Supratherapeutic International Normalized Ratio on Rivaroxaban and the Mechanisms behind it: A Systematic Review

Rivaroxaban is a direct oral anticoagulant that works by inhibiting factor Xa. There have been multiple reports of elevated international normalized ratio (INR) and incidents of bleeding in patients on rivaroxaban, which brings into question the potential need for monitoring. The purpose of this review is to differentiate the patients that may benefit from regular monitoring and to propose future directions for the implementation of monitoring. We conducted a systematic review of similar reports in the literature with the goal of identifying the factors that could influence rivaroxaban’s levels in the blood or its influence on the INR. We reviewed PubMed using keywords including “rivaroxaban”, “anti-Xa”, “DOAC”, “elevated”, “INR”, “bleeding”, “hemorrhage”, “pharmacology”, and “pharmacokinetics”. The literature revealed reports of INRs up to 5.2. Reviewing the pharmacokinetics of rivaroxaban indicated possibly higher drug levels in Caucasians, patients with a low body mass index (BMI), and patients with polymorphisms in the genes coding for CYP3A4, CYP2J2, or p-glycoprotein, assuming no renal or liver disease and no significant drug-drug or drug-food interactions. INR can be falsely normal if the thromboplastin reagent used to monitor the INR on warfarin is not sensitive to the changes in INR due to rivaroxaban. We suggest finding a thromboplastin reagent that is sensitive to INR changes with rivaroxaban, which could yield clinically relevant INRs on rivaroxaban allowing for accurate monitoring. We then suggest conducting studies to evaluate the cost-effectiveness of regular monitoring in at-risk patients.This article was previously presented as a meeting abstract at the 2022 American Heart Association: Scientific Sessions on Nov 7th, 2022.