Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: Results observed in four anticoagulation clinics

Abstract

Introduction: 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). Materials and 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 20 mg or 15 mg once-daily) and 99 on apixaban (73 and 26 taking 5 mg or 2.5 mg 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. Conclusion: 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.

Comparison of antithrombin‐dependent and direct inhibitors of factor Xa or thrombin on the kinetics and qualitative characteristics of blood clots

“…The target plasma concentrations of tinzaparin were 0.05, 0.1, 0.2, 0.4, 0.6, and 0.8 anti‐Xa IU/mL plasma. These concentration ranges were selected according to the pharmacokinetics of the studied agents after administration of a therapeutic relevant dose 18, 19, 20…”

Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: results from the START-Event registry

“…Due to the increasing prevalence of patients who are treated with DOACs in the general population, major bleedings will become a relatively frequent event in the emergency departments with an urgent need for improving diagnostic and therapeutic tools, and specific strategies related to the site of bleeding, type of drugs, anticoagulant levels, necessity of surgical, or interventional procedures [11,25]. Since patients are admitted to emergency departments after variable hours from the last DOAC dose intake and may present with several comorbidities, anticoagulant activity may not be exclusively predictable on the basis of the drug half-life and the evaluation of renal function, also because of the high inter-intra plasma level variability [26].…”

Changing the Approach to Anticoagulant Therapy in Older Patients with Multimorbidity Using a Precision Medicine Approach

“…It has been clearly demonstrated that variability in the circulating levels of DOACs increases the risk of clinically relevant complications. Testa et al studied 330 patients receiving DOACs therapy and reported that mean inter-individual variability expressed as overall coefficient variation values for any DOAC prescribed and taken by patients was lower at peak (CV = 46%) than at trough (CV = 63%) [23]. Mean intra-individual variability was 36.6% at trough and 34.0% at peak [23].…”

“…Testa et al studied 330 patients receiving DOACs therapy and reported that mean inter-individual variability expressed as overall coefficient variation values for any DOAC prescribed and taken by patients was lower at peak (CV = 46%) than at trough (CV = 63%) [23]. Mean intra-individual variability was 36.6% at trough and 34.0% at peak [23]. Correlation with creatinine clearance was poor for all DOAC drugs and only dabigatran, an inhibitor of factor IIa, showed a significant correlation at trough [23].…”

“…Mean intra-individual variability was 36.6% at trough and 34.0% at peak [23]. Correlation with creatinine clearance was poor for all DOAC drugs and only dabigatran, an inhibitor of factor IIa, showed a significant correlation at trough [23]. The importance of this study for our purposes is highlighted by the evidence that high DOAC inter-individual variability cannot be explained by renal function alone.…”