SummarY

• Routine monitoring of coagulation parameters is not required due to the predictable pharmacokinetics and pharmacodynamics of XARELTO.¹
• The international normalized ratio (INR) should not be used to monitor XARELTO.¹
• Without the need for routine coagulation monitoring, the safety and efficacy of XARELTO was established by clinical studies involving more than 60,000 patients.^2-10
• The pharmacodynamic effects of XARELTO, as measured by the prothrombin time (PT), are strongly affected by the type of PT reagent that is used.^1,11
• Preliminary findings support the use of anti-factor Xa assays for coagulation monitoring of direct factor Xa inhibitors.^12,13

effect on MONITORING tests

PT

• PT assay is not specific for factor Xa inhibitors and is not correlated to bleeding or other clinical outcomes.¹⁴
• There is a concentration-dependent relationship between XARELTO and prolongation of PT^15,16; however, there was considerable variability of PT measurements depending on the specific reagent used¹⁷.
  • When Neoplastin^® was used for the assay, the PT was found to be influenced by XARELTO in a dose-dependent way with a close correlation to plasma concentrations.^1,18-21
• This variability could not be corrected through conversion to INRs and was best addressed through expression of the results of PT measurements as plasma concentrations of XARELTO (in mcg/mL) rather than as a percentage of normal (ie, PT seconds or ratios).¹⁶
• In a human plasma study, STA Neoplastin Plus^® was found to be the most precise method for determination of XARELTO.²²
• At 2-4 hours after tablet intake, the PT range is 13-26 seconds. In patients undergoing major orthopedic surgery, PT was significantly prolonged 2 hours after XARELTO administration and was not significantly prolonged after 12 hours.²³

INR

The INR test is only calibrated and validated for vitamin K antagonists (ie, warfarin), and, therefore, should not be used to monitor XARELTO.^1,14

In contrast to warfarin, the clinical significance of coagulation assay results that fall outside the expected range with XARELTO is unknown.²⁴

Anti-Factor Xa

The effect of XARELTO can be measured if the assay is standardized for oral anticoagulants.²⁵ Unlike PT and activated partial thromboplastin time (aPTT), which vary depending on the thromboplastin reagent used, the results of the chromogenic assay were reproducible in a study across 9 laboratories.²⁶

• There is a dose-dependent relationship between concentration of XARELTO and activity of anti-factor Xa. Validation and standardization for anti-factor Xa assays of XARELTO are still needed.^12,14,26-29
• The results of a human plasma study indicated that at high levels of XARELTO, such as those observed in an overdose, anti-factor Xa levels may not be measured accurately with the assays evaluated.²²
• Different anti-factor Xa chromagenic assays were evaluated for accurate determination of XARELTO plasma levels. For all assays, there was a linear relationship between XARELTO concentrations obtained from HPLC-MS/MS and optical density. Falsely high XARELTO concentrations (even in plasma samples from controls) were detected with the assay using exogenous antithrombin.²⁷

Dilute Prothrombin Time (dPT)

There is a concentration-dependent relationship between XARELTO and prolongation of dPT; however, there was considerable variability of dPT measurements depending on the specific reagent used.^16,30

aPTT

The aPTT assay reflects the activity of factors II, V, and VII-XII.^16,25,31

• In a study of patients undergoing major orthopedic surgery, aPTT was significantly prolonged 2 hours after XARELTO administration, with no significant difference after 12 hours.²³

Activated Clotting Time (ACT)

Therapeutic levels of XARELTO were shown to have no effect on ACT.³²

Clotting Time

The HepTest is a relatively new assay and is not specific for factor Xa. XARELTO has been shown to prolong the HepTest clotting time in a dose-dependent fashion;¹⁶ however, a pharmacokinetic study of XARELTO in deep vein thrombosis patients observed a paradoxical shortened clotting time with lower XARELTO concentrations (ie, <0.2 mcg/mL).^1,16

Prothrombinase-induced clotting time has been studied in patients treated with XARELTO, although it is only approved for measuring the effects of unfractionated heparin and low-molecular weight heparins. Similar to the HepTest, lower concentrations of XARELTO have been found to paradoxically shorten clotting times.^{14,16,22,33,34}

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 06 February 2024.