OBJECTIVE: Although prescription of direct oral anticoagulants (DOACs) for epileptic patients on anti-seizure medications (ASMs) is on the increase, international guidelines pose strict restrictions because this may lead to pharmacologic interactions. However, current evidence on their clinical relevance remains scanty. This retrospective, case-control study assessed the frequency of ischemic/hemorrhagic events and epileptic seizures involving DOAC-ASM cotherapy in the real world, compared with DOAC and ASM monotherapy, in age- and gender-matched controls.
METHODS: Data on patients who had been prescribed a concomitant DOAC and ASM therapy for at least 6 months were extracted from the database of the Pharmaceutical Service of the Alessandria Province (Italy). After exclusions, the case group included 124 patients, 44 on valproic acid (VPA) and 80 on levetiracetam (LEV) concomitant with a DOAC, and it was compared with the DOAC-control and ASM-control groups. The clinical and laboratory data were extracted from the electronic archives of the hospitals in the same province.
RESULTS: Two (1.6%) ischemic and 2 (1.6%) major hemorrhagic events were observed in the case group. Four (3.2%) ischemic and no hemorrhagic events occurred in the DOAC-control group. There were no statistically significant differences in the ischemic and hemorrhagic events between the case group (patients on concomitant LEV or VPA who were prescribed a DOAC) and the DOAC-control group, and there was no difference in the recurrence rate of epileptic seizures between the case group and the ASM-control group.
CONCLUSIONS: Although this study has some limits, mainly the small sample size, our findings indicate that neither LEV nor VPA concomitant treatment significantly affects the effects of DOACs in a real-world setting.

Direct oral anticoagulants (DOACs) are the standard treatment for thromboembolic protection in atrial fibrillation (AF) patients. Epigenetic modifications, such as DNA methylation and microRNAs, have emerged as potential biomarkers of AF. The epigenetics of DOACs is still an understudied field. It is largely unknown whether epigenetic modifications interfere with DOAC response or whether DOAC treatment induces epigenetic modifications. To fill this gap, we started the miR-CRAFT (Circulating microRNAs and DNA methylation as regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation) research study. In miR-CRAFT, we follow, over time, changes in DNA methylation and microRNAs expression in naïve AF patients starting DOAC treatment. The ultimate goal of miR-CRAFT is to identify the molecular pathways epigenetically affected by DOACs, beyond the coagulation cascade, that are potentially mediating DOAC pleiotropic actions and to propose specific microRNAs as novel circulating biomarkers for DOAC therapy monitoring. We herein describe the study design and briefly present the progress in participant enrolment.

BACKGROUND: There is limited evidence to support definite clinical outcomes of direct oral anticoagulant (DOAC) therapy in chronic kidney disease (CKD). By identifying the important variables associated with clinical outcomes following DOAC administration in patients in different stages of CKD, this study aims to assess this evidence gap.
METHODS: An anonymised dataset comprising 97,413 patients receiving DOAC therapy in a tertiary health setting was systematically extracted from the multidimensional electronic health records and prepared for analysis. Machine learning classifiers were applied to the prepared dataset to select the important features which informed covariate selection in multivariate logistic regression analysis.
RESULTS: For both CKD and non-CKD DOAC users, features such as length of stay, treatment days, and age were ranked highest for relevance to adverse outcomes like death and stroke. Patients with Stage 3a CKD had significantly higher odds of ischaemic stroke (OR 2.45, 95% Cl: 2.10-2.86; p = 0.001) and lower odds of all-cause mortality (OR 0.87, 95% Cl: 0.79-0.95; p = 0.001) on apixaban therapy. In patients with CKD (Stage 5) receiving apixaban, the odds of death were significantly lowered (OR 0.28, 95% Cl: 0.14-0.58; p = 0.001), while the effect on ischaemic stroke was insignificant.
CONCLUSIONS: A positive effect of DOAC therapy was observed in advanced CKD. Key factors influencing clinical outcomes following DOAC administration in patients in different stages of CKD were identified. These are crucial for designing more advanced studies to explore safer and more effective DOAC therapy for the population.

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.

Comparison of clinical outcomes across anticoagulation regimens using different apixaban dosing or warfarin is not well-defined in patients with nonvalvular atrial fibrillation (AF) who are receiving dialysis. This study compared these outcomes in a US national cohort of patients with kidney failure receiving maintenance dialysis.
Retrospective cohort study.
Patients receiving dialysis represented in the US Renal Data System database 2013-2018 who had AF and were treated with apixaban or warfarin.
First prescribed treatment with apixaban dosed according to the label, apixaban dosed below the label, or warfarin.
Ischemic stroke/systemic embolism, major bleeding, and all-cause mortality.
Cox proportional hazards models with inverse probability of treatment weighting. Analyses simulating an intention-to-treat (ITT) approach as well as those incorporating censoring at drug switch or discontinuation (CAS) were also implemented. Inverse probability of censoring weighting was used to account for possible informative censoring.
Among 17,156 individuals, there was no difference in risk of stroke/systemic embolism among the label-concordant apixaban, below-label apixaban, and warfarin treatment groups. Both label-concordant (HR, 0.67 [95% CI, 0.55-0.81]) and below-label (HR, 0.68 [95% CI, 0.55-0.84]) apixaban dosing were associated with a lower risk of major bleeding compared with warfarin in ITT analyses. Compared with label-concordant apixaban, below-label apixaban was not associated with a lower bleeding risk (HR, 1.02 [95% CI, 0.78-1.34]). In the ITT analysis of mortality, label-concordant apixaban dosing was associated with a lower risk versus warfarin (HR, 0.85 [95% CI, 0.78-0.92]) while there was no significant difference in mortality between below-label dosing of apixaban and warfarin (HR, 0.97 [95% CI, 0.89-1.05]). Overall, results were similar for the CAS analyses.
Study limited to US Medicare beneficiaries; reliance on administrative claims to ascertain outcomes of AF, stroke, and bleeding; likely residual confounding.
Among patients with nonvalvular AF undergoing dialysis, warfarin is associated with an increased risk of bleeding compared with apixaban. The risk of bleeding with below-label apixaban was not detectably less than with label-concordant dosing. Label-concordant apixaban dosing is associated with a mortality benefit compared to warfarin. Label-concordant dosing, rather than reduced-label dosing, may offer the most favorable benefit-risk trade-off for dialysis patients with nonvalvular AF.

The aim of this study was to evaluate the risk of stroke and bleeding among patients with atrial fibrillation (AF) treated with direct oral anticoagulants (DOACs) despite anaemia at treatment initiation time.
All Danish patients (N = 41 321) diagnosed with incident AF, having a baseline haemoglobin (Hb), and subsequently initiated DOAC therapy between 2012 and 2019 were identified through administrative registry databases. Patients with anaemia were subdivided according to the World Health Organization classification of anaemia and evaluated regarding risk of stroke and composite bleeding endpoint [hospitalization due to urogenital, gastrointestinal (GI), or intracranial bleeding or epistaxis]. Standardized absolute 1-year risks of stroke and composite bleeding endpoint were calculated using multivariable Cox regression analyses. The standardized absolute 1-year risk difference for composite bleeding increased by 0.96% [95% confidence interval (CI) 0.38-1.54] for patients with moderate/severe anaemia compared with patients with no anaemia. This risk was mainly driven by an increase in standardized absolute 1-year risk for serious GI bleeding, which increased by 0.41% (95% CI 0.19-0.63). No significant difference in standardized absolute 1-year bleeding risk was observed among patients with mild anaemia compared with patients with no anaemia 0.36% (95% CI -0.10 to 0.82). No significant difference in standardized absolute 1-year risk of stroke was observed among patients with mild anaemia, -0.16% (95% CI -0.13 to 0.15), and moderate/severe anaemia, -0.47% (95% CI -0.16 to 0.19), compared with patients with no anaemia.
For AF patients receiving DOACs, moderate/severe anaemia is a risk factor for serious GI bleeding, while stroke risk is the same regardless of whether anaemia was present at baseline or not.

UNASSIGNED: The data of anti-FXa-IIa activity detection in Asian population is insufficient, and its potential role for drug adherence evaluation in patients with direct oral anticoagulants (DOACs) remains unclear. This study carried out multi-center anti-FXa-IIa activity detection in Asian, aiming to explore its applicability in Asian population and find its role in adherence evaluation.
UNASSIGNED: We assessed patients\' self-reported adherence using the Morisky, Green, and Levine Adherence Scale (MGLS) from six hospitals. Plasma samples were collected for peak and trough concentration determination, and anti-FXa-IIa chromogenic assay was conducted using rivaroxaban/dabigatran calibrators and controls. Multivariate logistic regression models, covariate adjustment and spearman\'s two-tailed test were conducted in the data analysis. This study had been registered in clinical trials (NCT03666962).
UNASSIGNED: In total, 271 patients taking rivaroxaban (n=149) or dabigatran (n=122) were enrolled. Among the 271 patients assessed by MGLS questionnaire, 188 persons (69.4%) showed high adherence, 77 persons (28.4%) was in intermediate adherence group, and only 6 patients (2.2%) had low adherence. Patients are more adherent dosed once daily of rivaroxaban compared to twice daily of dabigatran: 75.6% vs. 63.6%. Anti-FXa-IIa activity had good linear correlation with routine coagulation indexes (P<0.001), but no significant association was found between drug adherence and anti-FXa-IIa activity (P>0.05).
UNASSIGNED: This study confirms that anti-FXa-IIa activity detection based on target drug calibrations can be used as an effective index for pharmacodynamic evaluation in Asian population, but had limited value in drug adherence evaluation for DOACs. As the limited samples, these findings could serve as a hypothesis-generating effort, and should be validated in further studies with larger sample sizes.

There is limited data on the efficacy of direct oral anticoagulants (DOACs) for the treatment of left ventricular thrombus. Currently, vitamin K antagonists (VKAs) remain the preferred oral anticoagulant for left ventricular thrombus. In this retrospective study, we assessed the safety and efficacy of DOACs in comparison to VKAs in patients with a new diagnosis of left ventricular thrombus.
We retrospectively identified all patients admitted to the 5 Catholic Health Initiative Omaha hospitals with a diagnosis of left ventricular thrombus between January 2012 and March 2019 and were discharged on oral anticoagulants. Patients were stratified into 2 groups: VKAs or DOACs and followed for up to 1 year. We compared the outcomes of ischemic stroke, bleeding, and echocardiographic resolution of left ventricular thrombus between the 2 groups.
A total of 99 patients were included in this study (mean age: 61 years, 29% females). Of these, 80 (81%) were discharged on VKAs and 19 (19%) on DOACs. Stroke within 1 year of diagnosis occurred in 2 patients in the VKA group and none in the DOAC group (P = 0.49). Bleeding events were observed in 5 patients (4 in the VKA group and 1 in the DOAC group; P = 0.96). Ninety patients had follow-up echocardiogram; resolution of left ventricular thrombus was similar between the 2 groups (VKAs vs DOACs: 81% vs 80%; P = 0.9).
In patients with left ventricular thrombus, DOACs and VKAs had similar rates of stroke and bleeding. These findings need confirmation in randomized clinical trials.

Patients with sickle cell disease have an increased risk of venous thromboembolism (VTE) and with a mortality 2-fold higher. The anticoagulation of VTE in a young population is an important question. Indeed, hemorrhagic complications of anticoagulation may occur more frequently than in the general population. The use of a direct oral anticoagulant (DOAC) is not recommended for VTE in patients with sickle cell disease because those patients were not included in the clinical studies. We aimed to study the safety of using DOACs in a prospective cohort of patients with sickle cell disease and VTE. We prospectively followed the cohort of all sickle cell disease patients undergoing recent DOAC treatment for VTE at a sickle cell disease reference center. Twelve patients received rivaroxaban for VTE (eight women and four men). The median age was 27 years (20-45). The sickle cell disease variants included homozygous Hb SS (HBB: c.20A>T) in eight patients, Hb S-β+-thalassemia (Hb S-β+-thal) in two, Hb S-β0-thal in one and Hb S-Hb C (HBB: c.19G>A) in one. The cumulative duration of follow-up was 3134 days under rivaroxaban treatment. There were two thrombotic events, including a patient with a double positivity of antiphospholipid antibodies. No major bleeding was observed, and 6/12 patients presented minor bleeding (epistaxis: n = 4; anal fissure bleeding: n = 1; menorrhagia n = 4). Of these, 3/6 required their treatment to be switched to apixaban, which stopped the bleeding. Direct oral anticoagulants may be an alternative treatment for VTE in patients with sickle cell disease, except for an associated antiphospholipid syndrome.

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