Direct Acting Oral Anticoagulants Following Gastrointestinal Tract Surgery.

ABSTRACT: Direct-acting oral anticoagulants (DOACs) vary in bioavailability and sites of absorption in the gastrointestinal tract (GIT). Data on DOAC use after major GIT surgery are limited. The aim of this case series was to report the impact of surgical resection or bypass of the GIT on rivaroxaban and apixaban peak plasma concentrations. This was a case series of patients who received rivaroxaban or apixaban after GIT surgery, during the period of July 1, 2019, to December 31, 2020. Peak plasma concentrations of rivaroxaban and apixaban were assessed for the expected concentrations. Of the 27 assessed patients, 18 (66.7%) received rivaroxaban, and 9 (33.3%) received apixaban. After rivaroxaban therapy, 4 of 5 patients (80%) who underwent gastrectomy, and 3 of 3 patients (100%) who underwent duodenum and proximal jejunum exclusion had peak plasma concentrations of rivaroxaban lower than the effective range, whereas 11 of 11 patients (100%) who underwent distal bowel or ileostomy had peak rivaroxaban plasma within the effective range. After apixaban therapy, 5 of 6 patients (83.3%) who underwent total or partial gastrectomy achieved effective peak concentrations. All the patients who underwent proximal and distal bowel resection or bypass had peak concentrations of apixaban within the effective range. In conclusion, surgical resection or bypass of the upper GIT could affect DOAC absorption and subsequently peak plasma concentrations. This effect was more observed among rivaroxaban recipients. An injectable anticoagulant or vitamin K antagonist may be preferred if DOAC concentrations cannot be measured after GIT surgery.

A validated UPLC-MS/MS method for the determination of CX3002 in human plasma and its application to a pharmacokinetic study.

A simple, selective, rapid, and reliable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine CX3002 in human plasma using CX3002-d3 as the internal standard (IS). After a rapid protein precipitation with acetonitrile (3:1, v/v), the chromatographic separation of CX3002 and IS was performed on a Thermo Hypersil GOLD C18 column (2.1 mm × 50 mm, 1.9 µm) with gradient elution at a flow rate of 0.4 ml/min. Gradient elution was achieved with mobile phase A consisting of water containing 0.1% formic acid and 5 mmol/L ammonium formate and mobile phase B consisting of methanol containing 0.1% formic acid. The detection was performed on AB SCIEX QTRAP® 5500 tandem mass spectrometry in the positive ion mode. Multiple reactions monitoring (MRM) was used for quantitative analysis at transition of m/z 460.3 â†’ 199.3 for CX3002 and m/z 463.3 â†’ 202.3 m/z for IS. The method was fully validated and displayed good linearity over a concentration range of 0.2-400 ng/mL with the correlation coefficient above 0.997. The intra-run and inter-run precision (coefficient of variation, CV) ranged from 0.60%-16.46% and the accuracy bias ranged from -7.09%-9.75%. The mean IS-normalized extraction recovery ranged from 98.30% to 104.52%. The CV(%) of IS-normalized matrix factors at the low and high QC concentration were 4.09% and 1.68%, respectively. The storage stability under different conditions was in accordance with the bioanalytical guidelines. The method was successfully applied to the pharmacokinetic study of CX3002 (30 mg) in healthy Chinese subjects.

Investigating Intestinal Transporter Involvement in Rivaroxaban Disposition through Examination of Changes in Absorption.

PURPOSE: The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in rivaroxaban disposition based on in vitro studies, similar to what had previously been proposed for apixaban. We recently showed that these efflux transporters were not clinically relevant for apixaban disposition and examine here their relevance for this second Factor Xa inhibitor. METHODS: Using recently published methodologies to discern metabolic- from transporter- mediated drug interactions, a critical evaluation was undertaken of 9 rivaroxaban studies reporting 12 DDIs, one study of food effects and one study of hepatic function. RESULTS: Rationale examination of these clinical studies using basic pharmacokinetic theory finds little support for the clinical significance of intestinal efflux transporters in rivaroxaban disposition. Drug-drug interactions are most likely adequately predicted based on the level of CYP 3A metabolism. CONCLUSION: These analyses indicate that inhibition of efflux transporters appears to have negligible, clinically insignificant effects on the rivaroxaban absorption process, which is consistent with the concern that predictions based on in vitro measures may not translate to a clinically relevant interaction in vivo. We emphasize the need to evaluate gastric emptying, dissolution and other processes related to absorption when using MAT changes to indicate efflux transporter inhibition.

Pharmacokinetics of edoxaban in EGFR-mutated non-small cell lung cancer patients with venous thromboembolism.

BACKGROUND: The risk of venous thromboembolism (VTE) is increased 7-fold in patients with cancer than in those without. Low-molecular-weight heparin is the standard treatment for cancer-associated VTE. Direct oral anticoagulants (DOACs) are not inferior to low-molecular-weight heparin with respect to the general outcome of recurrent VTE. Warfarin is associated with a risk of bleeding when used in combination with gefitinib or erlotinib which are epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). It is unclear, however, whether combination treatments with EGFR-TKIs and DOACs pose the same risk. We aimed to identify anticancer drugs and anticoagulants that can be used safely in combination, as accompanying research to an observational study on VTE incidence rates in lung cancer patients (Rising-VTE/NEJ037 study). METHODS: Twelve patients receiving EFGR-TKI monotherapy and VTE treatment were enrolled. Blood samples were collected in time series after the first dose of edoxaban, and further samples were collected within 8-15 days after administering EGFR-TKIs. The pharmacokinetics (PK) of edoxaban were analyzed using a non-compartmental model. RESULTS: Edoxaban concentrations (30 mg once daily) were measured in eight patients. PK analyses showed no significant differences before and after co-administration of EGFR-TKIs (gefitinib, erlotinib, and afatinib). CONCLUSIONS: Our findings indicate that the PK of edoxaban was not considerably affected by co-administration of EGFR-TKIs (gefitinib, erlotinib, and afatinib).

Venous thromboembolism in burns patients: Are we underestimating the risk and underdosing our prophylaxis?

BACKGROUND: Burns patients exhibit all factors of Virchow's triad and are thus at high theoretical risk of venous thromboembolism (VTE). At our tertiary referral burns unit, a standard dose of low molecular weight heparin, which acts primarily by inhibiting Factor Xa, is given for thromboprophylaxis. However, the pharmacokinetics of enoxaparin are altered following a burn injury, and thus burns patients are likely underdosed on their thromboprophylaxis. The objectives of this study were to determine the incidence and risk factors for VTE among burns patients at the Victorian Adult Burns Service (VABS) and to determine the adequacy of the current enoxaparin thromboprophylaxis regimen through measurement of anti-factor Xa (AFXa) levels and comparison with established reference ranges. METHODS: This study consisted of two parts. In part 1, the Burns Registry of Australia and New Zealand (BRANZ) was reviewed for cases of VTE in burns patients admitted to the VABS from 2013 - 2018. Part 2 was a prospective study that determined peak and trough AFXa levels in patients admitted to the VABS with >10% total body surface area (TBSA) burns. RESULTS: Part 1. Totally, 1,475 patients were admitted to the VABS between 2013 - 2018. There were 20 cases of VTE (1.36%). Percent TBSA of burn (OR = 1.04, 95% CI: 1.03 - 1.06), full thickness burns (OR = 2.78, 95% CI: 1.15 - 6.73), ICU admission (OR = 15.08, 95% CI: 5.01 - 45.44), mechanical ventilation (OR = 10.62, 95% CI: 4.05 - 27.91), operative procedures (OR = 1.43, 95% CI: 1.29 - 1.59), and a longer hospital stay (OR = 1.05, 95% CI: 1.04 - 1.07) were all associated with an increased VTE risk. Part 2. A total of 20 participants with >10% TBSA burns were recruited to the prospective study. Peak anti Factor Xa (AFXa) levels were measured for all 20 participants with 15% recording an initial prophylactic peak AFXa level within reference range. Upon subsequent measurements, 50% of participants reached a prophylactic peak AFXa level. Trough AFXa levels were measured for 17 participants with no participant recording an initial or subsequent trough AFXa level at or above the prophylactic threshold. CONCLUSION: Our study demonstrates a high incidence of VTE among burns patients at the VABS, especially among the major burns patients, and a thromboprophylaxis protocol that is ineffective in achieving prophylactic levels of AFXa level. The evidence suggests a need to evaluate different dosing protocols among burns patients in order to improve AFXa levels, with the aim of decreasing incidence of VTE in high-risk patients.

Impact of gene polymorphisms in drug-metabolizing enzymes and transporters on trough concentrations of rivaroxaban in patients with atrial fibrillation.

Rivaroxaban is excreted from the body via multiple pathways involving glomerular filtration, drug-metabolizing enzymes and transporters. In this study, we aimed to examine the impact of single nucleotide polymorphisms in P-glycoprotein, breast cancer resistance protein, cytochrome P450 (CYP) 3A5 and CYP2J2 on the pharmacokinetics of rivaroxaban. Eighty-six patients with non-valvular atrial fibrillation (NVAF) undergoing AF catheter ablation were enrolled in this study. In these analyses, the dose-adjusted plasma trough concentration ratio (C0h /D) of rivaroxaban was used as the pharmacokinetic index. The median (quartile range) rivaroxaban C0h /D was 3.39 (2.08-5.21) ng/mL/mg (coefficient of variation: 80.5%). The C0h /D did not differ significantly among ABCB1 c.3435C>T, c.2677G>A/T, c.1236C>T, ABCG2 c.421C>A, CYP3A5*3 and CYP2J2*7 genotypes. Stepwise selection multiple linear regression analysis showed that the estimated glomerular filtration rate was the only independent factor influencing the C0h /D of rivaroxaban (R2  = 0.152, P < 0.001). There was a significant correlation between the C0h of rivaroxaban and prothrombin time (PT) (rho = 0.357, P = 0.001). In patients with NVAF, pharmacokinetic genotype tests are unlikely to be useful for prediction of the C0h of rivaroxaban.

Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.

This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (≥2 to <8 years), and 100 IU/kg every 12 hours (≥8 to <19 years).

Drug-drug interaction (DDI) with direct oral anticoagulant (DOAC) in patients with cancer.

Cancer-associated thrombosis (CAT) is the second leading cause of death in cancer patients after tumor progression. The treatment of CAT is challenging because of a high risk of VTE recurrence, a high risk of bleeding, common presence of comorbidities, poly-medication, and potential drug-drug interactions (DDI). Since 2018, direct oral anticoagulants (DOACs) represent a promising therapeutic alternative and have been recently included into the 2019 update of the International Initiative on Thrombosis and Cancer (ITAC-CME) clinical practice guidelines for management of CAT. However, pharmacokinetic studies suggest that concomitant treatment with P-gp or CYP3A4 inhibitors will result in an increased exposure to rivaroxaban and apixaban, but the clinical relevance of these studies is unknown. In addition, there is an important inter-individual variability in drug absorption, distribution, metabolism and elimination, even more in cancer patients. Overall, the risk of pharmacokinetic DDI should be estimated based on several individual (patient age, renal and liver function, number of comedications) and diseases-related factors, including inflammation, sarcopenia, and low body weight. In this context, DDI with clinical implications could be expected with anti-neoplastic agents or supportive care treatments, especially with drugs known to be moderate or strong inhibitors/inducers of CYP3A4 and P-gp. Consequently, in the presence of potential DDIs through CYP3A4, and/or P-gp, LMWHs remain the first-line anticoagulant of choice for the long-term treatment of CAT. Multidisciplinary consultation meetings and therapeutic patient education should be emphasized in the complex management of CAT.

Safe chest tube placement in a patient with tension pneumothorax receiving rivaroxaban therapy for non-valvular atrial fibrillation.

The number of patients treated with direct oral anticoagulants is increasing worldwide. Although bleeding complications associated with direct oral anticoagulants are lower than those associated with vitamin K antagonists, the increased number of patients treated with these anticoagulants suggests that a higher absolute number of patients are at risk. Tube thoracostomy is an invasive procedure with a high risk of bleeding. To date, among direct oral anticoagulants, only dabigatran has a well-studied antidote to reverse its effects during emergency procedure or surgery. This report describes a case in which emergency placement of a tube thoracostomy, in a patient with type 2 respiratory failure due to left tension pneumothorax and receiving the anticoagulant rivaroxaban, in the pharmacokinetics phase with greater anticoagulant effect, did not result in bleeding greater than that typically encountered during such interventions. The procedure ended successfully with no acute complications.

Rivaroxaban Precision Dosing Strategy for Real-World Atrial Fibrillation Patients.

Rivaroxaban is a direct-acting oral anticoagulant approved to prevent strokes in patients with atrial fibrillation. Dosage recommendations are approved for all adult patients to receive either 15 mg or 20 mg once daily depending upon renal function. There are a number of reasons to believe rivaroxaban dosing could be more effective and/or safer for more patients if increased dosing precision is available. Because real-world patients are more diverse than those studied in phase III clinical trials, we evaluated the extremes of creatinine clearance (CrCl) on rivaroxaban clearance using a published population pharmacokinetic model and applying exposure variation limits (±20%) based on published literature. The proposed dosing recommendations are 10 mg once daily (CrCl 15-29 ml/min), 15 mg once daily (CrCl 30-69 ml/min), 10 mg twice daily (CrCl 70-159 ml/min), and 15 mg twice daily (CrCl 160-250 ml/min). These new dosing recommendations should be prospectively tested for predictive accuracy and to assess the impact on AF patient efficacy and safety.

Value of quantifying ABC transporters by mass spectrometry and impact on in vitro-to-in vivo prediction of transporter-mediated drug-drug interactions of rivaroxaban.

ABC transporters, such as P-gp and BCRP, are involved in rivaroxaban pharmacokinetics and can lead to drug-drug interactions (DDIs). Investigations of the victim role for rivaroxaban and transporter-mediated DDI are commonly performed using in vitro models. However, interpretation of rivaroxaban efflux transport and DDI studies in cell models may be influenced by P-gp and BCRP transporter abundance. This study aimed to develop an LC-MS/MS quantification method for assessing the relationship between transporter expression and functionality in Caco-2ATCC, Caco-2ECACC, MDCK-MDR1, MDCK-BCRP cell models. First, the relative and absolute quantities of the transporters were determined by LC-MS/MS. P-gp and BCRP expression was then confirmed by western blotting and immunofluorescence staining. Finally, P-gp and BCRP functional activities and half-inhibitory concentrations (IC50s) of two specific inhibitors (verapamil and ko143) were determined by bidirectional transport experiments. P-gp and BCRP protein expression was detected at the cell membrane and was greater in the respective transfected models. Efflux ratios were correlated with P-gp and BCRP quantities. The lowest IC50s were obtained in the MDCK-MDR1 and MDCK-BCRP models for verapamil and ko143, respectively. In conclusion, this study demonstrated that LC-MS/MS can accurately quantify P-gp and BCRP efflux transporters and thereby improve the interpretation of transport data and in vitro-in vivo correlations.

Effect of CYP3A4, CYP3A5, ABCB1 Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Undergoing Total Hip and Knee Replacement Surgery.

INTRODUCTION: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. AIM: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. METHODS: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. RESULTS: The study revealed the following haplotypes: (1) ABCB1 rs1045642-CYP3A4 rs35599367 and (2) ABCB1 rs4148738-CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). CONCLUSION: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.

Rivaroxaban, a direct Factor Xa inhibitor, versus acetylsalicylic acid as thromboprophylaxis in children post-Fontan procedure: Rationale and design of a prospective, randomized trial (the UNIVERSE study).

BACKGROUND: The Fontan procedure is the final step of the 3-stage palliative procedure commonly performed in children with single ventricle physiology. Thrombosis remains an important complication in children after this procedure. To date, guideline recommendations for the type and duration of thromboprophylaxis after Fontan surgery are mainly based on extrapolation of knowledge gained from adults at risk for thrombosis in other clinical settings. Warfarin is being used off-label, and because of its multiple interactions with other drugs and food, a new alternative is highly desirable. Rivaroxaban, a direct Factor Xa inhibitor with a predictable pharmacokinetic profile, is a candidate to address this medical need. STUDY DESIGN: The UNIVERSE study is a prospective, open-label, active-controlled, multicenter study in children 2 to 8 years of age who have single ventricle physiology and had the Fontan procedure within the 4 months preceding enrollment. This study consists of 2 parts. In Part A, rivaroxaban pharmacokinetics, pharmacodynamics, safety, and tolerability are assessed to validate the pediatric dosing selected. In Part B, safety and efficacy of rivaroxaban versus acetylsalicylic acid are evaluated for thromboprophylaxis in children post-Fontan procedure. Children in each part will receive study drug for 12 months. Part A has been completed with 12 children enrolled. Enrollment into Part B is currently ongoing. CONCLUSIONS: The UNIVERSE study aims to provide dosing, pharmacokinetics/pharmacodynamics, safety, and efficacy information on the use of rivaroxaban, an oral anticoagulant, versus acetylsalicylic acid, an antiplatelet agent, in children with single ventricle physiology after the Fontan procedure.

Edoxaban for the prevention of stroke in patients with atrial fibrillation.

INTRODUCTION: Edoxaban is the last direct oral anticoagulant marketed for the prevention of stroke among patients with nonvalvular atrial fibrillation (AF). Areas covered: ENGAGE AF-TIMI 48 was the pivotal clinical trial that led to the approval of edoxaban 60 mg once daily. After the publication of this study, a great number of substudies and post hoc analyses have been published, together with some observational studies. The aim of this review was to update the current evidence about the use of edoxaban in AF patients. Expert opinion: In the ENGAGE AF-TIMI 48 trial, edoxaban 60 mg was noninferior to warfarin for the prevention of stroke or systemic embolism, but significantly reduced the risk of bleeding, major adverse cardiac events and death from cardiovascular causes. The relative efficacy and safety of edoxaban 60 mg compared with warfarin were independent of different clinical conditions, such as prior stroke, age, risk of falls, renal function, hepatic disease, ischemic heart disease, heart failure, valvular heart disease, or cancer. Data about the effectiveness and safety of edoxaban in real-life patients are scarce, but consistent with those of the pivotal clinical trial. Edoxaban seems a cost-effective alternative to warfarin among AF patients with moderate to high thromboembolic risk.

Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study.

PURPOSE: Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects. METHODS: Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects. RESULTS: A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5 days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration. CONCLUSIONS: We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.

Biodistribution and Pharmacokinetics of Amblyomin-X, a Novel Antitumour Protein Drug in Healthy Mice.

BACKGROUND: Amblyomin-X is a recombinant protein under development for cancer treatment owing to its selective cytotoxic activity over several tumour cell lines and tumour regression in mice models. The aim of this study was to examine the distribution and pharmacokinetics of amblyomin-X in healthy female mice. METHODS: Amblyomin-X was injected intravenously into the healthy animals and at controlled times plasma and organs were removed and analysed for identification and quantification of the protein. Alternatively, the labelled protein was injected into mice and tracked in an in vivo imaging system. RESULTS: Amblyomin-X was rapidly eliminated from plasma, probably because of its inability to bind to plasma albumin. After 10 min, the protein was found in the thymus and lungs, and later in the heart, liver and kidneys. In the liver, the protein was found until 24 h after a single injection. The in vivo analysis showed the same kinetics profile, besides the identification of amblyomin-X in the bladder region, indicating its elimination via urine. Only fragments of amblyomin-X were observed in the urine. CONCLUSIONS: These findings suggest that amblyomin-X is rapidly distributed to the tissues, metabolized by the liver or even kidneys, and eliminated in urine in healthy mice. There is no accumulation in any organ.

A level-headed approach to measuring direct oral anticoagulants: A 2-year retrospective analysis of DOAC levels from a tertiary UK centre.

INTRODUCTION: Direct oral anticoagulants (DOAC) are commonly prescribed and measuring drug levels may be useful in a number of contexts. However, data on DOAC level measurement and their clinical utility in real-world studies are limited. METHODS: We carried out a 2-year retrospective cohort study of DOAC levels measured at our institution. RESULTS: One hundred and sixty-nine levels measured in 113 patients were included in the final analysis. Our patients had a median age of 69.9. AF was the commonest indication for anticoagulation. Median turnaround time for inpatient levels was 92 minutes. Median FXa inhibitor levels within 6 hours of last dose and following one half-life were similar to those described previously. However, the range of levels was wider than expected. Importantly, some levels remained in an on therapy range even after 3 half-lives. There was no correlation between dabigatran level and time from last dose. The reason for request varied with setting; 23 outpatient levels were to monitor drug efficacy, whereas 54 and 43 inpatient levels were collected in the context of bleeding and emergency surgery respectively. 60.3% of levels had an impact on clinical decision making. CONCLUSION: Our real-world study demonstrates that DOAC levels can be performed in a timely manner to influence clinical decision making. In addition, it suggests there is a wide variation in levels such that it can be difficult to predict in the real world. Overall, this supports the wider use of DOAC levels to help guide clinicians in managing patients taking these drugs.

Creatinine Versus Cystatin C: Differing Estimates of Renal Function in Hospitalized Veterans Receiving Anticoagulants.

BACKGROUND: Current practice in anticoagulation dosing relies on kidney function estimated by serum creatinine using the Cockcroft-Gault equation. However, creatinine can be unreliable in patients with low or high muscle mass. Cystatin C provides an alternative estimation of glomerular filtration rate (eGFR) that is independent of muscle. OBJECTIVE: We compared cystatin C-based eGFR (eGFRcys) with multiple creatinine-based estimates of kidney function in hospitalized patients receiving anticoagulants, to assess for discordant results that could impact medication dosing. DESIGN: Retrospective chart review of hospitalized patients over 1 year who received non-vitamin K antagonist anticoagulation, and who had same-day measurements of cystatin C and creatinine. PARTICIPANTS: Seventy-five inpatient veterans (median age 68) at the San Francisco VA Medical Center (SFVAMC). MAIN MEASURES: We compared the median difference between eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) study equation using cystatin C (eGFRcys) and eGFRs using three creatinine-based equations: CKD-EPI (eGFREPI), Modified Diet in Renal Disease (eGFRMDRD), and Cockcroft-Gault (eGFRCG). We categorized patients into standard KDIGO kidney stages and into drug-dosing categories based on each creatinine equation and calculated proportions of patients reclassified across these categories based on cystatin C. KEY RESULTS: Cystatin C predicted overall lower eGFR compared to creatinine-based equations, with a median difference of - 7.1 (IQR - 17.2, 2.6) mL/min/1.73 m2 versus eGFREPI, - 21.2 (IQR - 43.7, - 8.1) mL/min/1.73 m2 versus eGFRMDRD, and - 25.9 (IQR - 46.8, - 8.7) mL/min/1.73 m2 versus eGFRCG. Thirty-one to 52% of patients were reclassified into lower drug-dosing categories using cystatin C compared to creatinine-based estimates. CONCLUSIONS: We found substantial discordance in eGFR comparing cystatin C with creatinine in this group of anticoagulated inpatients. Our sample size was limited and included few women. Further investigation is needed to confirm these findings and evaluate implications for bleeding and other clinical outcomes. NIH TRIAL REGISTRY NUMBER: Not applicable.

Twice-Daily Enoxaparin among Plastic Surgery Inpatients: An Examination of Pharmacodynamics, 90-Day Venous Thromboembolism, and 90-Day Bleeding.

BACKGROUND: Low anti-factor Xa level, indicative of inadequate enoxaparin dosing, has a significant association with 90-day venous thromboembolism events. The authors examined the pharmacodynamics of enoxaparin 40 mg twice daily and its correlation with anti-factor Xa level, postoperative venous thromboembolism, and bleeding. METHODS: Adult patients were admitted after plastic and reconstructive surgery and received enoxaparin 40 mg twice daily. Peak anti-factor Xa levels, which quantify enoxaparin's antithrombotic effect, were drawn, with a goal level of 0.2 to 0.4 IU/ml. Ninety-day symptomatic venous thromboembolism and clinically relevant bleeding were identified. RESULTS: The authors enrolled 118 patients who received enoxaparin 40 mg twice daily. Of these patients, 9.6 percent had low peak anti-factor Xa levels (<0.2 IU/ml), 62.6 percent had in-range peak anti-factor Xa levels (0.2 to 0.4 IU/ml), and 27.8 percent had high anti-factor Xa levels (>0.4 IU/ml). With enoxaparin 40 mg twice daily, 90.4 percent of patients received at least adequate prophylaxis. Patient weight predicted the rapidity of enoxaparin metabolism. Zero acute 90-day venous thromboembolism occurred. Eight patients (6.8 percent) had clinically relevant 90-day bleeding: clinical consequences ranged from cessation of enoxaparin prophylaxis to transfusion to operative hematoma evacuation. CONCLUSIONS: When enoxaparin 40 mg twice daily is provided, 90 percent of patients receive at least adequate venous thromboembolism prophylaxis (anti-factor Xa level >0.2 IU/ml). However, 27 percent of the overall population is overtreated (anti-factor Xa level >0.4 IU/ml). These pharmacodynamics data likely explain the low rate of 90-day acute venous thromboembolism (0 percent) and the high rate of clinically relevant bleeding (6.8 percent) observed. Future studies are needed to better optimize the risks and benefits of enoxaparin prophylaxis in plastic and reconstructive surgery patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.