Download PDF
Open Access
CC BY 4.0 · Thromb Haemost
DOI: 10.1055/a-2773-5810
Original Article: Stroke, Systemic or Venous Thromboembolism

Anticoagulation Therapeutic Ranges and Clinical Outcomes in Patients with a Mechanical Heart Valve Treated with Vitamin K Antagonists—a Nationwide Linked-data Dutch Study

Authors

  • Chantal Visser 

    1   Department of Hematology, Erasmus MC, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands

  • Eva K. Kempers 

    1   Department of Hematology, Erasmus MC, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands

  • Jaap Seelig

    2   Department of Cardiology, Rijnstate, Arnhem, The Netherlands
    3   Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands

  • Qingui Chen

    4   Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands

  • Henk J. Adriaansen

    5   Department of Thrombosis and Anticoagulation, Tergooi Medical Center, Hilversum, The Netherlands
    6   Department of Thrombosis and Anticoagulation, Trombosedienst Noord-West Veluwe, Harderwijk, The Netherlands

  • Maarten J. Beinema

    7   Anticoagulation Center, Deventer Hospital, Deventer, The Netherlands

  • Arina J. ten Cate-Hoek

    8   Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
    9   Thrombosis Expertise Center, Maastricht University Medical Center (MUMC + ), Maastricht, The Netherlands

  • Laura M. Faber

    10   Thrombosis Service Starlet DC, Alkmaar, The Netherlands

  • Frederikus A. Klok 

    11   Department of Medicine - Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands

  • Frank W.G. Leebeek

    1   Department of Hematology, Erasmus MC, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands

  • Sjef J.C.M. van de Leur

    12   Thrombosis Service, Isala Hospital Zwolle, Zwolle, The Netherlands

  • Melchior C. Nierman 

    13   Department of Thrombosis and Anticoagulation, Atalmedial Medical Diagnostic Centers, Amsterdam, The Netherlands

  • Ron Pisters

    2   Department of Cardiology, Rijnstate, Arnhem, The Netherlands

  • Roger K. Schindhelm

    14   Thrombosis Service Diagnost-IQ, Hoorn, The Netherlands

  • Alexander D.M. Stork

    15   Thrombosis Service Anna Hospital Geldrop, Geldrop, The Netherlands

  • Nynke M. Wiersma

    16   Diagnostic Center Unilabs (Saltro), Department of Thrombosis and Anticoagulation, Utrecht, The Netherlands

  • Raffaele De Caterina 

    17   Chair of Cardiology, University of Pisa, and Cardiology Division, Pisa University Hospital, Pisa, Italy

  • Suzanne C. Cannegieter

    4   Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
    11   Department of Medicine - Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands

  • Martin E.W. Hemels

    2   Department of Cardiology, Rijnstate, Arnhem, The Netherlands
    3   Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands

  • Hugo ten Cate 

    8   Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
    9   Thrombosis Expertise Center, Maastricht University Medical Center (MUMC + ), Maastricht, The Netherlands
    18   Department of Internal Medicine, Division of Vascular Medicine, Maastricht University Medical Center (MUMC + ), Maastricht, The Netherlands
    19   Department of Biochemistry, Laboratory for Clinical Thrombosis and Hemostasis, Maastricht University, Maastricht, The Netherlands

  • Maryam Kavousi

    20   Department of Clinical Epidemiology, Erasmus MC, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands

  • Marieke J.H.A. Kruip 

    1   Department of Hematology, Erasmus MC, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands
    21   Department of Quality and Patient Care, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
Further Information
  Permissions and Reprints


Graphical Abstract

Abstract

Aims

To examine the impact of different therapeutic international normalized ratio (INR) ranges on anticoagulation control and clinical outcomes in patients with mechanical heart valves (MHVs) treated with vitamin K antagonists (VKAs) in the Netherlands.

Methods

Data from 17 anticoagulation clinics (2013–2019) were linked to nation-wide data from Statistics Netherlands. Anticoagulation control metrics included significant dose adjustments, INR variance growth rate, and time in therapeutic range. Cause-specific Cox regression models were used to assess associations between therapeutic ranges and clinical outcomes, accounting for death as competing risk. Stratified analyses were performed for significant interactions by type of MHV recipient.

Results

Among 3,473 MHV patients (median age: 67.0 [IQR: 58.0-76.0], 61.7% male, 68.2% acenocoumarol, 26.5% phenprocoumon), patients with lower therapeutic ranges (N = 1,866) (2.0–3.0 for isolated aortic valve without risk factors; 2.5–3.5 for all remaining MHV patients) had poorer anticoagulation control compared to those with higher ranges (N = 1,607) (2.5–3.5 and 3.0–4.0, respectively). No association was found between therapeutic ranges and major/clinically relevant bleeding (fully adjusted hazard ratio [aHR]: 0.80 [95%CI: 0.57–1.1]). However, in patients with a non-aortic valve and/or additional risk factors a lower therapeutic range was potentially associated with increased thromboembolic risk (aHR: 1.3 [95%CI: 0.94–1.9]), while no association was observed in patients with an isolated aortic valve (aHR: 0.71 [95%CI: 0.38–1.3]).

Conclusion

A lower therapeutic range does not apparently increase thromboembolic risk in most MHV patients but may be associated with a higher thromboembolic risk in higher risk patients. Lower therapeutic ranges were not associated with lower bleeding risk.

Keywords

heart valve prosthesis - international normalized ratio - vitamin K antagonists - thromboembolism - bleeding

Data Availability Statement

This study used non-public microdata from Statistics Netherlands and the Federation of Dutch Anticoagulation Clinics. These data cannot be shared directly by the authors. Under certain conditions, these data are accessible for statistical and scientific research. For additional information: microdata@cbs.nl and/or fnt@fnt.nl


Contributors' Statement

C.V., E.K.K., J.S., Q.C., R.D.C., S.C.C., H.t.C., M.E.W.H., M.K., and M.J.H.A.K. designed the study; C.V. and E.K.K. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; H.J.A., M.J.B., A.t.C.H., L.M.F., F.A.K., S.J.C.M.v.d.L., M.C.N., R.K.S., A.D.M.S., N.M.W., and Q.C. are responsible for obtaining the data from participating anticoagulation clinics; C.V. and E.K.K. drafted the initial version of the manuscript; J.S., F.W.G.L., A.t.C.H., H.t.C., R.P., M.E.W.H., R.D.C., M.K., and M.J.H.A.K. contributed to the interpretation of the data. All authors critically revised the manuscript and approved the final version of the manuscript.


Supplementary Material



Publication History

Received: 05 September 2025

Accepted after revision: 15 December 2025

Accepted Manuscript online:
02 January 2026

Article published online:
15 January 2026

© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany