Direct Oral Anticoagulants Dosing Research Articles

Intravenous Thrombolysis in Patients Taking Direct Oral Anticoagulation Treatment Before Stroke Onset: Results from the Safe Implementations of Treatments in Stroke International Stroke Registry.

Intravenous thrombolysis (IVT) is contraindicated for acute ischemic stroke (AIS) patients taking direct oral anticoagulants (DOACs) within 48 hours before index stroke. Limited data exist on off-label use of IVT for these patients. We compared the safety and outcomes of IVT in AIS patients with DOAC treatment and patients with no OAC before index stroke. We analyzed data from the Safe Implementations of Treatments in Stroke (SITS) International Stroke Thrombolysis Registry during 2013-2024. Outcomes were symptomatic intracerebral hemorrhage (SICH) by the SITS Monitoring Study and European Cooperative Acute Stroke Study II definitions, functional independency (modified Rankin Scale score 0-2), and death by 3 months. Propensity score matching with a nearest neighbor matching algorithm with a ratio of 1:2 was used for relevant clinical variables. We also analyzed the time from last DOAC dose to IVT treatment. A total of 1,311 DOAC and 129,384 no OAC patients were included. We matched 894 patients with DOAC to 1,788 with no OAC. The mean age was 75 years versus 76 years, and the median National Institutes of Health Stroke Scale score 11 versus 12, respectively. Patients with DOAC had a similar proportion of outcomes compared with patients with no OAC: SICH per SITS Monitoring Study (1.1 vs 1.5%, p = 0.50), SICH per European Cooperative Acute Stroke Study II (4.0 vs 4.3%, p = 0.82), any parenchymal hematoma (6.3 vs 7.8, p = 0.22), and functional independency (47.9 vs 46.4%, p = 0.59) and death (25.1 vs 24.0%, p = 0.65) at 3-month follow-up. The time from last DOAC dose to IVT did not affect outcomes. In this observational study, we did not find any difference in outcomes after IVT therapy in AIS patients with DOAC compared with no OAC treatment before index stroke. ANN NEUROL 2025.

Clinical impact of inappropriate DOAC dosing in atrial fibrillation: Insights from a real-world registry.

A significant number of patients with atrial fibrillation (AF) on direct oral anticoagulants (DOACs) receives off-label or inappropriate doses. This study examines the prevalence, dosages, and clinical outcomes in AF-patients on DOAC therapy admitted to an emergency department (ED). This retrospective single-center observational study utilized data from the Heidelberg Registry of Atrial Fibrillation (HERA-FIB), consecutively including patients with AF presenting to the ED of the University Hospital of Heidelberg from June 2009 to March 2020. Rates of DOAC dosages at discharge from the ED were correlated with outcomes, focusing on a composite endpoint that included all-cause mortality, stroke, major bleeding, and myocardial infarction (MI). Among 10,222 patients included in the HERA-FIB registry, 4,239 (41.5%) were prescribed DOACs, and 3,031were eligible for the analysis. Of these, 2,199 (72.6%) received appropriate dosages, 627 (20.7%) were under-dosed, and 205 (6.8%) were over-dosed. Under-dosed AF-patients demonstrated a significantly increased risk of the composite endpoint compared to those receiving appropriate dosages (HR 1.84, 95%CI:1.55-2.18, p<0.0001). Over-dosage had no significant effect on the HR for the composite endpoint, all-cause mortality, stroke, MI, or major bleeding compared to correct dosing but was associated with higher risks of the composite endpoint (HR 1.43, 95%CI:1.04-1.96, p=0.029) relative to under-dosage. This study underscores the critical importance of accurate DOAC dosing in patients with AF presenting to an ED. Both under-dosing and over-dosing are linked to significant clinical risks, highlighting the urgent need for improved dosing protocols and careful monitoring to enhance patient outcomes.

Impact of Underdosing of Direct Oral Anticoagulants on Clinical Outcomes in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

Underdoses of direct oral anticoagulants (DOAC) are sometimes prescribed due to bleeding risk concerns in patients with atrial fibrillation (AF). We investigated the prevalence of DOAC underdosing and its impact on clinical outcomes in AF patients undergoing percutaneous coronary intervention (PCI). This multicenter observational cohort study enrolled patients with AF on DOAC undergoing PCI between January 2015 and March 2021 at 15 institutions across Japan. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE), all-cause mortality, ischemic stroke, and major bleeding events, were evaluated. Of 623 patients enrolled, 167 (26.8%) received underdoses, 224 (36.0%) received appropriate low doses, 210 (33.7%) received appropriate standard doses, and 22 (3.5%) received overdoses. Clinical outcomes were compared between patients with underdoses (n=167) and appropriate doses (n=434). Although the incidence of MACE, all-cause mortality, and major bleeding events did not differ significantly between the 2 groups (log-rank P=0.850, P=0.163, and P=0.711, respectively), ischemic stroke occurred more frequently in the underdose than appropriate-dose group (log-rank P=0.011). After propensity score matching, the same result was observed for the frequency of ischemic stroke (log-rank P=0.026). Compared with appropriate doses of DOAC, DOAC underdosing was associated with a higher incidence of ischemic stroke, despite no significant difference in MACE, all-cause mortality, and major bleeding events in AF patients undergoing PCI.

For Atrial Fibrillation, DOACs Outperform Warfarin in Patients with Reduced Kidney Function.

At standard doses, direct oral anticoagulants (DOACs) were associated with a reduced risk of systemic embolism and intracranial hemorrhage (ICH) when compared with warfarin, with a greater derived benefit at lower creatinine clearance (CrCl-down to 25 mL/min). Lower doses of DOACs were associated with increased overall mortality without a significant decrease in ICH and incident bleeding when compared with standard dose DOACs and warfarin, across all CrCl down to 25 mL/min.1.

Current Real-World Status of Off-Label Under- and Over-Dose of Direct Oral Anticoagulants After Atrial Fibrillation Ablation.

Off-label under- and overdosing of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is not uncommon in real-world practice. This study aimed to identify efficacy and safety of off-label DOACs dose after AF ablation. The RYOUMA registry was a prospective multicenter study of Japanese patients who underwent AF ablation between 2017 and 2018. DOAC prescriptions were categorized into on-label standard dose, on-label reduced dose, off-label underdose, and off-label overdose. The proportion of off-label doses among patients after AF ablation varied depending on the type of DOAC, ranging from 13.5% to 34.9%. Of 2821 patients, 366 (13.0%) were prescribed an off-label underdose and exhibited significantly higher CHADS2, CHA2DS2-VASc, CHA2DS2-VA, HELT-E2S2, and HAS-BLED scores, age, concomitant use of antiplatelets, and lower weight when compared to the on-label standard dose (n = 1809). While the incidence of ischemic stroke after 1 year of off-label underdose was notably low (0.28%), the rate of major bleeding was relatively high (1.7%). Off-label overdose was prescribed to 134 patients (4.8%), who showed a significantly higher incidence of major bleeding (3.0%) compared to on-label standard dose (0.91%; p = 0.02). The off-label overdose group did not have any particular background and its thromboembolic risk was, conversely, low. The most likely cause of off-label overdose was clinicians potentially overlooking dose criteria, including advanced age, low body weight, and low creatinine clearance. In patients after AF ablation, off-label DOAC overdose was infrequent, but significantly associated with higher incidence of major bleeding during the remote period after AF ablation. The study was registered as UMIN000026092 (University Hospital Medical Information Network-Clinical Trial Registry).

Anticoagulation stewardship in the ambulatory settings of long-term care and rehabilitation - A multi-centric descriptive pilot study.

Anticoagulants have consistently emerged as the leading cause of adverse drug events in both inpatient and outpatient settings. While literature on anticoagulation stewardship programs (ACSP) exists for hospital settings, there is a paucity of data in long-term care and rehabilitation settings. Assess the feasibility of a pharmacist led ACSP in the ambulatory healthcare settings of long-term care facilities (LTC) and rehabilitation centers (RC). We conducted a prospective pilot project in 3 rehabilitation centers and 7 long-term care facilities. Patients were selected over 5months in 2023. Patient and anticoagulant prescription-related characteristics were collected. The primary feasibility outcome was the proportion of anticoagulant prescription reviews leading to a pharmacist intervention. A total of 411 patients were enrolled. Common indications for anticoagulants were atrial fibrillation (n=255, 62.0%), medical thromboprophylaxis (n=52, 12.7%) and venous thromboembolism (n=53, 12.9%). Direct oral anticoagulants (DOAC) were most frequently prescribed (n=309, 75.2%). Of 411 prescription reviews, 93 led to at least one intervention (22.6%), for a total of 100 interventions. Interventions mainly concerned laboratory ordering (n=29) and DOAC dose adjustment (n=24). Baseline anticoagulant characteristics and outcomes varied by healthcare setting. Expanding ACSP into outpatient LTC and RC settings is feasible. ACSP should include both therapeutic and thromboprophylactic anticoagulants. Additional research is warranted to evaluate the viability of ongoing ACSP monitoring, and more extensive prospective studies are required to assess clinical outcomes effectively.

Patient Characteristics and Real-World Treatment of Very Elderly Patients with Nonvalvular Atrial Fibrillation in Japan: An Administrative Claims Database Study.

Very elderly patients with nonvalvular atrial fibrillation (NVAF) are at high risk for both ischemic and hemorrhagic events. This study aimed to understand the characteristics and real-world treatment of very elderly patients with NVAF in Japan. We conducted a retrospective analysis of electronic health records and claims data from acute care hospitals for very elderly patients with NVAF with medical records available on or after their 80th birthday. The outcomes of interest were (1) characteristics of very elderly patients and (2) patterns of anticoagulation and impact of clinical condition on anticoagulation. Of 1,278,404 patients with newly diagnosed atrial fibrillation (AF), 443,820 were eligible for the analysis. Mean ± standard deviation age was 84.5 ± 5.5years, CHADS2 score was 2.4 ± 1.0, and CHA2DS2-VASc score was 4.3 ± 1.3. Among patients diagnosed with NVAF before age 80years, 39.1% were not receiving anticoagulation therapy, while among those diagnosed with NVAF at age ≥ 90years, 46.1% were not prescribed any anticoagulant. Patients diagnosed with NVAF before 80years of age tended to stop anticoagulation therapy, especially those receiving warfarin, upon reaching 80years of age. Among those who were newly diagnosed with NVAF after 80years, most received reduced doses of direct oral anticoagulants (DOACs). A significant proportion of very elderly patients with NVAF in Japan were diagnosed with NVAF after the age of 80years and were not receiving anticoagulation therapy, particularly with increasing age. Furthermore, warfarin use declined with age, and patients on DOACs frequently received reduced doses.

Phenotypes of Patients with Direct Oral Anticoagulant (DOAC) Underdosing in Atrial Fibrillation: Results from the ARENA Registry.

Oral anticoagulation in patients with atrial fibrillation is crucial to prevent thrombus formation in the heart, a major cause of ischemic stroke. The appropriate dose of direct oral anticoagulants (DOAC) - either standard or reduced dose - must be chosen individually in accordance with defined patient characteristics. However, a significant proportion of patients receive inappropriately low DOAC doses (underdosing). With a novel medication-based approach, this study aims to facilitate the identification of patients at risk of DOAC underdosing. The prospective ARENA registry is a multi-centre study on patients with atrial fibrillation in Germany. Patients gave detailed information on medication, including over-the-counter preparations. Medication data were grouped according to the Anatomical Therapeutic Chemical (ATC) classification. In a bivariate analysis, the characteristics of patients on an appropriate versus inappropriate dose were compared (n = 866). To further evaluate variables for their association with underdosing, a model based on ATC third level medication data complemented with dose-adjustment criteria and validated clinical scores in all patients with complete information was built (n = 504). In 15% of patients, an inappropriately low dose was found. The number of DOAC drug interactions, concomitant antiplatelet therapy and the total drug count were the most important predictors of DOAC underdosing. Mineral supplements and better health-related quality of life (HrQoL) were predictive of correct DOAC dosing, among others. Medication-related data showed to be predictive of DOAC underdosing. Clinicians should check for inappropriately reduced DOAC doses, especially in patients undergoing antiplatelet therapy, polypharmacy and reduced HrQoL. NCT02978248; date of registration: 30 November 2016.

Safe and effective anticoagulation use: case studies in anticoagulation stewardship.

Anticoagulant use is prevalent and associated with significant potential for harm. Anticoagulation stewardship practice has emerged to address care gaps and promote safe, effective, and cost-conscious anticoagulation use across health care systems. We present 4 patient cases describing common challenges in anticoagulation management: inappropriate dosing of direct oral anticoagulants, the diagnosis and management of heparin-induced thrombocytopenia, periprocedural anticoagulation management, and heavy menstrual bleeding on anticoagulation. We discuss available examples of successful stewardship programs that can address the challenges of each case, demonstrating how an investment in anticoagulation stewardship can improve patient outcomes.

Determinants of Inappropriate Dosing of Direct Oral Anticoagulants in Non-Valvular Atrial Fibrillation in a Low-Income Country.

Introduction The appropriate use of direct oral anticoagulants (DOACs) is crucial in patients with non-valvular atrial fibrillation (NVAF) to prevent thromboembolic complications. The use of inappropriate doses is common, but information on its prevalence and determining factors in low-income countries is insufficient. Objective The objective of this study is to quantify the prevalence and identify demographic, clinical, and treatment-related factors associated with inappropriate dosing of DOACs in patients with NVAF in a low-income country. Methods A retrospective and observational study was conducted from June 2023 to July 2024 at the Dominican Institute of Cardiology Association. Outpatients over 18 years of age with a diagnosis of NVAF and treatment with DOACs were included and classified into two groups based on dose appropriateness. Univariate analyses, such as chi-square and Student's t-tests or Mann-Whitney U tests, were used, along with a multivariate logistic regression analysis, to adjust for potential confounding factors. Results In a study involving 392 patients with NVAF treated with DOACs, 72.19% (283 patients) received appropriate doses, whereas 27.81% (109 patients) were dosed inappropriately. Specifically, 15.56% were underdosed and 12.24% were overdosed. Among the 268 patients prescribed apixaban, 71.64% received an appropriate dose, whereas 28.36% were prescribed an inappropriate dose, with 80.26% of these cases involving low doses. Furthermore, a significantly greater proportion of these patients received apixaban at a reduced dose of 2.5 mg every 12 hours (p<0.001). In contrast, 73.39% of the 124 patients on rivaroxaban had appropriate dosing, but 26.61% were dosed inappropriately, all of which were overdoses. Patients who received inappropriate dosing were older (79.22 vs. 76.06 years; p=0.006), had higher serum creatinine levels (1.23 vs. 1.1 mg/dL; p=0.004), and had lower creatinine clearance (39.38 vs. 51.69 mL/min; p<0.001). The prevalence of vascular disease (15.60% vs. 7.77%; p=0.02) and anemia (7.34% vs. 1.77%; p=0.01) was also higher in this group. Multivariate analysis identified advanced age (OR=1.04; 95% CI: 1.01-1.06; p=0.006), vascular disease (OR=2.28; 95% CI: 1.11-4.67; p=0.024), and elevated creatinine levels (OR=2.00; 95% CI: 1.1-3.63; p=0.024) as significant predictors of inappropriate dosing. Conclusion The study found that 27.81% of patients with NVAF received inappropriate DOACs doses, primarily due to underdosing. Significant factors associated with dosing inadequacy included advanced age, reduced creatinine clearance, and vascular disease.

Off-Label Dosing of Direct Oral Anticoagulants: Prescribing Error or Opportunity in Treating Patients with Atrial Fibrillation?

Off-Label Dosing of Direct Oral Anticoagulants: Prescribing Error or Opportunity in Treating Patients with Atrial Fibrillation?

Predictors and Outcomes of Inappropriate Dosing of Direct Oral Anticoagulants in Patients Receiving Transcatheter Aortic Valve Implantation.

Direct oral anticoagulant (DOAC) dose adjustment is based on age, renal function, and body weight. There is a paucity of data describing the factors associated with the prescription of inappropriate dosage and their impact on clinical outcomes among patients receiving transcatheter aortic valve implantation (TAVI). In a single-center study, 432 patients who were on long-term DOAC therapy and underwent TAVI between 2015 and 2022 were included. We analyzed the predictors and outcomes of inappropriate dosing of DOACs; namely apixaban, dabigatran, edoxaban, and rivaroxaban. A composite endpoint, including all-cause mortality, life-threatening/major bleeding, stroke, peripheral thromboembolic complications, or myocardial infarction, was assessed after 1 year. In this TAVI cohort, inappropriate DOAC dosing was observed in 20.6% of patients. Inappropriate DOAC dosage was related to female gender (adj. odds ratio [OR] 2.72, 95% confidence interval [CI] 1.64-4.51, p < 0.001) as well as lower estimated glomerular filtration rate (eGFR) (adj. OR 0.99, 95% CI 0.98-1.00, p = 0.019), and to the administration of non-rivaroxaban DOACs (adj. OR 0.28, 95% CI 0.16-0.50, p < 0.001). After 1 year, patients on both appropriate and inappropriate DOAC dosage exhibited comparable rates of the composite endpoint (OR 0.88, 95% CI 0.53-1.46, p = 0.622). Old age (adj. OR 1.05, 95% CI 1.01-1.10, p = 0.018) as well as anemia (adj. OR 0.86, 95% CI 0.75-0.99, p = 0.031) emerged as independent predictors of the composite endpoint. In this TAVI cohort, female gender and renal insufficiency were associated with inappropriate DOAC dosage, whereas rivaroxaban was linked to appropriate dosing. Inadequate DOAC dosage did not translate into a worse outcome in our TAVI population. Prospective Segeberg TAVI Registry (ClinicalTrials.gov identifier: NCT03192774).

Can the Charlson comorbidity index help to guide DOAC dosing in patients with atrial fibrillation and improve the efficacy and safety of treatment? A subanalysis of the MAS study

BackgroundFrailty influences the effectiveness and safety of anticoagulant therapy in patients with atrial fibrillation (AF). The age-weighted Charlson comorbidity index may offer a valuable tool to assess the risk of adverse events in AF patients treated with direct oral anticoagulants (DOACs). This sub-analysis of MAS trial data aimed to assess whether using the Charlson index, instead of the standard criteria, would have led to different dosing and improved adverse event occurrence during treatment. MethodsThe MAS study looked for a relationship between DOAC levels assessed at baseline and adverse events during follow-up. The study is described in detail elsewhere. ResultsAmong the 1,657 patients studied, 832 (50.2 %) had a relatively low Charlson index (up to 6, general median class), of whom 132 (15.9 %) were treated with reduced doses. Conversely, among the 825 patients with a high Charlson index (≥7), 257 (31.1 %) received standard doses. A weak but statistically significant positive correlation (r = 0.1413, p < 0.0001 by ANOVA) was observed between increasing Charlson classes and DOAC levels standardized to allow comparability among drug results. However, no significant differences were found in the incidence or number of adverse events during follow-up, or in other parameters, between patients with low and high Charlson's scores. ConclusionsUtilizing the Charlson index would have led to notable differences in DOAC dosing compared to standard criteria. However, we found no evidence that its use would have improved the prediction of adverse events in AF patients enrolled in the MAS study.

Inappropriate dosing of direct oral anticoagulants in patients with atrial fibrillation undergoing percutaneous coronary intervention

Abstract Background Underdose (inappropriate low-dose) of direct oral anticoagulants (DOAC) is sometimes prescribed due to concerns of bleeding risk in patients with atrial fibrillation (AF). In AF patients with coronary artery disease requiring percutaneous coronary intervention (PCI), careful treatment is required to prevent bleeding events because of intensive antithrombotic therapy with a combination of oral anticoagulants and antiplatelet agents. Purpose The purpose of this study was to investigate the prevalence of underdose of DOAC and its impact on clinical outcomes in AF patients with coronary artery disease undergoing PCI. Methods This multicenter observational cohort study enrolled patients with AF on DOAC undergoing PCI between January 2015 and March 2021 at 15 institutions. Appropriateness of DOAC dose was determined according to the manufacturer's labeling recommendations in Japan. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE), all-cause mortality, ischemic stroke, and major bleeding events, were evaluated. Results Of 630 patients enrolled, 168 patients (26.7%) received underdose, 227 (36.0%) received appropriate low-dose, 213 (33.8%) received appropriate standard-dose, and 22 (3.5%) received overdose. Because of the extremely small number of patients in the overdose group, the primary analysis of the present study was a comparison between the underdose group (n=168) and the appropriate dose group (appropriate low-dose and standard-dose groups) (n=440). Although the incidence of MACE, all-cause mortality, and major bleeding events was not significantly different between the 2 groups (log-rank p=0.872, p=0.170, and p=0.725), ischemic stroke more frequently occurred in the underdose group compared with the appropriate dose group (log-rank p=0.010) (Figure 1). The multivariable Cox regression analysis determined underdose of DOAC as an independent predictor for ischemic stroke (adjusted HR 3.288, 95% CI: 1.189-9.088, p=0.022). Conclusions Compared with appropriate dose of DOAC, underdose was associated with a higher incidence of ischemic stroke, despite no significant difference in MACE, all-cause mortality, and major bleeding events, in AF patients undergoing PCI.Figure 1

Clinical outcomes of edoxaban treatment in atrial fibrillation patients with high bleeding risk: insights from the ETNA-AF-China 1-year follow-up

Abstract Background In China and many other countries, anticoagulated atrial fibrillation (AF) patients with high bleeding risk often raises clinical concern; the optimal dose of direct oral anticoagulants (DOACs) preventing stroke/systemic embolic events (SEE) in those population remains unclear. Purpose To assess the effectiveness and safety of edoxaban treatment in Chinese AF patients with high bleeding risk, and to compare 60 mg vs 30 mg dose in this real-world registry. Methods ETNA-AF-China is a prospective, observational study conducted in 89 centres across Chinese Mainland enrolling AF patients receiving edoxaban. This subgroup analysis was based on 1-year follow-up data. Patients were categorized to high bleeding risk group who had a DOAC score ≥6 (age, creatinine clearance, underweight, history of stroke/TIA/SEE, diabetes, hypertension, antiplatelet use, NSAIDs use, history of major/critical bleeding, liver disease) at baseline, or moderate-to-low bleeding risk group meeting criteria of DOAC score &amp;lt;6. The safety, effectiveness, and composite outcomes were reported by comparison between patient subgroups using Cox proportional hazards models. Results Of 4883 patients with 1-year follow-up, 1534 (31.4%, 60 mg: n=518, 30 mg: n=1016) were identified as high bleeding risk and 3349 (68.6%) as moderate-to-low bleeding risk. As expected, patients with high bleeding risk were more often elderly (48.2% ≥80 years), had lower body weight, worse renal function, higher CHA2DS2-VASc score than those with moderate-to-low risk (Figure 1). In both high risk and moderate-to-low risk subgroups, patients receiving 60 mg edoxaban were younger, with better renal function, lower CHA2DS2-VASc score compared with 30 mg. Annualised event rates of major bleeding (HR 2.95, 95%CI 1.62–5.36), all cause death (3.42, 2.29–5.09), CV death (3.27, 1.52–7.04), major adverse cardiac events (MACE, 2.61, 1.69–4.02) and all NCOs were significant higher in patients with high bleeding risk compared with moderate-to-low risk (Figure 2). After multivariable adjustment, edoxaban dose of 60 mg other than 30 mg were associated with significantly lower rates of all cause death (adjusted HR 0.41, 0.18–0.90) and lower trend of NCO3 (0.51, 0.28–0.92) and NCO4 (0.51, 0.30–0.88) by composite of stroke/SEE, major bleeding and death events in high risk subgroup; no significant difference between edoxaban doses and stroke or bleeding outcomes with cumulative low event rates were observed. Conclusion In routine clinical care, AF patients at high bleeding risk faces worse outcomes of death events, MACE, as well as the composite outcomes over moderate-to-low risk patients. Among patients with high bleeding risk, edoxaban use showed effectiveness and safety with overall low incidence, and potential better survival, composite endpoint benefit could be associated with 60mg. Further investigation is ongoing.

Thrombin generation to evaluate the complex hemostatic balance of hemophilia A plasma containing direct oral anticoagulant and supplemented by factor VIII

BackgroundThe incidence of cardiovascular diseases is increasing in persons with hemophilia A (HA). Therefore, anticoagulant therapy based on direct oral anticoagulants (DOACs) may be needed, despite the bleeding risk. In case of surgery or bleeding, such patients may be concomitantly treated with emicizumab (routine prophylaxis), factor (F)VIII products, and DOAC. Their concomitant presence constitutes a hemostatic challenge. Recent international guidelines stated that data are scarce on the hemostatic balance of plasma samples from patients with HA receiving emicizumab and DOAC. ObjectivesThe aim of this observational study was to assess the coagulation of FVIII-deficient plasma spiked with DOAC and emicizumab and to evaluate the effects of FVIII addition. MethodsProthrombin time, activated partial thromboplastin time, and thrombin generation (TG) using the calibrated automated thrombogram method were evaluated in aliquots of a commercial severe HA plasma supplemented with emicizumab (0, 12.5, 25, 50, and 100 ng/mL), DOAC (0, 50, 100, 200, and 400 ng/mL of apixaban, rivaroxaban, edoxaban, or dabigatran) and FVIII (0%, 5%, 15%, 50%, and 100%). ResultsDOAC rapidly induced a TG decrease. Emicizumab could counter this effect only for the lowest DOAC dose. FVIII addition to the FVIII-deficient plasma containing a DOAC and emicizumab improved TG and countered the anticoagulant effect of DOAC at ≤100 ng/mL. ConclusionOur findings indicate that FVIII can be safely used with emicizumab to counter the anticoagulant effect of DOAC at ≤100 ng/mL. The TG assay is an efficient tool to monitor plasma containing anti-FXa DOAC, but not dabigatran (anti-FIIa).

Efficacy and Safety of Low or Reduced Dose Direct Oral Anticoagulants Versus Dual Antiplatelet Therapy Following Left Atrial Appendage Closure: A Systematic Review and Meta-Analysis.

This meta-analysis aimed to compare the efficacy and safety of low-dose direct oral anticoagulants (DOACs) versus dual antiplatelet therapy (DAPT) in patients undergoing left atrial appendage closure (LAAC). A comprehensive literature search was conducted across multiple electronic databases, including PubMed, Embase, Cochrane Library, and Scopus, up to August 12, 2024. Studies comparing low-dose DOACs with DAPT in post-LAAC patients were included. The primary outcomes of interest were thromboembolic events, major bleeding, and all-cause mortality. Four studies, including two randomized controlled trials and two observational studies, met the inclusion criteria, with a total of 828 patients (319 in the DOAC group and 509 in the DAPT group). The meta-analysis revealed that patients treated with DOACs had a significantly lower risk of thromboembolic events compared to those receiving DAPT. DOACs were also associated with a significantly reduced risk of device-related thrombosis. Although the risk of stroke was lower in the DOAC group, the difference was not statistically significant. The risk of death did not differ significantly between the two groups. Regarding safety outcomes, patients receiving DOACs experienced fewer bleeding events compared to those on DAPT, with the difference being statistically significant. However, high heterogeneity was reported among the study results for bleeding events. These findings suggest that low-dose DOACs may be a more effective and safer alternative to DAPT for post-LAAC antithrombotic management, particularly in patients at high risk for both thromboembolic and bleeding events. DOACs demonstrated superior efficacy in reducing the risk of stroke, systemic embolism, and other thrombotic complications, while also minimizing bleeding risks.

Handling delayed or missed direct oral anticoagulant doses: model-informed individual remedial dosing

AbstractNonadherence to direct oral anticoagulant (DOAC) pharmacotherapy may increase the risk of thromboembolism or bleeding, and delayed or missed doses are the most common types of nonadherence. Current recommendations from regulatory agencies or guidelines regarding this issue lack evidence and fail to consider individual differences. This study aimed to develop individual remedial dosing strategies when the dose was delayed or missed for DOACs, including rivaroxaban, apixaban, edoxaban, and dabigatran etexilate. Remedial dosing regimens based on population pharmacokinetic (PK)-pharmacodynamic (PD) modeling and simulation strategies were developed to expeditiously restore drug concentration or PD biomarkers within the therapeutic range. Population PK-PD characteristics of DOACs were retrieved from previously published literature. The effects of factors that influence PK and PD parameters were assessed for their impact on remedial dosing regimens. A web-based dashboard was established with R-shiny to recommend remedial dosing regimens based on patient traits, dosing schedules, and delay duration. Addressing delayed or missed doses relies on the delay time and specific DOACs involved. Additionally, age, body weight, renal function, and polypharmacy may marginally affect remedial strategies. The proposed remedial dosing strategies surpass current recommendations, with less deviation time beyond the therapeutic range. The online dashboard offers quick and convenient solutions for addressing missed or delayed DOACs, enabling individualized remedial dosing strategies based on patient characteristics to mitigate the risks of bleeding and thrombosis.

Appropriateness of direct oral anticoagulant dosing in patients with atrial fibrillation at a tertiary care hospital in Thailand

BackgroundAppropriate dosing of direct oral anticoagulants (DOACs) has been associated with clinical efficacy and safety. Several studies have shown that DOAC dosing are often inconsistent with guideline recommendations. Little is known about this issue in Thailand. This study aimed to evaluate the appropriateness of DOAC dosing in Thai hospitalized patients with atrial fibrillation (AF). MethodThis was a retrospective descriptive study conducted on hospitalized patients at Rajavithi Hospital, a tertiary care hospital in Thailand. Inpatients diagnosed with AF and treated with DOACs between February 2021 and February 2023 were enrolled in the study. The appropriate dosing of DOACs was assessed according to the recommendation of the 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (EHRA). Descriptive statistics were used to analyze the data; median (interquartile range) for continuous variables, and numbers and percentages for categorical variables. ResultsA total of 120 patients with AF were evaluated for dosing. The patients received rivaroxaban in 47 cases (39.2 %), apixaban in 32 cases (26.7 %), edoxaban in 31 cases (25.8 %), and dabigatran in 10 cases (8.3 %). Most of the patients were elderly, with a median age of 77.5 (68–84) years. Females were predominant (57.5 %). Our findings indicate that the prevalence of appropriate dosing of DOACs was 63.3 %. However, approximately one-third of patients received inappropriate dosing, with 24 (20.0 %) being overdosed, and 20 (16.7 %) being underdosed. The highest overdosing and underdosing rates were seen in dabigatran (90.0 %) and apixaban (21.9 %), respectively. ConclusionInappropriate dosing of DOACs according to the 2021 EHRA recommendations was high in 36.7 %, with overdosing mostly occurring in 20.0 %. The high number of inappropriate dosing highlights the need for implementation of optimal strategies to select the appropriate dose of DOACs in Thai hospitalized patients with AF.

Pharmacist Use of a Population Management Dashboard for Safe Anticoagulant Prescribing: Evaluation of a Nationwide Implementation Effort.

Direct oral anticoagulants (DOACs) have complex dosing regimens and are often incorrectly prescribed. We evaluated a nationwide DOAC population management dashboard rollout whose purpose includes pharmacist review and correction of off-label dosing prescriptions. Using data from Veterans Health Affairs, we identified all patients prescribed DOACs for atrial fibrillation or venous thromboembolism between August 2015 and December 2019. Sites were grouped on the basis of the timing of moderate-high usage of the DOAC population management tool dashboard. Effectiveness was defined as the monthly rate of off-label DOAC prescribing and the rate of clinical adverse events (bleeding, composite of stroke or venous thromboembolism). Implementation was evaluated as the percentage of off-label DOAC prescriptions changed within 7 days. Among the 128 652 patients receiving DOAC therapy at 123 centers, between 6.9% and 8.6% had off-label DOAC prescriptions. Adoption of the DOAC population management tool dashboard before July 2018 was associated with a decline in off-label dosing prescriptions (8.7%-7.6%). Only 1 group demonstrated a significant reduction in monthly rates of bleeding following implementation. All sites experienced a reduction in the composite of venous thromboembolism or stroke following dashboard adoption. There was no difference in the implementation outcome of DOAC prescription change within 7 days in any of the adoption groups. Early adoption of the DOAC population management tool dashboard was associated with decreased rates of off-label DOAC dosing prescription and reduced bleeding. Following adoption of the DOAC population management tool dashboard, all sites experienced reductions in venous thromboembolism and stroke events.