Low-density lipoprotein cholesterol and intracranial hemorrhage risk in patients on direct-acting oral anticoagulants

Background and purpose: Direct-acting oral anticoagulants (DOACs) therapy reduces ischemic stroke (IS) risk but increases the risk of intracranial hemorrhage (ICH). Evidence regarding the safety of low low-density lipoprotein cholesterol (LDL-C) levels in patients undergoing DOACs therapy is limited. This study aimed to assess the dose–response relationship between LDL-C levels and ICH risk in patients on DOACs therapy. Methods: Using a new-user design, 24,794 DOACs-treated patients were identified from the medical and health data platform of Tianjin, China. During a 3-year follow-up, 188 ICH events, 718 IS events, and 2,472 deaths were recorded. The hazard ratios (HRs) between LDL-C levels and study outcomes were estimated using restricted cubic splines in Cox regression models. Results: A negative, non-linear relationship between baseline LDL-C levels and ICH risk was identified, with higher risk at low LDL-C levels (threshold value: LDL-C <70 mg/dL). After multivariable adjustment, low LDL-C levels were associated with increased ICH risk, reduced IS risk, and no significant impact on all-cause mortality, with the HRs of 1.58, 0.73, and 0.91; 95% confidence interval (95% CI) of 1.11–2.25, 0.59–0.92, and 0.81–1.01; and P values of 0.012, 0.007, and 0.083, respectively. Multiple sensitivity analyses confirmed these findings. Conclusions: LDL-C <70 mg/dL is an independent risk factor for ICH in patients receiving DOACs therapy in this province-wide cohort from China. Additional validation is required to optimize LDL-C targets and DOACs use to balance IS benefits against ICH risks.