Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulant and Warfarin in Cirrhotic Patients With Nonvalvular Atrial Fibrillation

Abstract

Background Liver cirrhotic patients with nonvalvular atrial fibrillation have been excluded from randomized clinical studies regarding oral anticoagulants for stroke prevention. Whether non-vitamin K antagonist oral anticoagulants ( NOAC s) are superior to warfarin for these patients remains unclear. Methods and Results This nationwide retrospective cohort study, with data collected from the Taiwan National Health Insurance Research Database, enrolled 2428 liver cirrhotic patients with nonvalvular atrial fibrillation taking apixaban (n=171), dabigatran (n=535), rivaroxaban (n=732), or warfarin (n=990) from June 1, 2012, to December 31, 2016. We used propensity score-based stabilized weights to balance covariates across study groups. Patients were followed until the occurrence of an event or the end date of study. The NOAC group (n=1438) showed risk of ischemic stroke/systemic embolism and intracranial hemorrhage comparable to that of the warfarin group (n=990) after adjustment. The NOAC group showed significantly lower risk of gastrointestinal bleeding (hazard ratio: 0.51 [95% CI, 0.32-0.79]; P=0.0030) and all major bleeding (hazard ratio: 0.51 [95% CI, 0.32-0.74]; P=0.0003) compared with warfarin group. Overall, 90% (n=1290) of patients were taking a low-dose NOAC (apixaban 2.5 mg twice daily, rivaroxaban 10-15 mg daily, or dabigatran 110 mg twice daily). The subgroup analysis indicated that both dabigatran and rivaroxaban showed lower risk of all major bleeding than warfarin. The advantage of lower gastrointestinal and all major bleeding with NOACs over warfarin is contributed by those subgroups with either nonalcoholic or nonadvanced liver cirrhosis. Conclusions NOACs have a risk of thromboembolism comparable to that of warfarin and a lower risk of major bleeding among liver cirrhotic Asian patients with nonvalvular atrial fibrillation. Consequently, thromboprophylaxis with low-dose NOAC s may be considered for such patients.

Keywords: atrial fibrillation; direct thrombin inhibitor; factor Xa inhibitor; hemorrhage; ischemic stroke; liver cirrhosis; mortality; warfarin.

Figure 1

Enrollment of patients with liver cirrhosis and nonvalvular atrial fibrillation. From June 1, 2012, to December 31, 2016, a total of 171, 535, and 732 NVAF patients with liver cirrhosis taking apixaban, dabigatran, and rivaroxaban and 990 patients taking warfarin were enrolled in the study. AF indicates atrial fibrillation; NOAC, non–vitamin K antagonist oral anticoagulant.

Figure 2

Cumulative incidence curves of IS/SE (A), all major bleeding (B), ICH (C), and major GI bleeding (D) for liver cirrhotic patients with nonvalvular atrial fibrillation according to initiated treatment after propensity score–based stabilized weighting. The NOAC group showed risk of IS/SE comparable to that of the warfarin group after adjustment. For the safety outcome, the NOAC group showed significantly lower risk of major GIB and all major bleeding than the warfarin group. GIB indicates gastrointestinal bleeding; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant.

Figure 3

Forest plot of the hazard ratio for each NOAC vs warfarin among liver cirrhotic patients with NVAF taking oral anticoagulants. The NOAC group was associated with reduced risk of major GIB and all major bleeding compared with the warfarin group. Among NOACs, rivaroxaban was associated with lower risk of major GIB and all major bleeding than warfarin. Dabigatran was associated with lower risk of all major bleeding than warfarin. A indicates apixaban; D, dabigatran; GIB, gastrointestinal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant; R, rivaroxaban; W, warfarin.

Figure 4

Forest plot of HRs for NOAC vs warfarin among patients with either alcoholic or nonalcoholic liver cirrhosis taking oral anticoagulants. In total, 222 (15%) and 143 (14%) patients with alcoholic liver cirrhosis were taking NOACs and warfarin, respectively. For those patients with alcoholic liver cirrhosis, the NOAC group has risks of thromboembolism and all major bleeding comparable to those of the warfarin group. For those patients with nonalcoholic liver cirrhosis, the NOAC group has lower risks of major GIB and all major bleeding than the warfarin group. GIB indicates gastrointestinal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant.

Figure 5

Forest plot of HRs for NOAC vs warfarin among patients with either advanced or nonadvanced liver cirrhosis taking oral anticoagulants. In total, 271 (19%) and 273 (27%) patients with advanced liver cirrhosis were taking NOACs and warfarin, respectively. For those patients with advanced liver cirrhosis, the NOAC group has lower risk of intracranial hemorrhage than the warfarin group. For those patients with nonadvanced liver cirrhosis, the NOAC group has lower risks of major GIB and all major bleeding than the warfarin group. GIB indicates gastrointestinal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant.