Monitoring Of Direct Oral Anticoagulants Research Articles

Анти-Ха активность у пациентов с неклапанной фибрилляцией предсердий на фоне приема апиксабана и ривароксабана

Direct oral anticoagulants (DOAC) are widely used for prevention of stroke in patients with atrial fibrillation. The need for therapeutic drug monitoring of DOACs remains unclear. Measurement of anti-Xa activity that directly correlates with serum drug concentration seems to be a promising approach for monitoring of Xa inhibitors.

Challenges to Laboratory Monitoring of Direct Oral Anticoagulants.

Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels-in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups.

Usefullness of Heparin Calibrated Anti-Xa Activity to Assess Anticoagulant Activity of Apixaban and Rivaroxaban in Emergency Patients Scheduled for Acute Interventions.

(1) Background: Direct oral anticoagulants (DOACs) require monitoring in some critical clinical situations. The specific tests for DOAC monitoring are not yet available in all labs. The aim of this study was to evaluate if a unique, more widespread heparin-calibrated anti-Xa assay could be suitable to estimate the concentrations of apixaban and rivaroxaban in order to establish an algorithm helping our clinicians in their therapeutic decision for patients treated with DOACs in emergencies. (2) Methods: A first retrospective part allowed us to determine of a conversion factor between the measured DOAC concentration and the deducted anti-Xa heparin activity based on optic density. During the second prospective part, both DOAC concentration (ng/mL) and anti-Xa activity heparin (UI/mL) were measured on the same sample, and the previously determined conversion factor was applied to each UI/mL value. We then compared the calculated and measured DOAC concentration values. (3) Results: The analysis of the derivation cohort confirmed a good correlation, especially between the anti-Xa heparin activity and the apixaban concentrations (r = 0.97). Additionally, we determined heparin-calibrated anti-Xa assay cut-offs for invasive procedures at 0.3 UI/mL and for intravenous thrombolysis at 0.51 UI/mL using ROC curves with a sensitivity at 98% and specificity at 95% for 0.3 UI/mL and a sensitivity at 97.7% and specificity at 88.2% for the cut-off of 0.51 UI/mL. In the validation cohort, we confirmed the agreement between measured and calculated DOAC concentrations for the low values, especially around cut-offs with an excellent negative predictive value for 0.51 UI/mL (94% for apixaban and 100% for rivaroxaban) and a good negative predictive value for 0.3 UI/mL (83.3% for apixaban and 85.7% for rivaroxaban). (4) Conclusions: Our results confirm that it is possible to correctly predict or exclude the presence of apixaban/rivaroxaban in emergency situations when specific tests are not readily available.

Therapeutic Drug Monitoring of Direct Oral Anticoagulants in Patients with Extremely Low and High Body Weight-Pilot Study.

Phase III clinical trials for individual direct oral anticoagulants (DOACs) contained a limited representation of subjects with abnormal body weight, which were mostly limited to a BMI > 40 kg/m2, or body weight > 120 kg for obese subjects, and <50 kg for underweight subjects. Although low or high body weight is not a contraindication to DOACs therapy, it can significantly affect the safety and effectiveness of treatment. Due to the limited amount of clinical data on the use of DOACs in extremely abnormal weight ranges, optimal pharmacotherapy in this group of patients is a matter of controversy. The objective of this study was to evaluate the pharmacokinetics of DOAC properties in patients with abnormal body weight beyond the established cut-off points in the phase III studies for rivaroxaban, apixaban, and dabigatran. In total, 38 patients took DOACs for at least 12 months for non-valvular atrial fibrillation in 2019-2021. Blood samples were collected before the planned intake of the drug and 4 h after its administration. The determined concentrations of DOACs were statistically analyzed in relation to body weight, age, and eGFR (estimated Glomerular Filtration Rate). Among subjects taking apixaban, rivaroxaban, and dabigatran, the smallest representation of patients who achieved therapeutic concentrations were those treated with dabigatran. The population of people with abnormal body weight is a potential risk group of patients, in which some of them do not reach the therapeutic range of DOACs.

Direct oral anticoagulant (DOAC) monitoring within primary care: a quality improvement project

BackgroundPoor monitoring of anticoagulants is a significant area of patient safety. It can lead to the dichotomous risk of haemorrhage/clotting without appropriate counselling and monitoring. While healthcare professionals may be...

A high-throughput LC-MS/MS method for simultaneous determination of direct oral anticoagulants in human plasma.

Direct oral anticoagulants are widely used in many indications to prevent thromboembolic events. Routine therapeutic monitoring is not required; however, there is increasing evidence suggesting the benefit of plasma level measurement in some situations. In addition, laboratory monitoring might help improve patient and drug non-compliance and thus individualize therapy. In the present study, we developed a sensitive and high throughput ultra-high-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma. A one-step extraction procedure in 96-well formate for phospholipid and protein removal was used for sample pre-treatment, and analytes were separated using gradient elution over 4.2 min. Analytes were detected on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode. The method was validated according to the European Medicine Agency guideline for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effects, extraction recovery, carryover, dilution integrity and stability over a concentration range of 3.0-1000 ng/mL for all analytes. The validated method was applied to real clinical samples of patients treated with one of the drugs. Therefore, we can conclude that our method is suitable for therapeutic drug monitoring of direct oral anticoagulants. This article is protected by copyright. All rights reserved.

To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical Practice.

The need for therapeutic drug monitoring of direct oral anticoagulants (DOACs) remains an area of clinical equipoise. Although routine monitoring may be unnecessary given predictable pharmacokinetics in most patients, there may be altered pharmacokinetics in those with end organ dysfunction, such as those with renal impairment, or with concomitant interacting medications, at extremes of body weight or age, or in those with thromboembolic events in atypical locations. We aimed to assess real-world practices in situations in which DOAC drug-level monitoring was used at a large academic medical center. A retrospective review of the records of patients who had a DOAC drug-specific activity level checked from 2016 to 2019 was included. A total of 119 patients had 144 DOAC measurements (apixaban (n = 62) and rivaroxaban (n = 57)). Drug-specific calibrated DOAC levels were within an expected therapeutic range for 110 levels(76%), with 21 levels (15%) above the expected range and 13 levels (9%) below the expected range. The DOAC levels were checked in the setting of an urgent or emergent procedure in 28 patients (24%), followed by renal failure in 17 patients (14%), a bleeding event in 11 patients (9%), concern for recurrent thromboembolism in 10 patients (8%), thrombophilia in 9 patients (8%), a history of recurrent thromboembolism in 6 patients (5%), extremes of body weight in 7 patients (5%), and unknown reasons in 7 patients (5%). Clinical decision making was infrequently affected by the DOAC monitoring. Therapeutic drug monitoring with DOACs may help predict bleeding events in elderly patients, those with impaired renal function, and in the event of an emergent or urgent procedure. Future studies are needed to target the select patient-specific scenarios where monitoring DOAC levels may impact clinical outcomes.

Monitoring of Anticoagulant Activity of Dabigatran and Rivaroxaban in the Presence of Heparins.

The routine monitoring of direct oral anticoagulants (DOACs) may be considered in patients with renal impairment, patients who are heavily obese, or patients requiring elective surgery. Using the heparin-binding copolymer (HBC) and polybrene, we aimed to develop a solution for monitoring the anticoagulant activity of DOACs in human plasma in the interfering presence of unfractionated heparin (UFH) and enoxaparin. The thrombin time (TT) and anti-factor Xa activity were monitored in pooled plasma from healthy volunteers. In these tests, plasma with dabigatran or rivaroxaban was mixed with UFH or enoxaparin and then incubated with HBC or polybrene, respectively. HBC and polybrene neutralized heparins and enabled monitoring of anticoagulant activity of dabigatran in the TT test. Both agents allowed for accurate measurement of anti-factor Xa activity in the plasma containing rivaroxaban and heparins in the concentration range reached in patients’ blood. Here, we present diagnostic tools that may improve the control of anticoagulation by eliminating the contamination of blood samples with heparins and enabling the monitoring of DOACs’ activity.

Pharmacist monitoring of direct oral anticoagulants for American Indians and Alaska Natives in the outpatient setting

BackgroundDirect oral anticoagulants (DOACs) call into question the role of traditional pharmacist-run clinics, and few studies have described the incorporation of DOAC’s into traditional anticoagulation management services (AMS) ObjectiveTo describe the incorporation of DOACs into a pharmacist-run AMS for American Indian and Alaska Native (AI/AN) patients and determine outcomes related to adherence, follow-up, and pharmacist interventions. Practice descriptionTraditional AMS embedded in ambulatory clinic. Warfarin managed by pharmacists under a collaborative practice agreement with supervising physician. Practice innovationDOACs incorporated into AMS by transitioning warfarin patients to rivaroxaban and apixaban and managing new patients with DOAC. Follow-up occurred via phone call and at longer intervals. Evaluation methodsSingle-center, retrospective, observational analysis of AI/AN patients who were followed up by pharmacy AMS. The outcomes measured include adherence to DOAC therapy, number of telephonic encounters versus face-to-face visits, frequency of follow-up, types of interventions made at each visit, and an estimate of face-to-face clinic time savings. ResultsA total of 50 patients were included for analysis. The average medication possession ratio was 91%. The majority of visits occurred over the phone (59%), and most follow-up visits occurred every 3 months (62%). The top 3 most frequent interventions were adherence education, initial DOAC education, and education on use of nonsteroidal anti-inflammatory drugs. Practice implicationsTraditional AMS can evolve by incorporating DOACs and maintaining follow-up. ConclusionPharmacist monitoring of DOACs may promote high levels of adherence and lead to time savings by reducing the amount of time spent in traditional AMS.

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

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

Automated Thrombin Generation Assay for Rivaroxaban, Apixaban, and Edoxaban Measurements.

Background: The thrombin generation assay (TG) is a promising approach to measure the degree of anticoagulation in patients treated with direct oral anticoagulants (DOAC). A strong association with plasma drug concentrations would be a meaningful argument for the potential use to monitor DOAC.Objectives: We aimed to study the correlation of TG with rivaroxaban, apixaban, and edoxaban drug concentrations in a large, prospective multicenter cross-sectional study.Methods: Five-hundred and fifty-nine patients were included in nine tertiary hospitals. The Technothrombin® TG was conducted in addition to an anti-Xa assay; LC-MS/MS was performed as the reference standard.Results: Correlation (rs) between thrombin generation measurements and drug concentrations was −0.72 for peak thrombin generation (95% confidence interval, CI, −0.77, −0.66), −0.55 for area under the curve (AUC; 95% CI −0.61, −0.48), and 0.80 for lag time (95% CI 0.75, 0.84). In contrast, rs was 0.96 with results of the anti-Xa activity (95% CI 0.95–0.97). Sensitivity with regard to the clinically relevant cut-off value of 50 μgL−1 was 49% in case of peak thrombin generation (95% CI, 44, 55), 29% in case of AUC (95% CI, 24, 34), and 64% in case of lag time (95% CI, 58, 69). Sensitivity of the anti-Xa assay was 95% (95% CI, 92, 97).Conclusions: The correlation of thrombin generation measurements with DOAC drug concentrations was weak, and clinically relevant drug levels were not predicted correctly. Our results do not support an application of TG in the monitoring of DOAC.

Therapeutic monitoring of direct oral anticoagulants — an 8-year observational study

Introduction: For years, anticoagulants have been the basic group of drugs that slow down, inhibit or prevent blood clotting by inhibiting thrombin formation or reducing its activity. Treatment with DOACs does not require routine anticoagulation monitoring due to their wide therapeutic index. However, there are circumstances where it may be necessary to know the drug levels to manage the risk of side effects or to confirm laboratory efficacy. In such a situation, an indication for DOAC laboratory testing could be the suspicion of excessively high or low DOAC levels. The aim of this article was to determine trends in concentrations of DOACs in a real life population of patients. Material and methods: Consultations in clinical pharmacology extended with DOAC level assessments were performer in the Department of Cardiology and Clinical Pharmacology. The trial was designed as a retrospective analysis of laboratory analyses and included 480 laboratory tests performed in 236 patients. Results: Mean CHA 2 DS 2- VASc scoring 3.91 ±1.92 and HAS-BLED scoring 3.57 ±1.75 indicated high risks of both thrombosis and bleeding. Geometric mean of trough concentrations for dabigatran, rivaroxaban and apixaban were 91.53 ng/mL, 62.74 ng/mL and 124.81 ng/mL, whereas peak concentrations for all DOACs were significantly higher, at 220.80 ng/mL ( p &lt; 0.0001), 116.59 ng/mL ( p &lt; 0.0001) and 186.18 ng/mL ( p =0.0354), respectively. Values for males and females did not differ significantly. Dose adjustment, performed according to rules described for every drug in registered drug characteristics, did not change significantly concentrations. Trough concentrations higher than 20 ng/mL were found at the 10 th percentile for all DOACs, but higher at 40 ng/mL at the 5 th percentile was found only for apixaban. Peak concentration lower than 400 ng/mL were for the 95 th percentile for apixaban and for the 90 th percentile for dabigatran and rivaroxaban. Conclusion: Monitoring-based pharmacotherapy with DOACs should be restricted only to specific clinical settings; in the general population, it is not necessary. Recently, in many experienced centers, therapeutic drug monitoring of DOACs has gained great importance in selected clinical settings and it very likely will soon become commonplace in clinical practice.

Assessment of a Pharmacist-Led Direct Oral Anticoagulant Monitoring Clinic

Direct oral anticoagulants (DOACs) are recommended as first-line therapy for treatment and prevention of venous thromboembolism (VTE) and prevention of stroke related to nonvalvular atrial fibrillation. Recent publications have suggested incorporating DOAC monitoring into anticoagulant management clinics. The Eastern Health Adult Outpatient Thrombosis Service (Newfoundland and Labrador) includes a pharmacist-led DOAC monitoring clinic that uses standardized evidence-based care processes. To describe a new pharmacist-led DOAC monitoring clinic and to assess patients' adherence to medication therapy, adherence to guideline-recommended frequencies for blood work, and adverse and non-adverse events. This retrospective chart review involved patients who attended their first visit to the DOAC clinic between October 10, 2017, and May 31, 2018. Patients were followed until November 30, 2018. Data were abstracted from electronic hospital records and the provincial pharmacy network. Descriptive statistics were used to analyze the data: categorical variables were presented as frequencies and percentages; continuous variables were analyzed and presented as means with standard deviations and, where applicable, as medians with interquartile ranges. Forty-seven patients, who attended a total of 74 clinic visits, were included. Twenty-eight patients (60%) were adherent to their DOAC therapy. All patients had blood work completed before each clinic appointment. The mean time between the first and second sets of blood tests was 6.2 (standard deviation [SD] 1.4) months and between the second and third sets of blood tests was 5.1 (SD 1.0) months. There were no episodes of VTE or major bleeding. There was 1 cerebrovascular accident (3.2 events per 100 person-years, 95% confidence interval [CI] 0.2-15.7) and 5 episodes of clinically relevant non-major bleeding (12.8 events per 100 person-years, 95% CI 4.1-30.1). Pharmacists identified 51 issues at the clinic appointments, of which 48 were medication-related. Referral to the Thrombosis Service physician was required to resolve 8 (16%) of the issues identified. A brief discussion between the Thrombosis Service physician and pharmacist was required to resolve 30 (59%) of the issues, with 13 (25%) resolved by the pharmacist alone. This study described the implementation and outcomes of a novel pharmacist-led DOAC clinic. Clinic patients underwent blood work at recommended intervals and received guidance on adherence and adverse events; as such, patients had follow-up that aligned with guideline recommendations.

Switching from vitamin K antagonists to direct oral anticoagulants: Treatment satisfaction and patient concerns

BackgroundSince direct oral anticoagulants (DOACs) have been introduced for treatment and prevention of thromboembolic diseases, patients on vitamin K antagonists (VKA) have to decide whether to remain on VKA or switch to DOAC. The goal of this study was to evaluate treatment satisfaction, preferences, and concerns among those who already have switched from VKA to DOAC. MethodsA questionnaire was sent to 2920 former patients of three anticoagulation clinics in the Netherlands, who switched from VKA to DOAC (2016‐2017). Questions concerned demographics, treatment satisfaction, concerns, perspectives on antidotes, and monitoring. To identify predictors for being concerned about adverse events, logistic regression was used to estimate crude‐ and adjusted (age and sex) odds ratios (OR) and 95% confidence intervals (95% CI). ResultsOne thousand, three hundred ninety‐nine questionnaires (response rate 48%) were used for analysis. DOAC treatment satisfaction was high (mean 8.8 of a maximum 10‐point score). A quarter of patients expressed concerns about adverse events. Predictors for being concerned were age < 60 years (vs age > 75 years, OR 4.1, 95% CI 2.6‐6.4), female sex (OR 1.3, 95% CI 1.0‐1.6), and high education (OR 1.6, 95% CI 1.2‐2.2). Fifty‐nine percent of all patients indicated antidote availability as important, 73% would be willing to participate in DOAC monitoring. ConclusionsDOAC treatment satisfaction was high. A substantial number of patients expressed concerns about adverse events, especially women, patients aged < 60 years, or highly educated patients. Our findings among patients who already had switched to DOAC may assist in the process of shared decision‐making when switching a patient from VKA to DOAC is considered.

Does One Dose Really Fit All? On the Monitoring of Direct Oral Anticoagulants: A Review of the Literature.

There is an increasing amount of literature on direct oral anticoagulant (DOAC) laboratory monitoring. The aims of the present review were to evaluate published data on monitoring DOACs, to provide clinical guidance on how to interpret results, and to summarize why, when, and how to monitor DOACs. The publications screened for this review were obtained through a PubMed search for articles published in English or French before April 2019 that had the following as their main themes: DOAC monitoring, DOAC exposure-effect relationship, DOAC drug interactions, and pharmacokinetics and pharmacodynamics of DOACs. DOACs show important inter- and intrapersonal concentration variability and a significant exposure-effect relationship. Concentrations out of the expected range have been shown to lead to an increased adverse event rate and a lower efficacy. No definitive therapeutic range exists for DOACs except for dabigatran for which trough levels of 40 to 200 ng/mL seem to be the consensus. Indications to monitor include suspected drug accumulation in special patient populations, suspected drug failure, and acute situations such as hemorrhagic or thrombotic events. There is a likely benefit to monitor DOACs in order to improve their safety and efficacy but randomized controlled trials are required to determine the therapeutic range of these drugs and evaluate whether DOAC monitoring can improve outcomes in a clinical setting.

The role of clinical pharmacy anticoagulation services in direct oral anticoagulant monitoring

The role of dedicated anticoagulation management services (AMS) for patients receiving direct oral anticoagulant (DOAC) therapy is unclear. The objective of our study was to describe DOAC management in patients who were and were not managed by an AMS. We conducted a retrospective cohort study among patients with atrial fibrillation at the University of Utah Health (UUH) who received DOAC therapy between January 2013 and June 2016. Patients in the AMS group were managed by a pharmacist-led AMS whereas those in the non-AMS group were managed by other providers. The number and type of provider encounters and interventions related to DOAC therapy and a composite endpoint of thromboembolism, bleeding, and all-cause mortality were recorded. Overall, 90 and 370 patients were managed in the AMS and non-AMS groups, respectively. AMS group patients had greater chronic disease burden as measured by the Charlson comorbidity index. AMS group patients had more frequent DOAC-related encounters than non-AMS group patients but both groups had similar DOAC therapy intervention rates. Over half of patients in the AMS group received potentially duplicative interventions from their regular clinicians. The composite endpoint occurred in 18.9% and 13.5% of AMS and non-AMS group patients, respectively (p = 0.29). Patients managed by AMS providers were more complex and had more frequent encounters regarding their DOAC therapy than those managed by non-AMS providers. However, there was evidence of duplicative DOAC therapy management efforts. No difference between AMS and non-AMS groups in the composite clinical endpoint was detected.

Perioperative management of patients with atrial fibrillation receiving anticoagulant therapy.

The number of patients with atrial fibrillation (AF) and the number of patients indicated for anticoagulant therapy have been increasing because AF would affect patient survival due to thromboembolism. Once AF develops, following the disappearance of pulsation, the circumstances within the atrium become prothrombotic and thrombus formation within the left atrium occurs in patients with AF. In recent years, not only warfarin but also new oral anticoagulants were introduced clinically and have become used as oral anticoagulants. In the perioperative period, the risk of major hemorrhage needs to be reduced. On the other hand, the suspension of anticoagulant therapy and neutralization of anticoagulant effects elevate the risk of thrombosis. The perioperative management of patients receiving anticoagulant therapy is different from that of scheduled surgery and emergency surgery. In addition, knowledge of the characteristics of each oral anticoagulant is required at drug cessation and resumption. Unlike warfarin, which has been used in the past five decades, direct oral anticoagulants (DOACs) do not have sensitive indicators such as prothrombin time-international normalized ratio. To avoid major hemorrhages and thromboembolism, quantitative assays can be implemented for DOAC monitoring and for reversal therapies in perioperative settings.

The acceptability of a direct oral anticoagulant monitoring regimen among patients with atrial fibrillation: a pilot study.

Background The direct oral anticoagulants (DOACs) offer several advantages over warfarin in the management atrial fibrillation, including the provision of fixed dosing without a requirement for regular monitoring. Recently however the subject of DOAC monitoring has been probed after several post-hoc analyses demonstrated an association between plasma levels and efficacy and safety events. Objective The aim of this pilot study was to explore the acceptability of DOAC plasma monitoring amongst patients with atrial fibrillation and the factors that may influence these attitudes. Method A simple DOAC monitoring schedule based on the dabigatran pharmacokinetic profile was developed. A cross-sectional survey was distributed to patients with atrial fibrillation asking them to indicate their likelihood of taking a particular DOAC subjected to plasma monitoring. Results Thirty patients participated in the study. Most patients (63.3%) favoured taking a DOAC subjected to monitoring under the proposed schedule, citing increased efficacy and reduced toxicity as the reasons for their response. Conclusion There is some suggestion that atrial fibrillation patients may in fact favour taking a DOAC subjected to infrequent monitoring if this enhanced safety and efficacy.

Impact of a Direct Oral Anticoagulant Population Management Tool on Anticoagulation Therapy Monitoring in Clinical Practice.

Background: The optimal monitoring and follow-up strategy for long-term direct oral anticoagulant (DOAC) therapy has not been established. Historically, at our medical center, DOAC patients were referred to a clinical pharmacy specialist managed anticoagulation clinic (AC) for monitoring via regularly scheduled encounters (face-to-face or telephone). Objective: To determine if implementation of a DOAC Population Management Tool (PMT) designed to identify patients who most likely require clinical review and possibly intervention, would improve the efficacy (interventions per patient) and efficiency (time invested to generate an intervention) of monitoring over AC practices. Methods: The DOAC PMT group included patients flagged as potentially having a dosing issue or history of valve replacement. The AC group included patients who were scheduled for routine DOAC follow-up. The quantity and character of interventions made were prospectively recorded and compared. Results: A total of 399 patients were included. Data were collected for 131 patients identified by the DOAC PMT, resulting in a review of 170 flags with a total of 94 interventions or 0.55 interventions per flag reviewed. For the AC group, 268 patients were evaluated, leading to 53 interventions or 0.20 interventions per patient encounter (P < 0.001 for comparison). The time to generate an intervention was 16 minutes in the DOAC PMT versus 64 minutes for the AC group. Conclusion and Relevance: A population-based approach to DOAC monitoring represents a more effective and efficient strategy to reduce missed opportunities for interventions between follow-up appointments while also increasing clinic access, particularly for patients who require immediate attention.

Dried-Blood-Spot Technique to Monitor Direct Oral Anticoagulants: Clinical Validation of a UPLC-MS/MS-Based Assay.

Plasma concentrations of direct oral anticoagulants (DOACs) vary largely between individuals, and they correlate well with desired and adverse outcomes. Although regular concentration monitoring of DOACs is not recommended, information on DOAC exposure could be useful in situations when multiple DOAC-clearance pathways are impaired or nonadherence is suspected. Self-sampling techniques, like the use of dried-blood spots (DBSs), would be particularly useful because they enable the collection of information in ambulatory patients at relevant points in time of the dosing interval (e.g., trough). We developed and validated a DBS-based assay to quantify all currently marketed DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in a single ultraperformance-liquid-chromatography-tandem-mass-spectrometry assay. It fulfilled all validation standards within a hematocrit range of 0.33-0.65 and was linear over the calibration ranges of 2.5-750 ng/mL (apixaban and rivaroxaban), 4.4-750 ng/mL (dabigatran), and 9.3-750 ng/mL (edoxaban). Only minor ion suppression (matrix effect ≤13%) was present, inter- and intra-assay precision was ≤13%, and inter- and intra-assay accuracies ranged between 88 and 110%. All DOACs were stable in DBSs up to 52 days at room temperature, if the DBSs were protected from light and humidity. The correlation between (whole blood) DBS and plasma concentrations was assessed in 33 patients under regular DOAC therapy. Deming-regression coefficients between simultaneously collected capillary DBSs and plasma samples were used to predict plasma concentrations from DBSs. Bland-Altman plots revealed a strong agreement between predicted and observed plasma concentrations, thus confirming the suitability of DBSs for DOAC monitoring as an important step toward the important aim of self-sampling at home.