Rivaroxaban-Mediated Vascular Relaxation As a Potential Cause of Headaches and Dizziness
Authors: Mabley Jon , Scutt Greg , Lang Kathryn Jane , Patel Jignesh P , Arya Roopen 
Published: October 2019

Abstract
The availability of the direct Xa inhibitors apixaban, edoxaban and rivaroxaban in clinical practice is leading a paradigm shift in anticoagulation for the management of venous thromboembolism (VTE) and stroke prophylaxis in the context of non-valvular atrial fibrillation (AF). A common side effect experienced by patients receiving rivaroxaban in clinical trials was dizziness and headache, with a reported incidence of between 1 in 10 and 1 in 100 patients. Clinical experience has seen patients reporting rivaroxaban associated headaches and dizziness, leading to discontinuation of therapy. Given that widespread use of these agents is likely to be within an older adult population, it is important to understand the mechanism behind clinical observations which may then allow us to determine why some patients are affected more than others. We hypothesise that rivaroxaban directly causes vascular arteriodilation, resulting in headaches and dizziness requiring discontinuation of treatment.
To test this hypothesis the effects of rivaroxaban on phenylephrine pre-contracted rat aortic rings was investigated. Thoracic aorta from male Sprague-Dawley rats (180-220g) were dissected and cut into rings of 2-3mm prior to being mounted under a preload tension of 1.5g in Krebs filled organ baths. Isometric tension of the rings was measured with isometric transducers (Danish Myo Technology, Aarhus, Denmark) digitised using a Power lab system. Following a phenylephrine dose-response curve the aortic rings were pre-contracted with 1 µM phenylephrine before measuring the relaxant effect of rivaroxaban (0.001-0.3 µM) or a similar volume of the vehicle dimethyl sulfoxide (DMSO). Statistical analysis was carried out using two-way ANOVA with Bonferroni's correction, where p<0.05 was considered significant.
Exposure of aortic rings to both rivaroxaban and the vehicle DMSO caused relaxation. However, the relaxation observed with rivaroxaban was significantly greater than that observed with the vehicle (Fig 1).
Our preliminary data suggests that rivaroxaban may have a direct arteriodilatory effect. This arteriodilatory effect of rivaroxaban may provide a possible explanation for dizziness and headaches experienced by some rivaroxaban treated patients. Further work is required to determine the underlying mechanism of rivaroxaban-mediated vaso-relaxant effect as well as determining if the other Xa inhibitors apixaban and edoxaban also share this physiological effect, and if so, to what extent.
Figure 1. Exposure of rat thoracic aorta rings to rivaroxaban and the vehicle DMSO caused relaxation. Rivaroxaban produced significantly more relaxation as compared to DMSO alone (p<0.05). Data is expressed as mean ± SEM from 12 animals; †p<0.05 vs. DMSO alone Figure 1. Exposure of rat thoracic aorta rings to rivaroxaban and the vehicle DMSO caused relaxation. Rivaroxaban produced significantly more relaxation as compared to DMSO alone (p<0.05). Data is expressed as mean ± SEM from 12 animals; †p<0.05 vs. DMSO alone

Disclosures
Patel: Bayer plc: Research Funding. Arya:Bayer plc: Research Funding.