Journal of Thrombosis and Thrombolysis

, Volume 48, Issue 1, pp 27–34 | Cite as

International normalized ratio control and subsequent clinical outcomes in patients with atrial fibrillation using warfarin

  • Patricia O. Guimarães
  • Renato D. LopesEmail author
  • John H. Alexander
  • Laine Thomas
  • Anne S. Hellkamp
  • Ziad Hijazi
  • Elaine M. Hylek
  • Bernard J. Gersh
  • David A. Garcia
  • Freek W.A. Verheugt
  • Michael Hanna
  • Greg Flaker
  • Dragos Vinereanu
  • Christopher B. Granger


We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with ≥ 3 INR values in the 180 days prior to the event, with the most recent ≤ 60 days prior to the event, who were on warfarin at the time of event (n = 545). Non-event patients were included in the control group if they had ≥ 180 days of warfarin exposure with ≥ 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R2 = 0.212). Historic TTR ≥ 80% had limited predictive ability to discriminate future TTR ≥ 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice.


International normalized ratio Clinical outcomes Warfarin Atrial fibrillation 



This work and the ARISTOTLE study were funded by Bristol-Myers Squib (Princeton, NJ) and Pfizer, Inc. (New York, NY). All analyses were conducted at the Duke Clinical Research Institute (DCRI, Durham, NC) and all authors had full access to all data. The DCRI coordinate the trial and managed the database. An academic steering committee designed the trial and was responsible for oversight of study conduct, reporting of all results, and takes responsibility for the accuracy and completeness of the data analyses. The authors are fully responsible for the study design, data collection, analysis and interpretation of the data, and writing of the manuscript. All authors agreed to submit the manuscript for publication. The sponsor played no role in the decision to submit the manuscript for publication.

Compliance with ethical standards

Conflict of interest

Lopes: Research grant: Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer; Consultant/Advisory Board: Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Merck, Portola, GlaxoSmithKline, Pfizer. Alexander: Research grant: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, Sanofi, Tenax Therapeutics; Consultant/Advisory Board: Cempra, CryoLife, CSL Behring, Pfizer, Portola Pharmaceuticals, VasoPrep Surgical. Hijazi: Honoraria: Boehringer Ingelheim, Roche Diagnostics, Pfizer and Bristol-Myers Squibb; Consultant/Advisory board: Pfizer, Bristol-Myers Squibb, Roche Diagnostics, and Merck, Sharp & Dohme. Hylek: Consultant: Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, Johnson & Johnson; Research grant: Bristol Myers Squibb/Pfizer, Johnson & Johnson. Gersh: Consulting fees/Honoraria: Xenon Pharmaceuticals; Data monitoring board: Armetheon Inc, Baxter Helathcare Corporation, CardioVascular Research Foundation, Janssen Research & Development, MEDTRONIC, Mount Sinai St. Lukes, Teva Pharmaceuticals, Thrombosis Research Institute; Other: Boston Scientific, Cipla Limited, Janssen Scientific Affairs LLC, St. Jude Medical, Inc. Garcia: Consultant/Advisory Board: BMS/Pfizer, Genzyme, Boehringer Ingelheim, Incyte, Alexion. Research Support: Daiichi Sankyo, Janssen, Incyte. Verheugt: Honoraia/Consultant: Bayer Healthcare, Boehringer-Ingelheim, BMS/Pfizer, and Daiichi-Sankyo. Hanna: An employee of the sponsor (BMS), received salary and stock as part of his employment compensation. Vinereanu: Research grant: GlaxoSmithKline, Pfizer, Bristol-Myers Squibb. Granger: Research Grant: Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GlaxoSmithKline, Janssen, Medtronic Foundation, Novartis, Pfizer, The Medicines Company; Consultant/Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Inc, GlaxoSmithKline, Hoffman LaRoche, Janssen, Medtronic, Novartis, Pfizer, The Medicines Company, Verseon. Guimarães, Thomas, Hellkamp, and Flaker authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all participants included in the study.

Supplementary material

11239_2019_1858_MOESM1_ESM.pdf (60 kb)
Supplementary material 1 (PDF 59 kb)


  1. 1.
    Baker WL, Cios DA, Sander SD, Coleman CI (2009) Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 15:244–252Google Scholar
  2. 2.
    Granger CB, Alexander JH, McMurray JJ et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992CrossRefGoogle Scholar
  3. 3.
    Wallentin L, Lopes RD, Hanna M et al (2013) Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. Circulation 127:2166–2176CrossRefGoogle Scholar
  4. 4.
    Lopes RD, Alexander JH, Al-Khatib SM et al (2010) Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 159:331–339CrossRefGoogle Scholar
  5. 5.
    Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E (1993) A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 69:236–239CrossRefGoogle Scholar
  6. 6.
    Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY (2010) A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 138:1093–1100CrossRefGoogle Scholar
  7. 7.
    Patel MR, Mahaffey KW, Garg J et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891CrossRefGoogle Scholar
  8. 8.
    Connolly SJ, Ezekowitz MD, Yusuf S et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151CrossRefGoogle Scholar
  9. 9.
    Giugliano RP, Ruff CT, Braunwald E et al (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369:2093–2104CrossRefGoogle Scholar
  10. 10.
    Wallentin L, Yusuf S, Ezekowitz MD et al (2010) Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 376:975–983CrossRefGoogle Scholar
  11. 11.
    Piccini JP, Hellkamp AS, Lokhnygina Y et al (2014) Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial. J Am Heart Assoc 3:e000521CrossRefGoogle Scholar
  12. 12.
    Lopes RD, Guimaraes PO, Kolls BJ et al (2017) Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. Blood 129:2980–2987CrossRefGoogle Scholar
  13. 13.
    Mearns ES, White CM, Kohn CG et al (2014) Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression. Thromb J 12:14CrossRefGoogle Scholar
  14. 14.
    DiMarco JP, Flaker G, Waldo AL et al (2005) Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 149:650–656CrossRefGoogle Scholar
  15. 15.
    Pokorney SD, Simon DN, Thomas L et al (2016) Stability of international normalized ratios in patients taking long-term warfarin therapy. JAMA 316:661–663CrossRefGoogle Scholar
  16. 16.
    Dallalzadeh LO, Go AS, Chang Y, Borowsky LH, Fang MC, Singer DE (2016) Stability of high-quality warfarin anticoagulation in a community-based atrial fibrillation cohort: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. J Am Heart Assoc 5:e003482CrossRefGoogle Scholar
  17. 17.
    Reiffel JA (2017) Time in the therapeutic range for patients taking warfarin in clinical trials: useful, but also misleading, misused, and overinterpreted. Circulation 135:1475–1477CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Patricia O. Guimarães
    • 1
  • Renato D. Lopes
    • 1
    Email author
  • John H. Alexander
    • 1
  • Laine Thomas
    • 1
  • Anne S. Hellkamp
    • 1
  • Ziad Hijazi
    • 2
  • Elaine M. Hylek
    • 3
  • Bernard J. Gersh
    • 4
  • David A. Garcia
    • 5
  • Freek W.A. Verheugt
    • 6
  • Michael Hanna
    • 7
  • Greg Flaker
    • 8
  • Dragos Vinereanu
    • 9
  • Christopher B. Granger
    • 1
  1. 1.Duke Clinical Research InstituteDurhamUSA
  2. 2.Uppsala Clinical Research Center, Department of Medical Sciences, CardiologyUppsala UniversityUppsalaSweden
  3. 3.Boston University Medical CenterBostonUSA
  4. 4.Department of Cardiovascular MedicineMayo Clinic College of MedicineRochesterUSA
  5. 5.Division of Hematology, Department of MedicineUniversity of Washington, Medical Center, University of Washington School of MedicineSeattleUSA
  6. 6.Afdeling Cardiologie, Hartcentrum OLVGAmsterdamThe Netherlands
  7. 7.Bristol-Myers SquibbPrincetonUSA
  8. 8.University of Missouri School of MedicineColumbiaUSA
  9. 9.University of Medicine and Pharmacy Carol DavilaBucharestRomania

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