Antithrombotic therapy and bleeding risk in the era of aggressive lipid-lowering: current evidence, clinical implications, and future perspectives

The clinical efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing major cardiovascular adverse events related to atherosclerotic cardiovascular disease (ASCVD) has been well established in recent large randomized outcome trials. Although the cardiovascular and all-cause mortality benefit of PCSK9i remains inconclusive, current cholesterol management guidelines have been modified toward more aggressive goals for lowering low-density lipoprotein cholesterol (LDL-C). Consequently, the emerging concept of the lower the better has become the paradigm of ASCVD prevention. However, there is evidence from observational studies of a U-shaped association between baseline LDL-C levels and all-cause mortality in population-based cohorts. Among East Asian populations, low LDL-C was associated with an increased risk for hemorrhagic stroke in patients not on antithrombotic therapy. Accumulating evidence showed that low LDL-C was associated with an enhanced bleeding risk in patients on dual antiplatelet therapy following percutaneous coronary intervention. Additionally, low LDL-C was associated with a higher risk for incident atrial fibrillation and thereby, a possible increase in the risk for intracranial hemorrhage after initiation of anticoagulation therapy. The mechanism of low-LDL-C-related bleeding risk has not been fully elucidated. This review summarizes recent evidence of low-LDL-C-related bleeding risk in patients on antithrombotic therapy and discusses potential measures for reducing this risk, underscoring the importance of carefully weighing the pros and cons of aggressive LDL-C lowering in patients on antithrombotic therapy.

Automated summary

The clinical efficacy of PCSK9 inhibitors in reducing major cardiovascular adverse events related to ASCVD has been established, but the mortality benefit remains inconclusive. Cholesterol management guidelines now emphasize more aggressive LDL-C lowering goals. However, there is evidence of a U-shaped association between baseline LDL-C levels and all-cause mortality, particularly in East Asian populations. Low LDL-C has been linked to an increased risk of hemorrhagic stroke, bleeding risk in patients on dual antiplatelet therapy, incident atrial fibrillation, and potential intracranial hemorrhage. This review highlights the importance of carefully weighing the pros and cons of aggressive LDL-C lowering in patients on antithrombotic therapy.