Efficacy and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Asians With Nonvalvular Atrial Fibrillation

Abstract

Background: Whether non-vitamin K antagonist oral anticoagulants (NOACs) are superior to warfarin among Asians with nonvalvular atrial fibrillation remains unclear.

Methods and results: In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, there were 5843, 20 079, 27 777, and 19 375 nonvalvular atrial fibrillation patients taking apixaban, dabigatran, rivaroxaban and warfarin, respectively, from June 1, 2012 to December 31, 2016. Propensity-score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any efficacy or safety outcome or the end date of study. Hazard ratios (95% confidence intervals) comparing apixaban, dabigatran, and rivaroxaban with warfarin were: ischemic stroke/systemic embolism (IS/SE), 0.55 (0.43-0.69), 0.82 (0.68-0.98), and 0.81 (0.67-0.97); major bleeding, 0.41 (0.31-0.53), 0.65 (0.53-0.80), and 0.58 (0.46-0.72); and all-cause mortality, 0.58 (0.51-0.66), 0.61 (0.54-0.68), and 0.57 (0.51-0.65). A total of 3623 (62%), 17 760 (88%), and 26 000 (94%) patients were taking low-dose apixaban (2.5 mg twice daily), dabigatran (110 mg twice daily), and rivaroxaban (10-15 mg once daily), respectively. Similar to all-dose NOACs, all low-dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. In contrast to other standard-dose NOACs, apixaban was associated with lower risks of IS/SE (0.45 [0.31-0.65]), major bleeding (0.29 [0.18-0.46]), and mortality (0.23 [0.17-0.31]) than warfarin.

Conclusions: All NOACs were associated with lower risk of IS/SE, major bleeding, and mortality compared with warfarin in the largest real-world practice among Asians with nonvalvular atrial fibrillation. All low-dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. Standard-dose apixaban caused a lower risk of IS/SE, major bleeding, and mortality compared with warfarin.

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

Figure 1

Enrollment of patients with non‐valvular AF. From June 1, 2012, to December 31, 2016, 5843, 20 079, and 27 777 nonvalvular AF patients receiving the apixaban, dabigatran, and rivaroxaban and 19 375 patients prescribed warfarin were enrolled in this study. AF indicates atrial fibrillation.

Figure 2

The cumulative incidence curves of IS/SE (A), AMI (B), all‐cause mortality (C), ICH (D), major GIB (E), and all major bleeding (F) for patients with nonvalvular AF taking oral anticoagulants before propensity score weighting. Apixaban, rivaroxaban, and dabigatran are associated with reduced risk of IS/SE, ICH, major GIB, all major bleeding, and all cause‐mortality compared with warfarin. AF indicates atrial fibrillation; AMI, acute myocardial infarction; GIB, gastrointestinal bleeding; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism.

Figure 3

The cumulative incidence curves of IS/SE (A), AMI (B), all‐cause mortality (C), ICH (D), major GIB (E), and all major bleeding (F) for patients with nonvalvular AF taking oral anticoagulants after propensity score weighting. Apixaban, rivaroxaban, and dabigatran are associated with reduced risk of IS/SE, ICH, all major bleeding, and all cause‐mortality compared with warfarin. AF indicates atrial fibrillation; AMI, acute myocardial infarction; GIB, gastrointestinal bleeding; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism.

Figure 4

The forest plot of hazard ratios for each NOAC vs warfarin comparison. Apixaban, rivaroxaban, and dabigatran are associated with reduced risks of IS/SE, ICH, all major bleeding, and all cause‐mortality compared with warfarin. AMI indicates acute myocardial infarction; CI, confidence interval; GIB, gastrointestinal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant.

Figure 5

The forest plot of hazard ratios for each standard‐dose NOAC (apixaban 5 mg twice daily, dabigatran 150 mg twice daily, and rivaroxaban 20 mg once daily) vs warfarin comparison. Standard‐dose apixaban is associated with lower risks of IS/SE, ICH, major GIB, and all major bleeding compared with warfarin. All NOACs have a lower risk of all‐cause mortality compared to warfarin. AMI indicates acute myocardial infarction; CI, confidence interval; GIB, gastrointestinal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant.

Figure 6

The forest plot of hazard ratios for each low‐dose NOAC (apixaban 2.5 mg twice daily, dabigatran 110 mg twice daily, and rivaroxaban 15/10 mg once daily) vs warfarin comparison. Apixaban, rivaroxaban, and dabigatran are associated with reduced risk of IS/SE, ICH, all major bleeding, and all‐cause mortality compared with warfarin. AMI indicates acute myocardial infarction; CI, confidence interval; GIB, gastrointestinal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant.

Figure 7

The forest plot of hazard ratios for each standard‐dose NOAC (apixaban 5 mg twice daily, dabigatran 150 mg twice daily, and rivaroxaban 20 mg once daily) vs low‐dose NOAC (apixaban 2.5 mg twice daily, dabigatran 110 mg twice daily, and rivaroxaban 15/10 mg once daily) comparison. In general, standard‐dose NOACs showed 6 comparable outcomes to low‐dose NOACs. It was noted that standard‐dose apixaban had lower risks of all‐cause mortality compared to low‐dose apixaban. AMI indicates acute myocardial infarction; CI, confidence interval; GIB, gastrointestinal bleeding; HR, hazard ratio; ICH, intracranial hemorrhage; IS/SE, ischemic stroke/systemic embolism; NOAC, non–vitamin K antagonist oral anticoagulant.