Reduced dose direct oral anticoagulants compared with warfarin with high time in therapeutic range in nonvalvular atrial fibrillation.

Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are dose-reduced in elderly and patients with impaired renal function. Only reduced dose dabigatran is concluded as having similar stroke risk reduction and lower risk of major bleeding than warfarin in the pivotal studies. In clinical practice, reduced dose is prescribed more often than expected making this an important issue. The objective of this study was to compare effectiveness and safety between reduced dose DOACs and high TTR warfarin treatment (TTR ≥ 70%) in NVAF. A Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 40,564 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) (11,083 patients) or warfarin treatment (29,481 patients) after exclusion of 374,135 patients due to not being warfarin or DOAC naïve, not being prescribed reduced dose, having previous mechanical heart valve (MHV), or being under 18 years old. The median durations of follow up were 365, 419, 432 and 473 days for apixaban, dabigatran, rivaroxaban and warfarin, respectively. Warfarin TTR identified from Auricula was 70.0%. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores. DOACs are associated with lower risk of major bleeding (HR with 95% CI) 0.85 (0.78-0.93), intracranial bleeding HR 0.64 (0.51-0.80), hemorrhagic stroke HR 0.68 (0.50-0.92), gastrointestinal bleeding HR 0.81 (0.69-0.96) and all-cause stroke HR 0.87 (0.76-0.99), than warfarin. Apixaban and dabigatran are associated with lower risk of major bleeding, HR 0.70 (0.63-0.78) and HR 0.80 (0.69-0.94), and rivaroxaban is associated with lower risk of ischemic stroke, HR 0.73 (0.59-0.96), with higher major bleeding risk, HR 1.31 (1.15-1.48), compared to warfarin. Apixaban is associated with higher all-cause mortality compared to warfarin, HR 1.12 (1.03-1.21). DOACs are associated with lower risk of major bleeding and all-cause stroke, than high quality warfarin treatment, with exception of rivaroxaban that carried higher risk of major bleeding and lower risk of stroke or systemic embolism. In this large observational registry-based NVAF cohort, DOACs are preferred treatment in patients with indication for DOAC dose reduction, even in a high TTR setting.

Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation.

INTRODUCTION: Direct oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran. MATERIALS AND METHODS: Patients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015. Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched using full optimal matching and directly compared. RESULTS: A total of 25,843 NVAF patients were included. Patients treated with standard dose apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54-0.88) and HR 0.64 (95% CI 0.48-0.87). Regarding reduced dose, patients treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44-0.88) and HR 0.45 (95% CI 0.33-0.61). In reduced dose, patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found. CONCLUSIONS: In this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.