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

Abstract

Aims We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. Methods The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. Results At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P < 0.01]. Conclusion At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. Clinical trial registration NCT02306824.

Acute Ischaemic Stroke in Patients Treated with Direct Oral Anticoagulants: Potential Causes, Clinical Characteristics, and Short-Term Outcomes

“…Higher risk of underdosing is associated with older age, congestive heart failure, arterial hypertension, history of minor bleeds, and low creatine clearance [ 26 ]. A study by Tütüncü et al showed that among 239 DOAC-treated AIS patients, 21.8% was underdosed before stroke onset [ 27 ]. In a case-control study by Paciaroni et al including 713 DOAC-treated AIS patients, 44.5% (317 patients) was treated with low-dose DOAC and 35% of those (111 patients) with off-label low doses.…”

Longer and better lives for patients with atrial fibrillation: the 9th AFNET/EHRA consensus conference

“…There is a residual risk of ischaemic stroke despite anticoagulant therapy (1–2%/year in the pivotal randomized controlled trials), calling for augmented therapy. 65 , 108 , 109 Patients experiencing a stroke on anticoagulation can potentially benefit from a call to A-C-T-I-O-N to improve outcome. 110 Sub-optimal treatment of comorbidities and treatment with anticoagulation and low, untested, and non-approved doses 111 may contribute to stroke and cardioembolism.…”

“… 110 Sub-optimal treatment of comorbidities and treatment with anticoagulation and low, untested, and non-approved doses 111 may contribute to stroke and cardioembolism. 109 The effects of LAAOS III 89 and EAST-AFNET 4 14 highlight the potential of treating atrial causes of stroke in patients with AF experiencing a stroke on anticoagulation. Whether novel FXIa inhibitors, 112 , 113 a distinct new class of drugs under investigation for thrombosis prevention, improve outcomes in patients with AF will be evaluated in ongoing registration trials.…”

Prolonged Secondary Stroke Prevention with Edoxaban: A Long-Term Follow-Up of the SATES Study

“…The main limitation of DOAC therapy consists of the relatively recent time of introduction on the market, especially for what concerns edoxaban, which was approved by the U.S. Food and Drug Administration (FDA) less than 10 years ago [7], leading to little evidence concerning the long-term follow-up. The lack of data is especially relevant for elderly patients (≥80 years), since, due to the fear of frailty-related bleeding risk, the proportion of patients erroneously treated with underdosed regimens [8] or with inappropriate antithrombotic therapies [9] is particularly high in these subjects.…”