Direct Oral Anticoagulants Concentrations Research Articles

Systematic errors in the choice of dose level of direct oral anticoagulants: urgency of an issue and approaches to its solution

The article presents updated information on the frequency of use of non-recommended low dosing of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban). It gives substantiation of the urgency of the issue of providing the maximum efficiency of the use of anticoagulants in clinical practice, taking into account the high prevalence of atrial fibrillation and the pharmacological characteristics of the most commonly used drugs. The effects of such an unreasonable reduction in anticoagulant doses in elderly and senile patients are discussed. The results of recent observational studies that assessed the relationship between the use of direct oral anticoagulants and the risk of adverse clinical outcomes are presented. The data on the relationship between the use of unreasonably low dosing of anticoagulants in patients with atrial fibrillation, which were recently obtained during the implementation of the GARFIELD-AF registry, are discussed. The data on a rather high variability of concentrations of direct oral anticoagulants are presented. The frequency of using apixaban in an unreasonably reduced dose, as well as the effects of using non-recommended doses of apixaban hold a specific place in the article. The unreasonableness of attempts to further reduce the risk of bleeding due to unreasonable reduction of apixaban dosing is emphasized, taking into account the stable data on the high safety of recommended dosing of apixaban, as well as the possible decrease in the effect if the dose reduction is not recommended. The data on the criteria for dose reduction, which are adopted in different countries, are presented. The proposed terms to designate different doses of direct oral anticoagulants, depending on their study in the course of large, randomized trials are discussed.

Assessment of exposure to direct oral anticoagulants in elderly hospitalised patients.

It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.

Impact of centrifugation time and pneumatic tube transport on plasma concentrations of direct oral anticoagulants

Rapid results are needed when plasma concentrations of direct oral anticoagulants (DOACs) are required in acute clinical settings. We evaluated the impact of centrifugation time and pneumatic tube transport on DOAC plasma concentrations with the overall aim of reducing turnaround time. Blood samples were spiked with rivaroxaban, apixaban or dabigatran in a low and a high concentration prior to centrifugation for 25minutes (3163g) or 5minutes (3000g) (n=20 for each DOAC). Both samples spiked with DOACs (n=20 for each DOAC) and patient samples (n=25 in total) were transported manually or by pneumatic tube system samples. For samples spiked with DOAC, statistically significant differences in DOAC plasma concentrations were found between centrifugation times for rivaroxaban in low (P<.05) and high (P<.05) concentrations. Relative bias was below 9% for all DOACs. Statistically significant differences were found between modes of transportation for rivaroxaban (P<.01) and dabigatran (P<.01) in high concentrations. Relative bias was 4%-23% for all DOACs. For patient samples, no statistically significant differences were found between modes of transportation, and relative bias was below 12% for all DOACs. Minor, clinically insignificant, differences regarding centrifugation times were found in DOAC plasma concentrations. Importantly, no significant differences were found according to transportation modes for samples collected from patients. Although statistically significant differences were found depending on mode of transportation of spiked samples, relative bias was clinically acceptable. Thus, reduced centrifugation time and pneumatic tube transport should be considered to reduce turnaround time for rapid measurement of DOAC plasma concentrations.

Development and validation of an ultra-high performance liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of direct oral anticoagulants in human plasma

Direct oral anticoagulants are widely used to treat and prevent thromboembolic disorders. With rising clinical application, monitoring concentrations of direct oral anticoagulants are necessary in certain clinical conditions. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of dabigatran etexilate, dabigatran, rivaroxaban, edoxaban, and apixaban, in human plasma. Protein precipitation with methanol was performed for sample preparation. The direct oral anticoagulants and internal standards were separated under gradient conditions using a C18 column, at an analytical run time of 8 min. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.3 mL/min. Mass detection was performed in multiple reaction monitoring using positive ionization mode. The method was validated over a range of 1.0–500 ng/mL for dabigatran etexilate, 0.1–500 ng/mL for dabigatran, and 0.5–500 ng/mL for edoxaban, rivaroxaban, and apixaban. The method detection limits of five analytes were in the range of 0.05–0.5 ng/mL. The lower limits of quantification of five analytes ranged from 0.1 to 1 ng/mL. The linearity (r2 values) was higher than 0.997. The accuracy of the low, medium, and high quality control samples were between 85.9 and 114%, and intra- and inter-day precision were below 9.47%. This validated method was successfully used to determine the plasma concentrations of rivaroxaban in 32 patients, and of dabigatran etexilate and dabigatran in 1 patient.

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

Effect on Plasma Protein S Activity in Patients Receiving the Factor Xa Inhibitors.

Aims: Measurement of protein S (PS) activity in patients taking direct oral anticoagulants (DOACs) using reagents based on a clotting assay results in falsely high PS activity, thus masking inherited PS deficiency, which is most frequently seen in the Japanese population. In this study, we investigated the effect of factor Xa (FXa) inhibitors on PS activity using the reagent on the basis of the chromogenic assay, which was recently developed in Japan. Methods: The study enrolled 152 patients (82 males and 70 females; the average age: 68.5±14.0 years) receiving three FXa inhibitors (rivaroxaban, edoxaban, and apixaban). PS activity was measured using the reagents on the basis of the clotting and chromogenic assays. Results: PS activity measured by the clotting assay reagents exhibited falsely high values depending on the plasma concentrations of FXa inhibitors in patients taking either rivaroxaban or edoxaban. However, none of the three FXa inhibitors affected PS activity when measured using the chromogenic assay. Conclusion: In patients taking rivaroxaban or edoxaban, inherited PS deficiency is likely missed because the levels of PS activity measured using the reagents based on the clotting assay are falsely high. However, we report that three FXa inhibitors do not affect PS activity measured by the chromogenic assay. When measuring the levels of PS activity in patients undergoing DOACs, the principles of each reagent should be understood. Furthermore, plasma samples must be collected at the time when plasma concentrations of DOACs are lowest or the DOAC-Stop reagent should be used.

The Impact of Strong Inducers on Direct Oral Anticoagulant Levels

PurposeThe concomitant use of direct oral anticoagulants (DOAC) and strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels. MethodsWe retrospectively identified hospitalized patients simultaneously receiving a DOAC and carbamazepine, phenobarbital, phenytoin, or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady state were included. DOAC peak or trough levels were compared with on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified. ResultsWe included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch). ConclusionOur data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug–drug interaction.

Anticoagulated patients exhibit intact endogenous thrombin potential using ST Genesia unlike the Calibrated Automated Thrombogram

BackgroundThe thrombin generation (TG) assay is a feasible but labor‐intensive method for detecting global coagulation. It enables comprehensive assessment of anticoagulation, while drug‐specific assays assess only exposure. Traditionally, the Calibrated Automated Thrombogram (CAT) has been used, however the ST Genesia (Diagnostica Stago) allows automated evaluation. ObjectiveWe aimed to observe coagulation using the ST Genesia and compare the data with those of CAT in anticoagulated patients. Patients and methodsIn total, 43 frozen‐thawed samples were studied using DrugScreen to assess direct oral anticoagulants (DOACs), warfarin, and low‐molecular‐weight heparin. Twenty samples (nine rivaroxaban, five apixaban, three warfarin, and three heparin) were also compared using CAT (5 pM tissue factor). ResultsTG reduction in DrugScreen depended on the specific drug and modestly correlated with DOAC levels (lag time R2 = 0.36; peak R2 = 0.50). The best correlation was observed with peak thrombin and rivaroxaban‐specified anti–activated factor X (anti‐Xa) activity (R2 = 0.60). When comparing ST Genesia with CAT, only the results for apixaban concorded (R2 = 0.97). Unlike CAT, ST Genesia yielded a normal endogenous thrombin potential (ETP) in 77% (24/31) activated factor X inhibitor cases, and it failed to give readouts at international normalized ratio (INR) ≥4.5 and at anti‐Xa ≥1.0 IU/mL. ConclusionThe ST Genesia data did not correlate with CAT, but it was independently associated with INR, anti‐Xa, and DOAC concentrations. The lag time and peak responses were similar; the major differences were that ST Genesia showed no ETP effect of DOACs and failed to give readout at high INR or anti‐Xa activity.

Effect of Enzyme-Inducing Antiseizure Medications on the Risk of Sub-Therapeutic Concentrations of Direct Oral Anticoagulants: A Retrospective Cohort Study.

BackgroundStroke and thromboembolic events occurring among patients taking direct oral anticoagulants (DOACs) have been associated with low concentrations of DOACs. Enzyme-inducing antiseizure medications (EI-ASMs) are associated with enhanced cytochrome-P450-mediated metabolism and enhanced P-glycoprotein-mediated transport.ObjectiveThe aim of this study was to evaluate the effect of concomitant EI-ASM use on DOAC peak concentrations in patients treated in clinical care.MethodsWe performed a retrospective cohort study of patients treated with DOACs for atrial fibrillation and venous thromboembolic disease in an academic general hospital. In total, 307 patients treated with DOACs between August 2015 and January 2020 were reviewed. Clinical characteristics and peak DOAC plasma concentrations of patients co-treated with an EI-ASM were compared with those of patients not treated with an EI-ASM. An apixaban dose score (ADS) was defined to account for apixaban dosage and the number of apixaban dose-reduction criteria.ResultsIn total, 177 peak DOAC plasma concentrations (including apixaban, rivaroxaban, and dabigatran) from 131 patients were measured, including 24 patients co-treated with an EI-ASM and 107 controls not treated with an EI-ASM. The proportion of patients with DOAC concentrations below the expected range was significantly higher among EI-ASM users than among patients not taking an EI-ASM (37.5 vs. 9.3%, respectively; p = 0.0004; odds ratio 5.82; 95% confidence interval [CI] 2.03–16.66). Most of these patients were treated with apixaban (85%); however, sensitivity analysis results were also significant (p = 0.031) for patients with non-apixaban DOACs. In patients co-treated with apixaban and an EI-ASM, median apixaban peak concentration was 106 ng/mL (interquartile range [IQR] 71–181) compared with 150 ng/mL (IQR 94–222) in controls (p = 0.019). In multivariable analysis, EI-ASM use was associated with 6.26-fold increased odds for apixaban concentration below the expected range (95% CI 2.19–17.90; p = 0.001). Apixaban concentrations were significantly associated with EI-ASM use, moderate enzyme inhibitor use, and ADS.ConclusionsConcurrent EI-ASM and DOAC use presents a possible risk for DOAC concentrations below the expected range. The clinical significance of the interaction is currently unclear.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-021-00795-z.

Direct oral anticoagulant plasma concentrations in obese and high body weight patients: An observational study

Direct oral anticoagulants (DOAC) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. However, outcomes from DOAC trials included few individuals ≥ 120 kg, and there is uncertainty whether high body weight reduces DOAC concentrations. We investigated the relationship between factor Xa (FXa) inhibitor concentrations, body weight, and renal function, and compared them in high body weight patients with those published for unselected populations. Consecutive patients in two UK centres, weighing ≥ 120 kg receiving 5 mg bid apixaban or 20 mg od rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays and expressed in mean or median (5th-95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration. One hundred patients were included; age range: 23-78, 31% were women, 58% had AF, creatinine clearance range: 67-474 mL/min. Median body weight was 139 kg, and 84% had BMI ≥ 40 kg/m 2 . DOAC peak and trough concentrations varied from 44 to 727 ng/mL and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and body weight or body mass index, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only 2 trough concentrations were below the expected range, and 109/116 were within the on-therapy range ( Fig. 1 ). These data indicate that obese or high body weight patients generally achieve therapeutic concentrations and hence therapeutic options should not be limited in these patients.

Activated clotting time monitoring during atrial fibrillation catheter ablation: Does the anticoagulant matter?

Atrial fibrillation (AF) catheter ablation is performed in patients receiving direct oral anticoagulants (DOACs). Guidelines recommend to perform the procedure with uninterrupted anticoagulation and intra-procedural unfractionated heparin (UFH) administration to achieve activated clotting time (ACT) at 300 seconds, as recommended for vitamin K antagonist (VKA). To determine whether ACT monitoring might be transposed from VKA to DOAC-treated patients. From 124 patients receiving either uninterrupted DOAC (dabigatran, rivaroxaban, apixaban) or VKA or being untreated, blood sampling was performed for anticoagulation testing. DOAC concentrations, and INR for VKA were measured. ACT was determined at baseline, and after spiking with UFH doses equivalent to 1000, 2500, 5000 and 10000 IU in vivo. At baseline, the extent to which oral anticoagulants prolonged ACT differed: despite similar concentrations, ACT was longer with dabigatran and shorter with apixaban (both P < 0.001). The relationship between ACT and the intensity of anticoagulation also differed: ACT strongly correlated with INR ( r = 0.73, P < 0.001) and dabigatran concentration ( r = 0.87, P < 0.0001), but poorly correlated with apixaban or rivaroxaban concentrations. Moreover, the effects of UFH on ACT prolongation depended on the anticoagulant onboard: dose-response curves in samples from VKA and dabigatran-treated patients were parallel whereas ACT prolongation in response to UFH was significantly lower in the presence of FXa-inhibitors, especially apixaban. UFH administration to achieve ACT at 300 seconds may be transposed from VKA to uninterrupted dabigatran-treated patients but not to patients receiving FXa inhibitors, especially apixaban: targeting 300 seconds might expose to UFH overdosing, and bleeding complications. These findings question the indiscriminate use of ACT in AF ablation.

Direct Oral Anticoagulant Concentrations in Obese and High Body Weight Patients: A Cohort Study.

Direct oral anticoagulants (DOACs) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. Outcomes from DOAC trials included few individuals ≥ 120 kg leading to uncertainty whether high body weight (BW) reduces DOAC concentrations. This article investigates the relationship between factor Xa (FXa) inhibitor concentrations, BW, and renal function, and compares them in high BW patients with unselected populations. Consecutive patients in two United Kingdom centers, weighing ≥ 120 kg receiving 5 mg twice daily apixaban or 20 mg once daily rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays, expressed in mean or median (5th-95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration. One hundred patients were included; age range: 23 to 78 years, 31% were women, 58% had AF, creatinine clearance range: 67 to 474 mL/min. Median BW was 139 kg, and 84% had body mass index (BMI) ≥ 40 kg/m2. DOAC peak and trough concentrations varied from 44 to 727 and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and BW or BMI, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only two trough concentrations were below the expected range, and 109/116 were within the on-therapy range. These data indicated that obese or high BW patients generally achieve therapeutic FXa inhibitor concentrations. However, further investigations assessing clinical outcomes are required.

Unveiling the complex effects of direct oral anticoagulants on dilute Russell's viper venom time assays

IntroductionDilute Russell viper venom time (dRVVT) assays can be affected by direct oral anticoagulants (DOACs), which may cause false‐positive results. However, there are conflicting results indicating significant differences between different reagents and DOACs. ObjectivesTo evaluate the effect of DOACs on dRVVT assays. Material and MethodsSamples were prepared by adding DOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) to pooled normal plasma in the concentration range 0 to 800 µg/L. Six integrated dRVVT reagents were used, all composed of a screen assay (low phospholipid content) and a confirm assay (high phospholipid content). The screen/confirm dRVVT results were expressed as normalized ratios. To further evaluate the observed differences between tests and DOACs, addition of synthetic phospholipids was used. ResultsThe dRVVT ratios increased dose dependently for all DOACs, with four of the six tests and the DOAC rivaroxaban having the greatest effect. With one test, the ratios were almost unaffected with increasing DOAC concentration, whereas another test revealed a negative dose dependency for all DOACs. Variable DOAC effects can be explained by different effects on dRVVT screen and confirm clotting time. Adding synthetic phospholipids to samples containing rivaroxaban resulted in greatly reduced screen clotting times and thereby lower calculated dRVVT ratios. ConclusionsThere is a great variability in the dRVVT test result with different DOACs. The dRVVT ratios are unaffected for some reagents and this can be explained by an equal dose‐dependent effect on both screen and confirm assays. The phospholipid type and content of the different reagents may contribute to the observed differences.

The Effect of Direct Oral Anticoagulants on Antithrombin Activity Testing Is Abolished by DOAC-Stop in Venous Thromboembolism Patients.

Direct oral anticoagulants (DOACs) may cause false negative results of antithrombin (AT) deficiency screening. To evaluate the impact of DOAC-Stop, an agent reversing in vitro effects of DOACs, on AT testing in anticoagulated patients. We assessed 130 venous thromboembolism patients aged 46.7 ± 13.5 years. Blood samples were collected 2 to 27 hours after DOAC intake from 49 patients on rivaroxaban, 54 on apixaban, and 27 on dabigatran. Antithrombin activity was assessed using the activated factor X (FXa)-based and the activated factor II (FIIa)-based method twice, before and after DOAC-Stop treatment, together with plasma DOAC levels using coagulometric assays. The use of DOAC-Stop did not influence AT activity measured using the FIIa-based assay, whereas there was a marked decrease in AT activity determined using the FXa-based assay (ΔAT = 16.9%; 95% CI, 12.9%-19.1%). The AT-FIIa assay revealed decreased AT level (<79%) in all 10 (7.7%) genetically confirmed AT-deficient patients treated with rivaroxaban or apixaban (n = 5 each), whereas the AT-FXa assay showed decreased AT activity (<83%) in 2 subjects on rivaroxaban and 1 on apixaban with low plasma DOAC concentrations (<90 ng/mL). After DOAC-Stop median AT-FXa activity lowered from 83.5% (interquartile range, 66%-143%) to 65.5% (interquartile range, 57%-75%; P = .005; ΔAT = 18%) in AT-deficient patients, without any false negative results. The ΔAT in the FXa-based assay correlated with rivaroxaban and apixaban concentrations in the AT-deficient patients (r = 0.99, P < .001). Application of DOAC-Stop enables reliable evaluation of AT deficiency screening in patients taking rivaroxaban or apixaban and tested using the FXa-based method.

Remaining activity of temporary interrupted direct oral anticoagulants and its impact on intra-ablation heparinization in patients with atrial fibrillation: Comparisons across four drugs and two dose regimens.

Atrial fibrillation (AF) ablation with minimally interrupted direct oral anticoagulants (DOACs) may raise a concern about their remaining activity. We tested the residual activity of four different DOACs and its impact on intraprocedural heparinization in patients undergoing AF ablation. We measured the anti-factor Χa activity for rivaroxaban, apixaban, and edoxaban, and serum DOAC concentration for rivaroxaban, apixaban, and dabigatran, 24 hours after the last intake in patients undergoing AF ablation treated with standard or reduced doses of DOACs. The heparin requirement during the procedure was also measured. We enrolled 34 patients with rivaroxaban, 35 with apixaban, 32 with edoxaban, and 31 with dabigatran, and among them, 30 were treated with reduced doses. The anti-factor Χa activity was the highest in the apixaban group among the patients with standard doses. The DOAC concentration was paradoxically lower in patients with standard doses than in those with reduced doses among the patients with rivaroxaban (34.3 ± 19.8 vs 56.6 ± 7.7 ng/mL; P = .01) and dabigatran (12.6 ± 10.6 vs 23.4 ± 14.7 ng/mL; P = .03). The total heparin requirement per body surface area had significant correlations with the anti-factor Χa activity (r = -.36) and DOAC concentration (r = -.32). Two different multiple linear regression models (adjusted R2 = 0.56 and 0.6, respectively) revealed that the anti-factor Χa activity (β = -.28; P = .002) and DOAC concentration (β = -.38; P < .001) were independent determinants of the total heparin requirement. Factors determining residual DOAC activity may include its type and dose regimen, and it may influence the heparin requirement during AF ablation.

Evaluation of a new thromboplastin reagent STA-NeoPTimal on a STA R Max analyzer for the measurement of prothrombin time, international normalized ratio and extrinsic factor levels.

We aimed at evaluating the performance of a new prothrombin time (PT) reagent (STA-NeoPTimal) with two other PT reagents (STA-Neoplastine R and STA-Neoplastine CI Plus) and the reference PT reagent used in our laboratory (ReadiPlasTin). Evaluation consisted in intra- and interassay precision assessment, determination of sensitivity to unfractionated heparin (UFH) or enoxaparin in spiked samples and to direct oral anticoagulants (DOACs) in patients (n=43). Method comparison of the 4 PT reagents, factor II, V, VII and X assays was tested on normal (n=20) and abnormal samples: VKA (n=47), preoperative (n=23), liver failure (n=12) and burned patients (n=37). Analytical performance met manufacturers' criteria for all reagents. All PT reagents gave correlation coefficients >0.8 and even >0.9 in many situations. In some VKA samples, differences≥0.5 INR units were found in samples within and above therapeutic ranges. For burned patients, PT correlations were good but with some minimal bias (<5.0%) while factor assays gave very consistent results (R>.8 and mainly >0.9). As expected, poor responsiveness of the PT to DOAC concentrations was observed with all four assays. The STA-NeoPTimal showed comparable performance to ReadiPlasTin, making it suitable for VKA control, detection of factors II, V, VII, X deficiency and assessment of liver disease coagulopathy. However, for patients receiving VKA, some significant differences were observed. We confirmed the inability of the PT assay to detect residual DOAC concentrations. Finally, burned patients results showed that recombinant thromboplastins were less sensitive to factor deficiencies in comparison to extraction thromboplastins.

Effects of direct oral anticoagulants on thromboelastographic parameters and fibrin clot properties in patients with venous thromboembolism.

Data concerning the impact of direct oral anticoagulants (DOACs) on the thromboelastography (TEG) indices in venousthromboembolism (VTE) patients are limited. The goal of this study was to compare the impact of DOACs on clot properties measured in whole blood using TEG kaolin test and in plasma obtained from real-life VTE patients. We assessed 53 patients, including 20 on rivaroxaban, 20 on apixaban, and 13 on dabigatran. Using the TEG® 5000, coagulation status was evaluated in whole blood samples, while plasma fibrin clot permeability (Ks) and its susceptibility to lysis (CLT) were assessed in citrated plasma. Plasma concentrations of rivaroxaban (99 [48 - 311] ng/ml) and apixaban (85 [40 - 105] ng/ml) were positively associated with Ks and inversely with CLT, while dabigatran concentrations (71 [39 - 98] ng/ml) correlated positively with Ks. Moreover, Ks was associated with clot formation times (R and K), time to maximum clot strength (TMA), coagulation index (CI) reflecting the overall coagulation status, and whole blood clot lysis time (TEG-CLT). Blood clot lysis index (CL30) was associated with plasma CLT in all patients on DOACs, while TMA correlated with CLT only in patients on apixaban. Higher DOAC concentrations were associated with longer retardation of whole blood clot formation and longer time needed to reach maximum level of its strength as well as with more permeable clots. We concluded that plasma fibrin clot properties correlate with corresponding TEG indices suggesting that TEG might be helpful in providing prognostic information about DOAC influence in VTE patients.

Drug-Drug Interactions with Direct Oral Anticoagulants.

A large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug–drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposure might prevent serious bleeding events. For other causes of increased exposure such as DDIs, management is often less well-defined. Considering that DOAC patients are often older and have multiple co-morbidities, polypharmacy is highly prevalent. However, the effect of multiple drugs on DOAC exposure, and especially the impact of DDIs when concurring with drug–disease interactions as observed in renal impairment, has not been thoroughly elucidated. In order to provide effective and safe anticoagulation with DOACs, understanding the mechanisms and magnitude of DDIs appears relevant. Instead of avoiding drug combinations with DOACs, more DDI trials should be conducted and new strategies such as dose adjustments based on therapeutic drug monitoring should be investigated. However, dose adjustments based on concentration measurements cannot currently be recommended because evidence-based data are missing.

Activated Clotting Time Monitoring during Atrial Fibrillation Catheter Ablation: Does the Anticoagulant Matter?

Atrial fibrillation (AF) catheter ablation is performed in patients receiving direct oral anticoagulants (DOACs) with intra-procedural unfractionated heparin (UFH) administration to achieve activated clotting time (ACT) at 300 s, as for vitamin K antagonist (VKA). We determined whether ACT monitoring might be transposed from VKA to DOAC-treated patients. Blood was taken from 124 patients receiving uninterrupted dabigatran, rivaroxaban, apixaban, or VKA or being untreated. DOAC concentration or INR (VKA) were measured. ACT was determined at baseline, and after spiking with UFH doses equivalent to 1000, 2500, 5000 and 10000 IU in vivo. At baseline, anticoagulants prolonged ACT differently, ACT was longer with dabigatran and shorter with apixaban despite similar concentrations. ACT strongly correlated with INR and dabigatran concentration, but not with apixaban or rivaroxaban concentrations. Moreover, UFH effects on ACT prolongation depended on the anticoagulant: dose-response curves in samples with VKA and dabigatran were parallel whereas ACT prolongation in response to UFH was significantly smaller with rivaroxaban and especially apixaban. Therefore, UFH to achieve ACT at 300 s might be transposed from VKA to uninterrupted dabigatran-treated patients but not to patients receiving FXa-inhibitors, especially apixaban. Targeting 300 s might expose to UFH overdosing and bleeding, questioning the current anticoagulation strategy.

Observational Study of the Inter-Individual Variability of the Plasma Concentrations of Direct Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) and the Effect of rs4148738 Polymorphism of ABCB1

Observational Study of the Inter-Individual Variability of the Plasma Concentrations of Direct Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) and the Effect of rs4148738 Polymorphism of ABCB1