Clinically relevant increases in the international normalized ratio and model of end-stage liver disease score by therapeutic doses of direct oral anticoagulants in patients with cirrhosis

Background Patients with cirrhosis are increasingly using direct oral anticoagulants (DOACs) in therapeutic doses for the treatment of portal vein thrombosis or for concomitant atrial fibrillation. DOACs may affect routine diagnostic tests of coagulation including the international normalized ratio (INR). The INR is a part of the model of end-stage liver disease (MELD) score, a validated score that predicts the mortality risk in patients with cirrhosis and is used to prioritize patients for liver transplantation. DOAC–induced increases in the INR may thus lead to artificial inflation of the MELD score. Objective We studied the effect of DOACs on INR prolongation in patients with cirrhosis. Methods We spiked plasma from 20 healthy individuals and 20 patients at the start of liver transplantation with DOACs in concentrations representing peak therapeutic levels. In addition, we studied INR increases in healthy controls and patients with mild cirrhosis who received the DOAC edoxaban for 1 week for study purposes. Results In controls and patients, the INR increased by an ex vivo addition of a DOAC, and the INR increase in patients was proportional to the baseline INR values. The increase in INR translated to a median increase of between 3 and 10 MELD points, depending on the DOAC used. In controls and patients alike, the INR increased on the ingestion of edoxaban, which translated to an increase in 5 MELD points. Conclusions Taken together, DOACs result in an INR increase that translates to clinically meaningful increases in MELD points in patients with cirrhosis, and precautions to avoid artificial inflation of the MELD score in these patients are warranted.

Patients with cirrhosis may develop substantial alterations in their hemostatic system that paradoxically may be associated with both bleeding and thrombosis [1]. There is an increasing awareness of the thrombotic risk in patients with cirrhosis, notably the risk for venous thromboembolism (deep vein thrombosis and pulmonary embolism) [2] and the risk for portal vein thrombosis [3]. Patients may, therefore, be treated with anticoagulant drugs for the prevention or treatment of venous thromboembolism or portal vein thrombosis, and in addition, patients may receive anticoagulant drugs to prevent thrombotic complications related to atrial fibrillation.
Long-term anticoagulation in patients with cirrhosis may be accomplished using vitamin K antagonists, low-molecular weight heparin, or direct oral anticoagulants (DOACs). Because vitamin K antagonists are difficult to dose in patients with cirrhosis and an elevated baseline international normalized ratio (INR), and daily injections with low-molecular weight heparin are a substantial burden for the patient, DOACs are gaining popularity in the cirrhotic patients, although data on safety and efficacy are still scarce [4]. Despite this lack of firm evidence, recent clinical guidance documents state that DOACs are a reasonable treatment option in patients with Child A or B cirrhosis [5,6].
In patients with cirrhosis that become liver transplant candidates, the model for end-stage liver disease (MELD) score is used to prioritize patients on the waiting list. The MELD score is calculated using the following formula: 9.57 × log e (creatinine) + 3.78 × log e (total bilirubin) + 11.2 × log e (INR) + 6.43. Because the MELD score includes the INR, the score is artificially inflated in patients receiving vitamin K antagonists. It has been previously proposed to use a simplified MELD score that does not include the INR to prioritize patients who use vitamin K antagonists [7]. Within Eurotransplant, the MELD score for waitlisted patients on vitamin K antagonists has to be calculated using the last value before starting vitamin K antagonists, or the vitamin K antagonists have to be stopped for at least 2 weeks to determine the current INR (https://www.eurotransplant.org/wp-content/uploads/2 022/03/H5-ELAS-MELD-March-2022.pdf).
In the general population, DOACs may also lead to prolongations in the INR [8,9]. The sensitivity of the INR for DOAC depends on the type of DOAC (with rivaroxaban having the most and apixaban the least profound effect) and the reagent and coagulation analyzer used.

| Patients
We studied samples from 20 adult patients undergoing liver transplantation at King's College Hospital, London, between September 2017 and December 2017, and 20 healthy individuals recruited in the same study. Patient characteristics have been described previously [10].
Only samples taken after the induction of anesthesia were studied. The study was approved by the NRES Committee London-Westminster, Study Number 17/LO/0527. In addition, samples from 16 adult patients with cirrhosis and 16 healthy volunteers recruited in the University Medical Center Groningen, the Netherlands, who received edoxaban (60 mg once daily, administered for 7 consecutive days) were studied.
Characteristics of patients and controls have been outlined previously [11]. Samples were taken twice at day 1 (baseline and 2 h after the first dose) and once on day 3 and day 7, 2 hours after ingestion of edoxaban.
The study protocol was approved by the local medical ethical committee (METc 2016/226) and was registered at the Netherlands Trial Register (NTR6397). Both studies were executed in accordance with both the Declarations of Helsinki and Istanbul, and written informed consent was obtained from each subject before inclusion in both studies.

| INR determination
INRs were measured on an automated coagulation analyzer (STA-Compact 3, Stago) with the use of reagents and protocols from the Essentials • Patients with chronic liver disease increasingly use direct oral anticoagulants (DOACs) to prevent or treat thrombosis.
• DOACs increase the international normalized ratio, a laboratory test used to prioritize patients for a donor liver.
• The model of end-stage liver disease score used for this prioritization process is substantially affected by DOACs.
• Measures to fairly and adequately prioritize waitlisted patients using DOACs are needed.

| Contribution of INR increase to the MELD score
We calculated the contribution of the INR to the MELD score as     Given the increasing number of sicker patients who use DOACs that may continue to use these drugs while on the waiting list or even up to transplantation [13][14][15], it will be important to take DOAC use into account in the current organ allocation procedures in order to avoid an unwanted favoring of DOAC users.

FUNDING
This study was funded by departmental funds of T.L.

AUTHOR CONTRIBUTIONS
T.L. conceived the study, analyzed data, and wrote the manuscript; W.B. supervised sample collection, interpreted data, and revised the manuscript; J.A. performed analyses, interpreted data, and revised the manuscript; P.W.K. supervised sample collection, interpreted data, and revised the manuscript; S.B. collected samples, interpreted data, and revised the manuscript; R.J.P. conceived the study, interpreted data, and revised the manuscript.

RELATIONSHIP DISCLOSURE
There are no competing interests to disclose.

DATA AVAILABILITY
The data that support the findings of this study are available from the corresponding author upon reasonable request.