Direct Oral Anticoagulants Levels Research Articles

Analysis of Direct Oral Anticoagulant Therapy With Concomitant Use of Interacting Antiretroviral Agents

Background: A theoretical interaction exists between human immunodeficiency virus (HIV) antiretroviral (ARV) agents and direct oral anticoagulants (DOACs), although the clinical significance is unclear. Objective: This study aimed to assess characteristics, prescribing patterns, and outcomes associated with concomitant therapy. Methods: A single-center, retrospective review was performed on patients older than 18 years prescribed a DOAC for any indication with concurrent interacting ARV(s) from June 2016 through June 2019. The primary endpoint was to assess prescribing and population characteristics. Secondary endpoints were to evaluate safety outcomes, DOAC level monitoring, readmissions, outpatient follow-up, and DOAC modification interventions. Results: Thirty-six patients (72 hospital admissions) were identified. The most common DOAC was apixaban (83.3%) and ARV was ritonavir (50%). Of the 72 encounters, 26 (36.1%) DOACs were dosed appropriately per guideline recommendations. Twenty pharmacy interventions for therapy modification were recognized. Eleven (30.6%) patients experienced bleeding and 2 (5.6%) thrombosis. Of the adverse events, all patients had renal impairment. Conclusions: As DOAC utilization grows, increasing use in HIV could be expected. More frequent adjustment or avoidance is recommended per guidelines. Our data suggest the majority of patients receive CYP3A4-inhibiting regimens. Caution should be employed with renal insufficiencies. Further studies are warranted to assess safety and efficacy within this population.

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.

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.

A Novel Laboratory Assay for Monitoring Unfractionated Heparin in Patients Taking Direct Oral Anticoagulants Prior to Hospital Admission

Introduction: As conditions like atrial fibrillation and venous thromboembolism (VTE) become more prevalent in the United States, the use of direct oral anticoagulants (DOACs) is increasing. Patients presenting to the hospital with indications of thrombosis are often started on unfractionated heparin (UFH) infusion, which has traditionally been monitored using laboratory based PTT and anti-Xa assays. While monitoring UFH with anti-Xa assays have been shown to correlate with better outcomes than dose adjustments guided by PTT, anti-Xa assays are susceptible to interferences from DOACs taken prior to admission and can result in inappropriate dose adjustments that can negatively impact patient care.Methods: We derived a novel assay, termed corrected heparin (CH), using quantified values from a chromogenic anti-Xa assay with heparin calibrators prior to and following heparinase treatment to detect any residual DOAC still present within the patient sample. We retrospectively assessed 79 adult patients admitted to our institution who had their UFH infusion monitored using the CH assay due to known DOAC use. These patients were continually monitored by the CH assay and the PTT (unreported) if they had detectable DOAC levels (>0.1 IU/mL by anti-Xa). Of the patients included in the study, 92% were administered apixaban, while 8% were administered rivaroxaban prior to admission and all received UFH while admitted.Results: To assess linearity of anti-Xa assay for this purpose, patient samples with both UFH and apixaban present were diluted with drug-free plasma and displayed good correlation (R2=0.999) throughout the linear range of the assay. Of the 79 patients, 53 patients reached the therapeutic range by the PTT and CH assays, 17 reached the therapeutic range by the CH assay only, 2 reached the therapeutic range by PTT only, and 2 never reached the therapeutic range with either assay. The average time to therapeutic dosing level for the CH assay was 9 hours after initiation of UFH infusion. Using the CH assay, we were able to determine how long the DOAC persisted and was detected by the anti-Xa assay. At 12 hours after the last DOAC dose, more than 80% of patients still had detectable DOAC levels capable of interfering with the anti-Xa assays. The majority of patients (80%) still had measurable anti-Xa assay interference from the DOAC until 72 hours after the last dose. We evaluated the role of kidney function as a predictor for prolonged interference in the anti-Xa assay however, clearance rates of apixaban were difficult to predict based on kidney function status alone.Conclusions: Our CH assay has provided clinicians with an assay that accounts for the presence of residual DOAC and allows patients to reach therapeutic heparin levels faster. Our study also highlights the delayed clearance of commonly prescribed DOACs, which can be longer than expected and independent of kidney function status resulting in prolonged interference in anti-Xa assays that can lead to improper dose adjustments and potentially negative outcomes for patients on UFH infusion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Laboratory assessment of the direct oral anticoagulants: who can benefit?

Direct oral anticoagulants (DOACs), apixaban, dabigatran, edoxaban, and rivaroxaban, are widely used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation as well as for prevention and treatment of venous thromboembolism. Although DOACs do not require routine laboratory monitoring of anticoagulant effect, there are special situations in which laboratory assessment may be warranted. Laboratory tests include quantitative assays, which measure plasma DOAC levels, and qualitative or semi-quantitative assays, which may be used to screen for the presence of clinically relevant DOAC levels. Indications for laboratory assessment include emergent indications (serious bleeding, urgent surgery, acute ischemic stroke with consideration of thrombolysis) and elective indications (extremes of bodyweight, renal hypo- or hyperfunction, liver disease, suspected drug-drug interactions, suspected gastrointestinal malabsorption). In general, quantitative assays that measure DOAC levels may be used for elective indications, whereas screening assays may be necessary for emergent indications if a quantitative assay with sufficiently rapid turnaround time is not available. Therapeutic ranges for DOACs have not been defined. In lieu of therapeutic ranges, data from pharmacokinetic studies may be used to determine whether a patient's plasma DOAC level falls within the expected range. If it does not, a change in therapy may be warranted. Depending on the clinical scenario, a change in therapy may involve adjustment of the DOAC dose, a change to a different DOAC, or a change to a different class of anticoagulant.

Direct oral anticoagulant blood level monitoring in daily practice

IntroductionRoutine monitoring is not required in direct oral anticoagulant (DOAC) treatment, yet it is frequently performed. Guidance on the interpretation and management of DOAC level measurements is lacking and it is key to investigate which patients would benefit from monitoring. Our aims were to investigate why DOAC levels are requested and if they lead to changes in anticoagulant management. MethodsWe retrospectively collected all clinically requested DOAC levels from 2012 until 2019 in two Dutch academic hospitals. Clinical data with regard to the first DOAC level of every patient was collected by chart review. Primary outcomes were settings, indications and changes in anticoagulant management of DOAC level measurement. In addition, we compared demographic and clinical characteristics in patients with and without changes in anticoagulant management. ResultsIn total, we included 604 DOAC levels. The majority was requested in an outpatient setting by the department of internal medicine. In 270 (45%) cases we identified a patient specific indication, with evaluation of DOAC accumulation being the most frequently requested. Of all 604 DOAC levels, 159 (26%) were followed by changes in anticoagulation management. The large majority of changes occurred in patients that had a patient specific indication. Patients who underwent changes were older and had more comorbidity than patients who did not (n ​= ​445). ConclusionAlmost half of the DOAC levels with a specific indication for monitoring were followed by a change in anticoagulant management. Future studies should investigate the relation between DOAC levels, the changes in anticoagulant management and clinical outcomes.

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.

How should we manage hip fracture patients on direct oral anticoagulants?

ObjectiveCurrently, there are no national protocols in place for managing hip fracture patients on direct oral anticoagulants (DOACs). Hence, various local management protocols exist. We compared three different local protocols...

Muscle Mass and Direct Oral Anticoagulant Activity in Older Adults With Atrial Fibrillation.

Direct oral anticoagulants (DOAC) are hydrophilic drugs with plasma levels inversely proportional to lean body mass. Sarcopenic patients with low muscle mass may be at risk for supra-therapeutic DOAC levels and bleeding complications. We therefore sought to examine the influence of lean body mass on DOAC levels in older adults with atrial fibrillation (AF). A prospective cohort study was conducted with patients 65 years of age or more receiving rivaroxaban or apixaban for AF. Appendicular lean mass (ALM) was measured using a bioimpedance device and a dual X-ray absorptiometry scanner. DOAC levels were measured using a standardized anti-Xa assay 4 hours after (peak) and 1 hour before (trough) ingestion. The cohort consisted of 62 patients (47% female, 77.0 ± 6.1 years). The prescribed DOACs were apixaban 2.5 mg (21%), apixaban 5 mg (53%), and rivaroxaban 20 mg (26%). Overall, 16% had supra-therapeutic DOAC levels at trough and 25% at peak. In the multivariable logistic regression model, lower ALM was independently associated with supra-therapeutic DOAC levels at trough (odds ratio per ↓ 1-kg 1.23, 95% confidence interval 1.02 to 1.49) and peak (odds ratio per ↓ 1-kg 1.18, 95% confidence interval 1.02 to 1.37). Addition of ALM to a model consisting of age, total body weight, and renal function resulted in improved discrimination for supra-therapeutic DOAC levels. Our proof-of-concept study has identified an association between ALM and DOAC levels in older adults with AF. Further research is needed to determine the impact of ALM on bleeding complications and the potential role of ALM-guided dosing for sarcopenic patients.

Australian and New Zealand Registry of Anticoagulation in the Obese: Prescribing Patterns, Drug Levels and Patient Outcomes

Background: There is limited data to guide prescribing of all available anticoagulants in obese patients, in particular those weighing &amp;gt; 150kg or with a BMI &amp;gt; 40kg/m2. We aimed to examine anticoagulant prescribing patterns in obese patients in Australia and New Zealand including choice of agent and dosing, determine whether patients with obesity achieve appropriate direct oral anticoagulant (DOAC) levels and evaluate the efficacy and safety of anticoagulation in obese patients. Methods: Patients with a BMI &amp;gt; 35kg/m2 or weight &amp;gt; 120kg receiving anticoagulant therapy are prospectively identified at 7 sites in Australia and New Zealand. Demographic data, indication for anticoagulation and choice of anticoagulant are collected at baseline. At follow-up visits, drug specific levels, dose adjustments and clinical progress (symptoms, imaging, recurrent thrombosis and adverse events) are recorded. Results: 155 patients have been recruited across seven sites (recruitment ongoing). The median age of patients was 53 (range 22-85) and 49% of patients were male. 77 (50%) of patients were anticoagulated for pulmonary embolus (PE) while 40% were anticoagulated for deep vein thrombosis (DVT) without PE. Initial anticoagulant prescribed was apixaban in 37 patients, dabigatran in 4 patients, rivaroxaban in 57 patients, low molecular weight heparin (LMWH) in 29 patients and warfarin in 28 patients (Table 1). A subset of patients initially received LMWH for 5-14 days prior to transition to a DOAC (rivaroxaban in 7, dabigatran in 6). There was cross-over between agents during the study period. Table 2 demonstrates median peak and trough DOAC levels. All peak apixaban levels and 25 of 37 (68%) peak rivaroxaban levels were within the therapeutic ranges published by the International Council for Standardization in Haematology (Gosselin, Thromb Haemost. 2018). Assessment of appropriate trough levels was limited by the limit of detection at different laboratories. 27 patients receiving enoxaparin had at least one peak Anti-Xa level (target peak 0.5-1.2U/ml). The median enoxaparin dose to achieve therapeutic peak Anti-Xa was 0.9mg/kg (range 0.52-1.3). 15 patients weighing &amp;gt; 150kg had a recorded peak Anti-Xa, 10 of these patients were prescribed a capped dose of 150mg BD (weight range 155-290kg) and nine had a therapeutic Anti-Xa and one had a supratherapeutic Anti-Xa measurement. One patient had a PE on apixaban 5mg twice daily (in the setting of suspected non-compliance), one patient had a new confirmed PE after 4 days of non-compliance with rivaroxaban 20mg daily and another patient had a confirmed recurrence on therapeutic warfarin. 1 patient had a PE when warfarin was withheld for emergency surgery. An equivocal recurrence occurred on enoxaparin with a supratherapeutic Anti-Xa (1.76 U.ml) and 1 DVT occurred on dabigatran for a cardiac indication (no drug level available). One patient had recurrent superficial thrombophlebitis on rivaroxaban 20mg daily (peak 301ng/L and trough &amp;lt;30ng/L). There was one episode of life-threatening gastrointestinal bleeding on dabigatran. Conclusion: There is limited data to guide prescribing of all anticoagulants in obese patients, in particular in patients weighing &amp;gt; 150kg or BMI &amp;gt; 40kg/m2. There is increasing use of DOACs in Australia and New Zealand in patients with obesity given the ease of administration and lack of monitoring required. Despite the recommendation to perform DOAC levels in this group of patients, interpretation of levels is difficult due to a lack of well validated therapeutic ranges with clinical correlation. Further data regarding the clinical utility of DOAC levels, appropriate dosing strategy for enoxaparin, and clinical outcomes in this population is required. Our registry provides data regarding drug levels in this population, prescribing characteristics and clinical outcome data. Disclosures No relevant conflicts of interest to declare.

Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation Study.

BackgroundIn the PAUSE (Perioperative Anticoagulant Use for Surgery Evaluation) Study, a simple, standardized, perioperative interruption strategy was provided for patients with nonvalvular atrial fibrillation taking direct oral anticoagulants (DOACs). Our objective was to define the factors associated with perioperative bleeding.Methods and ResultsWe analyzed bleeding as the composite of major and clinically relevant nonmajor bleeding. Putative predictors of bleeding, and preoperative DOAC level were prospectively collected during recruitment. We used stratified logistic regression models for analysis. All statistical analyses were performed in R version 3.6.0. There were 3007 patients requiring perioperative DOAC interruption. More than one third of the included patients underwent a high bleeding risk procedure. The 30‐day rates of major and clinically relevant nonmajor bleeding were 3.02% in apixaban (n=1257), 2.84% in dabigatran (n=668), and 4.16% for rivaroxaban (n=1082). Multivariate analysis stratified by region found more bleeding for hypertension (odds ratio [OR], 1.79; 95% CI 1.07‐2.99; P=0.027), and prior bleeding (OR, 1.71; 95% CI, 1.08‐2.71; P=0.021). Surgical bleed risk classification (high‐ versus low‐risk) as a predictor of bleeding was only significant in the univariate analysis. The prediction model for major and clinically relevant nonmajor bleeding had an area under the curve of 0.71, and the preoperative DOAC level did not improve the area under the curve of the model.ConclusionsIn patients treated with DOACs who required an elective surgery/procedure and were managed with standardized DOAC interruption and resumption, there we did not find reversible risk factors for bleeding, suggesting that adjustment of the PAUSE management protocol to mitigate against bleeding is not needed.

A prospective observational study of the rapid detection of clinically-relevant plasma direct oral anticoagulant levels following acute traumatic injury.

In urgent clinical situations, such as trauma, urgent surgery or before thrombolysis, rapid quantification of direct oral anticoagulant plasma drug levels is warranted. Using the ClotPro® analyser, we assessed two novel viscoelastic tests for detection of clinically-relevant plasma drug levels in trauma patients. The ecarin clotting time was used to assess the plasma concentration of dabigatran and Russell´s viper venom clotting time to determine the plasma concentration of direct factor Xa inhibitors. In parallel, plasma concentrations were analysed using plasma-based chromogenic assays. A total of 203 simultaneous measurements were performed.Strong to very strong linear correlations were detected between ecarin clotting time and plasma concentration of dabigatran (r=0.9693), and between Russell´s viper venom clotting time and plasma concentrations of apixaban (r=0.7391), edoxaban (r=0.9251) and rivaroxaban (r=0.8792), all p<0.001. An ecarin clotting time≥189seconds provided 100% sensitivity and 90% specificity for detecting plasma dabigatran concentrations≥50ng.ml-1 . Corresponding Russell´s viper venom clotting time cut-off values were≥136seconds for apixaban (80% sensitivity, 88% specificity), ≥ 168seconds for edoxaban (100% sensitivity, 100% specificity) and≥177seconds for rivaroxaban (90% sensitivity, 100% specificity). Detection of drug levels≥100ng.ml-1 was also investigated: for dabigatran, an ecarin clotting time≥315seconds yielded 92% sensitivity and 100% specificity; while Russell´s viper venom clotting time cut-offs of 191, 188 and 196seconds were calculated for apixaban (67% sensitivity, 88% specificity), edoxaban (100% sensitivity, 75% specificity) and rivaroxaban (100% sensitivity, 91% specificity), respectively. We have demonstrated strong positive correlations between plasma drug levels and clotting time values in the specific ClotPro assays. Cut-off values for detecting clinically-relevant drug levels showed high levels of sensitivity and specificity.

Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure

AbstractThe Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study prospectively evaluated a prespecified periprocedural-interruption strategy of direct oral anticoagulants (DOACs) among patients with atrial fibrillation. Logistic regression analyses were performed to identify clinical parameters associated with residual DOAC levels ≥30 ng/mL or ≥50 ng/mL. Patients undergoing low-bleed-risk procedures were more likely to have residual levels of ≥30 ng/mL and ≥50 ng/mL. For low-risk procedures, age ≥75 years, female sex, a creatinine clearance (CrCl) <50 mL/min, and an interruption of <36 hours were associated with a greater likelihood of levels ≥30 ng/mL, whereas age ≥75 years, female sex, a CrCl of <50 mL/min, and standard DOAC dosing were associated with levels ≥50 ng/mL. For high-risk procedures, weight of <70 kg, CrCl <50 mL/min, and standard DOAC dosing were associated with residual levels ≥30 ng/mL, whereas female sex was associated with levels ≥50 ng/mL. For low-risk procedures, apixaban was associated with a higher likelihood of levels ≥30 ng/mL as compared with dabigatran (P = .0019) and of levels ≥50 ng/mL when compared with rivaroxaban (P = .0003). For high-risk procedures, apixaban was marginally associated with a higher likelihood of residual levels ≥30 ng/mL when compared with dabigatran (P = .05), whereas rivaroxaban was associated with a higher likelihood of levels ≥30 ng/mL as compared with apixaban. Further study is required to determine whether adjustments to perioperative plans based on these clinical parameters could result in a lower risk of residual DOAC levels. The PAUSE trial was registered at www.clinicaltrials.gov as #NCT2228798.

Direct oral anticoagulants in patients with hematologic malignancies.

The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), which is considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation-therapy was maintained until the platelet count was ≥50 × 109 /L. In case of concomitant anticancer treatment and haemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135: 104/135 were on anticancer therapy. We did not observe either thrombotic or major haemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non-major (CRNM) in two patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent haemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs.

Functional lupus anticoagulant testing in a large retrospective cohort of thrombosis patients with direct oral anticoagulants

Functional tests for lupus anticoagulants (LA) as part of a thrombophilia workup are commonly performed in patients under anticoagulant therapy that may interfere with assay results. There is no consensus on how these tests should be assessed in patients on direct oral anticoagulants (DOACs). In this retrospective cohort study, we analysed data from patients with a history of thrombosis in whom dilute Russell viper venom time (dRVVT), LA-sensitive aPTT, and solid phase assays for antiphospholipid antibodies (aPL) were performed (n = 3,147, thereof 588 on rivaroxaban, 144 on apixaban, 1,179 on other anticoagulant drugs). The dRVVT ratio was correlated with rivaroxaban (r = 0.30, P < 10–4) but not with apixaban plasma levels. The LA-sensitive aPTT/aPTT ratio showed no correlation with DOAC levels. Correspondingly, the rate of patients with abnormal dRVVT test was significantly higher (P < 10–4) under rivaroxaban (88%) than in thrombosis patients without anticoagulant medication (6%), independent from their aPL plasma levels. No isolated positive results of functional LA testing in patients on anticoagulants could be confirmed in repeated testing after discontinuation of the medication (n = 40). These data indicate that rivaroxaban should be discontinued before functional LA testing is performed. However, viable interpretation of these tests appears to be less affected in patients on apixaban.

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.

Direct oral anticoagulant plasma levels’ striking increase in severe COVID‐19 respiratory syndrome patients treated with antiviral agents: The Cremona experience

BackgroundAntiviral drugs are administered in patients with severe COVID‐19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS‐CoV‐2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. MethodsAll consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C‐trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. ResultsOf the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID‐19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C‐trough levels were 6.14 times higher during hospitalization than in the pre‐hospitalization period. ConclusionDOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS‐CoV‐2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.

The management of patients with acute ischemic stroke while on direct oral anticoagulants (DOACs): data from an Italian cohort and a proposed algorithm.

Approximately 1-2% of patients with non-valvular atrial fibrillation have an acute ischemic stroke (AIS) while on direct oral anticoagulant (DOAC) treatment every year. However, current evidence on stroke subtypes, pathophysiology and factors leading to the failure of DOAC preventive therapy in a "real world" setting is still scanty. This study aimed at investigating whether there is any relationship between DOAC plasma levels and the stroke occurrence, on the basis of the phenotypic classification and pathophysiology of the stroke, in a cohort of DOAC-treated patients admitted to our hospital for AIS over 1-year period. A total of 28 patients had DOAC plasma levels determined in emergency and were included in the study, nine patients receiving dabigatran, 11 rivaroxaban and 8 apixaban. The DOAC levels were low in 8/28 patients (28.6% of the sample), intermediate in 4 (14.3%) and high in 16 (57.1%). The most prevalent stroke subtype was the small vessel disease, according to the A-S-C-O phenotypic classification, in 53.6% of our sample. The most common clinical presentation was "minor stroke" in 71.4% of the cases. There was a significantly higher proportion of patients with high DOAC levels in the small vessel group, compared to the cardioembolic group without other phenotypes. The question arises as to the most suitable clinical management of AIS in these patients on DOACs. In the current absence of clear evidence, taking into account the DOAC levels (low/intermediate/high) and the underlying stroke pathophysiology, we present a flowchart of our proposed clinical management of ischemic stroke in patients while on DOAC.

Ischaemic stroke and transient ischaemic attack on anticoagulants: outcomes in the era of direct oral anticoagulants

Clinical and imaging characteristics of patients receiving direct oral anticoagulants presenting with transient ischaemic attack or stroke are lacking. A retrospective review of all patients who presented to a high-volume primary stroke centre with acute stroke symptoms while prescribed an oral anticoagulant between January 2012 and June 2017. Clinical, radiological characteristics and functional outcomes were examined. Anticoagulated patients diagnosed with stroke or transient ischaemic attack shared similar disease and outcome characteristics irrespective of anticoagulants used. One-third of warfarin patients with sub-therapeutic international normalised ratios were treated with thrombolytics but no direct oral anticoagulants level was performed in any of the patients, with only one treated by intravenous thrombolysis.

Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study

Introduction In the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study a simplified, standardized, pharmacokinetic based perioperative interruption scheme was stablished for patients with non-valvular atrial fibrillation taking direct oral anticoagulants (DOACs). The rate of bleeding and thromboembolic outcomes was low, yet better awareness of bleeding predictors will aid the informed decision making for both clinicians and patients. Thus, we aimed to define the factors associated with perioperative bleeding events in the PAUSE cohorts. Methods The standardized interruption scheme is depicted in figure 1. We analyzed bleeding as the composite of major and clinically relevant non-major bleeding (MB/CRNM) according to the ISTH criteria. Putative predictors of bleeding were prospectively collected during the PAUSE recruitment. For patients taking dabigatran the dilute thrombin time was measured from a pre-operative blood sample. A DOAC-calibrated anti-factor Xa level was assessed preoperatively for patients taking factor Xa inhibitors. Continuous numeric variables were reported as means with SD; frequencies were reported when appropriate. We used stratified logistic regression models for analysis. All statistical analyses were performed in R version 3.6.0. Results There were 3007 patients requiring perioperative DOAC interruption, distributed in the apixaban (A) (N = 1,257), dabigatran (D) (N = 668), and rivaroxaban (R) (N = 1,082) cohorts. Characteristics of the patients who developed MB/CRNM are reported in table 1. More than one third of included patients underwent a high bleeding risk procedure. The rates of MB/CRNM were 3.02% in group A, 2.84% in group D, and 4.16% of group R patients from the point of DOAC interruption to 30 days after the procedure. In the univariate analysis, surgery bleeding risk was significantly associated with MB/CRNM (low vs high, OR 0.56, 95% CI 0.36-0.86; p=0.008). Multivariate analysis stratified by region found hypertension (OR 1.81, 95%CI 1.07-3.07; p=0.027), prior bleed or bleed predisposition (OR 1.62, 95% CI 1.02-2.58; p=0.043) were significantly associated with MB/CRNM (table 2); whereas surgery bleeding risk was not significant after adjusting other covariates. Female gender was associated with lower MB/CRNM risk (This result seems to be mainly driven by the rate of CRNM, 2.21% male had CRNM and 1.57% female had CRNM, and the signal disappeared in the model for MB). [Hypertension (OR 3.93, 95%CI 1.40-11.07; p=0.010), active cancer (OR 2.30, 95% CI 1.10-4.81; p=0.026) were significantly associated with MB (table 3)] Aspirin use was more prevalent among males (13.78%) than females (7.75%), but this did not fully explain the gender effect. The model for MB/CRNM had an area under the curve (AUC) of 0.65 (standard error 0.03). Drug level analysis was available for 2541 (84.5%) patients. In the stratified analysis with the DOAC level (&amp;gt;50ng/dL vs £50ng/dL) as a single predictor, there was no significant association with MB/CRNM observed (OR 1.07, 95% CI 0.38-2.96; p=0.902). In the multivariate model, adding DOAC level to the model did not improve the AUC. Discussion A standardized interruption scheme results in low risk of bleeding for patients with atrial fibrillation interrupting DOACs for surgery/invasive procedures. The protocol-defined surgical bleed risk in PAUSE was valid, and selected to numerically higher bleeding rates, but it was not independent predictor of bleeding when the interruption scheme and covariates are accounted for. Hypertension was the only potentially modifiable predictor of perioperative MB/CRNM bleeding. Likely selecting for a frail population, active cancer and hypertension were predictors of MB events. In the exploratory analyses, residual levels did not improve the predictive model. The multivariate model had a low performance and we do not advocate modification of the PAUSE-proposed interruption schema based on these results. The PAUSE trial is the first large scale study enabled to investigate the factors governing perioperative bleed among DOAC-Anticoagulated patients. Nonetheless, we did not have power to analyze DOAC cohorts independently due to the paucity outcomes. Overall, the results strengthen the validity of the PAUSE-proposed DOAC interruption scheme for atrial fibrillation patients who need surgery. Disclosures Tafur: Recovery Force: Consultancy; Janssen: Other: Educational Grants, Research Funding; BMS: Research Funding; Idorsia: Research Funding; Daichi Sanyo: Research Funding; Stago: Research Funding; Doasense: Research Funding. Spyropoulos:Bayer: Consultancy; Ingelheim: Consultancy; Portola: Consultancy; Janssen: Research Funding; Boehringer INgelheim: Research Funding; Janssen: Consultancy. Douketis:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Portola: Other: Consultant ; Janssen: Other: Consultant ; The Merck Manual: Patents &amp; Royalties; Up-to-Date: Patents &amp; Royalties.