions. (1)

ASCVD risk Prevalence in India:

ASCVD prevalence has decreased in the Western world but is skyrocketing in India. ASCVD occurs at an earlier age and has a more malignant course in Indians. (3) The Global Burden of Disease (GBD) study group reported a 2.3-fold increase in the prevalence of both ischemic heart disease (IHD) and stroke in the country between 1990 and 2016. Also, there was a two-fold increase in the number of prevalent cases of CV disease (IHD, Stroke, Rheumatic heart disease) from 25.7 million in 1990 to 54.5 million in 2016. (4,5)

The high burden of ASCVD risk in India is attributed to various factors such as hypertension(25.3%), diabetes(7.7%), smoking(24% in men), obesity(21%), and physical inactivity(54.4%). (6)

Aspirin in Prevention of ASCVD:

Aspirin has been the cornerstone for the management of patients with ASCVD for >3 decades. It exerts its biological action mainly by inhibition of cyclooxygenase (COX)-1 activity, and consequently of thromboxane A2 synthesis, leading to irreversible suppression of platelet activation and aggregation.(7)

Aspirin remains an inexpensive and accessible drug, with its once daily dosing regimen allowing better treatment adherence among patients relative to other antithrombotic agents that require twice daily dosing. Patients with higher CV risk and low risk of bleeding, including diabetes, young patients would benefit from a personalized approach that includes aspirin use for primary prevention. (8)

There is an increasing evidence building around the application of aspirin in primary prevention among individuals with elevated Lp(a).

Use of Aspirin in High Lp(a) – Review of Recent Clinical Evidence:

• Regular aspirin use was associated with a 52% lower risk of ASCVD mortality among adults without clinical ASCVD who had elevated Lp(a). (2)
• Individuals with elevated Lp(a) benefit more from low-dose aspirin therapy than the general population for primary prevention of ASCVD. (9)
• A reduction in coronary heart disease with aspirin therapy (p = 0.03) has also been observed in individuals with Lp(a) > 50mg/dl. (9)
• Aspirin may benefit older individuals with elevated lipoprotein(a) genotypes in primary prevention. (10)

Aspirin in Primary Prevention: Overview of International Guidelines

• The American College of Cardiology and American Heart Association recommended that low-dose aspirin use (75 to 100 mg/day) might be considered for the primary prevention of atherosclerotic CVD among selected adults aged 40 to 70 years at higher CVD risk but not at increased risk of bleeding. (11)
• The European Society of Cardiology suggests that among individuals at very high CVD risk, low-dose aspirin may be considered for primary prevention. (12)
• Diabetes, Cardiovascular Renal, and Metabolic (DCRM) diseases 2.0 multispecialty practice recommendations suggest the use of aspirin for primary prevention in patients with 2 or more risk factors for ASCVD and low bleeding risk. The ASCVD risk factors listed include elevated non-HDL-C, elevated LDL-C, elevated Lp(a), low HDL-C, DM, HTN, CKD, cigarette smoking, family history of ASCVD, and elevated CAC>100. (13)

Take Home Message:

• About 25% of Indians have elevated LP(a) levels. Lp(a) levels >50 mg/dL are associated with an increased risk of cardiovascular diseases.
• Lp(a) increases the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, thereby promoting the adhesion of monocytes to the endothelium and initiating atherosclerotic plaque formation.
• ASCVD burden is skyrocketing in India with a malignant course. This high prevalence is attributed to the brunt of various intermediate CV risk factors and their poor control.
• As per recent studies, aspirin is beneficial for primary prevention of ASCVD in patients with elevated Lp(a).
• International clinical practice guidelines like ACC/AHA, ESC, and DCRM 2.0 guidelines also recommend aspirin use for primary prevention where it outweighs risk and is associated with 2 or more risk factors.

References:

1. Khashayar farzam et al. Lipoprotein A. Treasure Island (FL): Statpearls publishing; Jan 24.

2. Alexander C Razavi et al. Aspirin use for primary prevention among US adults with and without elevated Lipoprotein(a). Am J of Preventive Cardiology 2024;18: 100674.

3. P Barton Duell et al. The epidemic of atherosclerotic cardiovascular disease in India. J of Clinical Lipidology 2020; 14(2): 170-2.

4. The changing patterns of cardiovascular diseases and their risk factors in the states of India: the global burden of disease study 1990–2016. Lancet Glob Health 2018;6:e1339-e1351.

5. Kalra A, Jose AP, Prabhakaran P. The burgeoning cardiovascular disease epidemic in Indians- perspectives on contextual factors and potential solutions. Lancet Reg Health Southeast Asia 2023:12:100156.

6. Ashish kumar et al. Atherosclerotic Cardiovascular disease risk score: Are Indians underestimating the risk of cardiovascular disease? Indian Heart J 2019; 71(4): 364-5.

7. G M Gravel et al. Revisiting the role of aspirin for the primary prevention of cardiovascular disease. Circulation 2019; 140(13); 1115-1124.

8. Francesca Santilli et al. Needs-based considerations for the role of low dose aspirin along the CV risk continuum. Am J of Preventive cardiology 2024; 18: 100675.

9. Mohamad Hekmat Sukkari et al. Is there a benefit of aspirin therapy for primary prevention to reduce the risk of atherosclerotic cardiovascular disease in patients with elevated Lp(a) - A review of the evidence. Am J of Preventive Cardiol 2023; 15: 100579.

10. Paul Lacaze et al. Aspirin for primary prevention of cardiovascular events in relation to lipoprotein(a) genotypes. J Am Coll Cardiol 2022; 80: 1287-98.

11. Arnett DK et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of ACC/AHA task force on clinical practice guidelines. Circulation 2019; 140(11): e596-e646.

12. Visseren FLJ et al. ESC National Cardiac societies; ESC scientific Document group 2021. ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021; 42(34): 3227-3337.

13. Yehuda Handelsman et al. DCRM 2.0: Multispeciality practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases. Metabolism 159 (2024) 155931.