Impact of Regular Aspirin Use on ASCVD Mortality in Adults with Elevated Lipoprotein(a) Levels

With a rising incidence of cardiovascular disease (CVD) among younger individuals aged below 55 years(1),particularly in India, where it occurs about a decade earlier than in Western countries, the age-standardized mortality rate is notably higher. (2)

Lifestyle interventions and cardioprotective therapies are crucial for preventing and managing cardiovascular disease. Given this concerning trend, statins, and aspirin have proven crucial in preventing atherosclerotic cardiovascular disease (ASCVD). Statins address cholesterol levels with plaque stabilization, and aspirin mitigates platelet aggregation, together providing a robust strategy for reducing cardiovascular risk (3,4).

Aspirin has a role in ASCVD prevention which is often underutilized due to fear of bleeding risk. We reviewed the scope of aspirin in primary prevention of ASCVD when appropriately indicated, in the light of emerging evidence.

Aspirin for ASCVD Prevention

For several decades, aspirin has been a valuable treatment in both secondary and primary prevention of cardiovascular disease. (5) Landmark randomized controlled trials have highlighted its effectiveness in reducing the risk of fatal myocardial infarction (MI) and, in some cases, nonfatal MI. (6) Aspirin remains important in modern clinical practice, especially when combined with statins. (7) It is beneficial even for individuals with elevated Lp(a) levels. There is emerging favorable evidence in this direction, discussed ahead.

Elevated Lipoprotein(a) Lp(a) – CV Risk Enhancer

Lipoprotein(a) [Lp(a)] has been a risk factor for atherosclerosis and other cardiovascular disease, with elevated levels above 50 mg/dL linked to increased CV risk. (8) Screening for high Lp(a) can identify individuals who might benefit from intensified cardiovascular risk management. The American Heart Association (AHA) and American Association of Clin`ical Endocrinologists (AACE) recommend testing Lp(a) in cases of family & personal history of premature ASCVD, moderate to severe ASCVD risk, and patients refractory to current lipid-lowering therapies. (9)

Elevated Lp(a) and Coronary Atherosclerosis – Latest 2024 Updates

In a long-term study using serial coronary computed tomography angiography (CCTA) imaging, elevated Lp(a) was associated with increased coronary plaque burden, particularly high-risk non-calcified plaques, and elevated peri-coronary adipose tissue inflammation. This suggests that elevated Lp(a) contributes to the progression of coronary atherosclerosis and the development of inflammatory, rupture-prone plaques over time.(10)

Aspirin Offers Substantial Primary Prevention Benefits in Individuals with Elevated Lp(a)

A study conducted by Razavi, Alexander C et al. evaluated the impact of regular aspirin use on ASCVD mortality among individuals with elevated Lp(a) compared to those without elevated Lp(a) levels. Data were collated from the Third National Health and Nutrition Examination Survey (NHANES III) with a 26-year follow-up. Among 2,990 participants aged 40–70 years without clinical ASCVD, regular aspirin use (defined as ≥30 times per month) was associated with a significant 52% reduction in ASCVD mortality in those with elevated Lp(a) [≥50 mg/dL] compared to those without elevated Lp(a) [<50 mg/dL] Specifically, the ASCVD mortality rate was lower in those with elevated Lp(a) who used aspirin regularly (1.2 per 1,000 person-years) versus those who did not (3.9 per 1,000 person-years). These findings suggest that regular aspirin use may offer substantial benefits for primary prevention in individuals with elevated Lp(a). (11)

Figure 1: Cumulative probability of ASCVD mortality based on aspirin use, categorized by normal Lp(a) levels (A) versus elevated Lp(a) levels (B).

Balancing Benefits and Risks: The Impact of Aspirin Discontinuation on Thrombotic Risk and the Importance of Precision in Primary Prevention: Aspirin uniquely inhibits cyclooxygenase enzymes (COX-1 more than COX-2) at low doses, leading to a reduction in thromboxane A2 (which promotes platelet aggregation and vasoconstriction) while preserving prostaglandin I2 (which inhibits platelets and dilates blood vessels). (12) This mechanism demonstrates aspirin's efficacy in preventing thrombosis and cardiovascular events. Discontinuing daily aspirin may elevate thrombotic risk due to a "rebound" increase in platelet aggregation, potentially driven by a rebound rise in platelet thromboxane synthesis. (13)Studies indicate a threefold increase in thrombotic events within 10 days of stopping aspirin. (14)

The focus should shift to evaluating the optimal risk-benefit profile for aspirin use, emphasizing precision and informed decision-making. A validated bleeding risk calculator utilizing data from recent aspirin trials is essential for clinicians to effectively balance the benefits and risks of low-dose aspirin in primary prevention. The Aspirin-Guide app, created by Brigham and Women’s Hospital and Harvard Medical School researchers, aids clinicians in evaluating the balance between cardiovascular benefits and bleeding risks of low-dose aspirin. It integrates cardiovascular history, demographics, and health conditions to support personalized treatment decisions.

Effect of Statin Therapy on the Overall Risk-Benefit Balance of Aspirin Therapy

Khan et al. examined the effects of aspirin therapy with and without statin therapy in adults without known ASCVD. Their meta-analysis of 16 randomized controlled trials found that aspirin reduced the risk of MI by 15%. At the same time, statin therapy lowered the risks of both bleeding and MI, with the benefits proportional to the level of ASCVD risk. For every 10,000 adults, aspirin reduced MI events (from 3 to 49, depending on CV risk). Concomitant statin therapy reduced the absolute risk reduction for MI associated with aspirin but did not affect the bleeding risk. (15)

Summary:

ASCVD is increasingly affecting younger populations due to evolving risk factors and underscores aspirin's role in primary prevention. Despite evolving risk factors and the wide utilization of statin therapy, aspirin remains beneficial, showing substantial benefits, particularly for individuals with elevated Lp(a), where it can reduce ASCVD mortality by 52%. Aspirin remains effective in lowering the risk of myocardial infarction. It should be considered alongside statins for optimal cardiovascular protection, and current guidelines recommend its use alongside statins to optimize cardiovascular risk management when appropriately indicated. Digital tools such as the Aspirin-Guide app assist clinicians in weighing the cardiovascular benefits against the bleeding risks of aspirin use in primary prevention, allowing its optimal utilization.

References:

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2. Kalra, Ankur et al. “The burgeoning cardiovascular disease epidemic in Indians - perspectives on contextual factors and potential solutions.” The Lancet regional health. Southeast Asia vol. 12 100156. 10 Feb. 2023, doi:10.1016/j.lansea.2023.100156

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8. Farzam K, Zubair M, Senthilkumaran S. Lipoprotein A. [Updated 2024 Feb 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570621/

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10. Nurmohamed, Nick S et al. “Lipoprotein(a) and Long-Term Plaque Progression, Low-Density Plaque, and Pericoronary Inflammation.” JAMA cardiology, e241874. 17 Jul. 2024, doi:10.1001/jamacardio.2024.1874

11. 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

12. Warner, Timothy D et al. “Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy.” British journal of clinical pharmacology vol. 72,4 (2011): 619-33. doi:10.1111/j.1365-2125.2011.03943.x

13. Ferrari, Emile et al. “Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis.” Journal of the American College of Cardiology vol. 45,3 (2005): 456-9. doi:10.1016/j.jacc.2004.11.041

14. Rodríguez, Luis A García et al. “Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care.” BMJ (Clinical research ed.) vol. 343 d4094. 19 Jul. 2011, doi:10.1136/bmj.d4094

15. Khan, Safi U et al. “Aspirin With or Without Statin in Individuals Without Atherosclerotic Cardiovascular Disease Across Risk Categories.” JACC. Advances vol. 2,2 100197. 8 Feb. 2023, doi:10.1016/j.jacadv.2022.100197