Direct Oral Anticoagulants Plasma Levels Research Articles

Detection of direct oral anticoagulants with the diluted Russel's viper venom time.

The activity of direct oral anticoagulants (DOAC) is important in acute clinical situations. Recent studies have suggested a strong influence of DOAC on the diluted Russel's Viper Venom Time (dRVVT). Therefore, it may be a suitable screening parameter for antithrombotic plasma activity of different DOAC. This prospective study aims to evaluate the sensitivity and specificity of dRVVT to detect residual DOAC activity at recommended plasma level thresholds. A total of 80 patients were recruited, with 20 each treated with one of the four approved DOAC (apixaban, edoxaban, rivaroxaban or dabigatran), respectively. Blood plasma was collected before (baseline), at plasma peak time, and 6 and 12 h after DOAC. DRVVT was measured using the screen (LA1) and confirm (LA2) assay for lupus anticoagulant and compared with DOAC plasma levels. A reference range was calculated based on the dRVVT values of 61 healthy blood donors. All DOAC significantly prolonged the dRVVT especially at higher DOAC plasma levels. The LA1 time ≥41 s had a sensitivity ≥98% to detect edoxaban, dabigatran and rivaroxaban plasma levels ≥30 ng/mL but it was only 87% for apixaban. Sensitivity was ≥98% for all DOAC with the LA2 assay ≥36 s. The negative predictive value of a DOAC plasma level <30 ng/mL and dRVVT LA2 <36 s was 99%. The dRVVT confirm assay (LA2) reliably detects residual DOAC plasma levels ≥30 ng/mL and could be useful to rapidly rule out relevant DOAC activity in emergency situations and to guide treatment decisions.

Predictors of Plasma Levels of Direct Oral Anticoagulants Among Patients with Atrial Fibrillation in Need of Elective Cardiac Procedures.

The withdrawal timing of direct oral anticoagulants (DOACs) among patients in need of elective invasive surgery is based on DOAC pharmacokinetics in order to perform the procedure out of the DOAC peak plasma concentration. We aimed to investigate the prevalence and predictors of plasma levels of DOACs out of trough range in patients with atrial fibrillation (AF) in need of elective cardiac procedure. We evaluated all consecutive AF patients on DOAC therapy in need of elective cardiac procedure, admitted to our division from January 2022 to March 2022. All patients underwent DOAC plasma dosing the morning of procedure day. They were categorized as in range, above range, and below range, according to the DOAC reference range at the downstream point. The timing of discontinuation of DOAC therapy was considered as appropriate or not, according to the current recommendations. The clinical predictors of out-of-range DOAC plasma levels have been evaluated. We included 90 consecutive AF patients (56.6% male, mean age 72.95 ± 10.12years); 74 patients (82.22%) showed DOAC concentration out of the expected reference range. In half of them (n, 37), the DOAC plasma concentration was below the trough reference range. Of the study population, 17.7% received inappropriate DOAC dosages (10% overdosing, 7% underdosing), and 35.5% had incorrect timing of DOAC withdrawal (26% prolonged, 9.5% shortened). At multivariable analysis, inappropriate longer DOAC withdrawal period (OR 10.13; P ≤ 0.0001) and increased creatinine clearance (OR 1.01; P = 0.0095) were the independent predictors of plasma DOAC levels below the therapeutic trough range. In contrast, diabetes mellitus (OR 4.57; P = 0.001) was the only independent predictor of DOAC plasma level above the therapeutic trough range. Increased creatinine clearance and inappropriate longer drug withdrawal period are the only independent predictors of DOAC plasma levels below the reference range; in contrast, diabetes is significantly correlated with DOAC plasma levels above the reference.

DOAC plasma concentration upon hospital admission in a cohort of trauma patients. An observational real-life study.

Due to a better safety profile, direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. However, little is known about DOAC plasma concentrations in trauma patients upon hospital admission. Thus, we investigated the frequency and extent of DOAC possible over- and underdosing in trauma patients upon hospital admission. In this single-center retrospective study, DOAC plasma concentrations of adult trauma patients were analyzed with specific calibrated anti-IIa (dabigatran) and anti-Xa (apixaban, edoxaban and rivaroxaban) tests within 4h after hospital admission. A total of 210 trauma patients, admitted between 2019 and 2022, were included in the analyses. Low DOAC levels < 30ng/mL were detected in 13.3% of the patients. In 7.1% of the patients, DOAC plasma levels ranged between 300-399ng/mL and further 7.1% exhibited plasma concentrations > 400ng/mL. The highest incidence of high to very high DOAC plasma concentration was observed for patients on rivaroxaban and dabigatran. A moderate correlation was observed between dabigatran plasma concentration and estimated glomerular filtration rate (rho = - 0.5338, p = 0.0003). For rivaroxaban no clear association between plasma concentration and liver or renal function could be detected. Patients on statins had significantly higher DOAC concentration in comparison with those not taking statins (153 (76-274) vs 108 (51-217) ng/mL, p = 0.046). The current study revealed that patients on dabigatran and rivaroxaban were prone to higher DOAC plasma levels upon hospital admission in comparison with apixaban and edoxaban. DOAC plasma level measurement in trauma patients might be warranted due to unpredictively low or high plasma concentrations. However, the clinical impact of altered plasma levels on both, bleeding and thromboembolic events, remains to be determined by future studies.

The efficacy of direct oral anticoagulants in patients on concomitant treatment with levetiracetam

Guidelines do not support the combination of direct oral anticoagulants (DOACs) and the antiepileptic drug levetiracetam, due to potential relevant P-glycoprotein (P-gp) mediated interaction that might result in decreased DOACs concentrations and increased thromboembolic risk. However, there is no systematic data on the safety of this combination. The aim of this study was to find patients concurrently treated with levetiracetam and DOAC, assess their plasma concentrations of DOAC, and the incidence of thromboembolic events. From our registry of patients on anticoagulation drugs we identified 21 patients concomitantly treated with levetiracetam and DOAC, 19 patients with atrial fibrillation and two patients with venous thromboembolism. Eight patients received dabigatran, 9 apixaban and 4 rivaroxaban. For each subject blood samples were collected for determination of trough DOAC and trough levetiracetam concentrations. The average age was 75 ± 9 years, 84% were males, HAS-BLED score was 1.8 ± 0.8, and in patients with atrial fibrillation CHA2DS2-VASc score was 4.6 ± 2.0. The average trough concentration level of levetiracetam was 31.0 ± 34.5 mg/L. Median trough concentrations of DOACs were for dabigatran 72 (range 25–386) ng/mL, for rivaroxaban 47 (range 19–75) ng/mL, and for apixaban 139 (range 36–302) ng/mL. During the observation period of 1388 ± 994 days none of the patients suffered a thromboembolic event. Our results did not demonstrate a reduction in DOACs plasma levels during levetiracetam treatment, suggesting that levetiracetam could not be an important P-gp inducer in humans. DOAC in combination with levetiracetam remained effective therapy to protect against thromboembolic events.

Gender-Associated Variation in DOAC Levels.

Direct oral anticoagulants (DOAC) such as Xa inhibitors rivaroxaban (riva) and apixaban (apix) are increasingly replacing Vitamin K antagonists in prophylaxis and treatment of venous thromboembolism (VTE). Measurements of DOAC plasma levels may be necessary in certain clinical conditions to determine the further dosage. Making decisions is made more difficult by the fact that the peak and trough plasma levels are subject to strong inter-individual fluctuations with overlapping reference ranges. We wanted to find out whether the peak and trough levels can be narrowed if they are determined based on age and gender. Therefore, we collected data on peak and trough anti-Xa concentrations in patients treated with either rivaroxaban (n = 93) or apixaban (n = 51) in one center. After exclusion of blood samples of uncertain oral intake, 83 samples for rivaroxaban and 49 samples for apixaban remained for further analysis. Differences between male (riva n = 42, apix n = 28) and female (riva n = 41 and apix n = 21) as well as young (≤ 60 years, riva n = 44, apix n = 23) and elder (> 60 years) patients (riva n = 39 and apix n = 26) were analyzed by Student`s t-test and retrospective regression. We found no differences in age and gender for the apix peak levels. But women had significantly higher riva peak concentrations than men (308.8 ± 178.1 ng/mL versus 206.4 ± 80 ng/mL, p = 0.013). Patients older than 60 years had significantly higher riva peak levels than those younger than 60 (293.7 ± 126.7 ng/mL versus 211.7 ± 158.4 ng/mL, p = 1.29 x 10-8). In search of narrowing standard peak and trough levels in patients' sera we found significant differ-ences between patients below and above sixty years of age. Gender-associated differences were found in rivaroxa-ban levels possibly explaining DOAC associated hypermenorrhea. In conclusion, gender and age should be included in the determination of peak blood concentration references.

EMERGING DATA FOR CANCER ASSOCIATED THROMBOSIS TREATMENT

Venous thromboembolism (VTE) is a common complication in patients with malignancies,resulting in deep vein thrombosis, pulmonary embolism and central venous catheter VTE, and is responsible for high morbidity and mortality (1). The prevalence of cancer-associated thrombosis is increasing because of multiple factors, including longer patient survival, anticancer therapies, increased detection of incidental VTE during surveillance imaging, and wider use of central venous catheters. Anticoagulant therapy with low-molecular-weight heparins (LMWHs) was the standard of care for the treatment of cancer-associated thrombosis, with vitamin K antagonists providing a secondary treatment option, until direct oral anticoagulants (DOAC) emerged as alternative first-line treatment options in 2016 (2). Rivaroxaban, Edoxaban and Apixaban are recommended as initial treatment in patients with cancer-associated thrombosis who are not at high risk of gastrointestinal or genitourinary bleeding (3). LMWHs and Fondaparinux are still recommended for prophylaxis of VTE in medically-treated patients with cancer. Rivaroxaban and Apixaban can be used selectively for thromboprophylaxis in patients with malignancies at high risk of VTE, for example in patients with pancreatic cancer or myeloma (4,5). Anticoagulant choice should incorporate a personalised medicine approach that considers cancer type, VTE and bleeding risk factors, drug–drug interactions (DDI), and patient preferences. Patients with cancer often experience narrow therapeutic index polypharmacy and undergo treatment for several simultaneous comorbidities. In this setting the risk of DDI is high in particular during therapy with tyrosine kinase inhibitors (6). Concerns on DDI management include decreased efficacy and bleeding risk. In general, DOAC use is not advisable in combination with drugs that are strong inhibitors of both P-gp and/or CYP3A4 for high bleeding risk and in combination with strong inducers of Pgp and/or CYP3A4 that could markedly reduce DOAC plasma levels. Routine use of plasma level measurements for DOAC, only available in few laboratory centres, is not currently recommended (7). Nevertheless it has recently become increasingly clear that clinicians need to assess the anticoagulant status of a patient receiving anticancer therapies. The global coagulation Test of thrombin generation (TGT) a sensitive method to assess the anticoagulant therapy, provides a global measure of anticoagulant effect by measuring the inhibition of formation of thrombin (FIIa), a common endpoint for both LMWH and FXa inhibitors (8). Furthers studies are warranted to better define the future role of this coagulation test in this subgroup of patients.

Role of DOAC plasma concentration on perioperative blood loss and transfusion requirements in patients with hip fractures.

There is an ever-increasing number of hip fracture (HF) patients on direct oral anticoagulants (DOAC). The impact of DOAC plasma level prior to HF surgery on perioperative blood loss and transfusion requirements has not been investigated so far. In this retrospective study of HF patients on DOACs admitted to the AUVA Trauma Center Salzburg between February 2015 and December 2021. DOAC plasma levels were analysed prior to surgery. Patients were categorized into four DOAC groups: Group A < 30ng/mL, Group B 30-49ng/mL, Group C 50-79ng/mL, and Group D ≥ 80ng/mL. Haemoglobin concentration was measured upon admission, prior to surgery, after ICU/IMC admission, and on day 1 and 2 post-surgery. Difference in the blood loss via drains, transfusion requirements and time to surgery were compared. A total of 155 subjects fulfilled the predefined inclusion criteria. The median age of the predominantly female patients was 86 (80-90) years. Haemoglobin concentration in Group D was lower upon admissions but did not reach statistical significance. The decrease in haemoglobin concentration over the entire observation time was comparable between groups. Blood transfusion requirements were significantly higher in Group D compared to Group A and B (p = 0.0043). Time to surgery, intra- and postoperative blood loss via drains were not different among groups. No strong association between the DOAC plasma levels and perioperative blood loss was detected. Higher transfusion rates in patients with DOAC levels ≥ 80ng/mL were primarily related to lower admission haemoglobin levels. DOAC concentration measurement is feasible and expedites time to surgery.

Performance of a Qualitative Point-of-Care Strip Test to Detect DOAC Exposure at the Emergency Department: A Cohort-Type Cross-Sectional Diagnostic Accuracy Study.

An accurate point-of-care test for detecting effective anticoagulation by direct oral anticoagulants (DOACs) in emergencies is an unmet need. We investigated the accuracy of a urinary qualitative strip test (DOAC Dipstick) to detect relevant DOAC exposure in patients who presented to an emergency department. In this prospective single-center cohort-type cross-sectional study, adults on DOAC treatment were enrolled. We assessed clinical sensitivity and specificity of DOAC Dipstick factor Xa and thrombin inhibitor pads to detect DOAC plasma levels ≥30 ng/mL using urine samples as the testing matrix. Liquid chromatography coupled with tandem-mass spectrometry was used as the reference standard method for plasma and urine measurement of DOAC concentrations. Of 293 patients enrolled, 265 patients were included in the analysis, of whom 92 were treated with rivaroxaban, 65 with apixaban, 77 with edoxaban, and 31 with dabigatran. The clinical sensitivity and specificity of the dipstick on urine samples to detect ≥30 ng/mL dabigatran plasma levels were 100% (95% confidence interval [CI]: 87–100%) and 98% (95% CI: 95–99%), respectively. The sensitivity and specificity of the dipstick to detect ≥30 ng/mL factor Xa inhibitor plasma levels were 97% (95% CI: 94–99%) and 69% (95% CI: 56–79%), respectively. The DOAC Dipstick sensitively identified effective thrombin and factor Xa inhibition in a real-world cohort of patients presenting at an emergency department. Therefore, the dipstick might provide a valuable test to detect relevant DOAC exposure in emergencies, although further studies will be needed to confirm these findings.

Variation in Plasma Levels of Apixaban and Rivaroxaban in Clinical Routine Treatment of Venous Thromboembolism.

Direct oral anticoagulants (DOACs) apixaban and rivaroxaban are broadly used in the management of venous thromboembolism (VTE). Although not routinely required, measurement of their plasma concentration is advised for an increasing number of indications. Due to the lack of therapeutic ranges, current guidelines recommend reporting DOAC plasma levels together with expected levels from previous pivotal studies. The aim of this study was to assess DOAC level variation in a large VTE patient population. Drug concentrations determined by measurement of the anti-Xa-activity using drug-specific calibrators in citrated plasma samples from patients on rivaroxaban (n = 1471) or apixaban (n = 725) were analyzed. Observed 5th–95th percentile ranges of apixaban peak/trough levels (63–299/13–114 ng/mL for 5 mg, 37–161/7–68 ng/mL for 2.5 mg twice daily) were similar to previously reported mass-spectrometry-based reference data, and 10th–90th percentile ranges of rivaroxaban peak/trough levels (98–367/8–55 ng/mL for 20 mg, 51–211/5–27 ng/mL for 10 mg once daily) were even narrower. Age and drug levels correlated weakly (r ≤ 0.330). Drug levels measured repeatedly in subgroups of patients showed a strong correlation (r ≥ 0.773). In conclusion, anti-Xa-activity-based measurement of apixaban and rivaroxaban yields reliable results. However, the paucity of levels off-range underlines the need for evidence-based thresholds to better assist clinical decision making.

Monitoring of direct oral anticoagulants plasma levels for secondary stroke prevention

BackgroundPatients with atrial fibrillation have a relevant risk for ischemic stroke despite the recommended use of direct oral anticoagulants (DOAC). The risk correlates with the functional DOAC plasma levels in clinical trials, but the value of their measurement in community use remains undetermined. ObjectivesWe aim to investigate the clinical implications and the prognostic value of DOAC plasma level measurement during steady state. MethodsIn this observational clinical cohort study among patients with ischemic stroke and atrial fibrillation, 397 individuals on oral anticoagulants for secondary stroke prevention were included between 2016 and 2020. The functional DOAC plasma levels were measured during steady state. Early stroke recurrence within 3 months was recorded as the main outcome parameter. ResultsThree hundred ninety‐seven patients (201 female, mean age 78 [±9] years, median CHA2DS2VASc‐Score 6 [interquartile range 5–7]) were included. Mean DOAC plasma trough level was 95.9 (±66.9) ng/ml. A high glomerular filtration rate (GFR) was an independent predictor of lower levels in a multivariate model (R coefficient: −0.174, P= .014). During follow‐up, 10 patients (3%) suffered from early ischemic stroke recurrence despite the use of DOAC, while 10 clinically relevant bleeding complications occurred (3%). Ischemic stroke recurrence was associated with numerical lower plasma levels for patients on apixaban and dabigatran after propensity score matching. ConclusionsMonitoring of DOAC plasma levels could help to identify patients with increased risk for stroke recurrence and should be considered for certain subgroups, including patients with high GFR.

Management of DOAC in Patients Undergoing Planned Surgery or Invasive Procedure: Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. About a quarter of the anticoagulated patients require temporary cessation of direct oral anticoagulants (DOACs) or vitamin K antagonists for a planned intervention within 2 years from anticoagulation inception. Several clinical issues about DOAC interruption remain unanswered: many questions are tentatively addressed daily by thousands of physicians worldwide through an experience-based balancing of thrombotic and bleeding risks. Among possible valuable answers, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) proposes some experience-based suggestions and expert opinions. In particular, FCSA provides practical guidance on the following issues: (1) multiparametric assessment of thrombotic and bleeding risks based on patients' individual and surgical risk factor, (2) testing of prothrombin time, activated partial thromboplastin time, and DOAC plasma levels before surgery or invasive procedure, (3) use of heparin, (4) restarting of full-dose DOAC after high risk bleeding surgery, (5) practical nonpharmacological suggestions to manage patients perioperatively. Finally, FCSA suggests creating a multidisciplinary “anticoagulation team” with the aim to define the optimal perioperative management of anticoagulation.

Carbamazepine, phenytoin, and oral anticoagulants: Drug‐drug interaction and clinical events in a retrospective cohort

BackgroundCarbamazepine and phenytoin are potent inducers of enzymes that metabolize oral anticoagulants. ObjectivesTo determine the clinical impact of drug‐drug interactions between these anticonvulsants and oral anticoagulants, and whether they affect the treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs). Material and methodsData on patients cotreated with carbamazepine or phenytoin and an oral anticoagulant were retrospectively retrieved from medical records from 2011 to 2020. Outcomes were time in therapeutic range (TTR), DOAC levels, thromboembolic events, major bleeding, and all‐cause mortality. ResultsAmong 85 patients (37% female, median age 68 years) treated with carbamazepine (n = 43 [51%]) or phenytoin (n = 42 [49%]), 53 (62%) were initially treated with VKAs and 32 (38%) with DOACs. TTR in VKA patients was 63%, which improved in year 2. Four of seven trough and five of 12 peak DOAC plasma levels were lower than expected. The incidence rate (95% confidence interval) per 100 person‐years for thromboembolism was 3.6 (3.1‐4.2) for VKA patients and 4.4 (3.5‐5.6) for DOAC patients; for major bleeding 1.8 (1.5‐2.1) and 1.5 (1.2‐1.9), and for all‐cause mortality 3.6 (3.1‐4.2) and 1.5 (1.2‐1.9), respectively. Incidence rates between VKAs and DOACs and between carbamazepine and phenytoin were similar. ConclusionThere was a high incidence of thromboembolism in patients cotreated with anticoagulants and carbamazepine or phenytoin. The incidence rates of thrombotic and bleeding events were similar between VKA and DOAC patients. DOAC levels were lower than expected in 47% of cases tested, without correlation with clinical outcomes.

Plasma levels of direct oral anticoagulants in atrial fibrillation patients at the time of embolic stroke: a pilot prospective multicenter study.

Patients with atrial fibrillation (AF) who are on long-term direct oral anticoagulants (DOAC) with low anti-Xa or anti-IIa levels may be at higher risk of recurrent stroke. However, no prospective post-marketing study has investigated these DOAC plasma levels at the time of embolic stroke. The aim of this study was to assess the anti-Xa (rivaroxaban, apixaban) and anti-IIa (dabigatran) plasma levels in DOAC-treated AF patients at the time of acute embolic stroke. We prospectively identified 43 patients with AF on long-term DOAC who experienced embolic strokes. We compared the DOAC plasma levels of these patients with a control sample of 57 patients who tolerated long-term therapeutic dose DOAC therapy without any adverse event. DOAC levels were assessed with drug-specific anti-Xa chromogenic analysis (rivaroxaban, apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients with stroke had significantly lower anti-IIa levels when compared with the trough (40.7 ± 36.9 vs. 85.4 ± 57.2ng/mL, p < 0.05) and peak samples of the controls (40.7 ± 36.9 vs. 138.8 ± 78.7ng/mL, p < 0.001). Similarly, there were significantly lower anti-Xa levels in apixaban-treated patients with stroke compared to the trough control samples (72.4 ± 46.7 vs. 119.9 ± 81.7ng/mL, p < 0.05), and in rivaroxaban- and apixaban-treated patients when compared to peak control samples (rivaroxaban: 42.7 ± 31.9 vs. 177.6 ± 38.6ng/mL, p < 0.001; apixaban: 72.4 ± 46.7 vs. 210.9 ± 88.7ng/mL, p < 0.001). This observational study showed significantly lower anti-IIa and anti-Xa plasma levels in AF patients with embolic stroke compared to those who tolerated long-term therapeutic dose DOAC therapy.

Detection of direct oral anticoagulants with the dilute Russels viper venom time – observations in a real life setting

Abstract Background The detection of direct oral anticoagulants (DOACs) in emergency settings still remains challenging, especially when dedicated anti-Xa or anti-IIa tests are not readily available or the specific DOAC is unknown. The dilute Russel's viper venom time (dRVVT) is widely known in lupus anticoagulant (LA) testing and may also provide helpful information regarding the residual antithrombotic activity of DOACs. Yet real world data describing the effect of DOACs on the dRVVT is scarce. Objective The study aimed to evaluate the sensitivity and specificity of dRVVT for different DOAC plasma levels. Methods A total of 80 patients were recruited – 20 patients for each approved DOAC (apixaban, edoxaban, rivaroxaban and dabigatran). Blood plasma was sampled before (baseline), 6 and 12 hours after DOAC-intake and at plasma peak time. DRVVT was measured using the LA1 screening assay for lupus anticoagulant. Plasma levels were measured by calibrated anti-Xa or anti-IIa tests. Additionally, activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured. Results All DOACs significantly prolonged the dRVVT. The effects were more pronounced at higher DOAC plasma levels. The area under the receiver operating characteristic (ROC) curve regarding a plasma level cut-off of 30 ng/ml was 0.92 (95% confidence interval (CI) 0.823 to 1.00) for apixaban, 0.97 (95% CI 0.902 to 1.00) for edoxaban, 0.87 (95% CI 0.649 to 1.00) for rivaroxaban and 0.96 (95% CI 0.871 to 1.00) for dabigatran. Conclusion A dose dependent effect of all approved direct oral anticoagulants (DOACs) on the dilute Russel's viper venom time (dRVVT) was documented in our real world setting, while relevant DOAC plasma levels did not affect standard coagulation tests. The negative predictive value for the dRVVT was high even at low DOAC plasma levels. The dRVVT could therefore be helpful to rule out relevant antithrombotic plasma activity caused of DOACs in emergency situations. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Universität Leipzig Figure 1. ROC curves

Influence of direct oral anticoagulants on thrombin generation on Ceveron TGA.

Monitoring of direct oral anticoagulants (DOACs) with calibrated anti-Xa assay is limited by the high intra- and interindividual variations of the test results. Thrombin generation (TG) is a global hemostatic assay that reflects the patient´s individual coagulation status. The aim of this study was to investigate the influence of DOACs on TG measured with a fully automated assay system. All consecutive patients under apixaban and rivaroxaban coming to the outpatient coagulation center MVZ Limbach, Magdeburg, Germany between October 2017 and April 2020 were included. DOAC plasma levels were correlated with TG assessed using the fully automated Ceveron TG analyzer. A total of 703 rivaroxaban and 252 apixaban containing plasma samples were included. There was a significant correlation between DOAC plasma levels and all TG parameters except for lag time regarding apixaban. Time to peak and peak thrombin followed an exponential regression curve, while this was linear for the endogenous thrombin potential (ETP). Apixaban showed a lower correlation coefficient for all TG parameters compared with rivaroxaban, and thrombin generation was less influenced by apixaban than rivaroxaban at plasma levels >100ng/ml. The sensitivity and negative predictive value of normal TG parameters for the prediction of DOAC plasma levels <30ng/ml was >85%. The present data show a moderate predominantly nonlinear correlation between TG parameters and plasma levels of apixaban and rivaroxaban. Rivaroxaban has a stronger effect on TG than apixaban.

Direct oral anticoagulant plasma levels in hospitalized COVID-19 patients treated with dexamethasone.

Direct oral anticoagulants (DOACs) are not recommended in COVID-19 patients receiving dexamethasone because of potential drug-drug and drug-disease interactions affecting anticoagulant concentration and activity. To evaluate short- and long-term pharmacokinetic interactions, serial through and peak DOAC plasma levels were prospectively measured during and after dexamethasone therapy, as well as during the acute phase and after recovery from COVID-19 in hospitalized, non-critically ill patients undergoing treatment with DOACs. Thirty-three (18 males, mean age 79 years) consecutive patients received DOACs (17 apixaban, 12 rivaroxaban, 4 edoxaban) for atrial fibrillation (n = 22), venous thromboembolism (n = 10), and acute myocardial infarction (n = 1). Twenty-six patients also received dexamethasone at a dose of 6 mg once daily for a median of 14 days. Trough DOAC levels on dexamethasone were within and below expected reference ranges respectively in 87.5 and 8.3% of patients, with no statistically significant differences at 48–72 h and 14–21 days after dexamethasone discontinuation. Peak DOAC levels on dexamethasone were within expected reference ranges in 58.3% of patients, and below ranges in 33.3%, of whom over two thirds had low values also off dexamethasone. No significant differences in DOAC levels were found during hospitalization and after resolution of COVID-19. Overall, 28 patients were discharged alive, and none experienced thrombotic or bleeding events. In this study, dexamethasone administration or acute COVID-19 seemed not to affect DOAC levels in hospitalized, non-critically ill COVID-19 patients.

A retrospective study of indications and consequences of monitoring direct oral anticoagulant plasma concentrations on patient care in a university hospital: The Retro-AOD study

IntroductionThe use of direct oral anticoagulants (DOAC) is increasing. Specific concentrations are available and have been proven to be reliable and reproducible in optimising patient care. This retrospective, monocentric study aimed to describe the indications and consequences of monitoring DOAC plasma levels on patient care. Materials and methodsWe collected data of patients hospitalised at the Bordeaux University Hospital between January 2017 and December 2018. These included demographics, indications, type, dose of DOAC, standard coagulation tests, creatinine clearance and DOAC plasma concentration using specifically calibrated rivaroxaban and apixaban anti-Xa and dabigatran anti-IIa assays. The date of last DOAC intake, the time between intake and plasma level measurement were also collected and analysed. ResultsA total of 2197 DOAC assays in 1488 patients were obtained in various clinical situations: urgent or elective procedures, context of acute renal failure, suspicion or occurrence of ischemic strokes, intra-cranial and other bleeding sites. Interpretation of these assays led physicians to maintain, postpone or cancel invasive and high haemorrhagic risk procedures in 757, 261 and 56 cases respectively. The remaining 1123 assays were associated with no significant modification of patient care. DOAC plasma concentration was ≤30 ng ml-1 (sensitivity 85.4%, specificity 73.6%, positive predictive value 71.1%, negative predictive value 86.7%, AUC 0.81) after a last intake of at least 2 days. ConclusionsOur study is, to date, the largest report of real-life measurement of specific DOAC plasma level at a single institution. Patient care was not modified in more than half of the assays.

Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study.

Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants.

The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC-apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12hours after starting DOAC for quantification of drug levels and TG. The baseline TG before DOAC intake showed inter-individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti-Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti-Xa inhibitors. All DOACs showed a nonlinear dose-response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient-specific baseline TG level and the drug-specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

Safety and efficacy of direct oral anticoagulants under long-term immunosuppressive therapy after liver, kidney and pancreas transplantation.

The safety of direct oral anticoagulants (DOACs) in patients after solid organ transplantation (SOT) is not well defined. This study aimed at describing the safety and efficacy of DOACs in patients after SOT. Patients after kidney and/or liver transplantation under maintenance immunosuppression treated with rivaroxaban (n=26), apixaban (n=20) and edoxaban (n=1) were included. Clinical data were collected retrospectively and using a questionnaire. DOAC plasma levels and thrombin generation (TG) were measured in patients after SOT and compared with nontransplanted controls receiving DOACs. DOACs were administered for 84.6 patient-years. Mean immunosuppressive trough levels after DOAC initiation increased from baseline by 18.8±29.6% compared to 3.0±16.5% in matched controls (P=0.004), without significant differences in dose adjustments. No transplant rejection or significant change in liver or renal function was observed. There was one major bleeding after the observation period but no thromboembolic complication. DOAC plasma levels reached the expected range in all patients. The intrinsic hemostatic activity in transplanted patients was higher compared to nontransplant controls. Treatment with DOACs after SOT is safe and effective. Immunosuppressive trough levels should be monitored after DOAC initiation, particularly in the early phase after SOT. These data should be confirmed in a prospective study.