Direct Xa Inhibitor Levels

Use to measure apixaban concentration

Use to measure edoxaban concentration

Use to measure rivaroxaban concentration

A subset of direct oral anticoagulants (DOACs) directly inhibit coagulation factor Xa. These direct Xa inhibitors, including rivaroxaban, apixaban, and edoxaban, do not require routine laboratory monitoring. There are some clinical scenarios in which efficacy or safety may be a concern and a measurement of direct Xa inhibitor activity may be useful. Drug-specific anti-Xa activity assays calibrated for a single direct Xa inhibitor may be used to make quantitative measurements of drug level. There is currently no definitive clinical trials evidence for adjusting apixaban, rivaroxaban, or edoxaban dose based on an anti-Xa activity result.

Testing Strategy

Possible Appropriate Scenarios for Ordering DOAC-specific Anti-Xa Assaysa
Testing Scenario Type of Level Timing Indication Target

Concern for efficacy (to ensure adequate absorption)

Peak
(steady state)

2-3 hours after DOAC dose

Severe obesity (BMI >40)

Peak >5th percentile

Questionable impaired absorption (eg, gastric bypass)

Use of a p-glycoprotein and/or CYP3A4 inducer

Random level

Any time in the dosing interval

Suspected DOAC treatment failure

N/Ab

Concern for safety (to ensure no DOAC accumulation)

Trough
(steady state)

Right before a scheduled DOAC dose

Moderate to severe renal impairment

(defined as CrCl <30 mL/min)

Trough <95th percentile

Use of a p-glycoprotein and/or CYP3A4 inhibitor

aIf initial testing is performed while as an inpatient, consider repeating as an outpatient.

bA random level trough <5th percentile may indicate that a failure occurred in the setting of significantly reduced drug concentrations (eg, due to noncompliance, drug interaction, etc.) and could represent an inability to maintain an on-therapy drug level.

CrCl, creatinine clearance

Test Interpretation

Clinical and/or Analytical Sensitivity

Lower limit of assay detection by drug:

  • Apixaban: 23 ng/mL
  • Edoxaban: 20 ng/mL
  • Rivaroxaban: 25 ng/mL

Results

  • Because laboratory monitoring of direct Xa inhibitors is not required, there are no established therapeutic ranges for these drugs.
  • Expected on-therapy ranges are published in the literature and derived from direct Xa inhibitor clinical trials. These on-therapy ranges:
    • Are specific to a given drug dose and treatment indication.
    • Describe observed peak and trough drug levels during clinical trials.
  • ARUP reports will include on-therapy ranges from published clinical trials for on-therapy peak and trough levels observed with specified drug doses for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).
  • Select on-therapy range information is included in the table below. Further on-therapy range information, including information about on-therapy ranges with adjusted dosing for renal impairment, may be found in the listed references.
On-Therapy Range Informationa
Drug Dose Indication Peak Trough

Apixaban

5 mg twice daily

Treatment of DVT and PE

59-302 ng/mL (5th-95th percentile)

22-177 ng/mL (5th-95th percentile)

5 mg twice daily

Stroke prevention in nonvalvular atrial fibrillation

91-321 ng/mL (5th-95th percentile)

41-230 ng/mL (5th-95th percentile)

2.5 mg twice daily

Prevention of VTE following elective hip or knee replacement surgery

41-146 ng/mL (5th-95th percentile)

23-109 ng/mL (5th-95th percentile)

Edoxaban

60 mg daily

Treatment of DVT and PE

149-317 ng/mL (interquartile range)

10-39 ng/mL (interquartile range)

60 mg daily

Stroke prevention in non-valvular atrial fibrillation

125-245 ng/mL (1.5 X interquartile range)

19-62 ng/mL (interquartile range)

Rivaroxaban

20 mg daily

Treatment of DVT and PE

189-419 ng/mL (5th-95th percentile)

6-87 ng/mL (5th-95th percentile)

20 mg daily

Stroke prevention in non-valvular atrial fibrillation (CrCl >50 mL/min)

184-343 ng/mL (5th-95th percentile)

12-137 ng/mL (5th-95th percentile)

10 mg daily

Prevention of VTE following hip replacement surgery

91-196 ng/mL (5th-95th percentile)

1-38 ng/mL (5th-95th percentile)

aFor more details, including information about on-therapy ranges with adjusted dosing for renal impairment, see Additional Resources.

VTE, venous thromboembolism

Sources: European Medicines Agency, 2021 ; Mueck, 2014 ; Ruff, 2015 ; Weitz, 2010 

Limitations

  • Anti-Xa activity assays can only be used to accurately measure the specific drug for which they are calibrated (eg, apixaban can only be accurately measured in an anti-Xa assay that includes an apixaban calibrator).
  • Anti-Xa activity results are not reliable when more than one drug with anti-Xa activity is present in a plasma sample. Any drug with activity against factor Xa (eg, unfractionated heparin, low molecular weight heparin, fondaparinux, apixaban, edoxaban, rivaroxaban) will show effect in any of the anti-Xa activity assays. That is, if more than one drug is present (eg, unfractionated heparin and rivaroxaban), the effects of both drugs will be detected in the anti-Xa activity assay, regardless of the drug for which the assay is calibrated.
  • Grossly hemolyzed specimens are not suitable for testing due to potential coagulation factor activation and chromogenic assay interference.
  • Grossly icteric samples are not suitable for testing as bilirubin may interfere with chromogenic assays.