Association between coagulation factor XI level and cardiovascular events: a prospective cohort study in patients with suspected functionally relevant coronary artery disease

Introduction Coagulation factor XI (FXI) inhibitors are emerging anticoagulants for the prevention of atherothrombotic events with lower bleeding rates than current anticoagulants, but inconsistent data on efficacy and some concern regarding an increase in heart failure (HF). Revisiting the association between FXI levels and the incidence of cardiovascular events could provide additional insights. Purpose We aimed to test the association between FXI levels and 1) the prevalence of HF, 2) the incidence of HF, and 3) the incidence of major cardiovascular events (MACE) including cardiovascular death, non-fatal myocardial infarction, and stroke. We hypothesized that FXI levels would not be associated with the prevalence or incidence of HF, but lower FXI levels would be associated with a lower risk of MACE. Methods This analysis included patients from a prospective cohort study with suspected functionally relevant coronary artery disease (fCAD) and available FXI measurements. The prevalence of HF was centrally adjudicated by an independent cardiologist according to guidelines based on cardiac imaging and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. FXI levels were measured in a blinded fashion using the SomaScan (version 4.1) assay. The incidence of HF and MACE were adjudicated by independent cardiologists using 8-year clinical follow-up. Cox and logistic regression models adjusting for confounders were used to test the associations. Results Among 2,073 patients eligible for the MACE analysis (median age 68 years, 32% female, 47% known CAD), 504 patients developed MACE during follow-up. Lower FXI levels were associated with a significantly higher risk of MACE, even after adjustment for confounders (HR 1.91 (95%CI, 1.41-2.59), adjusted HR 1.49 (95%CI, 1.07-2.06), Figure). FXI levels were neither associated with the prevalence (adjusted HR 1.37 (95%CI, 0.93-2.02) nor the incidence of HF (adjusted HR 1.62 (95%CI, 0.83-3.19)). Conclusion In contrast to our hypothesis, lower FXI levels were associated with a higher (not lower) incidence of MACE. This finding raises concern as it challenges the widespread assumption of beneficial effects of low FXI levels. No association with prevalent and incident HF was found.