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.

Keywords: Atrial fibrillation; Ischemic stroke; NOAC; Under-dosing.

Conflict of interest statement

ST, MO, CK, CF, DZ, CM, BD, JMR, TEH and HCK report no conflict of interests outside the submitted work. DGN has received speaker’s honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Daiichi Sankyo, Novartis and Pfizer. CHN received research grants from German Ministry of Research and Education, German Center for Neurodegenerative Diseases, German Center for cardiovascular Research, and speaker and/or consultation fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer Pharma, Abbott and W.L. Gore and Associates. JD received a research grant from the Karl and Veronica Carstens Foundation. EV reports that his unmarried partner works for Pfizer. WD reports speaker fees and advisory honoraria from Aimediq, Bayer, Boehringer Ingelheim, Lilly, Medtronic, Pfizer, Sanofi-Aventis, Sphingotec, Vifor Pharma and research support from Vifor Pharma, ZS Pharma outside of the submitted work. AK received speakers honoraria from Bayer, Pfizer and Novartis. PUH reports grants from Charité—Universitätsmedizin Berlin during study conduct (within MonDAFIS for biometry; member scientific board); research grants from German Ministry of Research and Education, German Research Foundation, European Union, Charité – Universitätsmedizin Berlin, Berlin Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert Koch Institute, German Heart Foundation, Federal Joint Committee (G-BA) within the Innovationfond, University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo), University Göttingen (within FIND-AF randomized; supported by an unrestricted research grant to the University Göttingen from Boehringer-Ingelheim), outside the submitted work. ME reports grants from Bayer and fees paid to the Charité from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Ever, Glaxo Smith Kline, MSD, Novartis and Pfizer. KGH reports speaker’s honoraria, consulting fees, lecture honoraria and/or study grants from AstraZeneca, Abbott, Bayer Healthcare, Sanofi, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, Premier Research, Bristol-Myers Squibb, Biotronik, Medronic, Portola, W.L. Gore and Associates and Edwards Lifesciences.

© 2021. The Author(s).

Figures

Fig. 1

Dosing of NOACs at stroke onset and at hospital discharge in patients with known AF before stroke and in patients with a first episode of AF after acute ischemic stroke/TIA as well as in all AF patients at hospital discharge. *Not categorized due to missing value (e.g., eGFR or body weight)