Effects of Rivaroxaban on Biomarkers of Coagulation and Inflammation: A Post Hoc Analysis of the X-VeRT Trial

Abstract

Introduction This X-VeRT (eXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion) substudy evaluated the effects of treatment with rivaroxaban or a vitamin-K antagonist (VKA) on levels of biomarkers of coagulation (D-dimer, thrombin-antithrombin III complex [TAT] and prothrombin fragment [F1.2]) and inflammation (high sensitivity C-reactive protein [hs-CRP] and high-sensitivity interleukin-6 [hs-IL-6]) in patients with atrial fibrillation (AF) who were scheduled for cardioversion and had not received adequate anticoagulation at baseline (defined as, in the 21 days before randomization: no oral anticoagulant; international normalized ratio <2.0 with VKA treatment; or <80% compliance with non-VKA oral anticoagulant treatment). Methods Samples for biomarker analysis were taken at baseline ( n = 958) and treatment completion (42 days after cardioversion; n = 918). The influence of clinical characteristics on baseline biomarker levels and the effect of treatment on changes in biomarker levels were evaluated using linear and logistic models. Results Baseline levels of some biomarkers were significantly associated with type of AF (D-dimer and hs-IL-6) and with history of congestive heart failure (hs-CRP, D-dimer, and hs-IL-6). Rivaroxaban and VKA treatments were associated with reductions from baseline in levels of D-dimer (-32.3 and -37.6%, respectively), TAT (-28.0 and -23.1%, respectively), hs-CRP (-12.5 and -17.9%, respectively), and hs-IL-6 (-9.2 and -9.8%, respectively). F1.2 levels were reduced from baseline in patients receiving a VKA (-53.0%) but not in those receiving rivaroxaban (2.7%). Conclusion Anticoagulation with rivaroxaban reduced levels of key inflammation and coagulation biomarkers to a similar extent as VKAs, with the exception of F1.2. Further investigation to confirm the value of these biomarkers in patients with AF is merited.

Keywords: anticoagulants; atrial fibrillation; biomarkers; inflammation; rivaroxaban.

Fig. 1

Patient flow and overview of biomarker collection. EoT, end of treatment; hs-CRP, high-sensitivity C-reactive protein; mITT, modified intention-to-treat; OAC, oral anticoagulant. ^a Patients in the mITT population in whom a left atrial thrombus was not diagnosed during transesophageal echocardiography performed before the first planned cardioversion. ^b Reasons for missing results, for example, specimen not frozen, insufficient quantity, hemolysis. ^c Availability of samples based on available hs-CRP measurements; end of treatment samples could still be collected from patients without a baseline sample.

Fig. 2

Influence of pretreatment with OACs on F1.2 levels at baseline. F1.2, prothrombin fragment 1 + 2; OAC, oral anticoagulant; ULOQ, upper limit of quantification. Note: Upper lines of the box denote the upper quartiles, midlines denote the medians and lower lines denote the lower quartiles; crosses denote the geometric means, and upper and lower lines denote maximum and minimum values, excluding outliers (i.e., values that are >1.5 times the interquartile range further apart from the box).

Fig. 3

Influence of a history of congestive HF on hs-CRP levels at baseline. HF, heart failure; hs-CRP, high-sensitivity C-reactive protein; LLOQ, lower limit of quantification; OAC, oral anticoagulant. Note: Upper lines of the box denote the upper quartiles, midlines denote the medians and lower lines denote the lower quartiles; crosses denote the geometric means, and upper and lower lines denote maximum and minimum values, excluding outliers (i.e., values that are >1.5 times the interquartile range further apart from the box).

Fig. 4

Influence of type of AF on levels of D-dimer at baseline. AF, atrial fibrillation; FEU, fibrinogen equivalent units; LLOQ, lower limit of quantification; OAC, oral anticoagulant. Note: Upper lines of the box denote the upper quartiles, mid-lines denote the medians and lower lines denote the lower quartiles; crosses denote the geometric means, and upper and lower lines denote maximum and minimum values, excluding outliers (i.e., values that are >1.5 times the interquartile range further apart from the box).

Fig. 5

Relative changes of biomarker levels from baseline to the end of treatment, model-adjusted for biomarker baseline level, and treatment duration. F1.2, prothrombin fragment 1 + 2; hs-CRP, high-sensitivity C-reactive protein; hs-IL-6, high-sensitivity interleukin-6; TAT, thrombin–anti-thrombin III complex; VKA, vitamin-K antagonist. Note: Upper lines of the box denote the upper quartiles, mid-lines denote the medians and lower lines denote the lower quartiles; crosses denote the geometric means, and upper and lower lines denote maximum and minimum values, excluding outliers (i.e., values that are >1.5 times the interquartile range further apart from the box).