Left atrial thrombus resolution in non-valvular atrial fibrillation or flutter: biomarker substudy results from a prospective study with rivaroxaban (X-TRA)

Abstract

Background: Non-vitamin K antagonist oral anticoagulants including rivaroxaban are widely used for stroke prevention in patients with atrial fibrillation (AF). We investigated the relationship between plasma biomarkers (indicative of thrombogenesis, fibrinolysis and inflammation) and left atrial thrombus resolution after rivaroxaban treatment.

Methods: This was an ancillary analysis of the X-TRA study, which was a prospective interventional study evaluating the use of rivaroxaban for left atrial/left atrial appendage (LA/LAA) thrombus resolution in AF patients. We assessed various biomarkers of thrombogenesis/fibrinolysis [D-dimer, plasminogen activator inhibitor-1 (PAI-1), prothrombin fragment 1 + 2 (F1,2), thrombin–antithrombin (TAT) complexes, von Willebrand factor (vWF)] and inflammation [high-sensitivity interleukin-6 (hsIL-6), and high-sensitivity C-reactive protein (hsCRP)], measured at baseline and after 6 weeks’ of rivaroxaban treatment.

Results: There was a significant decrease in the mean levels of hsCRP, D-dimer, vWF, and TAT from baseline to end of treatment with rivaroxaban. Although none of the thrombogenesis/fibrinolysis biomarkers showed a significant relationship with thrombus resolution, high inflammatory biomarkers at baseline were significantly associated with an increased chance of the thrombus being completely resolved (hsIL-6) or reduced/resolved (hsCRP).

Conclusions: Biomarkers of inflammation are significantly associated with LA/LAA thrombus outcomes in AF patients prospectively treated with rivaroxaban.

KEY MESSAGES

• Changes in the thrombogenesis/fibrinolysis biomarker levels reflected the expected pharmacodynamics of rivaroxaban.

• Higher levels of inflammation biomarkers were significantly associated with thrombus being completely resolved or reduced.

KEYWORDS:

• Atrial fibrillation
• non-vitamin K antagonist oral anticoagulant
• thrombus resolution
• biomarker

Acknowledgements

The authors very appreciated the excellent work done by the X-TRa investigators (see Appendix B. List of investigators in Am Heart J 2016; 178:133)¹⁸, the Study Outcome Committee (chair: Martin Prins; members: Trang Ding and Bas Kietselaer) and Bayer study team during the clinical trial. We thank the Covance Laboratories for the measurement of all biomarkers. We also would like to thank Adam Skubala and Sebastian Voss (Fa. Chrestos Concept GmbH & Co. KG, Essen, Germany) for performing the data analysis and Sonja Schiffer (Clinical Sciences - Experimental Medicine, Bayer AG, Wuppertal, Germany) for her support in data analysis and interpretation.

Disclosure statement

The X-TRA study including this biomarker sub-study was supported by Bayer AG.

Additional information

Funding

KM and DP has received no funding. FM has received funding for research from Instituto Carlos III, Madrid, Spain (CIBER-CV CB16/11/00395 and PI13/01551), acted as a consultant for Bayer, Daiichi Sankyo, Pfizer and Boehringer Ingelheim. CH has received research grants from Sanofi-Aventis and has received speaker’s honoraria from Bayer, Boehringer Ingelheim and Pfizer. RC has received consultancy fees or research funding from Boston Scientific, Medtronic, St. Jude, Biosense Webster, Boehringer Ingelheim, Bayer, Abbott, ELA Sorin, Pfizer and BARD medical, and has equity and intellectual property rights in Cameron. ILM, AS, FK and MvE are employees of Bayer AG. AC has received a research grant for research nurses (RESICARD) and consultant and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline and Sanofi-Aventis. GYHL is a member of various guideline and position statement committees (including ESC, EHRA, NICE); a member of steering committees for various phase II, phase III and health economics and outcomes research studies; an investigator in various clinical trials in cardiovascular disease, including those on antithrombotic therapies in atrial fibrillation, acute coronary syndrome; has been a consultant for Bayer/Janssen, Astellas, Merck, Sanofi, Bristol-Myers Squibb/Pfizer, Biotronik, Medtronic, Portola, Boehringer Ingelheim, Microlife and Daiichi Sankyo; and a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche and Daiichi Sankyo. The X-TRA study was supported by Bayer AG.