The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial

Scott R. Garrison; Lee Green; Michael R. Kolber; Christina S. Korownyk; Nicole M. Olivier; Balraj S. Heran; Mary E. Flesher; G. Michael Allan

doi:10.1370/afm.2488

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RE: The Effect of Warfarin Administration Time on INR
Jessica T Behnam and Dorina Idrizi

Published on: 08 November 2020
RE: The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial
Marius J Coetzee

Published on: 16 September 2020

Published on: (8 November 2020)
Page navigation anchor for RE: The Effect of Warfarin Administration Time on INR
RE: The Effect of Warfarin Administration Time on INR
Jessica T Behnam, Pharmacy Student, The University of Illinois at Chicago - College of Pharmacy
Other Contributors:
Dorina Idrizi, Pharmacy Student
Anticoagulants, such as vitamin K antagonists and direct oral anticoagulants (DOACs), are used for various indications, including stroke prevention in patients with atrial fibrillation (a-fib) and treatment and prophylaxis of thromboembolic events. DOACs have been gaining more utilization as studies showed either non-inferiority or superiority compared to warfarin in patients with a-fib[1]. Consequently, since DOACs have been introduced on the market, prescribing warfarin has been declining. For example, in 2018, according to Stanford Medicine, only 20% of patients with a-fib were prescribed warfarin[2]. In addition, the findings of these studies led to the current guidelines. Both the Canadian Cardiovascular Society (CCS) guidelines and the American College of Chest Physicians (ACCP) guidelines recommend using DOACs over warfarin in patients with a-fib[3,4]. Similarly, for deep vein thrombosis (DVT) and pulmonary embolism (PE) management, the American Society of Hematology (ASH) guideline recommends DOACs over warfarin unless contraindicated[5]. One of the benefits of using DOACs is that they generally have fixed dosing and can be adjusted based on the renal/hepatic function. Other advantages include the lack of food interactions, fewer drug-drug interactions than warfarin, and no INR monitoring requirement. Although DOACs have some advantages over warfarin, warfarin remains the therapy choice in patients with severe mitral stenosis, mechanical heart valves, or renal impa...
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Anticoagulants, such as vitamin K antagonists and direct oral anticoagulants (DOACs), are used for various indications, including stroke prevention in patients with atrial fibrillation (a-fib) and treatment and prophylaxis of thromboembolic events. DOACs have been gaining more utilization as studies showed either non-inferiority or superiority compared to warfarin in patients with a-fib[1]. Consequently, since DOACs have been introduced on the market, prescribing warfarin has been declining. For example, in 2018, according to Stanford Medicine, only 20% of patients with a-fib were prescribed warfarin[2]. In addition, the findings of these studies led to the current guidelines. Both the Canadian Cardiovascular Society (CCS) guidelines and the American College of Chest Physicians (ACCP) guidelines recommend using DOACs over warfarin in patients with a-fib[3,4]. Similarly, for deep vein thrombosis (DVT) and pulmonary embolism (PE) management, the American Society of Hematology (ASH) guideline recommends DOACs over warfarin unless contraindicated[5]. One of the benefits of using DOACs is that they generally have fixed dosing and can be adjusted based on the renal/hepatic function. Other advantages include the lack of food interactions, fewer drug-drug interactions than warfarin, and no INR monitoring requirement. Although DOACs have some advantages over warfarin, warfarin remains the therapy choice in patients with severe mitral stenosis, mechanical heart valves, or renal impairment[1]. In addition, given warfarin's relative low cost, it can be used as an option for those who have barriers to access and coverage.
Despite the lack of supporting evidence regarding warfarin administration time, it is prevalent for healthcare providers to recommend taking warfarin in the evening. This can be due to the convenience of dose adjustments that come with the evening regimen. Due to the lack of studies in this area, the authors conducted this pragmatic RCT with a primary goal of evaluating whether the administration time of warfarin would have a clinical impact on INR stability. The primary endpoint was evaluated by the percent change in the proportion of time outside the target INR range was purposefully chosen to be +/-20% as this percentage positively correlates with the risk for thrombus formation and increased adverse events. This study has found that warfarin administration, whether in the morning or evening, does not have any statistical or clinical significance on the stability of warfarin's anticoagulant effect.
This study is unique as it addressed the commonly recommended practice of advising patients to take warfarin in the evening without present supporting evidence. Strengths and limitations should be highlighted. One strength is the large number of primary care physicians participating across different clinics spanning more than 50 communities in Canada. This increases external validity as the findings can be extrapolated since the study did not represent only one clinic rather a whole region. Another strength of the trial is the way that randomization occurred. The randomization was based on the percentage of INR readings within the therapeutic range in three different subsets: <50%, 50% to 80%, and >80%. This ensures that the morning and evening groups had a similar number of patients who fall into the specified INR ranges to eliminate any potential impact that baseline INR could have on the study outcome. For example, if the morning group had more people in the <50% of their target INR compared to the evening group, the results may have been falsely skewed to show that the evening dose provides better outcomes and thus clinically desired.
Conversely, there are some limitations as well. One limitation, as the authors discussed, is that the primary endpoint was a surrogate marker. A more clinically relevant endpoint may have been more beneficial (i.e., endpoints assessing the incidence of adverse events related to warfarin as well as thromboembolic events). Another limitation is that although there was a similarity in patients' utilization of over the counter (OTC) medications and herbal supplements between the two groups, there was no further information on what type of OTC medications or vitamins and herbal supplements the patients were using. This would have been clinically helpful, as numerous products can potentially interact with warfarin. Also, some supplements and herbs may contain considerable amounts of vitamin K.
In conclusion, we believe in the novelty of the trial as it addresses a commonly prescribing behavior that is not supported by scientific evidence. This is the first study to suggest that warfarin administration time does not affect the stability of warfarin's anticoagulant effect. We agree that there are numerous strengths yet some areas from which further studies can stem. We suggest it would be essential to investigate clinical outcomes (such as thromboembolic events or any adverse effects like minor or major bleeding) as primary endpoints in future studies.

References:
[1] January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons [published correction appears in Circulation. 2019 Aug 6;140(6):e285]. Circulation. 2019;140(2):e125-e151. doi:10.1161/CIR.0000000000000665
[2] Stafford, R. Understanding Afib: Blood Thinners Simplified. Scope Blog website. https://scopeblog.stanford.edu/2018/10/11/understanding-afib-blood-thinn.... Published Oct 11, 2018. Accessed Nov 6, 2020.
[3] Andrade JG, Verma A, Mitchell LB, et al. 2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2018;34(11):1371-1392. doi:10.1016/j.cjca.2018.08.026
[4] Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018;154(5):1121-1201. doi:10.1016/j.chest.2018.07.040
[5] Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
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Competing Interests: None declared.
Published on: (16 September 2020)
Page navigation anchor for RE: The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial
RE: The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial
Marius J Coetzee, Laboratory hematologist, Department of Haematology and Cell Biology, University of the Free State and NHLS, Bloemfontein, South Africa
I wish to congratulate the authors on a thorough and useful study.(1)

The authors are correct in that the 36-42-hour half-life of racemic warfarin(2) largely explains why the time of day at which the daily dose warfarin is taken does not have much influence on the INR.

I want add my anecdotal experience of being involved in the INR clinic of an academic hospital over the last 30 years. If patients were struggling to stabilise their INR, I first tried to exclude common issues like compliance, drug interactions and a highly variable diet. Then I suggested that they drink their warfarin on an empty stomach when they wake up in the morning. I suggested that they follow their daily routine of taking their other medication a bit later, and that they need not change their breakfast routine.

My rationale was firstly that the warfarin might be at least partially absorbed before the other drugs are taken. Secondly, it appears to me that most people’s breakfasts tend not to vary as much as their evening meals do. Therefore, the interaction between diet and warfarin would probably be more predictable than if it were taken at night. The authors also mention that foods that are rich in vitamin K are usually not eaten in the morning. Unfortunately I do not have experimental evidence to support my suggestions. To my knowledge patients have never complained that the suggestion worsened their INR control, but a number have thanked me profusely. I would appreciate feedba...
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I wish to congratulate the authors on a thorough and useful study.(1)

The authors are correct in that the 36-42-hour half-life of racemic warfarin(2) largely explains why the time of day at which the daily dose warfarin is taken does not have much influence on the INR.

I want add my anecdotal experience of being involved in the INR clinic of an academic hospital over the last 30 years. If patients were struggling to stabilise their INR, I first tried to exclude common issues like compliance, drug interactions and a highly variable diet. Then I suggested that they drink their warfarin on an empty stomach when they wake up in the morning. I suggested that they follow their daily routine of taking their other medication a bit later, and that they need not change their breakfast routine.

My rationale was firstly that the warfarin might be at least partially absorbed before the other drugs are taken. Secondly, it appears to me that most people’s breakfasts tend not to vary as much as their evening meals do. Therefore, the interaction between diet and warfarin would probably be more predictable than if it were taken at night. The authors also mention that foods that are rich in vitamin K are usually not eaten in the morning. Unfortunately I do not have experimental evidence to support my suggestions. To my knowledge patients have never complained that the suggestion worsened their INR control, but a number have thanked me profusely. I would appreciate feedback.

1. Garrison SR, Green L, Kolber MR, et al. The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial. The Annals of Family Medicine 2020;18:42-9. doi:10.1370/afm.2488.
2. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and Management of the Vitamin K Antagonists. Chest 2008;133:160S-98S. doi:10.1378/chest.08-0670.
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Competing Interests: None declared.