The importance of time in therapeutic range of warfarin for stroke prevention in atrial fibrillation

Tze-Fan Chao12Chih-Min Liu12Jo-Nan Liao12
1Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
2Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan

Related article

by Aktan et al.

Correspondence to:

Tze-Fan Chao, MD, PhD,

Division of Cardiology, Department of Medicine,

Taipei Veterans General Hospital,

no. 201, sec. 2, Shih-Pai Road, Taipei, Taiwan,

phone: 886 2 2875 7156,

e-mail: eyckeyck@gmail.com

Copyright by the Author(s), 2023

DOI: 10.33963/KP.a2023.0050

Received: February 16, 2023

Accepted: February 16, 2023

Early publication date: February 25, 2023

Atrial fibrillation (AF) is associated with significantly higher risk of ischemic stroke [1], and stroke prevention with oral anticoagulants (OACs) is the cornerstone of the management of AF patients [2]. Although non-vitamin K antagonist OACs (NOACs) are more and more commonly prescribed in daily practice [3], warfarin is still important in stroke prevention considering the cost issue. For warfarin, a good treatment quality assessed by the international normalized ratio (INR) and time in therapeutic range (TTR) is crucial since a higher TTR is significantly associated with lower risk of ischemic stroke and intracerebral hemorrhage (ICH) [4]. There are 2 fundamental issues regarding warfarin use what is the target range of the INR and the goal of TTR?

The target range of the INR of 23 has been used for years and was mainly based on relatively small-sized studies performed decades ago. Patients receiving warfarin enrolled in pivotal trials of NOACs provided a great opportunity to re-visit the optimal INR range. In a pooled analysis of warfarin-treated patients (n = 21 883) from three clinical trials (RE-LY, ARISTOTLE, and ENGAGE AF-TIMI 48), an INR range between 2.0 and 2.5 appeared to offer a good balance between ischemic stroke and ICH, which was also associated with the lowest rate of all-cause death [5, 6]. These findings were not at variance with the widely adopted INR range of 23 but may provide a reasonable indication to keep the INR within the low end of the range for patients with bleeding risk.

Most international AF guidelines have clear suggestions for TTR levels. In the recently published Asia Pacific Heart Rhythm Society (APHRS) AF guidelines, for example, an individual TTR of >65% (ideally >70%) was suggested [7]. The 2020 AF guidelines of the European Society of Cardiology stated that in patients on warfarin with a low TTR range (e.g. TTR <70%), switching to NOACs to improve TTR was recommended [8]. Although the guidelines have clear recommendations about required TTR levels for warfarin users, large-scale randomized trials comparing the high-quality warfarin treatment (e.g. TTR >70%) to NOACs are lacking. The highest quality data currently available were from the sub-analysis of NOAC trials. In the ENGAGE trial, the principal results of the comparisons between the high-dose edoxaban regimen and warfarin were consistent in subgroups with a center level TTR > or <66.4% [9]. However, a trend suggested that a greater relative reduction in major bleeding with edoxaban was observed at the centers that achieved a center-based TTR of less than 66.4% (P for interaction = 0.06). In the RE-LY trial, the benefits of 150 mg dabigatran in reducing stroke, 110 mg dabigatran in reducing bleeding, and both doses in reducing intracranial bleeding vs. warfarin were consistent irrespective of those centers’ TTR (less than 57·1%, 57·165·5%, 65·52·6%, and greater than 72·6%) [10]. In a pooled analysis of 4 NOAC trials with a median TTR of 65%, it seems that advances of NOACs in reducing major bleeding compared to warfarin were only evident for the subgroup with a center-based TTR <66% (relative risk [RR], 0.69; 95% confidence interval [CI], 0.590.81), but not for those with a center-based TTR >66% (RR, 0.93; 95% CI 0.761.13); P for interaction = 0.022 [11]. These data from clinical trials provided important insights into the use of warfarin and emphasized the importance of a high TTR. However, data from routine daily practice on this issue were relatively limited.

In this issue, Aktan and colleagues [12] presented an interesting study to compare the one- and five-year risks of ischemic cerebrovascular disease (CVD)/transient ischemic attack, hemorrhagic CVD, and mortality in 254 patients who received warfarin with effective TTR (>60%) and 886 patients who received NOACs. The results showed that one-year mortality, five-year mortality, and ischemic or hemorrhagic CVD were similar between the warfarin and NOAC groups. The authors should be congratulated on their important work. However, some data may be helpful to make the conclusions applicable in practice more easily. First, for NOAC users, what was the dosing of each NOACs, and how many percentages of these dosing were prescribed according to labelling? A previous study demonstrated that underdosing or overdosing NOACs was not uncommon and was associated with higher risk of ischemic stroke and major bleeding, respectively, compared to on-label dosing [13]. Therefore, the information about NOAC dosing is crucial since it might change the results of the comparisons between warfarin and NOACs. Second, some important safety endpoints, such as risks of major bleeding, gastrointestinal bleeding, and intracranial hemorrhage were not reported. Third, a considerable number of patients crossed over to different OACs (n = 568), and it may potentially confound the authors’ analyses. The intention-to-treat design for efficacy endpoints and on-treatment analysis for safety endpoints can further confirm the present findings. Lastly, 554 patients receiving warfarin were actually excluded from the study due to a TTR lower than 60%. This patient number was two-fold higher than the number of patients with effective TTR (n = 245). It may show how difficult it is to maintain a good TTR for warfarin users.

Overall, the study by Aktan et al. [12] provides some unique data, and a high TTR should be encouraged and incorporated into the Atrial Fibrillation Better Care (ABC) Pathway to reduce the risks of adverse clinical outcomes in patients with AF [14].

Article information

Conflict of interest: None declared.

Funding: None.

Open access: This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, which allows downloading and sharing articles with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. For commercial use, please contact the journal office at kardiologiapolska@ptkardio.pl.


  1. Chao TF, Liu CJ, Tuan TC, et al. Lifetime risks, projected numbers, and adverse outcomes in Asian patients with atrial fibrillation: a report from the Taiwan nationwide AF cohort study. Chest. 2018; 153(2): 453466, doi: 10.1016/j.chest.2017.10.001, indexed in Pubmed: 29017957.
  2. Chao TF, Joung B, Takahashi Y, et al. 2021 focused update consensus guidelines of the Asia Pacific Heart Rhythm Society on stroke prevention in atrial fibrillation: executive summary. Thromb Haemost. 2022; 122(1): 2047, doi: 10.1055/s-0041-1739411, indexed in Pubmed: 34773920.
  3. Chao TF, Chiang CE, Lin YJ, et al. Evolving changes of the use of oral anticoagulants and outcomes in patients with newly diagnosed atrial fibrillation in Taiwan. Circulation. 2018; 138(14): 14851487, doi: 10.1161/CIRCULATIONAHA.118.036046, indexed in Pubmed: 30354355.
  4. Gallagher AM, Setakis E, Plumb JM, et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost. 2011; 106(5): 968977, doi: 10.1160/TH11-05-0353, indexed in Pubmed: 21901239.
  5. McDowell TY, Lawrence J, Florian J, et al. Relationship between international normalized ratio and outcomes in modern trials with warfarin controls. Pharmacotherapy. 2018; 38(9): 899906, doi: 10.1002/phar.2161, indexed in Pubmed: 29920722.
  6. Chao TF, Guo Y. Should we adopt a standard international normalized ratio range of 2.0 to 3.0 for Asian patients with atrial fibrillation? An appeal for evidence-based management, not eminence-based recommendations. Thromb Haemost. 2020; 120(3): 366368, doi: 10.1055/s-0040-1702230, indexed in Pubmed: 32135562.
  7. Chao TF, Joung B, Takahashi Y, et al. 2021 Focused update of the 2017 consensus guidelines of the Asia Pacific Heart Rhythm Society (APHRS) on stroke prevention in atrial fibrillation. J Arrhythm. 2021; 37(6): 13891426, doi: 10.1002/joa3.12652, indexed in Pubmed: 34887945.
  8. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021; 42(5): 373498, doi: 10.1093/eurheartj/ehaa612, indexed in Pubmed: 32860505.
  9. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369(22): 20932104, doi: 10.1056/NEJMoa1310907, indexed in Pubmed: 24251359.
  10. Wallentin L, Yusuf S, Ezekowitz MD, et al. 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. 2010; 376(9745): 975983, doi: 10.1016/S0140-6736(10)61194-4, indexed in Pubmed: 20801496.
  11. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014; 383(9921): 955962, doi: 10.1016/S0140-6736(13)62343-0, indexed in Pubmed: 24315724.
  12. Aktan A, Güzel T, Aslan B, et al. Comparison of the real-life clinical outcomes of warfarin with effective time in therapeutic range and NOACs: Insight from AFTER-2 Trial. Kardiol Pol. 2023; 81(2): 132140, doi: 10.33963/KP.a2022.0287, indexed in Pubmed: 36594528.
  13. Chan YH, Chao TF, Chen SW, et al. Off-label dosing of non-vitamin K antagonist oral anticoagulants and clinical outcomes in Asian patients with atrial fibrillation. Heart Rhythm. 2020; 17(12): 21022110, doi: 10.1016/j.hrthm.2020.07.022, indexed in Pubmed: 32702416.
  14. Krittayaphong R, Winijkul A, Methavigul K, et al. Impact of Achieving Blood Pressure Targets and High Time in Therapeutic Range on Clinical Outcomes in Patients With Atrial Fibrillation Adherent to the Atrial Fibrillation Better Care Pathway: A Report From the COOL-AF Registry. J Am Heart Assoc. 2023; 12(3): e028463, doi: 10.1161/JAHA.122.028463, indexed in Pubmed: 36695303.


Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp. z o.o., ul. Świętokrzyska 73 , 80–180 Gdańsk, Poland

phone:+48 58 320 94 94, fax:+48 58 320 94 60, e-mail: viamedica@viamedica.pl