title: Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation.
abstract: BACKGROUND
  The direct factor-Xa inhibitor apixaban is approved e.g. for the prevention of stroke in patients with atrial fibrillation (AF). Although routine monitoring of apixaban therapy is currently not recommended, selective monitoring could be useful to optimize efficacy and safety in certain clinical situations. We studied the exposure and effect of apixaban using different laboratory methods in a clinical setting with a well-defined cohort of AF patients.
  
  
  METHODS
  Seventy AF patients (72±7.4years, 64 % men, mean CHADS2 score 1.7) treated with apixaban 2.5 (n=10) or 5mg BID (n=60). Trough plasma apixaban concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays Anti-factor Xa, PT-INR and aPTT.
  
  
  RESULTS
  The apixaban plasma concentration determined by LC-MS/MS varied more than 10-fold overall. The range was between 15-83 and 29-186ng/mL for the 2.5mg BID and 5mg BID respectively, with patients receiving 5mg BID having significantly higher apixaban concentrations (p<0.001). A strong correlation between LC-MS/MS and anti-FXa-assay was found (p<0.001), while aPTT and PT-INR were not sensitive enough. There were no significant correlations between gender, creatinine clearance, body weight or age and apixaban exposure.
  
  
  CONCLUSIONS
  Anti-FXa-assay performed well upon apixaban concentrations in a normal exposure range. Still LC-MS/MS remains the "gold standard" method, covering also low concentrations. Compared to clinical trials, we observed relatively lower apixaban exposure and a more pronounced difference between high and low dose. Additional information regarding apixaban exposure and benefit-risk profile is needed in order to individualize treatment.
authors.affiliation: Department of Medicine Solna, Karolinska Institutet & Department of Cardiology, Danderyd Hospital, Stockholm, Sweden. Electronic address: mika.skeppholm@ds.se.
authors.forename: Mika
authors.initials: M
authors.lastname: Skeppholm
authors.affiliation: Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Fadiea
authors.initials: F
authors.lastname: Al-Aieshy
authors.affiliation: Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet, & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Berndtsson
authors.affiliation: Department of Clinical Sciences, Cardiology Unit, Karolinska Institutet, Danderyd's Hospital, and Stockholm Heart Center, Stockholm, Sweden.
authors.forename: Faris
authors.initials: F
authors.lastname: Al-Khalili
authors.affiliation: Department of Laboratory Medicine Huddinge, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Rönquist-Nii
authors.affiliation: Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet, & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Söderblom
authors.affiliation: Department of Laboratory Medicine Huddinge, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Annika Y
authors.initials: AY
authors.lastname: Östlund
authors.affiliation: Department of Laboratory Medicine Huddinge, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anton
authors.initials: A
authors.lastname: Pohanka
authors.affiliation: Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet, & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jovan
authors.initials: J
authors.lastname: Antovic
authors.affiliation: Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rickard E
authors.initials: RE
authors.lastname: Malmström
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000188:drug therapy*; D002853:Chromatography, Liquid / Q000379:methods; D016903:Drug Monitoring / Q000379:methods*; D065427:Factor Xa Inhibitors / Q000097:blood* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods; D008297:Male; D010314:Partial Thromboplastin Time / Q000379:methods; D011517:Prothrombin Time / Q000379:methods; D011720:Pyrazoles / Q000097:blood* / Q000627:therapeutic use; D011728:Pyridones / Q000097:blood* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban
keywords: Anti-FXa-assay; Apixaban concentration; Atrial fibrillation; LC-MS/MS; aPTT