Ischemic stroke and dose adjustment of oral Factor Xa inhibitors in patients with atrial fibrillation

Abstract

Background Oral Factor Xa inhibitors for the prevention of stroke in atrial fibrillation require dose adjustment based on certain clinical criteria, but the off-label use of the reduced doses is common. Methods Data from an observational registry including patients admitted with acute cerebral ischemia while taking oral Factor Xa inhibitors for atrial fibrillation between April 2016 and December 2018 were investigated. The dose regimen of the Xa inhibitor was classified as "appropriate", "underdosed" and "overdosed" in conformity with the European Medicines Agency labelling. The effect of underdosing on the functional factor Xa plasma level on admission, the clinical stroke severity and the functional outcome after 3 months were investigated. Results 254 patients with cerebral ischemia while on Factor Xa inhibitors were included. The dose regimen of the Factor Xa inhibitor was appropriate in 166 patients (65%), underdosed in 67 patients (26%) and overdosed in 21 patients (8%). Underdosing was associated with female sex, diabetes mellitus and higher CHA 2 DS 2-Vasc scores. Underdosing independently predicted lower anti-Xa plasma levels on admission [median 69.4 ng/ml (IQR 0.0-121.6) vs. 129.2 ng/ml (65.5-207.2); p < 0.001], was associated with higher NIHSS scores on admission [median 5 (IQR 1-10) vs. 3 (1-7); p = 0.041] and worse functional outcome after 3 months (favorable outcome 26.9% vs. 46.9%; p = 0.025). Conclusion One in three patients with ischemic stroke during treatment with oral Xa inhibitors used inappropriate dose regimens. Underdosing was associated with lower functional plasma levels, higher clinical stroke severity and worse functional outcome.

Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry

“…This finding is in line with a German single-center observation based on 254 acute stroke patients with known AF, reporting an off-label dose in one out of three patients on factor Xa inhibitors. [32] In the Berlin Atrial Fibrillation Registry, under-dosing of apixaban and rivaroxaban at stroke onset was associated with old age, which is in line with prospective AF registries like ORBIT AF II, including only a subset of patients with prior (but not acute) ischemic stroke [14][15][16][17]. Compared to on-label dosing, under-dosing of apixaban or rivaroxaban was not significantly associated with stroke severity on hospital admission or at hospital discharge.…”

Etiology of Ischemic Strokes of Patients with Atrial Fibrillation and Therapy with Anticoagulants

“…Rivaroxaban, the factor Xa inhibitor with the most variable available doses in different indications [ 16 ], was the NOAC showing the highest rate of medication errors. Another study recently reported a rate of up to 65% of patients with Factor Xa inhibitor treatment having received an inappropriate dose regimen before stroke [ 17 ]. Furthermore, lower plasma levels at admissions were associated with greater stroke severity [ 17 , 18 ].…”

“…Another study recently reported a rate of up to 65% of patients with Factor Xa inhibitor treatment having received an inappropriate dose regimen before stroke [ 17 ]. Furthermore, lower plasma levels at admissions were associated with greater stroke severity [ 17 , 18 ]. Although different available doses principally enhance the possibility to better tailor individual medications, our data underline the growing need to educate prescribing physicians.…”

Off-label use of reduced dose direct oral factor Xa inhibitors in subjects with atrial fibrillation: a review of clinical evidence

“…In a prospective cohort study on 1124 atrial fibrillation patients aged 85 years and older treated with vitamin K antagonists (58.7%) or DOACs (41.3%), no thrombotic events occurred in the small group of underdosed DOAC patients. 88 Recent studies demonstrated that oFXaIs' underdosing was associated with a higher stroke severity in patients admitted with ischaemic stroke, 89 and with a higher rate of major vascular occlusion in patients admitted with suspected ischaemic stroke. 90 In conclusion, despite inherent limitations of observational studies, and with few exceptions, 40,86,88 there is consistent evidence that underdosing of oFXaIs is not associated with a significant reduction of bleeding events and is possibly associated with an increased risk of thromboembolic events.…”