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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

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The International Normalized Ratio or the INR is used to harmonize PT results among laboratories regardless of the instrument reagent combination. It is used to monitor Vitamin K antagonists, mostly warfarin. The question is, does it play a role in any way in patients that are on the direct oral anticoagulants (DOACs). One of the advantages of DOACs is that they do not require monitoring, so many patients are being placed on these anticoagulants. However, DOACs have been shown to be harmful or ineffective in patients with mechanical heart valves, left ventricular thrombi as well as antiphospholipid syndrome¹, so warfarin is here to stay.

What is the INR?

The INR is used to determine if warfarin dosing is appropriate and is regulated by the FDA. The FDA states:
"INR monitoring refers to the measurement of the prothrombin time (PT) that is used to assess the level of anticoagulant therapy and its presentation as the International Normalized Ratio compared to the prothrombin time of normal blood plasma. Applications of the INR monitor include the management of the therapeutic level of anticoagulant used in the treatment of a variety of conditions."²

The INR is a type of correction factor that is derived from the PT and calculated based on the sensitivity of the manufacturer's reagent or the International Sensitivity Index (ISI). This is derived based on the comparison of the PT of the manufacture's reagent versus the PT obtained using the standardized preparation of human brain thromboplastin developed by the World Health Organization (WHO).

The formula is:

The therapeutic range is between 2.0-3.0, except in patients with mechanical heart valves which uses 2.5-3.5. Having a narrow therapeutic range can be challenging since it can be affected by patient characteristics, comorbidity, diet and drug interactions. The INR above 4.9 is considered critical. Point of Care (POC) monitors tend to overestimate low INR values and underestimate high values.³ They should be verified by the laboratory coagulation analyzer.

The PT/INR can be prolonged in warfarin use due to the inhibition of factors II, VII, IX and X which are the Vitamin K dependent factors. Other anticoagulants such as heparin, DOACs and fondaparinux can prolong the PT and or aPTT. Prolongation can also occur in liver dysfunction, Vitamin K deficiency, factor deficiency as well as antiphospholipid antibodies.³

DOACs and Monitoring:

One of the advantages of DOACs is that they do not need monitoring which includes the INR. Patients on warfarin must have their INR checked anywhere between weekly or up to 4 weeks.⁴

There is only 1 test that is FDA approved to monitor a DOAC. Werfen (IL) has an FDA approved Apixaban which is 510K cleared at this time for calibrators and controls. There are no rivaroxaban, dabigatran or edoxaban cleared tests.

Routine testing may be used as follows:

Dabigatran:

1. TT is normal can assume patients risk of bleeding is low.
2. PT/ INR is insensitive and not useful
3. POC INR shouldn't be used
4. APTT: high levels, no clot, prolonged 2 fold at peak levels, and 1.5 fold at 12 hours. Very reagent dependent^5,6

For Rivaroxaban or Apixaban:

1. PT response is assay dependent, should be prolonged
2. anti-Xa levels using drug as a calibrator
3. Normal levels of PT, APTT and TT qualitative indicator of absence of drug⁷

These tests are not sufficient to assess the degree of anticoagulant effect that is seen with the INR for management of VKA therapy. Quantitative tests do not have an established clinical role, since standardized therapeutic ranges have not been established and quantitative test results have not been correlated with clinical outcomes.⁸

What is the value of the INR with regard to DOACs

There may be situations in which patients may require to be placed on or off of DOAC therapy. This may be done when switching patients between anticoagulants and periprocedural management.⁸ Because of DOACs’ fast onset and offset, periprocedural bridging is generally not required; however, it is important to note the length of time to hold regimens before and after procedures.⁹

The reasons that would require transitioning from one anticoagulant to another may be due to cost, comorbid condition, patient preference, hospitalization, thrombotic or bleeding complications, or procedures. The scenarios that may occur during transitioning may be:

1. VKA to DOAC
2. DOAC to VKA
3. DOAC to DOAC⁸

It has been well established that DOAC's prolong the PT and the INR may be beneficial in the transitioning process. As a result, INRs should be checked just before the dose of the DOAC because of their ability to elevate INR values. The INRs should be monitored frequently for at least the first month until INR stability has been achieved (ie, ≥3 consecutive INR readings at goal).⁸

INR Considerations When Transitioning Between VKA and DOAC

VKA-to-DOAC Conversion

INR ≤2   Start DOAC immediately

INR 2–2.5   Start DOAC immediately or preferably the next day

INR 2.5–3   Postpone DOAC; Recheck INR in 1–3 days

INR ≥3   Postpone DOAC; Recheck INR in 3–5 days⁸

DOAC-to-VKA Conversion

INR ≥2  Continue DOAC (half-dose for edoxaban) while INR remains ≤2
    Recheck INR in 1–3 d (before DOAC intake)

INR >2  Stop DOAC
    Recheck INR 1 d after discontinuing DOAC⁸

Conclusions:

While the INR is not recommended for monitoring the anticoagulant activity of DOACs it can be useful in the transitioning among anticoagulants. An elevated INR can point to the likelihood that a high INR may be due to a high concentration of apixaban. However, if DOACs and Warfarin are co-administered the INR may not be useful in determining the appropriate dose of warfarin. It is important to use the INR parameter correctly to ensure that the patient is not placed at a risk for either thrombosis or bleeding.

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References

1. Lee JJ, Ha ACT, Dorian P, Verma M, Goodman SG, Friedrich JO. Meta-analysis of safety and efficacy of direct oral anticoagulants versus warfarin according to time in therapeutic range in atrial fibrillation. Am J Cardiol. 2021;140:62-68.
2. www.fda.gov/medical-devices/in-vitro-diagnostics/warfarin-inr-test-meters
3. Sufana Shikdar; Rishik Vashisht; Priyanka T. Bhattacharya, International Normalized Ratio (INR), STATPEARLS,: May 8, 2022. https://www.ncbi.nlm.nih.gov/books/NBK507707/
4. Kajy M, Shokr M, Ramappa P. Use of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: Systematic Review of Current Literature. Am J Ther. 2020 Nov/Dec;27(6):e584-e590.
5. Schulman, Crowther, Blood, published on line February 1, 2012.
6. Nalezinski, S, Laboratory Medicine, 53:336-343.
7. Barrett YC, Wang Z, Frost C, Shenker A. Thromb Haemost 2010; 104:
8. Ashley Chen, Eric Stecker and Bruce A. Warden, Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges, 15 Jun 2022, Journal of the American Heart Association
9. Doherty JU, Gluckman TJ, Hucker WJ, Januzzi JL, Ortel TL, Saxonhouse SJ, Spinler SA. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol. 2017; 69:871–

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