Effect of apixaban compared with warfarin on coagulation markers in atrial fibrillation

Abstract

Objectives: Compare the effect of apixaban and warfarin on coagulation and primary haemostasis biomarkers in atrial fibrillation (AF).

Methods: The biomarker substudy from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial included 4850 patients with AF randomised to treatment with apixaban or warfarin. Sixty per cent of patients used vitamin K antagonist (VKA) within 7 days before randomisation. Prothrombin fragment 1+2 (F1+2), D-dimer, soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) antigen were analysed at randomisation and after 2 months of study treatment.

Results: In patients not on VKA treatment at randomisation, F1+2 and D-dimer levels were decreased by 25% and 23%, respectively, with apixaban, and by 59% and 38%, respectively, with warfarin (p<0.0001 for treatment differences for both). In patients on VKA at randomisation, F1+2 and D-dimer levels increased by 41% and 10%, respectively, with apixaban and decreased by 37% and 11%, respectively, with warfarin (p<0.0001 for treatment differences for both). sCD40L levels were slightly increased at 2 months, regardless of VKA or randomised treatment. Apixaban and warfarin also both reduced vWF antigen regardless of VKA treatment. The efficacy (stroke) and safety (bleeding) of apixaban compared with warfarin was similar irrespectively of biomarker levels at 2 months.

Conclusions: Treatment with apixaban compared with warfarin for stroke prevention in patients with AF was associated with less reduction in thrombin generation and fibrin turnover. This effect of apixaban could contribute to the clinical results where apixaban was superior to warfarin both in stroke prevention and in reducing bleeding risk.

Trial registration number: NCT00412984.

Keywords: atrial fibrillation.

Conflict of interest statement

Competing interests: CC: lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Novartis. LW: institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co, Roche Diagnostics; holds two patents involving GDF-15. UA: institutional research grant from Bristol-Myers Squibb/Pfizer. JHA: research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, FDA, NIH, CryoLife, Tenax Therapeutics, VoluMetrix; honoraria from Bristol-Myers Squibb, CSL Behring, Janssen Pharmaceuticals, Merck, NovoNordisk Pharmaceuticals, Pfizer, VA Cooperative Studies Program, Zafgen; consultancy/advisory board fees from AbbVie, Bristol-Myers Squibb, CSL Behring, Janssen Pharmaceuticals, Merck, NovoNordisk Pharmaceuticals, Pfizer, Portola Pharmaceuticals, VA Cooperative Studies Program, Zafgen. MA: speaker’s bureau from Pfizer; honoraria from Pfizer; consultant/advisory board from Bristol-Myers Squibb, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Pfizer. RDC: research grants from Bayer, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo; speaker’s bureau from Daiichi Sankyo, Bristol-Myers Squibb/Pfizer; honoraria from Daiichi Sankyo, Bayer, Bristol-Myers Squibb/Pfizer; consultant/advisory board from Bayer, Daiichi Sankyo. BJG: data safety monitoring board from Boston Scientific, Cardiovascular Research Foundation, Duke Clinical Research Institute, Duke University, Icahn School of Medicine at Mount Sinai, Janssen Research & Development, Kowa Research Institute, Medtronic, Mount Sinai St Lukes, Teva Pharmaceutical Industries, Myokardia; consultancy fees from Coretherapix SLU, Janssen Scientific Affairs, Sirtex Medical. CBG: research grants from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo; Duke Clinical Research Institute, FDA, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic Foundation, Novartis, Pfizer; consultancy/advisory board fees from AbbVie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medscape, Medtronic, Merck, NIH, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex, Verseon. SH: honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Merck, Sanofi. MH: former employee of and has stock ownership in Bristol-Myers Squibb. KH: speaker’s bureau from Daiichi Sankyo. EMH: research grants from Janssen Pharmaceuticals; honoraria from Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim; consultancy/advisory board fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Medtronic, Portola. RDL: research grants from Amgen, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Medtronic PLC, Sanofi-Aventis; consultant/advisory board fees from Bristol-Myers Squibb/Pfizer, Bayer, Boehringer Ingelheim. B-HO: grant and personal fees from Novartis. AS: institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Roche Diagnostics, GlaxoSmithKline; consultancy fees from Olink Proteomics.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

The concentrations of fragment 1+2 (F1+2) (A), D-dimer (B), soluble CD40 ligand (sCD40L) (C) and von Willebrand factor (vWF) antigen (D) in the apixabanand warfarin treatment groups stratified by warfarin (vitamin K antagonist (VKA)) status at randomisation. Boxes represent the 25th–75th percentiles with the median marked by a black line. Whiskers represent the 10th and 90th percentiles.

Figure 2

Efficacy of apixaban relative to warfarin for fragment 1+2 (F1+2) and D-dimer levels at 2 months (A). Efficacy of apixaban relative warfarin for soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) levels at 2 months (B). Cox proportional hazards model with biomarker level, treatment and interaction between biomarker level and treatment as covariates. CRNM, clinically relevant non-major; SE, systemic embolism.