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Arrhythmias and sudden death
Original research article
Effect of apixaban compared with warfarin on coagulation markers in atrial fibrillation
  1. Christina Christersson1,
  2. Lars Wallentin1,2,
  3. Ulrika Andersson2,
  4. John H Alexander3,
  5. Marco Alings4,
  6. Raffaele De Caterina5,
  7. Bernard J Gersh6,
  8. Christopher B Granger3,
  9. Sigrun Halvorsen7,
  10. Michael Hanna8,
  11. Kurt Huber9,
  12. Elaine M Hylek10,
  13. Renato D Lopes3,
  14. Byung-Hee Oh11,
  15. Agneta Siegbahn2,12
  1. 1 Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
  2. 2 Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden
  3. 3 Medical Duke Clinical Research Institute, Duke University, Medical Center, Durham, North Carolina, USA
  4. 4 Working Group on Cardiovascular Research, Utrecht, The Netherlands
  5. 5 Gabriele d’Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy
  6. 6 Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  7. 7 Department of Cardiology B, Oslo University Hospital and University of Oslo, Oslo, Norway
  8. 8 Bristol-Myers Squibb, Princeton, New Jersey, USA
  9. 9 3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, and Sigmund Freud University, Medical School, Vienna, Austria
  10. 10 Boston University Medical Center, Boston, Massachusetts, USA
  11. 11 Seoul National University Hospital, Seoul, Korea
  12. 12 Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Christina Christersson, Department of Medical Sciences, Cardiology, Uppsala University, Uppsala SE-751 85, Sweden; christina.christersson{at}medsci.uu.se

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.

  • atrial fibrillation

https://doi.org/10.1136/heartjnl-2018-313351

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    Footnotes

    • Contributors CC, LW and AS contributed substantially to the design of the present biomarker substudy in the ARISTOTLE trial. CC, LW, AS, JHA, CBG, MH, BJG, RDL and EMH contributed to the design of the ARISTOTLE biomarker substudy as members of the ARISTOLE biomarker substudy committee. CC, KH, RDC, MA, B-HO and SH contributed to the acquisition of data as ARISTOTLE investigators. AS was responsible for the plasma measurements of F1+2, D-dimer, sCD40 ligand, and vWF at the UCR laboratory. UA performed the statistical analyses. CC and AS provided the first draft of the manuscript. All coauthors participated in the interpretation of data and critically revised the manuscript. All authors have approved the final version of the manuscript. The first (CC) and senior (AS) authors and the statistician (JHA) had full access to the database and take responsibility for the integrity and of the data and the data analyses.

    • Funding The ARISTOTLE trial was funded by Bristol-Myers Squibb, Princeton, New Jersey and Pfizer, New York, New York, and coordinated by the Duke Clinical Research Institute (DCRI), USA, and by Uppsala Clinical Research Center (UCR), Uppsala, Sweden.

    • 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.

    • Patient consent Not required.

    • Ethics approval Approval by the appropriate ethics committees was obtained at all sites.

    • Provenance and peer review Not commissioned; externally peer reviewed.