Aspirin for Heart Disease Prevention: Can Genetics Help Solve the Puzzle?

White aspirin tablets spill from a prescription bottle, illustrating their role in heart disease prevention strategies.

Simple explanation:

For years, taking a daily low-dose aspirin was considered a simple way to prevent heart attacks and strokes. Today, doctors know the decision is far more complicated. For many people, the heart benefits of aspirin are closely matched by the risk of serious bleeding, especially as we age. This has made aspirin one of the most debated tools in preventive cardiology.

New research published in 2025 suggests that genetic testing may finally help clarify who truly benefits from aspirin and who does not.

Why Aspirin Is a Prevention Dilemma

Aspirin helps prevent blood clots, which can block arteries and cause heart attacks or strokes. At the same time, it interferes with the body’s ability to protect the stomach and intestines, increasing the risk of gastrointestinal bleeding and, less commonly, bleeding in the brain.

Large studies in people without known heart disease show:

• A small reduction in heart attacks and strokes

• A similar increase in serious bleeding events

As people get older, bleeding risk rises sharply, while the heart benefit stays about the same. This shifting balance is why aspirin is no longer routinely recommended for prevention.

What Current Guidelines Say

The U.S. Preventive Services Task Force updated its guidance in 2022:

• Ages 40–59 with higher heart risk (≥10% over 10 years):

  
  

  Aspirin may be considered on an individual basis after discussing bleeding risk with a clinician.

• Age 60 and older:

  
  

  Do not start aspirin for prevention if you have never had a heart attack or stroke.

These recommendations focus on starting aspirin. If you are already taking aspirin, do not stop without medical advice.

A Genetic Clue: Lipoprotein(a)

Some people inherit high levels of a cholesterol-related particle called lipoprotein(a), or Lp(a). Elevated Lp(a) increases heart disease risk not only by contributing to plaque buildup, but also by promoting blood clot formation.

A specific genetic variant, called LPA rs3798220, is present in about 3–4% of people. Those who carry it:

• Have much higher Lp(a) levels

• Face about double the risk of heart attacks

Why This Matters for Aspirin

The 2025 review analyzed data from three large studies involving nearly 45,000 people. The findings were striking:

• People without the LPA variant:

  
  

  Aspirin offered very little heart protection.

• People with the LPA variant:

  
  

  Daily low-dose aspirin dramatically reduced heart attacks, bringing their risk down to the same level as people without the genetic risk.

In this group, the benefit of aspirin was comparable to that of statin medications, and the increase in bleeding risk was not proportionally higher.

A More Personalized Approach to Prevention

This research suggests that aspirin works best in people whose genetics put them at higher clot-related risk. For them, aspirin’s anti-clotting effect appears especially protective.

A key advantage:

• The LPA genetic test is inexpensive (about $25–$50)

• It only needs to be done once in a lifetime

• Results can meaningfully guide prevention decisions

Who Might Consider Testing?

Genetic testing may be worth discussing if you:

• Are between 40 and 59 years old with elevated heart risk

• Have a family history of early heart disease

• Have been told you have high Lp(a) on blood testing

• Are considering aspirin and want a more personalized risk-benefit assessment

The Bottom Line

Aspirin is no longer a one-size-fits-all solution for heart disease prevention. For most people, the benefits and risks are too closely matched. But genetic testing for the LPA rs3798220 variant identifies a small group who may gain substantial protection from aspirin with less downside.

This is an important step toward precision prevention, using your individual biology to guide smarter, safer health decisions.

If you’re thinking about aspirin for heart disease prevention, talk with your healthcare professional about whether Lp(a) testing or genetic screening might be right for you.

Aspirin for Heart Disease Prevention: A Genetic Solution to the Conundrum? A more technical take.

Aspirin use for preventing heart disease has become a clinical conundrum because the cardiovascular benefits are closely matched by serious bleeding risks, and these risks change dramatically with age, making what seems like a simple preventive measure surprisingly nuanced. However, genetic testing for a specific lipoprotein(a) gene variant may help identify patients who benefit most from daily aspirin, potentially resolving this longstanding dilemma.

The Balancing Act: Benefits vs. Harms

Aspirin reduces the risk of heart attacks and strokes, but it also increases the risk of major bleeding events. The medical literature shows that aspirin reduces nonfatal myocardial infarction and ischemic stroke by approximately 10-12%, but simultaneously increases major gastrointestinal bleeding and intracranial hemorrhage.[1] The absolute benefits and harms are nearly equivalent, for every cardiovascular event prevented, there's a comparable increase in serious bleeding.[2]

What makes this particularly challenging is that bleeding risks increase substantially with age, while cardiovascular benefits remain relatively constant. This creates a moving target where the risk-benefit calculation shifts unfavorably as patients get older.[2]

Current USPSTF Recommendations

The United States Preventive Services Task Force updated its guidance in 2022, making age-stratified recommendations that reflect this complexity:[3][2]

For adults aged 40-59 years with ≥10% 10-year CVD risk:

- Grade C recommendation: The decision should be individualized

- Evidence indicates a small net benefit in this group

- Patients not at increased bleeding risk who are willing to take daily aspirin are more likely to benefit

For adults 60 years or older:

- Grade D recommendation: Do NOT initiate aspirin for primary prevention

- The harms outweigh benefits when starting aspirin at this age

Importantly, these recommendations apply only to initiating aspirin. Patients already taking aspirin who started at younger ages may still benefit from continuing.[2]

The Genetic Breakthrough: LPA rs3798220

A 2025 paper provides compelling evidence for a precision medicine approach to aspirin use based on genetic testing for the LPA rs3798220 polymorphism.[4][5][6]

What is the LPA variant?

The rs3798220 polymorphism is a genetic variant in the apolipoprotein(a) component of lipoprotein(a) [Lp(a)] that:

- Occurs in approximately 3-4% of Caucasians (though prevalence varies by ethnicity)

- Significantly increases Lp(a) blood levels (heterozygotes ~80 mg/dL, homozygotes ~154 mg/dL, compared to 30 mg/dL in non-carriers)

- Confers approximately 2-fold increased risk for coronary heart disease independent of traditional risk factors[4][6][7]

The aspirin response difference

Three major clinical trials, the Women's Health Study (WHS), the Atherosclerosis Risk in Community study (ARIC), and the Aspirin in Reducing Events in the Elderly (ASPREE): involving a total of 44,698 subjects have now demonstrated that:

1. In patients WITHOUT the LPA variant: Daily aspirin provides minimal cardiovascular benefit, with a Number Needed to Treat (NNT) of 833 in WHS and 250 in ASPREE

2. In patients WITH the LPA variant: Daily aspirin dramatically reduces cardiovascular events, with an NNT of only 38 in WHS and 34 in ASPREE, comparable to statin therapy[8]

Most remarkably, carriers of the LPA variant randomized to aspirin had their cardiovascular event rate reduced to the same level as subjects who did not carry the variant, essentially eliminating the genetic risk.[8]

The Clinical Utility: Number Needed to Treat

The paper provides striking data on the clinical relevance of LPA genotype testing:

In the ASPREE trial specifically, aspirin reduced major adverse cardiovascular events (MACE) by 11.4 events per 1,000 person-years in rs3798220-C carriers, without significantly increased bleeding risk, a dramatic shift in the benefit-harm balance.[8]

Why Does This Work?

The mechanism appears related to Lp(a)'s similarity to plasminogen and its prothrombotic properties. Aspirin may exert its beneficial effects in the LPA subgroup through a thrombotic pathway rather than by lowering Lp(a) blood levels.[9][10] Interestingly, the prothrombotic properties of elevated Lp(a) may also explain why these patients don't experience higher bleeding rates with aspirin compared to those without the variant.[8]

The Practical Implications

Genetic testing availability: The LPA rs3798220 test is commercially available for approximately $25-$50 and needs to be performed only once in a lifetime.[8][9]

Who should consider testing?

- Individuals aged 40-59 with elevated cardiovascular risk (≥10% 10-year risk)

- Those with family history of premature heart disease

- Patients with elevated Lp(a) levels (>50 mg/dL) on blood testing

- Anyone considering aspirin for primary prevention who wants to optimize the benefit-harm balance

Treatment implications:

- LPA variant carriers may derive substantial cardiovascular benefit from daily low-dose aspirin (100 mg)

- This provides an inexpensive treatment option for a high-risk genetic subgroup

- The benefit appears particularly relevant given the lack of currently approved therapies specifically targeting Lp(a)-mediated risk (though new medications are in development)[9][10]

Important Limitations and Considerations

Ethnic diversity: The rs3798220 polymorphism prevalence varies significantly across different ethnic populations, which could impact the generalizability of these findings.[8] Most data comes from European ancestry populations.

Broader Lp(a) elevation: The rs3798220 variant identifies only 3-4% of the population, but 20-30% of people have elevated Lp(a) levels (>30 mg/dL).[5][8] A 43-variant lipoprotein(a) genetic risk score (LPA-GRS) has been developed to identify a larger group, with promising but less definitive results.[8]

Need for validation: While three studies support these findings, they represent post-hoc genetic analyses of trials not originally designed to test this hypothesis. Prospective randomized trials specifically enrolling LPA variant carriers would provide more definitive evidence.[9][10]

The Bottom Line

The aspirin conundrum exists because we're weighing small benefits against comparable harms in most patients. However, genetic testing for the LPA rs3798220 variant identifies a high-risk subgroup, approximately 3-4% of the population, who derive substantial cardiovascular benefit from daily aspirin without proportionally increased bleeding risk.[8]

This represents a meaningful advance toward precision medicine in cardiovascular prevention, providing clinicians and patients with objective data to guide individualized decision-making about aspirin therapy. For the relatively small investment of a one-time genetic test, patients can determine whether they fall into the group most likely to benefit from this inexpensive, widely available preventive therapy.

As new Lp(a)-lowering therapies emerge from clinical trials, the landscape may shift again. But for now, LPA genotype testing offers a practical tool to help resolve the aspirin conundrum for a meaningful subset of patients at elevated cardiovascular risk.[5][7][9]

The most striking finding is that aspirin essentially eliminates the excess cardiovascular risk conferred by the LPA variant, reducing event rates in carriers down to the same level as non-carriers. This represents a genuine precision medicine approach to a longstanding clinical dilemma.

References

1. Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. Guirguis-Blake JM, Evans CV, Perdue LA, Bean SI, Senger CA. JAMA. 2022;327(16):1585-1597. doi:10.1001/jama.2022.3337.

2. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. JAMA. 2022;327(16):1577-1584. doi:10.1001/jama.2022.4983.

3. Aspirin Use to Prevent Cardiovascular Disease: Preventive Medication. Karina W. Davidson PhD MASc, Michael J. Barry MD, Carol M. Mangione MD MSPH, et al. United States Preventive Services Task Force (2022).

4. The Lipoprotein(a) Rs3798220 and Rs10455872 Polymorphisms and Coronary Heart Disease: A Meta-Analysis of 55,647 Participants. Li YY, Wang H, Zhang YY. The American Journal of the Medical Sciences. 2025;:S0002-9629(25)01282-0. doi:10.1016/j.amjms.2025.12.002.

5. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42(1):e48-e60. doi:10.1161/ATV.0000000000000147.

6. Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease. Clarke R, Peden JF, Hopewell JC, et al. The New England Journal of Medicine. 2009;361(26):2518-28. doi:10.1056/NEJMoa0902604.

7. Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review. Duarte Lau F, Giugliano RP. JAMA Cardiology. 2022;7(7):760-769. doi:10.1001/jamacardio.2022.0987.

8. Aspirin for Primary Prevention of Cardiovascular Events in Relation to Lipoprotein(a) Genotypes. Lacaze P, Bakshi A, Riaz M, et al. Journal of the American College of Cardiology. 2022;80(14):1287-1298. doi:10.1016/j.jacc.2022.07.027.

9. Aspirin and Lipoprotein(a) in Primary Prevention. Bhatia HS. Current Opinion in Lipidology. 2023;34(5):214-220. doi:10.1097/MOL.0000000000000891.

10. Role of Aspirin in Reducing Risk for Atherosclerotic Cardiovascular Disease in Individuals With Elevated Lipoprotein(A). Razavi AC, Bhatia HS. Current Atherosclerosis Reports. 2025;27(1):49. doi:10.1007/s11883-025-01296-w.

11. H. Robert Superko, John Sninsky, Brenda Garrett, The aspirin heart disease preventionconundrum,American Journal of Preventive Cardiology, Volume 22, 2025, 101013, ISSN 2666-6677, https://doi.org/10.1016/j.ajpc.2025.101013.