Estimation of dabigatran plasma concentrations in the perioperative setting

Abstract

The perioperative management of dabigatran is challenging, and recommendations based on activated partial thromboplastin time (aPTT) and thrombin time (TT) are unsatisfactory. Dedicated coagulation tests have limitations at plasma concentrations < 50 ng/ml. Therefore, a more sensitive test, which is available 24/7, is required. It was the aim of this study to investigate the performance of the Hemoclot Thrombin Inhibitors® LOW (HTI LOW) kit, a diluted thrombin time, and the STA® - ECA II(ECA-II) kit, a chromogenic variant of the ecarin clotting time, that were developed to measure low dabigatran concentrations, compared to reference dabigatran analysis by liquid chromatography tandem mass-spectrometry (LC-MS/MS). This study included 33 plasma samples from patients treated with dabigatran etexilate who had plasma concentrations < 200 ng/ml. HTI LOW and ECA-II were performed along with HTI, aPTT (STA®-C. K.Prest® and SynthasIL®) and TT (STA® - Thrombin). All procedures were performed according to recommendations by the manufacturers. Linear (or curvilinear) correlations and Bland-Altman analyses were calculated. For free dabigatran concentrations < 50 ng/ml, the R² of linear correlations were 0.69, 0.84 and 0.61, with HTI, HTI LOW and ECA-II, respectively. The R² for TT, STA®-C. K.Prest® and SynthasIL® were 0.67, 0.42 and 0.15. For HTI, HTI LOW and ECA-II, Bland-Altman analyses revealed mean differences of -6 ng/ml (95 %CI: -25-14 ng/ml), 1 ng/ml (95 %CI: -18-19 ng/ml) and -1 ng/ml (95 %CI: -25-23 ng/ml), demonstrating that tests dedicated to measuring low concentrations are more accurate than HTI. In conclusion, the use of HTI LOW or ECA-II to assess low plasma dabigatran concentrations is supported by our findings.

Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation

“…However, whether the suggested algorithms are actually feasible in real life situations has not been tested yet. APTT, PT and TT are both widely and rapidly available in emergency situations, but one should be careful with the interpretation of these tests [ 22 – 25 ]. One needs to realize that these standard coagulation tests with low screening sensitivity might lead to a false reassurance when indicating absent drug levels.…”

Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation

“…However, whether the suggested algorithms are actually feasible in real life situations has not been tested yet. APTT, PT and TT are both widely and rapidly available in emergency situations, but one should be careful with the interpretation of these tests [ 22 – 25 ]. One needs to realize that these standard coagulation tests with low screening sensitivity might lead to a false reassurance when indicating absent drug levels.…”

Evaluation of the chromogenic anti-factor IIa assay to assess dabigatran exposure in geriatric patients with atrial fibrillation in an outpatient setting

“…These data support further evaluation of strategies to individualize treatment. The literature on coagulation monitoring to guide dabigatran therapy is evolving with several studies and comprehensive reviews now published [ 4 , 5 , 34 , 44 , 50 – 55 ]. Evidence supports that dabigatran levels are correlated to bleeding risk and efficacy [ 4 ].…”

“…Although the chomogenic anti-factor II assay may be performed manually or using an automated coagulometer as indicated in the assay specifications, manual methods may be a potential source of measurement bias. The timing of trough levels was often not within 1 h of the next scheduled dose due to patient availability, as suggeted to be optimal for pharmacokinetic studies [ 50 ]. Our data reflects a practical scenario that resembles the ‘real world’ clinical setting.…”

Laboratory Monitoring of Direct Oral Anticoagulants (DOACs)

“…Commercial assays report LoD ranges of 2–8 ng/mL and LoQ ranges of 20–30 ng/mL. These limits (LoD and LoQ) can be improved using a low-range protocol (lower sample dilution) in combination with low calibrators and controls (HEMOCLOT™ TI low-range protocol with an LoQ of about 5 ng/mL) [ 72 , 73 , 74 ].…”

Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation

“…However, whether the suggested algorithms are actually feasible in real life situations has not been tested yet. APTT, PT and TT are both widely and rapidly available in emergency situations, but one should be careful with the interpretation of these tests [ 22 – 25 ]. One needs to realize that these standard coagulation tests with low screening sensitivity might lead to a false reassurance when indicating absent drug levels.…”

Evaluation of the chromogenic anti-factor IIa assay to assess dabigatran exposure in geriatric patients with atrial fibrillation in an outpatient setting

“…These data support further evaluation of strategies to individualize treatment. The literature on coagulation monitoring to guide dabigatran therapy is evolving with several studies and comprehensive reviews now published [ 4 , 5 , 34 , 44 , 50 – 55 ]. Evidence supports that dabigatran levels are correlated to bleeding risk and efficacy [ 4 ].…”

“…Although the chomogenic anti-factor II assay may be performed manually or using an automated coagulometer as indicated in the assay specifications, manual methods may be a potential source of measurement bias. The timing of trough levels was often not within 1 h of the next scheduled dose due to patient availability, as suggeted to be optimal for pharmacokinetic studies [ 50 ]. Our data reflects a practical scenario that resembles the ‘real world’ clinical setting.…”

Laboratory Monitoring of Direct Oral Anticoagulants (DOACs)

“…Commercial assays report LoD ranges of 2–8 ng/mL and LoQ ranges of 20–30 ng/mL. These limits (LoD and LoQ) can be improved using a low-range protocol (lower sample dilution) in combination with low calibrators and controls (HEMOCLOT™ TI low-range protocol with an LoQ of about 5 ng/mL) [ 72 , 73 , 74 ].…”

Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation

“…However, whether the suggested algorithms are actually feasible in real life situations has not been tested yet. APTT, PT and TT are both widely and rapidly available in emergency situations, but one should be careful with the interpretation of these tests [ 22 – 25 ]. One needs to realize that these standard coagulation tests with low screening sensitivity might lead to a false reassurance when indicating absent drug levels.…”

Evaluation of the chromogenic anti-factor IIa assay to assess dabigatran exposure in geriatric patients with atrial fibrillation in an outpatient setting

“…These data support further evaluation of strategies to individualize treatment. The literature on coagulation monitoring to guide dabigatran therapy is evolving with several studies and comprehensive reviews now published [ 4 , 5 , 34 , 44 , 50 – 55 ]. Evidence supports that dabigatran levels are correlated to bleeding risk and efficacy [ 4 ].…”

“…Although the chomogenic anti-factor II assay may be performed manually or using an automated coagulometer as indicated in the assay specifications, manual methods may be a potential source of measurement bias. The timing of trough levels was often not within 1 h of the next scheduled dose due to patient availability, as suggeted to be optimal for pharmacokinetic studies [ 50 ]. Our data reflects a practical scenario that resembles the ‘real world’ clinical setting.…”

Laboratory Monitoring of Direct Oral Anticoagulants (DOACs)

“…Commercial assays report LoD ranges of 2–8 ng/mL and LoQ ranges of 20–30 ng/mL. These limits (LoD and LoQ) can be improved using a low-range protocol (lower sample dilution) in combination with low calibrators and controls (HEMOCLOT™ TI low-range protocol with an LoQ of about 5 ng/mL) [ 72 , 73 , 74 ].…”