Low LDL-cholesterol drives the risk of bleeding in patients treated with aspirin: A 15-year study in a real-world large population

We aimed to investigate the link between LDL cholesterol (LDL-C) levels and hemorrhage risk over an extended period, both in subjects taking aspirin and in individuals not receiving any antiplatelet agent. We calculated the predicted adjusted relative hazard of bleeding by LDL-C concentration for the whole cohort and the aspirin-treated subgroup. The study included 39,784 individuals with a mean follow-up of 14.9 years, totaling over 500,000 patient-years. Across the cohort, 3380 bleeding events were reported, with a higher incidence in patients with LDL-C < 70 mg/dL compared to those with LDL-C ≥ 70 mg/dL (9.9 % vs 8.4 %). In aspirin-treated patients, multivariable analysis revealed that hemorrhagic events were significantly associated with aging, male sex, body mass index, hypertension, and LDL-C < 70 mg/dL. These patients had a significantly lower event-free survival probability if their LDL-C was < 70 mg/dL compared to ≥ 70 mg/dL. Low LDL-C values were a significant risk factor (HR >1) while higher LDL-C values were protective (HR <1). A stepwise increase of 10 mg/dL in LDL-C from < 30 to ≥ 200 mg/dL was associated with a decreasing trend for bleeding events in both the entire cohort and the aspirin-treated subgroup. This is the first report specifically addressing the relationship between LDL-C levels and bleeding risk in a population receiving low-intensity antithrombotic therapy. Our data demonstrate that in patients taking aspirin, LDL-C levels below 70 mg/dL significantly increase the risk of bleeding, with major implications for long-term cardiovascular risk management.