title: Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: Results observed in four anticoagulation clinics.
abstract: BACKGROUND
  Direct oral anticoagulant (DOAC) intra- and inter-individual variability was previously reported, but its magnitude is still considered negligible for patient management.
  
  
  OBJECTIVE
  To evaluate inter- and intra-individual variability in real-world atrial fibrillation patients on dabigatran, rivaroxaban or apixaban in four Italian anticoagulation clinics and to assess the correlation between DOAC plasma concentration and creatinine-clearance (CrCl).
  
  
  METHODS
  A total of 330 consecutive patients were enrolled, of which 160 were on dabigatran (70 and 90 taking 150 mg or 110 mg twice-daily, respectively), 71 on rivaroxaban (37 and 34 taking 20mg or 15 mg once-daily) and 99 on apixaban (73 and 26 taking 5mg or 2.5mg twice-daily). Blood was taken at trough and peak within the first month (15-25 days) of treatment. Diluted-thrombin-time (dTT) calibrated for dabigatran and anti-FXa calibrated for rivaroxaban or apixaban was performed.
  
  
  RESULTS
  Mean inter-individual variability expressed as overall CV values for all drugs was lower at peak (CV=46%) than at trough (CV=63%). Mean CV% intra-individual variability was 36.6% at trough and 34.0% at peak. Correlation with CrCl was poor for all drugs and only dabigatran at trough showed a significant correlation.
  
  
  CONCLUSIONS
  This multicenter study confirms high DOAC inter-individual variability that cannot be explained by the rate of renal clearance to which the three DOAC were subjected since the correlation with CrCl was relatively poor. This poor correlation suggests caution in using CrCl as the sole laboratory parameter to indirectly evaluate residual circulating DOAC.
authors.affiliation: Haemostasis and Thrombosis Center, Department of Laboratory Medicine, AO Istituti Ospitalieri, Cremona, Italy. Electronic address: s.testa@ospedale.cremona.it.
authors.forename: Sophie
authors.initials: S
authors.lastname: Testa
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Tripodi
authors.affiliation: Angiology and Blood Coagulation, University Hospital of Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Legnani
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, University Hospital of Padua, Padua, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Pengo
authors.affiliation: Thrombosis Centre, Department of Heart and Vessels, University Hospital of Florence, Florence, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.affiliation: Haemostasis and Thrombosis Center, Department of Laboratory Medicine, AO Istituti Ospitalieri, Cremona, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dellanoce
authors.affiliation: Department of Laboratory Medicine, ULSS 16 and University-Hospital of Padova.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carraro
authors.affiliation: Angiology and Blood Coagulation, University Hospital of Bologna, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Salomone
authors.affiliation: Thrombosis Centre, Department of Heart and Vessels, University Hospital of Florence, Florence, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Paniccia
authors.affiliation: Haemostasis and Thrombosis Center, Department of Laboratory Medicine, AO Istituti Ospitalieri, Cremona, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Paoletti
authors.affiliation: Department of Laboratory Medicine, ULSS 16 and University-Hospital of Padova.
authors.forename: Daniela
authors.initials: D
authors.lastname: Poli
authors.affiliation: Cardiovascular Diseases, University of Bologna, Bologna, Italy.
authors.forename: Gualtiero
authors.initials: G
authors.lastname: Palareti
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D001682:Biological Availability; D015897:Comorbidity; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D015995:Prevalence; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013923:Thromboembolism / Q000097:blood* / Q000453:epidemiology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants
keywords: Anti-FXa; Creatinine clearance; DOAC; Dilute thrombin time; Inter-individual variability; Intra-individual variability