Routine Coagulation Monitoring Research Articles

Latest advances in the reversal strategies for direct oral anticoagulants.

Since the late 2000s, Europe has granted approval for various thrombotic risk-related uses of direct oral anticoagulants (DOACs). Unlike traditional anticoagulants, DOACs do not necessitate routine coagulation monitoring. Nevertheless, clinical practice often encounters bleeding events associated with these medications, making the need for effective reversal strategies evident. The study aims to take stock of current reversal strategies for DOACs, with a particular emphasis on the latest compounds that have been developed or are currently under development. For obtaining information regarding the ongoing reversal strategies and the compounds under development, we referred to ClinicalTrials website, PubMed, and Google Scholar. In 2024, two specific antidotes to DOACs have already received approval when reversal of anticoagulation is needed owing to life-threatening or uncontrolled bleeding: idarucizumab that reverses the effects of dabigatran, and andexanet alfa, designed to counteract activated factor X inhibitors such as apixaban and rivaroxaban. Furthermore, ciraparantag, a potential universal reversal agent, is currently in advanced stages of clinical development. Concerns remain regarding the safety of specific reversal agents, especially concerning the risk of thrombosis. Additionally, the cost of these antidotes remains high. Consequently, nonspecific strategies to counteract anticoagulant medications, including activated charcoal, hemodialysis, and concentrates of coagulation factors, still have utility. With the validation of specific and nonspecific antidotes, DOACs could supplant traditional oral anticoagulants. This progress represents a significant advancement in anticoagulation therapy. However, ongoing research is crucial to address remaining safety concerns of the specific reversion agents of DOACs in clinical practice.

Direct oral anticoagulants (DOACs): From the laboratory point of view.

Direct oral anticoagulants (DOACs) represent a new generation of drugs that have been increasingly used in the prevention and treatment of thromboembolic states. According to the mechanism of anticoagulant action, DOACs are divided into two groups: direct inhibitors of thrombin (dabigatran) and direct inhibitors of activated factor X (FXa) (rivaroxaban, apixaban, edoxaban, betrixaban). Compared to the vitamin K antagonists, DOACs are superior in terms of onset of action, pharmacokinetic and pharmacodynamics properties and fixed daily dose without the need for routine coagulation monitoring. Despite these advantages, there are clinical conditions in which laboratory measurement of DOACs should be performed. Although DOACs have an impact on screening haemostasis assays (prothrombin time, PT; activated partial thromboplastin time, aPTT; and thrombin time, TT), these tests are not appropriate for quantifying drug levels. Therefore, specific quantitative methods (LC-MS/MS as a gold standard method for all DOACs, coagulometric and chromogenic assays for dabigatran, and chromogenic anti-Xa assays with drug-specific calibrators for inhibitors of FXa) should only be used for determination of DOACs concentration. The aim of this review is to present all aspects of laboratory assessment of DOACs, including pre-analytical, analytical and post-analytical factors in the overall testing process with a special accent on the available specific quantitative methods for measurement of DOACs in circulation.

Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients.

Although predictable pharmacokinetic and pharmacodynamic of rivaroxaban allow fixed dosing regimens without routine coagulation monitoring, there is still the necessity to monitor and predict the effects of rivaroxaban in specific conditions and different populations. The current study was designed and conducted to analyze the rivaroxaban population pharmacokinetics in Iranian patients and establish a pharmacokinetic/pharmacodynamic model to predict the relationship between rivaroxaban concentration and its anticoagulant activity. A sequential nonlinear mixed effect pharmacokinetic/pharmacodynamic modeling method was used to establish the relation between rivaroxaban concentration and anti-factor Xa activity, prothrombin time, and activated partial thromboplastin time (aPTT) as pharmacodynamic biomarkers in a population of sixty-nine Iranian patients under treatment with oral rivaroxaban. Rivaroxaban plasma concentration was quantified by a validated high-performance liquid chromatography-tandem mass spectrometry. The typical population values (inter-individual variability%) of the oral volume of distribution and clearance for a one-compartment model were 61.2 L (21%) and 3.68 L·h-1 (61%), respectively. Creatinine clearance and Child-Turcotte-Pugh score were found to affect the clearance. A direct link linear structural model best fitted the data for both prothrombin time and aPTT. The baseline estimates of aPTT and prothrombin time in the population were 35.0 (15%) and 12.6 (2%) seconds, respectively. The slope of the relationship between apTT, prothrombin time, and rivaroxaban concentration was 0.033 (28%) and 0.018 (54%) s·ml·ng-1 , respectively. The selected model for anti-factor Xa activity consisted of a direct link inhibitory Emax model with Hill coefficient. The maximum level of inhibition (Emax ) was 4 IU·ml-1 . The concentration of rivaroxaban producing 50% of the maximum inhibitory effect (EC50 ) was 180 (24%) ng·ml-1 , and Hill coefficient (γ) was 1.44 (108%). No covariates showed a statistically significant effect on PT and activated partial thromboplastin time prolonging properties and anti-factor Xa activity. Our results confirmed that pharmacokinetic/pharmacodynamic models similar to those of the other studies describe the relationship between the rivaroxaban concentration and its anticoagulant effect in Iranian patients. However, considerable differences were observed in the parameters of the pharmacodynamics-pharmacokinetic models with the results of other reports that can explain the unpredictable effects of rivaroxaban in some patients.

Use of Non-Vitamin K Dependent Oral Anticoagulant in Ischemic Stroke

Atrial fibrillation (AF) is associated with an increased incidence of ischemic stroke and transient ischemic attack. A confluence of various factors such as blood stasis, endothelial dysfunction, and prothrombotic state could be contributing to the thrombogenesis in AF. Anticoagulation is the first-line therapy for the prevention of thromboembolism by AF. In current days, non-vitamin K dependent oral anticoagulants (NOAC) are considered as the preferred choice of anticoagulants to prevent ischemic stroke in patients with AF. NOACs have comparable good efficacy and better safety with a predictable anticoagulant effect without the routine coagulation monitoring compared to vitamin K dependent oral anticoagulant. However, the proper use of NOACs needs a careful approach to many practical aspects for balancing the preventing thromboembolic events and bleeding risk. Thus, understanding the drug metabolism and indication of NOAC for a specific situation is essential. In this article, we review major clinical trials, the mechanism, and the use of NOACs in the actual clinical setting of managing ischemic stroke patients.

The Effect of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in Patients with Nonvalvular Atrial Fibrillation

Introduction: Rivaroxaban, an oral factor Xa inhibitor, reduces the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) when given in fixed doses without routine coagulation monitoring. An exposure-response analysis was conducted to evaluate the impact of rivaroxaban exposure and clinical risk factors on efficacy and safety outcomes in patients with NVAF to assess whether concentration-based dose adjustment would improve the benefit-risk profile of rivaroxaban in this patient population.Methods: Efficacy/safety outcome data were taken from the rivaroxaban-treated group enrolled in the ROCKET AF trial (NCT00403767) in which 14 264 patients with NVAF were randomized to receive either rivaroxaban 20 mg once daily (15 mg in patients with moderate renal impairment) or dose-adjusted warfarin. Individual rivaroxaban exposure metrics (peak concentration, trough concentration [Ctrough], and daily area under the curve at steady-state) were derived based on an integrated population pharmacokinetic (PK) model (which was previously developed using pooled data from 4918 patients in seven clinical trials across all approved rivaroxaban indications) that incorporated PK-related individual covariates and prothrombin time values measured in a central laboratory. Composite efficacy outcomes were 1) ischemic stroke and non-CNS systemic embolism (ISNSM), and 2) ischemic stroke and non-CNS systemic embolism and death from all causes (ISNSMD). Safety outcomes were 1) major plus non-major clinically relevant (NMCR) bleeding, and 2) major bleeding (MB). Kaplan-Meier analyses stratified by quartiles of exposures were performed with efficacy and safety outcomes. A multivariable Cox model was applied to link individual exposures and clinical risk factors related to efficacy/safety with the time-to-event outcomes.Results: For efficacy outcomes, the event rates were 2.2% and 5.1% (154 and 357 out of 7061 patients) for ISNSM and ISNSMD. Kaplan-Meier analyses showed no apparent trend among the quartiles of exposure metrics and the efficacy event rates. Cox regression analyses revealed no association between exposures and the two efficacy outcomes (e.g., p=0.733 and p=0.82 for the association of Ctrough with ISNSM and ISNSMD, respectively). For safety outcomes, the event rates were 20.7% and 5.6% (1475 and 375 out of 7111 patients) for major plus NMCR bleeding and MB, respectively. Kaplan-Meier analyses showed that cumulative major plus NMCR bleeding and MB event rates increased when rivaroxaban exposure levels increased. Cox regression revealed that the hazard ratio (HR) for these two safety outcomes increased with rivaroxaban exposure. The impact of increasing from the median Ctrough to the 95th percentile was a HR of 1.26 (p=0.00002) for major plus NMCR bleeding (Figure 1) and a HR of 1.25 (p=0.021) for MB (Figure 2). However, as shown in Figures 1 and 2, these HRs appeared to be of lower magnitude when compared with several clinical risk factors (e.g., HR 1.47, p=0.00089 and HR 2.55, p<0.0001 for history of gastrointestinal bleeding vs no history; HR 1.35, p<0.0001 and HR 1.41, p=0.0045 for age > 75 years vs age 65-75 years; HR 1.27, p=0.006 and HR 1.93 p<0.0001 for low baseline hemoglobin values [hemoglobin <13 g/dL for males and <12 g/dL for females] vs normal).Conclusions: The relatively small impact of exposure on the HR for safety outcomes and lack of relationship for efficacy outcomes suggest that for the approved dosing regimen, rivaroxaban exposure is not an important risk factor for the occurrence of either bleeding or ischemic events. Several clinical risk factors are more impactful than rivaroxaban exposure on these efficacy and safety outcomes. Therefore, it is unlikely that concentration-based dose adjustment would further enhance the benefit-risk profile of rivaroxaban in patients with NVAF. [Display omitted] DisclosuresYan:Janssen Research & Development: Employment. Peters:Janssen Research & Development: Employment. Sharma:Janssen Research & Development: Employment. Nandy:Janssen Research & Development: Employment. Nessel:Janssen Research & Development: Employment. Garmann:Bayer AG: Employment. Willmann:Bayer AG: Employment. Hermanowski-Vosatka:Janssen Research & Development: Employment. Solms:Bayer AG: Employment. Berkowitz:Bayer US: Employment. Spiro:Bayer US: Employment. Fox:Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; AstraZeneca: Research Funding. Weitz:Novartis Pharmaceuticals: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Schmidt:Bayer HealthCare Pharmaceuticals: Consultancy. Piccini:GlaxoSmithKlein: Consultancy; Johnson & Johnson: Consultancy; Abbott Medical: Research Funding; Gilead: Research Funding; Spectranetics: Consultancy, Research Funding; Janssen Pharmaceuticals: Research Funding; ARCA biopharma: Research Funding; Boston Scientific: Research Funding; Allergan: Consultancy; Medtronic: Consultancy. Patel:Astra Zeneca: Other: Attended advisory board, Research Funding; Bayer US: Other: Attended advisory board; Janssen Research & Development: Other: Attended advisory board. Becker:IONIS pharmaceuticals: Other: Safety Committee for new compound that lowers LPa; Portola Pharmaceutics: Other: DSMB for clinical trial of anticoagulant reversal compound. Zhang:Janssen Research & Development: Employment.

The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in Patients Treated for Venous Thromboembolism

Introduction: The oral factor Xa inhibitor rivaroxaban has previously demonstrated a predictable pharmacokinetic (PK) and pharmacodynamic profile, and has been developed for fixed dose administration without the need for routine coagulation or therapeutic drug monitoring (TDM). The objectives of this study were to investigate the relationship between rivaroxaban exposure and efficacy/safety outcomes, and to evaluate the relative influence of relevant clinical risk factors in patients receiving rivaroxaban for treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) to assess whether TDM might further improve the benefit-risk profile of rivaroxaban in this population.Methods: An exposure-response analysis was conducted using data from patients receiving rivaroxaban (15 mg twice daily [BID] for 21 days followed by 20 mg once daily [OD] for up to 12 months) in the phase 3 EINSTEIN-DVT (NCT00440193) and EINSTEIN-PE (NCT00439777) trials (BID period, N = 4130; OD period, N = 3953). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the concentration-time curve, maximum concentration [Cmax] and trough concentration [Ctrough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by application of an adjustment function based on a linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in phase 2/3 rivaroxaban studies. Composite efficacy outcomes were: (1) objectively-documented recurrent DVT, or fatal or non-fatal PE; and (2) recurrent DVT, fatal or non-fatal PE, or death from any cause. Safety outcomes were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding. Relationships between exposure/clinical risk factors and outcomes were evaluated using logistic regression for the 21-day BID dosing period and Cox regression for the subsequent OD dosing period.Results: Of the estimated exposure parameters, Ctrough displayed the strongest associations for efficacy and safety during both dosing periods. The first and second composite efficacy outcomes occurred in 1.0% and 1.1% of patients, respectively, in the BID period, and 1.0% and 1.6% of patients, respectively, in the OD period. Individual predicted Ctrough was significantly associated with the first efficacy outcome in both dosing periods (Table 1), and with recurrent DVT, fatal or non-fatal PE, or death from any cause in the BID period only (Figure 1, Table 1). Patients with reduced creatinine clearance (CrCL; < 50 mL/min) were more likely than patients with CrCL > 80 mL/min to develop one of the composite efficacy outcomes during the BID and OD dosing periods (Figure 1, Table 1). Active malignancy at randomization was significant for the second efficacy endpoint in the OD period (hazard ratio 5.31 [95% CI: 2.97-9.51]). Major bleeding and major and NMCR bleeding occurred in 0.4% and 4.3% of patients, respectively, in the BID period and in 0.6% and 6.0% of patients, respectively, in the OD period. None of the investigated exposure metrics was a significant predictor of major bleeding or major and NMCR bleeding in either dosing period. Clinical variables including a history of bleeding, low baseline hemoglobin and non-steroidal anti-inflammatory drug use were, however, significant predictors of bleeding events (Table 2). CrCL was not a significant predictor of bleeding events.Conclusions: Estimated rivaroxaban exposure was significantly associated with efficacy outcomes but not with bleeding outcomes in patients with DVT or PE enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Clinical risk factors had a substantial impact on outcomes. Based on these findings, it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban treatment in patients with venous thromboembolism. [Display omitted] DisclosuresBerkowitz:Bayer US: Employment. Weitz:Daiichi-Sankyo: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria. Schmidt:Bayer HealthCare Pharmaceuticals: Consultancy. Fox:AstraZeneca: Research Funding; Janssen Biotech, Inc.: Consultancy, Honoraria; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria. Garmann:Bayer AG: Employment. Kubitza:Bayer AG: Employment. Mueck:Bayer AG: Employment. Peters:Janssen Research & Development: Employment. Reinecke:Bayer AG: Employment; Bayer AB: Employment. Solms:Bayer AG: Employment. Spiro:Bayer US: Employment. Yan:Janssen Research & Development: Employment. Zhang:Janssen Research & Development: Employment. Willmann:Bayer AG: Employment.

The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in the Prevention of Venous Thromboembolism after Elective Hip or Knee Replacement Surgery

Introduction: The oral factor Xa inhibitor rivaroxaban has previously demonstrated a predictable pharmacokinetic (PK) and pharmacodynamic profile, and has been developed for fixed dose administration without routine coagulation or therapeutic drug monitoring (TDM). The objectives of this study were to investigate the relationship between rivaroxaban exposure and efficacy/safety outcomes, and to evaluate the relative influence of relevant clinical risk factors in patients receiving rivaroxaban for venous thromboembolism prevention (VTE-P) after elective total hip replacement (THR) or total knee replacement (TKR) surgery to assess whether TDM might further improve the benefit-risk profile of rivaroxaban in this population.Methods: An exposure-response analysis was conducted using data from patients receiving rivaroxaban (10 mg once daily [OD] for ≤35 days after THR or ≤14 days after TKR) in the phase 3 REgulation of Coagulation in ORthopedic Surgery to prevent DVT and PE (RECORD) trials (efficacy population, n = 4246; safety population, n = 6097). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the plasma concentration-time curve, maximum concentration and trough concentration [Ctrough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by applying an adjustment function based on the linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in the phase 2/3 rivaroxaban studies. The composite efficacy outcome was total VTE (any objectively-documented asymptomatic or symptomatic deep vein thrombosis [proximal and/or distal], non-fatal pulmonary embolism and death). Safety endpoints were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding occurring (1) ≤3 days after surgery (days 1-4) and (2) >3 days after surgery (after day 4). The relationships between exposure/clinical risk factors and outcomes in terms of event rates were evaluated using logistic regression models.Results: The model-estimated rivaroxaban exposures are summarized in the Table. In the final model, age and creatinine clearance were included as forced variables for all endpoints. Exposure was not found to be a significant predictor of total VTE, major bleeding (days 1-4 and after day 4), or of the composite safety endpoint of major and NMCR bleeding during days 1-4. For major and NMCR bleeding after day 4, a statistically significant exposure-response relationship was observed, with Ctrough displaying the strongest association. The odds ratios (ORs) associated with Ctrough in the 5th and 95th percentiles versus the median were 0.82 (95% confidence interval [CI]: 0.77-0.87) and 1.68 (95% CI: 1.21-2.33), respectively. The relationship was shallow, with a predicted absolute increase in major and NMCR bleeding of ~1% at the 5th percentile of Ctrough to 2% at the 95th percentile (Figure). No clinical risk factors were predictors of total VTE or of major bleeding (days 1-4 and after day 4), or of major and NMCR bleeding after day 4. Male versus female sex (OR: 3.05; 95% CI: 1.92-4.93) and geographical region (OR: 1.63; 95% CI: 0.98-2.70, for the USA/Canada vs Western Europe) were significant predictors (p < 0.00001 and p <0.001, respectively) of major and NMCR bleeding during days 1-4.Conclusions: An exposure-response relationship for total VTE and major bleeding events was not observed in patients enrolled in the RECORD trials despite significant reductions in VTE with rivaroxaban versus the comparator enoxaparin, indicating a favorable benefit-risk ratio over the range of rivaroxaban concentrations observed with the 10 mg OD fixed dose. Exposure, and particularly Ctrough, was the predominant predictor of major and NMCR bleeding after day 4. These data are consistent with rivaroxaban phase 2 VTE-P studies, in which no significant dose-response relationship was observed for total VTE, but post-operative bleeding events increased dose dependently over the ranges of rivaroxaban doses of 5-40 mg OD and 2.5-30 mg twice daily. Based on these findings it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban for VTE prevention after THR and TKR. [Display omitted] DisclosuresBerkowitz:Bayer US: Employment. Fox:Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; AstraZeneca: Research Funding; Janssen Biotech, Inc.: Consultancy, Honoraria. Schmidt:Bayer HealthCare Pharmaceuticals: Consultancy. Weitz:Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria. Garmann:Bayer AG: Employment. Kubitza:Bayer AG: Employment. Mueck:Bayer AG: Employment. Peters:Janssen Research & Development: Employment. Reinecke:Bayer AB: Employment; Bayer AG: Employment. Solms:Bayer AG: Employment. Spiro:Bayer US: Employment. Yan:Janssen Research & Development: Employment. Zhang:Janssen Research & Development: Employment. Willmann:Bayer AG: Employment.

Challenges of treatment adherence with direct oral anticoagulants in pandemic.

Direct oral anticoagulants (DOAC) are crucial for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation. Drug adherence by the patient but also adherence to guidelines by the physician are suboptimal. This review highlights aspects of DOAC treatment during the coronavirus disease 2019 (COVID-19) pandemic and selected challenging scenarios. For patients with a newly diagnosed indication for oral anticoagulation, a new interim clinical guidance recommends starting DOAC instead of vitamin K antagonists if DOAC are not contraindicated. The goal is to reduce the potential exposure of patients to severe acute respiratory syndrome coronavirus during the routine coagulation monitoring visits. As COVID-19 can lead to kidney failure, we discuss the challenges of DOAC dosing in kidney failures. Finally, we discuss two common challenges - when to start a DOAC after an ischemic stroke linked to atrial fibrillation, and whether cerebral microbleeds, including their count, are per se a contraindication to DOAC. There are still open challenges regarding DOAC treatment on the patient and physician side, both related and unrelated to the pandemic.

Abstract 15194: The Distribution of Anti-factor Xa Activity Values, Prothrombin Time and Activated Partial Thromboplastin Time Assessed at Multiple Points in Patients on Edoxaban Therapy

Introduction: Edoxaban is one of the direct oral anticoagulants (DOACs) used for non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Chromogenic anti-factor Xa activity (AXA) is the appropriate assay to measure the pharmacodynamics of a factor Xa inhibitor and to estimate plasma drug concentrations. Although patients taking DOACs do not require routine coagulation monitoring, the distributions of AXA values have not been assessed at multiple points in the previous study. Purpose: To clarify the distribution of AXA values at two-hour intervals in patients taking edoxaban. Methods: Sixteen patients (66.8 ± 9.6 years, 11 males) with NVAF or VTE on edoxaban therapy were enrolled in the study. We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, at two-hour intervals (from immediately before the intake of edoxaban to 8 hours after the intake). The dosage of edoxaban was 30 mg (n=11) once daily (OD) or 60 mg (n=5) OD according to the prescribing information. Results: The distributions of AXA values of 30 mg OD at 0, 2, 4, 6 and 8 hours after the intake of edoxaban were 0.12±0.08, 0.80±0.48, 0.94±0.48, 0.72±0.34 and 0.53±0.32 (IU/mL), respectively. The distributions of AXA values of 60 mg OD at 0, 2, 4, 6 and 8 hours after the intake of edoxaban were 0.17±0.04, 1.59±0.76, 1.43±0.34, 1.29±0.32 and 0.96±0.21 (IU/mL), respectively. Conclusions: Our findings reveal that the peak time of AXA values might be different depending on the dosage. The peak time of 30 mg OD is between 0 to 4 hours, whereas that of 60 mg OD is between 2 to 6 hours after the intake of edoxaban. In addition, the AXA values of 60 mg OD are almost twice as much as that of 30 mg at each point.

A novel whole blood coagulometer for NOAC testing

Abstract Background While use of the non-vitamin K antagonist oral anticoagulants (NOACs) does not currently require routine coagulation monitoring, this can be highly desirable in at-risk patients, including those suffering major trauma or having to undergo emergency surgery, especially when a NOAC reversal agent is used. However, a point-of-care (PoC) device for the rapid measurement of clotting times in patients on NOACs is currently not available. Purpose To characterize the sensitivity of a novel PoC coagulometer to NOAC-induced anticoagulation, as well as quantify instrument precision, via venous whole blood samples freshly spiked with rivaroxaban, apixaban and edoxaban. Methods This study was conducted using healthy volunteers with normal coagulation lab values, including PT/INR and aPTT, confirmed via laboratory testing. Whole blood samples from two volunteers per NOAC were spiked with either 0 (sham), 75, 150, or 300 ng/mL of rivaroxaban, apixaban or edoxaban, in randomized order, each day for five days of testing. Each day, each spiked sample was run on five PoC coagulometers simultaneously for replicate measurement. Results PoC coagulometer clotting times exhibited a high degree of linearity spanning the measuring range, with R2 values approaching 1, and high sensitivity across NOAC concentrations tested (i.e. each concentration was statistically significantly different from the others), as well as a high level of precision across the five days of testing. Furthermore, the PoC coagulometer yielded notably low %CVs at each concentration tested, for each subject and anticoagulant, ranging from approximately 3–7% (Fig. 1, rivaroxaban and apixaban data from individual subjects shown). Conclusions These results suggest that this PoC coagulometer could be a valuable tool to assess the pharmacodynamic effects of the NOACs in emergency and other settings. The PoC coagulometer yields results within minutes at a patient's bedside, requiring only a drop of whole blood. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Perosphere Technologies Inc.

The distribution of anti-factor Xa activity value, PT and APTT at peak and trough times in patients with direct anti-factor Xa inhibitors

Abstract Background Although patients taking direct oral anticoagulants (DOACs) do not require routine coagulation monitoring, the distribution of anti-factor Xa activity (AXA) values, prothrombin time (PT), PT-international normalized ratio (INR) and activated partial thromboplastin time (APTT) in patients on apixaban, edoxaban and rivaroxaban therapy is still not clear. Purpose The aim is to set the standard values of AXA values, PT, PT-INR and APTT in patients using DOACs. Methods We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, PT, PT-INR and APTT at trough and peak times in 224 patients with non-valvular atrial fibrillation and venous thromboembolism, of whom 90 received apixaban, 100 received edoxaban and 34 received rivaroxaban. The peak time was defined as 3 hours after the intake of apixaban or rivaroxaban, and 2 hours after the intake of edoxaban. The trough time was defined as that immediately before the intake. The AXA values, PT, PT-INR and APTT were measured at least 72 hours after the start of treatment. The dosage of DOACs is defined according to the prescribing information in Japan. Results (The order of results below is apixaban, edoxaban and rivaroxaban, respectively.) The average AXA values were 2.29, 0.23 and 0.39 (IU/mL) at trough time, and 3.04, 1.01 and 1.70 (IU/mL) at peak time. The average PT values were 17.9, 12.9 and 13.1 (s) at trough time, and 19.7, 15.5 and 17.5 (s) at peak time. The average PT-INR values were 1.49, 1.07 and 1.08 at trough time, and 1.65, 1.29 and 1.45 at peak time. The average APPT values were 34.5, 31.3 and 32.0 (s) at trough time, and 39.5, 35.9 and 39.8 (s) at peak time. Conclusion Our findings reveal the standard values of AXA, PT, PT-INR and APTT in patients using apixaban, edoxaban and rivaroxaban in each dosage. The DOACs should be changed if the measured value is out of those standard values in 90% confidence interval. Funding Acknowledgement Type of funding source: None

The correlations between anti-factor Xa activity values and PT/APTT at peak and trough times in patients with venous thromboembolism using high dose of apixaban

Abstract Background The high dose (20mg/day) of apixaban is used for the initial treatment of venous thromboembolism for the first week. Although patients taking direct oral anticoagulants do not require routine coagulation monitoring, the correlations between anti-factor Xa activity (AXA) and routine coagulation markers such as prothrombin time (PT) and activated partial thromboplastin time (APTT) at peak and trough times especially when using high dose of apixaban have not been reported so far. Purpose The purpose is to assess the correlations between AXA values and PT/APTT at peak and trough times in patients with venous thromboembolism using high dose of Apixaban. Methods Twenty-six patients (10 male; 71±15 years) with proximal venous thromboembolism or pulmonary embolism using high dose (20mg/day) of apixaban were enrolled. We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, PT and APTT at peak and trough times. The peak time was defined as 3 hours after the intake of apixaban, and the trough time was defined as that immediately before the intake of apixaban. Results A significant and strong positive correlation was observed between AXA and PT at both peak and trough times (R=0.795, p&amp;lt;0.01 and R=0.766, p&amp;lt;0.01, respectively). A significant and moderate positive correlation was observed between AXA and APTT at trough time (R=0.527, p&amp;lt;0.01), but no correlation was observed between AXA and APTT at peak time (R=0.366, p=0.07). Conclusion Our findings reveal the relationship between AXA and PT at peak and trough times has a significant strong correlation. These results suggest measuring of PT may be alternative and effective way of monitoring of AXA values when using high dose of apixaban. Figure 1 Funding Acknowledgement Type of funding source: None

28 Analytical Validation of a Novel Point-of-Care Coagulometer for DOAC and Heparin Testing

While use of the direct oral anticoagulants (DOACs) and low molecular weight heparin do not currently require routine coagulation monitoring, this can be highly desirable in at-risk patients, including those suffering major trauma or requiring emergency surgery. However, a point-of-care (PoC) device for the rapid measurement of clotting times in these patients is currently not available. The current study characterizes the performance of Perosphere Technologies’ PoC Coagulometer to DOAC- and enoxaparin-induced anticoagulation, as well as characterizes instrument precision, via a methods comparison to manual whole blood clotting time (mWBCT). For each study, whole blood samples from healthy volunteers were spiked with either 0 (sham), 30, 75, 150, 300 and 400 (apixaban, edoxaban) or 450 (rivaroxaban) ng/mL of a DOAC, or 0 (sham), 1, 2, 3, 4, and 5 μg/mL for enoxaparin, in randomized order. A single concentration was tested per day, over 6 days, and samples were tested on 5 PoC Coagulometers and by 5 operators performing mWBCT, simultaneously, for comparison. To assess the agreement of PoC Coagulometer and Manual WBCT measurements, the percent rise of clotting time using Manual WBCT was dichotomized as: 1 when %Rise <=10%, and 0 when %Rise >10%. Each of the five PoC Coagulometers used in the study was randomly paired with one of the five operators for Manual WBCT. The ROC analysis was performed for each anticoagulant using percent rise of clotting time from PoC Coagulometer against the binary status categorized by manual WBCT’s percent rise. Across all concentrations, the sensitivity of the PoC Coagulometer was significantly higher when compared to mWBCT, with absolute values of mWBCT measuring roughly twice those of the PoC Coagulometer. A strong linear correlation was observed for these methods, with R2 values of nearly 1. For individual subjects, mean baseline clotting time, and % rise of clotting time relative to baseline at the lowest and highest anticoagulant concentrations tested for each subject, for both Perosphere Technologies’ PoC Coagulometer and Manual WBCT measurements are compared in Figure 1. The sensitivity of the coagulometer proved to be roughly double that of manual WBCT across the range of concentrations tested. Similarly, the correlation coefficient of clotting time between the two methods for individual subjects yielded R >0.98, indicating a strong correlation between the two methods for individual subject for each anticoagulant. For each individual anticoagulant, the AUC of the ROC curve for coagulometer-operator pairs yielded values of 1 or close to 1 (pair 1 data are shown in Figure 1). Similarly, the other four coagulometer-operator pairs also yielded 1 or close-to-1 AUCs for each individual anticoagulant. These results indicated that the anticoagulant drug response determined by PoC WBCT agreed greatly with the anticoagulant drug response determined by manual WBCT. These results suggest that this PoC Coagulometer could be an ideal measure to assess the pharmacodynamic effects of the DOACs, delivering results within minutes, requiring only a drop of fresh whole blood.

Rivaroxaban treatment for young patients with pulmonary embolism (Review).

Pulmonary embolism (PE) is a serious, life-threatening condition that affects young populations (>18 and <50 years old, according to most literature reviews) with improved recognition of its clinical manifestations and the widespread use of sensitive imaging techniques, PE is increasingly diagnosed in younger patients. At present, there is limited understanding of the clinical features and adequate anticoagulant treatment options for this population. Most studies to date have yet to demonstrate significant differences in PE pathophysiology or symptoms between young and elderly patients. Although the overall incidence of PE is lower in young populations compared with elderly patients, important risk factors also apply for young patients. Hereditary thrombophilia is common and is a major cause of PE in younger patients. Immobilization, trauma, obesity, smoking and infection are also becoming increasingly frequent in young patients with PE. Among female patients, oral contraceptive use, pregnancy and postpartum status are predominant risk factors underlying PE. Rivaroxaban is a direct oral anticoagulant with a rapid onset of action that is associated with less drug-drug interactions compared with other therapies. Because the drug is administered at fixed doses with no requirement for routine coagulation monitoring, it is becoming an attractive option for anticoagulation treatment in young patients with PE. Therefore, the present literature review focuses on the clinical characteristics of PE and rivaroxaban therapy in younger patients.

THE DISTRIBUTION OF ANTI-FACTOR XA ACTIVITY VALUES IN PATIENTS ONDIRECT ORAL ANTICOAGULANTS

Although patients taking direct oral anticoagulants (DOACs) do not require routine coagulation monitoring, anti-factor Xa activity (AXA) values in patients on apixaban, edoxaban and rivaroxaban therapy are still not clear. 158 patients taking DOACs (apixaban; N=45, edoxaban; N=87 and rivaroxaban; N

Pharmacokinetic Properties of Rivaroxaban in Healthy Human Subjects.

Direct oral anticoagulants (DOACs) have predictable pharmacokinetics and pharmacodynamics, limited potential for drug to drug interactions, and can be given at fixed doses without the need for routine coagulation monitoring, which makes them a very attractive alternative to vitamin K antagonists. DOACs act by specifically targeting a single coagulation factor, such as Factor Xa or thrombin. Rivaroxaban is a direct Factor Xa inhibitor and has been approved for use in several thromboembolic disorders, such as the prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and the prevention of recurrent deep vein thrombosis and pulmonary embolism in adult patients. This review aimed to provide an overview of the mechanism of action of rivaroxaban and outline its pharmacokinetic properties (absorption, distribution, metabolism, and excretion) in healthy adult subjects.

Validation of apixaban anti-factor Xa assay and impact of body weight

BackgroundDirect oral anticoagulants (DOACs) are widely used as therapies for venous thromboembolism and other cardiovascular diseases. However, routine coagulation monitoring is not required, but may be clinically indicated in high risk populations including obese patients. ObjectivesThe aims of this study were two fold; to validate a chromogenic assay for anti-factor Xa measurement in patients taking apixaban, and correlate it with PT/INR and PTT, and to measure anti-factor Xa levels in patients who weighed >120 kg. Patients/methodsPatients who were taking apixaban had 3 blood samples drawn over a 4 h period. Apixaban levels were determined using an anti-factor Xa activity assay (STA-Liquid Anti-Xa) using STA-Apixaban Calibrator and STA-Apixaban Controls. The PT/INR was determined using standard methodology. Apix MS, using manufacturer provided apixaban standard, was performed on plasma. Results and conclusions18 normal weight patients, 39 obese patients and 14 controls were enrolled. There was a strong correlation between apixaban anti-factor Xa activity compared to plasma Apix MS (r = 0.95). In patients >120 kg, there was a statistically significant decreased rate of change in anti-factor Xa levels after ingestion. Further, the area under the curve for apixaban anti-factor Xa levels was significantly lower in patients over 120 kg. While INR correlated with apixaban MS and apixaban anti-factor Xa activity in both normal weight and obese patients, the association was not sufficiently strong to clinically manage patients, normal weight or obese. Given these findings, research is necessary to investigate the clinical utility of apixaban anti-factor Xa activity measurement in selected populations.

Long-Term Management of Venous Thromboembolism: Lessons from EINSTEIN CHOICE and Other Extension Trials.

Many patients with venous thromboembolism (VTE) are at risk of recurrence if anticoagulant therapy is stopped. Whereas 3 months of anticoagulation treatment is sufficient for patients with VTE provoked by major surgery or trauma, in many cases a longer course is needed. Extended therapy with vitamin K antagonists (VKAs) requires frequent coagulation monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range; furthermore, there is a risk of major bleeding even if a therapeutic INR is maintained. Therefore, more convenient and safer anticoagulants are needed.The non-VKA oral anticoagulants (NOACs)-apixaban, dabigatran, edoxaban and rivaroxaban-simplify extended therapy because they can be given in fixed doses without routine coagulation monitoring. Randomized clinical trials have demonstrated the efficacy and safety of NOACs for extended VTE treatment, but bleeding remains a concern. Patients and physicians may, therefore, be reluctant to continue anticoagulation beyond 3 to 6 months except in patients at high risk of recurrence. Acetylsalicylic acid (ASA) is often prescribed instead of an anticoagulant because of its perceived lower risk of bleeding; however, the recent EINSTEIN CHOICE trial demonstrated that once-daily rivaroxaban at a dose of either 20 or 10 mg reduced the risk of recurrent VTE by 70% compared with ASA without significantly increasing the risk of bleeding. In this review, we discuss the EINSTEIN CHOICE trial in the context of previous trials for extended VTE treatment and examine some of the lessons that can be applied to clinical practice.

Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants.

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

The Non-Vitamin K Antagonist Oral Anticoagulants in Heart Disease: Section V-Special Situations.

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.