Testing for the lupus anticoagulant: the good, the bad, and the ugly.

Lupus anticoagulant (LA) represents 1 of the laboratory criteria for classification of patients as having definite antiphospholipid syndrome (APS). The other 2 laboratory criteria are anticardiolipin antibodies and anti-beta2-glycoprotein I antibodies. At least 1 of these antiphospholipid antibody (aPL) tests need to be positive, with evidence of persistence, together with evidence of at least 1 clinical criterion for APS, before a patient can be classified as having definite APS. LA and other aPL assays are also important for diagnosis or exclusion of APS, as well as for risk stratification, with triple-positive patients carrying the greatest risk. Whereas LA is identified through "uncalibrated" clot-based assays, the other aPL assays (anticardiolipin and anti-beta2-glycoprotein I antibodies) represent immunological assays, identified using calibrated solid-phase methods. Because LA is identified using clot-based assays, it is subject to considerable preanalytical and analytical issues that challenge accurate detection or exclusion of LA. In this narrative review, we take a look at the good, the bad, and the ugly of LA testing, primarily focusing on the last 10 years. Although harmonization of LA testing as a result of International Society on Thrombosis and Haemostasis guidance documents and other international activities has led to improvements in LA detection, many challenges remain. In particular, several anticoagulants, especially direct oral anticoagulants and also vitamin K antagonists, given as therapy to treat the pathophysiological consequences of aPL, especially thrombosis, interfere with LA assays and can generate false-positive or false-negative LA findings. Overcoming these diagnostic errors will require a multifaceted approach with clinicians and laboratories working together.

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.

Ex Vivo Antiplatelet Effects of Oral Anticoagulants.

BACKGROUND: The impact of non-vitamin K antagonist oral anticoagulants (NOACs) on platelet function is still unclear. We conducted a comprehensive ex vivo study aimed at assessing the effect of the four currently marketed NOACs on platelet function. METHODS: We incubated blood samples from healthy donors with concentrations of NOACs (50, 150 and 250 ng/mL), in the range of those achieved in the plasma of patients during therapy. We evaluated generation of thrombin; light transmittance platelet aggregation (LTA) in response to adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), human γ-thrombin (THR) and tissue factor (TF); generation of thromboxane (TX)B2; and expression of protease-activated receptor (PAR)-1 and P-selectin on the platelet surface. RESULTS: All NOACs concentration-dependently reduced thrombin generation compared with control. THR-induced LTA was suppressed by the addition of dabigatran at any concentration, while TF-induced LTA was reduced by factor-Xa inhibitors. ADP- and TRAP-induced LTA was not modified by NOACs. TXB2 generation was reduced by all NOACs, particularly at the highest concentrations. We found a concentration-dependent increase in PAR-1 expression after incubation with dabigatran, mainly at the highest concentrations, but not with FXa inhibitors; P-selectin expression was not changed by any drugs. CONCLUSIONS: Treatment with the NOACs is associated with measurable ex vivo changes in platelet function, arguing for antiplatelet effects beyond the well-known anticoagulant activities of these drugs. There are differences, however, among the NOACs, especially between dabigatran and the FXa inhibitors.

Apixaban-Induced Spontaneous Hemorrhagic Cardiac Tamponade.

Direct oral anticoagulants (DOACs), such as apixaban, are used for the prevention and management of thromboembolic diseases. Here, we present a case of a 72-year-old African American woman who presented to the hospital with shortness of breath and precordial chest pain for three days. The patient was diagnosed with volume overload associated with the progression of chronic kidney disease (CKD) and subsequently admitted to the hospital. Since the patient failed to adequately respond to diuretics, hemodialysis was initiated. During the hospital stay, she developed paroxysmal atrial fibrillation. Along with amiodarone, apixaban was started for primary stroke prophylaxis. Within 72 hours, the patient developed worsening chest pain. An echocardiogram revealed a large pericardial effusion with cardiac tamponade. She was taken for an emergent open pericardial window placement to relieve cardiac tamponade, where 600 mL of blood was drained. Considering the timeline of the development of a large bloody pericardial effusion following initiation of apixaban, spontaneous hemorrhagic cardiac tamponade attributed to the use of apixaban was diagnosed. The patient was eventually taken off all anticoagulants. In considering potential mechanisms, impaired hepatic and renal metabolism of apixaban could be factored in this case. In addition, CKD can increase bleeding risk, due to platelet dysfunction and impaired interaction of von Willebrand factor with GPIIb-IIIa. Moreover, renal secretion of apixaban is mediated by p-glycoprotein and amiodarone is an inhibitor of this protein. Although extremely rare, spontaneous hemorrhagic cardiac tamponade can occur with the use of DOACs, such as apixaban. Prompt recognition and urgent treatment remain keys to avoiding adverse patient outcomes.

International Normalized Ratio Predicts Recurrence and Bleeding in Patients With Acute Venous Thromboembolism Who Undergo Direct Oral Anticoagulants.

Prothrombin time/international normalized ratio (PT/INR) is related to both antithrombotic effect and risk of bleeding. Its role in the prediction of venous thromboembolism (VTE) recurrence and bleeding for patients with acute VTE who undergo direct oral anticoagulants (DOACs) treatment is unclear, despite previous studies revealed some association between them. The predictive efficiency of INR for VTE recurrence and bleeding were analyzed in a retrospective cohort with VTE patients who underwent DOACs treatment. Then its predictive efficiency for VTE recurrence and bleeding were validated in a prospective cohort with the acquired cutoffs range, and compared with anti-Xa level, DASH and VTE-BLEED scores. In the retrospective cohort (n = 1083), the sensitivity and specificity of INR for the prediction of VTE recurrence were 79.4% and 92.8%, respectively. The area under the curve (AUC) was 0.881 (0.803-0.960)(P = .025). The cutoff value of INR was 0.9. The sensitivity and specificity of INR for the prediction of bleeding were 85.7% and 77.9%, respectively. The AUC was 0.876 (0.786-0.967)(P < .001). The cutoff value of INR was 2.1. In the prospective cohort (n = 202), the calibration showed that there were 4 (50%) patients with VTE recurrence, 156 (97.5%) patients with non-recurrence and bleeding (non-R&B), and 20 (58.8%) patients with bleeding in the low (INR < 0.9)(n = 8), intermediate (0.9 ≤ INR ≤ 2.1)(n = 160), and high (INR > 2.1)(n = 34) groups, respectively. The baseline PT/INR value at the initiation of DOACs treatment is an independent predictor for VTE recurrence and bleeding in patients with acute VTE who undergo DOACs treatment.

Clinical guidelines for prevention and treatment of CAT in Japan and other countries.

Cancer-associated thrombosis (CAT) is an important prognostic factor for an increasing number of cancer patients. Understanding of CAT among cancer care providers has grown in recent years, and guidelines for the prevention and treatment of CAT have been published in Japan and around the world. In this article, we introduce these major guidelines and discuss differences we identified between the Japanese guidelines and those of other countries, with a focus on problems and issues. Insurance coverage of low-molecular-weight heparin and indications for primary prevention with direct oral anticoagulants in particular require urgent consideration.

A real-world exploration into clinical outcomes of direct oral anticoagulant therapy in people with chronic kidney disease: a large hospital-based study.

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.

Non-valvular atrial fibrillation in patients on peritoneal dialysis, prevalence, treatment and professionals involved.

Atrial fibrillation is the most frequent chronic arrhythmia in patients with chronic kidney disease. Oral anticoagulation with vitamin K antagonists and now direct oral anticoagulants have been and are the fundamental pillars for the prevention of thromboembolic events. However, there are no randomized clinical trials on the risk-benefit profile of oral anticoagulation in patients with chronic kidney disease stage 5 on peritoneal dialysis and there is little evidence in the literature in this population. The objective of our study was to know the prevalence, treatment and professionals involved in the management of atrial fibrillation in peritoneal dialysis patients. For this purpose, we performed a descriptive analysis through a survey sent to different peritoneal dialysis units in Spain. A total of 1,403 patients on peritoneal dialysis were included in the study, of whom 186 (13.2%) had non-valvular atrial fibrillation. In addition, the assessment of the scores of thromboembolic and bleeding risks for the indication of oral anticoagulation was mainly carried out by the cardiologist (60% of the units), as well as its prescription (cardiologist 47% or in consensus with the nephrologist 43%). In summary, patients on peritoneal dialysis have a remarkable prevalence of non-valvular atrial fibrillation. Patients frequently receive oral anticoagulation with vitamin K antagonists, as well as direct oral anticoagulants. The data obtained regarding the scores used for the assessment of thromboembolic and bleeding risk, treatment and involvement by Nephrology indicates that there is a need for training and involvement of the nephrologist in this pathology.

Fibrilación auricular no valvular en pacientes en diálisis peritoneal: prevalencia, tratamiento y profesionales implicados / Non-valvular atrial fibrillation in patients on peritoneal dialysis: prevalence, treatment and professionals involved

La fibrilación auricular (FA) es la arritmia crónica más frecuente en pacientes con enfermedad renal crónica (ERC). La anticoagulación oral con antagonistas de la vitamina K (AVK) y actualmente los anticoagulantes orales de acción directa (ACOD) han sido el pilar fundamental para la prevención de eventos tromboembólicos. Sin embargo, no existen ensayos clínicos aleatorizados de su perfil riesgo-beneficio en pacientes con ERC estadio 5 en diálisis peritoneal (DP) y son pocas las evidencias en la literatura sobre esta población. El objetivo del estudio fue conocer la prevalencia, tratamiento y profesionales implicados en el manejo de la FA en DP en nuestro entorno mediante el análisis descriptivo de una encuesta enviada a diferentes unidades de DP de España. Se incluyeron en el estudio 1.403 pacientes en programa de DP, de los cuales 186 (13,2%) presentaban FA no valvular (FANV). Además, observamos que la valoración de los scores para el inicio del tratamiento anticoagulante la realizaba mayoritariamente el cardiólogo (60% de los centros), así como la prescripción de anticoagulación (cardiólogo 47% o en conjunto con el nefrólogo 43%). En conclusión, los pacientes en DP presentan una notable prevalencia de FANV. Reciben frecuentemente anticoagulación oral (ACO) con AVK, así como con ACOD. Los datos obtenidos respecto a las escalas utilizadas para la valoración de riesgo tromboembólico y de sangrado, tratamiento e implicación por parte de Nefrología indican que existe una necesidad de formación e involucramiento del nefrólogo en esta patología.(AU)

Atrial fibrillation is the most frequent chronic arrhythmia in patients with chronic kidney disease. Oral anticoagulation with vitamin K antagonists and now direct oral anticoagulants have been and are the fundamental pillar for the prevention of thromboembolic events. However, there are no randomized clinical trials on the risk-benefit profile of oral anticoagulation in patients with chronic kidney disease stage 5 on peritoneal dialysis and there is little evidence in the literature in this population. The objective of our study was to know the prevalence, treatment and professionals involved in the management of atrial fibrillation in peritoneal dialysis patients. For this purpose, we performed a descriptive analysis through a survey sent to different peritoneal dialysis units in Spain. A total of 1403 patients on peritoneal dialysis were included in the study, of whom 186 (13.2%) had non-valvular atrial fibrillation. In addition, the assessment of the scores of thromboembolic and bleeding risks for the indication of oral anticoagulation was mainly carried out by the cardiologist (60% of the units), as well as its prescription (cardiologist 47% in consensus with the nephrologist 43%). In summary, patients on peritoneal dialysis have a remarkable prevalence of non-valvular atrial fibrillation. Patients frequently receive oral anticoagulation with vitamin K antagonists, as well as direct oral anticoagulants. The data obtained regarding the scales used for the assessment of thromboembolic and bleeding risk, treatment and involvement by Nephrology indicates that there is a need for training and involvement of the nephrologist in this pathology.(AU)

Situación actual de los anticoagulantes orales de acción directa en atención primaria de España. Posicionamiento de SEMERGEN en 2023 / Current situation of direct oral anticoagulants in primary care in Spain: Positioning of SEMERGEN in 2023

La anticoagulación oral es clave para disminuir el riesgo de ictus en la fibrilación auricular. Aunque clásicamente los antagonistas de la vitaminaK (AVK) se han empleado para este fin, han sido ampliamente superados por los anticoagulantes orales de acción directa (ACOD), como lo demuestran las evidencias provenientes de los ensayos clínicos, estudios de vida real y poblacionales. De hecho, todas las guías de práctica clínica recomiendan su uso de manera preferencial sobre los AVK. Sin embargo, en España la prescripción de los ACOD está subordinada a un visado de inspección que recoge las condiciones clínicas definidas en el Informe de Posicionamiento Terapéutico de la Agencia Española del Medicamento, y que todavía impone importantes restricciones a su uso, limitando los beneficios del empleo de los ACOD en los pacientes con fibrilación auricular (FA), y generando además inequidades entre las diferentes comunidades autónomas. De hecho, el empleo de los ACOD en España es muy inferior a los países de nuestro entorno. Esto ha provocado que en otros países ha disminuido la incidencia de ictus isquémico a nivel poblacional, junto con una reducción del coste por paciente con FA, pero en España este descenso ha sido discreto. Por todo ello, y en aras de la sostenibilidad del sistema sanitario, pedimos la eliminación del visado para que los ACOD se puedan prescribir de acuerdo a las recomendaciones realizadas por las guías. Además, también apostamos por el refuerzo de la formación y de las decisiones consensuadas con el paciente, siendo el médico de familia un actor clave en la protección del paciente con FA.(AU)

Oral anticoagulation is the key to reduce the risk of stroke in atrial fibrillation. Although vitaminK antagonists (VKA) have classically been used for this purpose, they have been largely overcome by direct oral anticoagulants (DOAC), as demonstrated by evidence from clinical trials, real-life and population studies. In fact, all clinical practice guidelines recommend their use preferentially over VKA. However, in Spain the prescription of DOAC is subordinated to an inspection visa that includes the clinical conditions defined in the Therapeutic Positioning Report of the Spanish Medicines Agency, and that still imposes important restrictions on their use, limiting the benefits of using DOACs in patients with atrial fibrillation (AF), and also generating inequalities between the different autonomous communities. In fact, the use of DOAC in Spain is much lower than that observed in neighboring countries. This has made that while in other countries the incidence of ischemic stroke has decreased at the population level, along with a reduction in the cost per patient with AF, in Spain this decrease has been modest. For all these reasons, and for assuring the sustainability of the health care system, we ask for the elimination of the visa so that DOAC can be prescribed according to the recommendations made by the guidelines. In addition, we are also committed to reinforce medical education and decisions made by consensus with the patient, with the primary care physician acquiring a key role in the protection of the patient with AF.(AU)

Recommendations for the safe use of direct oral anticoagulants in patients with cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data.

PURPOSE: The popularity of direct oral anticoagulants (DOACs) is increasing among patients with cirrhosis. Cirrhosis has a major impact on the pharmacokinetics of drugs, potentially increasing adverse events. Safe use of drugs in cirrhosis requires a diligent risk-benefit analysis. The aim of this study is to develop practice recommendations for safe use of DOACs in cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data. METHODS: We conducted a systematic literature search to identify studies on pharmacokinetics, pharmacodynamics and safety of DOACs in cirrhosis. Data were collected and presented in summary tables by severity of cirrhosis using the Child-Turcotte-Pugh (CTP) classification. A multidisciplinary expert panel evaluated the results and classified the DOACs according to safety. RESULTS: Fifty four studies were included. All DOACs were classified as 'no additional risks known' for CTP A. For CTP B, apixaban, dabigatran and edoxaban were classified as 'no additional risks known'. Apixaban and edoxaban showed fewer adverse events in patients with cirrhosis, while dabigatran may be less impacted by severity of cirrhosis based on its pharmacokinetic profile. Rivaroxaban was classified as 'unsafe' in CTP B and C based on significant pharmacokinetic alterations. Due to lack of data, apixaban, dabigatran and edoxaban were classified as 'unknown' for CTP C. CONCLUSION: DOACs can be used in patients with CTP A cirrhosis, and apixaban, dabigatran and edoxaban can also be used in CTP B. It is recommended to avoid rivaroxaban in CTP B and C. There is insufficient evidence to support safe use of other DOACs in CTP C cirrhosis.

How the Hemostasis Laboratory Can Help Clinicians to Manage Patients on Oral Anticoagulants.

Oral anticoagulants are widely used to treat or prevent cardiovascular diseases in millions of patients worldwide. They are the drugs of choice for stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation and prosthetic heart valves, as well as for treatment/prevention of venous thromboembolism. Oral anticoagulants include vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). The hemostasis laboratory plays a crucial role in the management of treated patients, spanning from dose adjustment based on laboratory testing that applies to VKAs to the measurement of drug concentrations in special situations that apply to DOACs. This article aims to overview how the hemostasis laboratory can help clinicians manage patients on oral anticoagulants. Special interest is devoted to the international normalized ratio, used to manage patients on VKAs and to the measurement of DOAC concentrations, for which the role of the laboratory is still not very well defined, and most interferences of DOACs with some of the most common hemostatic parameters are not widely appreciated.

Secondary Prophylaxis of Venous Thromboembolism (VTE) with Low Dose Apixaban or Rivaroxaban: Results from a Patient Population with More than 2 Years of Median Follow-up.

Background: Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Nowadays, DOACs represent the gold standard for long-term anticoagulation, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit low-intensity apixaban and rivaroxaban are approved for clinical usage as secondary VTE prophylaxis, there are few literature data regarding their efficacy and safety with a long follow-up. Objectives: The aim of our study was to evaluate the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis in patients at high risk of VTE recurrence. Methods: We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily with a follow-up ≥ 12 months. Results: The examined patients were 323. The median low-dose DOAC administration time was 25.40 months (IQR 13.93-45.90). Twelve (3.7%) VTE recurrences were observed; 21 bleeding events were registered (6.5%), including one episode of Major bleeding (MB) (0.3%), 8 Clinically relevant nonmajor bleeding (CRNMB) (2.5%) and 12 minor bleeding (3.7%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between the rivaroxaban and apixaban groups. Patients included in the study for multiple episodes of VTE presented a significantly higher risk of a new VTE recurrence during low-intensity DOAC. Conclusions: Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis in patients at high risk of VTE recurrence; however, attention might be needed in their choice in such a scenario for patients who experienced multiple episodes of VTE.

Epicardial left atrial appendage clipping versus direct oral anticoagulant to reduce stroke risk in non-paroxysmal atrial fibrillation (LAA-CLIP): rationale, design and study protocol for a multicentre randomised controlled trial.

INTRODUCTION: The prevalence of atrial fibrillation (AF) is increasing globally, and stroke prevention is the key to reduce the morbidity and mortality related to AF. Currently, direct oral anticoagulants (DOACs) are the primary options for stroke prevention, while it increases risk of bleeding. Left atrial appendage (LAA) is suspected as a vital source of cerebral emboli and may lead to ischaemic stroke, and thoracoscopic LAA clipping procedure provides an alternative option for stroke prevention in high-risk patients. However, high-quality evidence comparing LAA clipping to DOACs in terms of stroke prevention is lacking. This trial is designed to assess whether the efficacy of thoracoscopic LAA clipping is superior to DOACs for stroke prevention in AF patients at high risk of thrombosis (CHA2DS2-VASc≥2 in men and ≥3 in women)[CHA2DS2-VASc stands for "congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female)"]. METHODS AND ANALYSIS: This is a prospective, multicentre, open-labelled, randomised controlled study. This trial will randomly assign 290 patients with non-paroxysmal AF to thoracoscopic LAA clipping group or DOAC therapy group in a 1:1 randomisation. The primary endpoint is defined as a composite endpoint event consisting of stroke, systemic embolism, all-cause mortality, major bleeding events and clinically relevant non-major bleeding events at 24 months after randomisation. The secondary endpoints consist of the components of the primary composite endpoint, surgery-related adverse events and minor bleeding events. ETHICS AND DISSEMINATION: The central ethics committee at Fuwai Hospital approved the trial entitled "Epicardial left atrial appendage clipping versus direct oral anticoagulant to reduce stroke risk in non-paroxysmal atrial fibrillation (LAA-CLIP trial)". The results of this study will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT06021808.

Management of direct oral anticoagulant drug interactions in hospitalized patients.

Moderate-strong CYP3A4 or Pgp inhibitors and inducers alter direct oral anticoagulant (DOAC) pharmacokinetics. Whether the presence of a DOAC drug-drug interaction (DDI) prompts in- hospital changes in management remains unknown. We identified all hospitalized patients at our institution who were admitted with a clinically relevant DOAC DDI from 01/2021 to 06/2021. Clinically relevant DOAC DDIs were defined as those listed in the prescribing information or FDA CYP3A4/Pgp inhibitors clinical indexes. We assessed the prevalence of DOAC DDIs and categorized their management as: drug stopped, drug held, or drug continued. For drugs that were continued we assessed whether the dose of the DOAC or interacting drug was increased, decreased or unchanged during the admission. We ascertained the number of DOAC DDIs that prompted an automated prescribing alert in our electronic health record (EHR). Finally, we conducted a logistic regression model to compare users of DOACs with DDI who had their regimen adjusted versus those without adjustments, focusing on outcomes of rehospitalization and death, adjusting for age and gender. Among 3,725 hospitalizations with a DOAC admission order, 197 (5%) had a clinically relevant DOAC DDI. The DOAC and the interacting drug were continued at discharge for 124 (63%) hospitalizations. The most frequent adjustments were stopping the interacting drug (73%) and stopping the DOAC (15%). Only 7 (4%) of DOAC DDIs prompted an EHR alert. The adjusted odds ratios for rehospitalizations and death, respectively, among patients whose regimens were adjusted compared to those whose were not, were 1.29 (95% CI, 0.67 to 2.48; P = 0.44) and 1.88 (95% CI, 0.91 to 3.89; P = 0.09). Clinically relevant DDIs with DOACs occur infrequently among hospitalized patients and usually are managed without stopping the DOAC. The clinical impact of such DDIs and subsequent adjustments on thrombotic and hemorrhagic outcomes requires further investigation.

Anticoagulation in venous thromboembolism for the general physician.

Venous thromboembolism (VTE) is frequently encountered across various specialties. The management of VTE has become more nuanced, requiring consideration of several factors when deciding on the choice and duration of anticoagulation. This evidence-based review article summarises the current practice and evidence behind anticoagulation in VTE, incorporating national and international guidelines. Factors influencing decision-making around the choice and duration of anticoagulation, along with special circumstances such as cancer and antiphospholipid syndrome, are discussed. The clinical utility of thrombophilia screening is also addressed.

Real-world Data on Treatment Patterns and Bleeding in Cancer-associated Thrombosis: Data from the TROLL Registry.

Background International guidelines are increasingly recommending direct oral anticoagulants (DOACs) as the first-line treatment for cancer-associated thrombosis (CAT). However, data regarding treatment patterns and adherence to guidelines in patients with CAT are scarce. Objectives This study aimed to explore anticoagulant treatment patterns in patients with CAT and to calculate the incidence rates of bleeding events. Methods Patients ≥18 years with active cancer and a first-time venous thromboembolism between 2005 and 2020 were identified through the Venous T hrombosis R egistry in Østf OL d Hospita L . Outcome measures were patterns of anticoagulant treatment during the study period and bleeding events. We calculated overall incidence rates per 100 person-years and 6- and 12-month cumulative incidence of major and clinically relevant nonmajor bleeding (CRNMB) during anticoagulant treatment. Results Median age of 842 CAT patients at the time of thrombosis was 69 years (interquartile range 61-77), and 443 (52.6%) were men. In total, 526 patients (62.5%) had pulmonary embolism and 255 (30.3%) had deep vein thrombosis. Low molecular weight heparin (LMWH) was prescribed to 713 (85.8%) patients, whereas 64 (7.7%) received DOACs and 54 (6.5%) received vitamin K antagonists as the initial anticoagulant treatment. Prescription of DOACs as initial treatment increased from 3.0% in 2013/2014 to 18.0% in 2019/2020. The incidence rate of major bleeding was 6.9 (95% confidence interval [CI] 5.2-9.2) and 10.1 (95% CI 8.0-12.9) in CRNMB. Conclusion Most patients were treated with LMWH. However, a gradual shift in treatment toward DOACs was observed. Overall, bleeding complications were rare and comparable to those reported in randomized trials.

Management of isolated distal deep vein thrombosis.

Isolated distal deep vein thrombosis (DVT) represents up to 50% of all lower limb DVT in ultrasound series and is a frequent medical condition, which management is not well established. Data arising from registries and non-randomized studies suggest that most distal DVTs do not extend to the proximal veins and have an uneventful follow-up when left untreated. This data had some impact on international recommendations like the American College of Chest Physicians (ACCP), whose last version stated that ultrasound surveillance might be an option for selected low-risk patients. However, robust data arising from randomized studies are scarce. Indeed, only seven randomized trials assessing the need for anticoagulation for calf DVT have been published. Many of these trials had an open-label design and were affected by methodological limitations. When considering randomized placebo-controlled trials, one included low-risk patients and was hampered by a limited statistical power (CACTUS study). Nevertheless, data from this trial tend to confirm that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE but is associated with a higher risk of bleeding. A second randomized placebo-controlled trial did not assess the necessity of anticoagulant treatment but rather the long-term risk of recurrence and compared 6 weeks versus 12 weeks of treatment with rivaroxaban (RIDTS study). Finally, the last available randomized trial compared a 3-month versus a 12-month edoxaban treatment in patients with cancer and mainly asymptomatic distal DVT, detected by systematic compression ultrasonography. Overall, available data suggest that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE. High risk patients (previous VTE, active cancer, inpatients) might benefit from a course of anticoagulant treatment. However, the optimal anticoagulant intensity and duration are uncertain and further studies are needed.

Drug-related problems associated with direct oral anticoagulants: an observational cross-sectional study of medical record review by pharmacists in a large teaching hospital.

Background: Prescribing DOACs presents with challenges in the elderly and patients with renal and hepatic impairment. To mitigate safety risks, pharmacists have a role in detection, prevention, and resolution of DOAC-associated drug-related problems (DRPs). Objectives: To identify the types of DOAC-associated DRPs in patients on DOAC therapy and factors that predispose patients to DOAC-associated DRPs. Methods: An observational cross-sectional study was conducted in SGH from January 1, 2017, to May 31, 2019, on patients prescribed with a DOAC (rivaroxaban, dabigatran, and apixaban). Data were electronically extracted for patient demographics, clinical characteristics, and details of DOAC-related DRPs identified by pharmacists. Matching of DRP group to non-DRP group at a ratio of 1:2 based on gender, race, and DOAC was performed. The DRP group included patients with detected DRPs while non-DRP group included patients without them. Descriptive analysis was used to summarize patient characteristics and types of DOAC-associated DRPs. In the matched population, conditional logistic regression was used to calculate unadjusted (UOR) and adjusted odds (AOR) ratio to detect association of DOAC-associated DRPs with age, renal function, ≥2 comorbidities, and DOAC indication (atrial fibrillation [AF] vs venous thromboembolism). Results: A total of 8432 patients prescribed DOACs were analyzed, which consisted of 827 (9.8%) and 7602 (90.2%) patients with DRPs and no DRPs, respectively. The top DOAC-associated DRP was inappropriate drug regimen (n = 487, 60.1%). After matching, 2403 patients were analyzed, consisting of 801 patients from DRP group and 1602 from non-DRP group. Factors associated with DOAC-associated DRPs were statistically significant for renal function at creatinine clearance (CrCl) of >30 to 50 mL/min/1.73 m2 (AOR: 1.42; 95% CI: 1.14-1.76; P = .002), 15 to 30 mL/min/1.73 m2 (OR: 1.94; 95% CI: 1.42-2.66; P < .001), and <15 mL/min/1.73m2 (OR: 2.35; 95% CI: 1.13-4.88; P = .022), respectively, compared with a CrCl of >50 mL/min/1.73 m2 and DOAC indication for AF (AOR: 1.84; 95% CI: 1.47-2.30; P < .001) compared with venous thromboembolism. Conclusion: Inappropriate drug regimen was the most common DOAC-associated DRP. Impaired renal function and patients with AF increased the likelihood of DOAC-associated DRPs.

Predictors of Plasma Levels of Direct Oral Anticoagulants Among Patients with Atrial Fibrillation in Need of Elective Cardiac Procedures.

BACKGROUND: The withdrawal timing of direct oral anticoagulants (DOACs) among patients in need of elective invasive surgery is based on DOAC pharmacokinetics in order to perform the procedure out of the DOAC peak plasma concentration. We aimed to investigate the prevalence and predictors of plasma levels of DOACs out of trough range in patients with atrial fibrillation (AF) in need of elective cardiac procedure. MATERIALS AND METHODS: We evaluated all consecutive AF patients on DOAC therapy in need of elective cardiac procedure, admitted to our division from January 2022 to March 2022. All patients underwent DOAC plasma dosing the morning of procedure day. They were categorized as in range, above range, and below range, according to the DOAC reference range at the downstream point. The timing of discontinuation of DOAC therapy was considered as appropriate or not, according to the current recommendations. The clinical predictors of out-of-range DOAC plasma levels have been evaluated. RESULTS: We included 90 consecutive AF patients (56.6% male, mean age 72.95 ± 10.12 years); 74 patients (82.22%) showed DOAC concentration out of the expected reference range. In half of them (n, 37), the DOAC plasma concentration was below the trough reference range. Of the study population, 17.7% received inappropriate DOAC dosages (10% overdosing, 7% underdosing), and 35.5% had incorrect timing of DOAC withdrawal (26% prolonged, 9.5% shortened). At multivariable analysis, inappropriate longer DOAC withdrawal period (OR 10.13; P ≤ 0.0001) and increased creatinine clearance (OR 1.01; P = 0.0095) were the independent predictors of plasma DOAC levels below the therapeutic trough range. In contrast, diabetes mellitus (OR 4.57; P = 0.001) was the only independent predictor of DOAC plasma level above the therapeutic trough range. CONCLUSION: Increased creatinine clearance and inappropriate longer drug withdrawal period are the only independent predictors of DOAC plasma levels below the reference range; in contrast, diabetes is significantly correlated with DOAC plasma levels above the reference.