How long should stable patients be seen for warfarin PT/INR monitoring?

Comment by InpharmD Researcher

Guidelines recommend monitoring warfarin INR/PT every 12 weeks instead of every 4 weeks in patients who have been on a stable dose for >6 months. This recommendation stems from a 2015 randomized, controlled trial that found warfarin monitoring can be safely reduced to every 12 weeks in patients who maintain therapeutic INRs on stable doses.

Background

A 2016 guideline for practical management of warfarin therapy for treatment of venous thromboembolism (VTE) recommends INR testing should not exceed every six weeks for the first three months of warfarin therapy. After three months of therapy in patients with consistently stable INR, testing can increase up to 12 weeks. For INRs > 4.0 or <1.5, the Veterans Administration health care system suggests testing within seven days, and within 14 days for INRs 3.1 to 3.9 or 1.6 to 1.9. INR testing should not exceed three days following an INR > 5.0. If Vitamin K antidote was administered, next-day follow-up testing is recommended to avoid overcorrection of INR. [1]

According to the American College of Chest Physicians, patients with consistently stable INRs can be tested every 12 weeks rather than every four weeks. While there are no specific recommendations on the frequency of INR testing when initiating vitamin K antagonist (VKA) therapy, the guidelines state warfarin should be started with 10 mg for the first two days and then titrated based on INR measurements rather than the estimated dose. [2]

A 2015 review states that when initiating warfarin, INR should be measured daily for the first five days. Once the patient has two consecutive INRs in the target range, the INR can be tested at increasing intervals depending on its stability. When the warfarin dose and INR are stable, patients can usually be well controlled with INR measurements every four to six weeks, but some patients might require more frequent testing. Dose adjustment is not required for minor INR fluctuations if the result remains within the patient’s target range. [3]

References:

[1] Witt DM, Clark NP, Kaatz S, Schnurr T, Ansell JE. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):187-205.
[2] Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-84S.
[3] Tideman PA, Tirimacco R, St. John A, Roberts GW. How to manage warfarin therapy. Aust Prescr. 2015;38(2):44-8.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

How long should stable patients be seen for warfarin PT/INR monitoring?

Please see Table 1 for your response.


 

Warfarin Dose Assessment Every 4 Weeks Versus Every 12 Weeks in Patients With Stable International Normalized Ratios: A Randomized Trial

Design

Randomized, single-center, open-label, sham-controlled, noninferiority, phase 2 trial

N= 250

Objective

To investigate whether assessment of warfarin dosing every 12 weeks is as safe as assessment every 4 weeks

Study Groups

4-weeks (n= 126)

12-weeks (n= 124)

Inclusion Criteria

Receiving long-term warfarin treatment with a therapeutic international normalized ratio (INR) range of 2.0-3.0 or 2.5-3.5; managed at the study clinic for at least 6 months prior to enrollment; warfarin maintenance dose unchanged for at least 6 months; had previous records of prothrombin time (PT) measurements

Exclusion Criteria

Age <18 years; life expectancy <1 year; were not geographically accessible

Methods

Eligible participants at a single Canadian center were randomized 1:1 to undergo warfarin dose assessments scheduled every 4 or every 12 weeks for 1 year. Following randomization, all patients had a baseline complete blood count and an open-label INR measurement. Assessments took place at a separate laboratory, and the results were forwarded to the clinic and treating physicians. Following the blood work, all warfarin dose assessments for the study took place by telephone.

Patients scheduled for PT and INR tests every 12 weeks had the true results reported to the treating physician every first, second, or third visit in a separate randomization scheme; for the other 2 visits, sham results were reported as values of 1.8-3.5 for patients with a therapeutic INR range of 2.0-3.0 or 2.0-4.0 for patients with a therapeutic INR range of 2.5-3.5.

A physician reviewed all true INR results in the 12-week group for extreme values (<1.5 or >4.5). When INR results that were to have been reported as sham values were extreme, the true result was forwarded to the treating physician, as were any follow-up measures (usually 1 week after an extreme INR was found).

Duration

Recruitment: November 2006 to December 2008

1 year

Outcome Measures

Primary: percentage of time in the therapeutic range (TTR), calculated from monthly (and associated) INR results

Secondary: extreme INRs, change in warfarin dosing, major bleeding

Baseline Characteristics

 

4-weeks (n= 126)

12-weeks (n= 124)

 

Age, years (range)

72 (29-93) 70 (23-92)  

Male

69% 70%  

Warfarin indication

Atrial fibrillation

Heart valve replacement

Venous thromboembolism

>2 indications

 

58%

41%

14%

16%

 

56%

41%

15%

14%

 

Therapeutic INR range

2.0-3.0

2.5-3.5

 

88%

12%

 

88%

12%

 

Concominant antiplatelet*

40% 36%  

* Aspirin or clopidogrel

Results

Endpoint

4-weeks (n= 126)

12-weeks (n= 124)

p-value

Mean time in therapeutic range, %

74.1 ± 18.8 71.6 ± 20.0 0.020**

Mean number of INRs in therapeutic range

8.4 ± 2.8 8.4 ± 2.9 ---

Patients with extreme INRs

≥4.5

≤1.5

 

15 (11.9%)

12 (9.5%)

 

8 (6.5%)

11 (8.9%)

---

Number of extreme INRs

0

≥1

 

78.6%

21.4%

 

86.3%

13.7%

 

---

0.11

Warfarin dose changes

≥1 dose change

≥4 dose changes

 

55.6%

6.3%

 

37.1%

3.2%

 

0.004

---

** For noninferiority

Adverse Events

There was no significant difference in major bleeding events between the groups (0.8% vs 1.6%; p= 0.55) or thrombotic events (0.8% vs 0%; p= 0.32).

Seven patients died during the course of the study (4% vs 1.6%; p= 0.25). Three of the 5 deaths in the 4-week group were due to thromboembolism; however, only one of these was objectively verified.

Study Author Conclusions

Assessment of warfarin dosing every 12 weeks seems to be safe and noninferior to assessment every 4 weeks. A comparison of INR testing, patient contact, and warfarin dose assessment every 12 weeks versus every 4 weeks is necessary before INR testing every 12 weeks can be routinely recommended for practice.

InpharmD Researcher Critique

Limitations of this study involve the use of surrogate outcomes and single-center design. Patients in the 12-week group still had testing and contact with clinical staff every 4 weeks; however, the true values were only given to the clinicians every 12 weeks.
References:

Schulman S, Parpia S, Stewart C, Rudd-Scott L, Julian JA, Levine M. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med. 2011;155(10):653-W203. doi:10.7326/0003-4819-155-10-201111150-00003