Risk Beyond Control: Inherited and Causal CV Risk Factors and the Role of Aspirin

Cardiovascular diseases (CVDs) are the leading cause of non-communicable disease (NCD) deaths in India, accounting for nearly 48% of all NCD mortality. [1] The risk of CVD in Indians is 3–4 times higher than that of White Americans, sixfold higher than that of Chinese, and twentyfold higher than that of the Japanese populations. Additionally, Indians tend to develop CVD at a younger age, highlighting the need to address factors beyond modifiable risk factors. Therefore, it seems prudent that CV risk should be managed more aggressively in Indian patients. [2]

Inherited and Causal CV Risk Factors: Inherited factors, such as a family history of ASCVD, premature ASCVD, low HDL-C, and causal risk drivers like elevated Lp(a), form the core of India’s residual cardiovascular risk profile. [3]

Family History of ASCVD or CV risk: Having a family history of ASCVD independently increases CVD risk by around 40% if a sibling is affected, and by 60–75% if one or both parents have CVD. [4] Indian data (LASI Wave 1, n=58,734) reveal CVD incidence nearly doubles with family history when combined with hypertension (18.6% with vs. 11.3% without family history) or diabetes (20.5% with vs. 5.0% without family history). [5]

Family history of premature ASCVD: A family history of early‐onset ASCVD (before 55 years in men, 65 in women) independently increases the recurrent event risk. In the SWEDEHEART registry (n = 25,615), such history was linked to a 22% higher adjusted risk of recurrent ASCVD after myocardial infarction. [6] Similarly, Indian data indicate that a family history of premature ASCVD increases the risk of premature ASCVD in the next generation by 2–7 fold. [7]

High Lipoprotein (a) [Lp(a)]: High Lp(a) [ >50 mg/dL] is present in approximately 25% of Indians and is known to increase the risk of premature ASCVD by 30% for each 50 mg/dL increase in Lp(a) levels. The new ESC 2025 guidelines (ESC Congress 2025, Madrid) now recognize elevated Lp(a) as a causal cardiovascular factor, with mounting evidence linking it to poor cardiovascular outcomes. [1,8]

Studies presented at ESC Congress 2025 further highlighted the role of Lp(a) in cardiovascular risk assessment. A retrospective study (n=3,710) showed 30–40% higher Lp(a) levels in CAD patients compared with normal subjects (13-14 vs. 10 mg/dL, p<0.001). [9] A large cohort (n=526,848) demonstrated that elevated Lp(a) (≥95 mg/dL) combined with high BMI increased 10-year ASCVD risk to 26% versus 16% with high BMI alone. [10]

Low HDL-C: Low HDL-C (<35 mg/dL) is reported in 66.9% of Indians and is associated with an eight-fold higher incidence of ASCVD compared to individuals with HDL-C levels greater than 65 mg/dL.[1,11]

Aspirin: Targeting the Thrombotic Link

Aspirin has shown distinct benefit in individuals with elevated lipoprotein(a) [Lp(a)], which exerts pro-thrombotic effects by interacting with platelet receptors and enhancing aggregation. Emerging data suggest that aspirin may directly lower Lp(a) levels by suppressing apo(a) mRNA expression in the liver—an effect independent of COX-1 inhibition. This Lp(a)–modulating action, along with its established ability to reduce thromboxane A2-mediated platelet activation, supports aspirin’s potential role in reducing ASCVD risk specifically in patients with high Lp(a). [12]

Aspirin in Primary Prevention: Clinical Evidence

Aspirin in Primary Prevention- Latest September 2025 Research: The Chronic Renal Insufficiency Cohort study (n=2,552) assessed the association of aspirin use in CKD patients without clinical CVD (mean eGFR 47 mL/min/1.73 m²) over a median 15.7-year follow-up. Among individuals with Lp(a) ≥50 mg/dL (27% of cohort), aspirin was associated with a 38% lower MI risk (HR: 0.62; 95% CI: 0.42-0.91) and 28% lower ESRD risk (HR: 0.72; 0.59-0.89). Aspirin was not associated with stroke or major bleeding events in either Lp(a) group, suggesting a favorable benefit-to-risk profile for CKD patients with elevated Lp(a) in primary prevention. [13]

A meta-analysis (n=49,871) presented at ESC Congress 2025 demonstrated that aspirin significantly reduced MACE risk in patients with elevated Lp(a) ≥50 mg/dL (HR 0.51, 95% CI 0.35-0.75) and rs-3798220-C carriers/LPA carriers (HR 0.59, 95% CI 0.36-0.98), without increasing bleeding risk, supporting aspirin's role in primary prevention for high Lp(a) populations. [14]

Clinical Perspective: Integrating Non-Modifiable and Preventive Strategies

Guidelines such as USPSTF, ESC, AHA/ACC, and DCRM 2024 recommend individualized use of low-dose aspirin in adults with multiple cardiovascular risk factors and low bleeding risk.[15,16] The DCRM 2.0 (2024) guidelines list 10 cardiovascular risk factors, including elevated Lp(a), family history of ASCVD, and CAC >100, and recommend considering low-dose aspirin for primary prevention when two or more risk factors are present, provided that the bleeding risk is carefully assessed.[15]

Early screening for Lp(a) and family history, along with lifestyle measures and statins, remains key. Clinicians should balance benefit and bleeding risks using tools like AspirinGuide for shared decision-making.

Key Messages

Inherited risk factors, such as family history, premature ASCVD, along with causal risk factors like elevated Lp(a) and low HDL-C, substantially amplify long-term cardiovascular risk. Individualized low-dose aspirin may offer preventive benefit in select high CV-risk individuals after careful assessment of Lp(a), family history, and bleeding risk.

Abbreviations: ASCVD – Atherosclerotic Cardiovascular Disease, CVD – Cardiovascular Disease, NCD – Non-Communicable Disease, CAD – Coronary Artery Disease, HDL-C – High-Density Lipoprotein Cholesterol, Lp(a) – Lipoprotein(a), COX-1 – Cyclooxygenase-1, CKD – Chronic Kidney Disease, eGFR – Estimated Glomerular Filtration Rate, ESRD – End-Stage Renal Disease, MI – Myocardial Infarction, CHD – Coronary Heart Disease, MACE – Major Adverse Cardiovascular Events, T2D – Type 2 Diabetes, RRR – Relative Risk Reduction, HR – Hazard Ratio, CI – Confidence Interval, NNT – Number Needed to Treat, USPSTF – United States Preventive Services Task Force, ESC – European Society of Cardiology, EAS – European Atherosclerosis Society, AHA – American Heart Association, ACC – American College of Cardiology, DCRM – Diabetes, Cardiorenal, and Metabolic (consensus platform)