title: On the monitoring of dabigatran treatment in "real life" patients with atrial fibrillation.
abstract: BACKGROUND
  The oral direct thrombin inhibitor dabigatran is increasingly used to prevent thromboembolic stroke in patients with atrial fibrillation (AF). Routine laboratory monitoring is currently not recommended, but measurements of dabigatran and/or its effect are desirable in certain situations. We studied dabigatran exposure and compared different tests for monitoring of dabigatran in a real-life cohort of AF patients.
  
  
  METHODS
  Ninety AF patients (68 ± 9 years, 67% men, mean CHADS2 score 1.5) were treated with dabigatran 150 (n=73) or 110 mg BID (n=17). Trough plasma concentrations of total and free dabigatran by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to indirect measurements by Hemoclot thrombin inhibitors (HTI) and Ecarin clotting assay (ECA), as well as PT-INR and aPTT.
  
  
  RESULTS
  Total plasma dabigatran varied 20-fold (12-237 ng/mL with 150 mg BID) and correlated well with free dabigatran (r(2)=0.93). There were strong correlations between LC-MS/MS and HTI or ECA (p<0.001) but these assays were less accurate with dabigatran below 50 ng/mL. The aPTT assay was not dependable and PT-INR not useful at all. There were weak correlations between creatinine clearance (Cockcroft-Gault) and LC-MS/MS, HTI and ECA (p<0.001 for all). A high body weight with normal kidney function was associated with low dabigatran levels.
  
  
  CONCLUSIONS
  HTI and ECA reflect the intensity of dabigatran anticoagulation, but LC-MS/MS is required to quantify low levels or infer absence of dabigatran. Most real life patients with a normal creatinine clearance had low dabigatran levels suggesting a low risk of bleeding but possibly limited protection against stroke.
authors.affiliation: Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Department of Cardiology, Danderyd Hospital & Department of clinical sciences, Karolinska Institutet, Stockholm, Sweden. Electronic address: mika.skeppholm@ds.se.
authors.forename: Mika
authors.initials: M
authors.lastname: Skeppholm
authors.affiliation: Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Hjemdahl
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 P
authors.initials: JP
authors.lastname: Antovic
authors.affiliation: Department of Cardiology, Danderyd Hospital & Department of clinical sciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Josephine
authors.initials: J
authors.lastname: Muhrbeck
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: Jaak
authors.initials: J
authors.lastname: Eintrei
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 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 Laboratory Medicine Huddinge, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Beck
authors.affiliation: Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rickard E
authors.initials: RE
authors.lastname: Malmström
mesh_terms: D000368:Aged; D000991:Antithrombins / Q000097:blood* / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000097:blood / Q000188:drug therapy*; D001562:Benzimidazoles / Q000097:blood* / Q000627:therapeutic use*; D001780:Blood Coagulation Tests; D002853:Chromatography, Liquid; D000069604:Dabigatran; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran
keywords: Dabigatran; Drug concentration; ECA; Hemoclot; LC-MS/MS; aPTT