Lower dose direct oral anticoagulation and warfarin in atrial fibrillation. Ischemic stroke, intracranial hemorrhage and mortality in a nationwide registry study
Authors: Halminen O , Luojus A , Haukka J , Aro A L , Lehtonen O , Tiili P , Putaala J , Linna M , Mustonen P , Kinnunen J , Niemi M , Hartikainen J , Airaksinen K E J , Lehto M 
Published: November 2023

Abstract

Background and aims
Direct oral anticoagulants (DOACs) have replaced Vitamin-K antagonists as the primary choice of oral anticoagulation (OAC) in atrial fibrillation (AF). However, after several years of experience with DOACs, no studies have been made comparing the efficacy and safety of reduced dose DOACs and warfarin when the quality of warfarin treatment (time in the therapeutic range, TTR) information is available.

Methods
The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide study of AF patients combining data from several Finnish healthcare registers. We included all new-onset AF patients from 2011 to 2018 in Finland with purchases of either reduced dose DOAC or warfarin with eligible laboratory data. For patients on warfarin, we calculated TTR percentages and divided patients into TTR quartiles.
Occurrence of ischemic stroke (IS), intracranial haemorrhage (ICH), or death during OAC use were recorded as outcomes during a maximum follow-up of 730 days. Crude and weighted rates of IS, ICH and mortality are provided. To minimize confounding by baseline characteristics and concomitant medications, an inverse probability of treatment weighted analysis was applied.

Results
A total of 52,022 new-onset AF patients with OAC therapy (46.1% male, mean age 75.7 years, 43 548 on warfarin) were followed for 56 382 patient-years (py).
The rate of IS among patients was 1.63/100 py for dabigatran (n=2 672), 1.64/100 py for apixaban (n=3 936), 1.49 /100 py for rivaroxaban (n=1 866). For patients with warfarin, the rates of IS in TTR quartiles were 3.45, 1.79, 1.18 and 0.74/100 py from the lowest (mean TTR 32%) to the highest TTR quartile (mean TTR 90%). The weighted rates of IS were 1.34, 0.96 and 1.25/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.70, 1.87, 1.21 and 0.97/100 py.
The rates of ICH were 0.68, 1.09 and 1.06/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.60, 0.99, 0.51 and 0.32/100 py. The weighted rates of ICH were 0.70, 0.70 and 0.90/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.80, 1.03, 0.54, 0.34 and 0.97/100 py.
For mortality, raw incidences rates were 4.31, 11.40, and 8.11/100 py for for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 16.45, 5.33, 2.31, and 1.53/100 py. The weighted rates were 3.97, 7.97, and 6.78, for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 18.08, 5.86, 2.58, and 1.73/100 py. Figures portray cumulative IS incidence and mortality.

Conclusion
The incidence rates of all three outcomes were highest among patients on warfarin in the lowest TTR quartiles. For reduced dose DOAC patients, weighted IS rates were highest for those on dabigatran, ICH rates for those on rivaroxaban, and mortality rates for those on apixaban.Cumulative Incidence of Ischemic StrokeCumulative mortality