Dynamic changes in liver fibrosis and the risk of death and bleeding in non-cirrhotic patients with atrial fibrillation treated with NOACs
T Bucci, A G Rigutini, A Perrotta, A Moffa, C Seviroli, M Giustozzi, M C Vedovati, C BecattiniAbstract
Background
FIB-4, a widely used non-invasive marker of liver fibrosis, has been associated with an increased risk of bleeding and death in patients with atrial fibrillation (AF). However, whether liver fibrosis in the absence of cirrhosis independently predicts bleeding and mortality in patients treated with non–vitamin K antagonist oral anticoagulants (NOACs) remains insufficiently characterized. Moreover, the clinical relevance of dynamic changes in FIB-4 over time and its prognostic impact following bleeding events are poorly defined.
Methods
This prospective observational study enrolled consecutive AF patients treated with NOACs at the Emergency Medicine Department, between 2013 and 2016. Patients with cirrhosis were excluded. Patients were stratified according to the FIB-4 score using the 2.67 cut-off to identify advanced fibrosis, according to the American Association for the Study of Liver Diseases. Multivariable Cox regression models were used to assess the association between FIB-4 and study outcomes. The primary outcomes were all-cause death and clinically relevant bleeding (CRB) (including major and clinically relevant non-major bleeding). Secondary outcomes were cardiovascular events (including myocardial infarction and ischaemic stroke). Landmark analyses were performed to evaluate the risk of all-cause death only: (i) across groups defined by FIB-4 trajectories between baseline and the second follow-up visit between 3 months and 1 year and (ii) after a bleeding episode according to FIB-4 levels.
Results
Overall, 733 patients (median age 80.2 [74.3–85.1] years; 360 (49%) women) were included. During a mean follow-up of 4.21 years (3.01–5.1), 226 deaths (30.8%), 200 bleedings (27.3%), and 43 cardiovascular events (5.9%) occurred. After multivariable adjustment, high FIB-4 was independently associated with increased risk of all-cause death (HR 1.56, 95% CI 1.18–2.07) and CRB (HR 1.53, 95% CI 1.13–2.07), whereas no significant association was observed for cardiovascular events (HR 1.21, 95% CI 0.61–2.40). Among patients with serial measurements, both persistently high and worsening FIB-4 trajectories were associated with increased mortality compared with stable low FIB-4 (HR 2.69, 95% CI 1.72–4.21 and HR 1.79, 95% CI 1.05–3.05, respectively; Figure 1). In patients experiencing a bleeding event during follow-up, elevated FIB-4 levels were associated with higher subsequent mortality (HR 1.82, 95% CI 1.18–2.81; Figure 2).
Conclusions
In AF patients treated with NOACs, FIB-4 identifies patients at increased risk of death and bleeding. Serial assessment of FIB-4 may provide incremental prognostic information by capturing dynamic changes in risk. Bleeding events occurring in patients with elevated FIB-4 are associated with significantly worse survival.Figure 1Figure 2