SummarY

• Monitoring for anticoagulation effect of rivaroxaban using anti-FXa activity or a clotting test is not recommended.¹
• Routine monitoring of coagulation parameters is not required due to the predictable pharmacokinetics and pharmacodynamics of XARELTO.²
• The international normalized ratio (INR) should not be used to monitor XARELTO.²
• Without the need for routine coagulation monitoring, the safety and efficacy of XARELTO was established by clinical studies involving more than 60,000 patients.^3-11
• The pharmacodynamic effects of XARELTO, as measured by the prothrombin time (PT), are strongly affected by the type of PT reagent that is used.^2,12
• Preliminary findings support the use of anti-factor Xa assays for coagulation monitoring of direct factor Xa inhibitors.^13,14

PRODUCT LABELING

• Please refer to the following section of the enclosed Full Prescribing Information that is relevant to your inquiry: CLINICAL PHARMACOLOGY, Pharmacodynamics.¹

Pharmacodynamics

Rivaroxaban produces dose-dependent inhibition of FXa activity. Clotting tests, such as PT, activated partial thromboplastin time (aPTT) and HepTest^®, are also prolonged dose-dependently. In children treated with rivaroxaban, the correlation between anti-factor Xa to plasma concentrations is linear with a slope close to 1.¹

• Monitoring for anticoagulation effect of rivaroxaban using anti-FXa activity or a clotting test is not recommended.¹

effect on MONITORING tests

PT

• PT assay is not specific for factor Xa inhibitors and is not correlated to bleeding or other clinical outcomes.¹⁵
• There is a concentration-dependent relationship between XARELTO and prolongation of PT^16,17; however, there was considerable variability of PT measurements depending on the specific reagent used¹⁸
  • 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.^2,19-22
• 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 (i.e., PT seconds or ratios).¹⁷
• In a human plasma study, STA Neoplastin Plus^® was found to be the most precise method for the determination of XARELTO.²³
• 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.²⁴

INR

The INR test is only calibrated and validated for vitamin K antagonists (i.e., warfarin), and, therefore, should not be used to monitor XARELTO.^2,15

In contrast to warfarin, the clinical significance of coagulation assay results that fall outside the expected range with XARELTO is unknown.²⁵

Anti-Factor Xa

The effect of XARELTO can be measured if the assay is standardized for oral anticoagulants.²⁶ Unlike PT and aPTT, which vary depending on the thromboplastin reagent used, the results of the chromogenic assay were reproducible in a study across 9 laboratories.²⁷

• There is a dose-dependent relationship between the concentration of XARELTO and activity of anti-factor Xa. Validation and standardization for anti-factor Xa assays of XARELTO are still needed.^13,15,27-30
• Results from 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.²³
• Different anti-factor Xa chromagenic assays were evaluated for the 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.²⁸
• An ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMS/MS) method was developed and validated for the analysis of rivaroxaban in dried blood spots (DBS) and plasma samples. The method to analyze DBS samples required 20 μL of blood and was shown to be a practical lowvolume alternative to venipuncture sampling. Regression analysis comparing rivaroxaban concentration in DBS and plasma samples from drug-spiked blood showed a strong correlation between concentrations measured in DBS and plasma samples (R²=0.9961). Clinical applications in 18 patients with venous thrombosis showed significant correlations between rivaroxaban concentrations in DBS and PT (r=0.6744; P=0.0021) and INR (r=0.6125; P=0.0069). In plasma samples, rivaroxaban concentrations significantly correlated with aPTT (r=0.506; P=0.0323), PT (r=0.676; P=0.0021), and INR (r=0.626; P=0.0055).³¹
• A prospective study evaluated the correlation between rivaroxaban concentrations measured using HPLCMS/MS (MSRiva) and the results obtained from chromogenic antiXa assays, PT, aPTT, and thromboelastography reaction time (TEG Rtime) in 104 patients with atrial fibrillation or venous thromboembolism. There was a significant and very strong correlation between MSRiva and chromogenic antiXa assays (r=0.986, P<0.001), with significant correlations also observed for PT (r=0.884, P<0.001), aPTT (r=0.741, P<0.001), and TEG Rtime (r=0.739, P<0.001). The mass spectrometry peak demonstrated a significant and very strong correlation with the chromogenic anti-Xa assay (r=0.977, P<0.001). It also showed significant moderate correlations with PT (r=0.670, P<0.001), aPTT (r=0.571, P<0.001), and TEG R-time (r=0.481, P<0.001).³²

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.^17,33

aPTT

The aPTT assay reflects the activity of factors II, V, and VII-XII.^17,26,34

• 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.²⁴

Activated Clotting Time (ACT)

Therapeutic levels of XARELTO were shown to have no effect on ACT.³⁵

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;¹⁷ however, a pharmacokinetic study of XARELTO in deep vein thrombosis patients observed a paradoxical shortened clotting time with lower XARELTO concentrations (i.e., <0.2 μg/mL).^2,17

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 time.^{15,17,23,36,37}

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 16 January 2026.