Impact of prior oral anticoagulation therapies on post-discharge outcomes after COVID-19: Results from a global federated health network analysis.

BACKGROUND: The impact of chronic oral anticoagulant (OACs) use on long-term post-discharge outcomes after coronavirus disease 2019 (COVID-19) hospitalisation remains unclear. Herein, we compared clinical outcomes up to 2-years after COVID-19 hospitalisation between patients on vitamin K antagonists (VKAs), direct-acting OACs (DOACs) and no OAC therapy. METHODS: Data from TriNetX, a global federated health research network, were used. Adult patients on VKAs, DOACs or no OAC therapy at diagnosis of COVID-19 between 20 January 2020 and 31 December 2021, who were hospitalised for COVID-19, were included. The primary outcomes were all-cause mortality, ischaemic stroke/transient ischaemic attack (TIA)/systemic embolism (SE) and the composite of intracranial haemorrhage (ICH)/gastrointestinal bleeding, at 2 years after COVID-19 hospitalisation. RESULTS: We included 110,834 patients with COVID-19. Following propensity score matching (PSM), we identified a decreased mortality risk in DOAC-treated patients compared to the no OAC cohort (RR .808, 95% CI .751-.870). A higher risk of ischaemic stroke/TIA/SE was observed in VKA users compared to DOAC users (RR 1.100, 95% CI 1.020-1.220) and in VKA users compared to patients not taking OAC (RR 1.400, 95% CI 1.140-1.720). VKA use was associated with a greater risk of ICH/gastrointestinal bleeding than DOAC users (RR 1.198, 95% CI 1.066-1.347), while DOAC users had a lower risk compared to no OAC-treated patients (RR .840, 95% CI .754-.936). CONCLUSION: COVID-19 patients taking prior DOACs were associated with lower long-term mortality risk and ICH/gastrointestinal bleeding than patients not taking OAC. Compared to patients on DOACs, VKA users were associated with higher risks of mortality, ischaemic stroke/TIA/SE and ICH/gastrointestinal bleeding.

Rethinking the use of direct oral anticoagulants for secondary thromboprophylaxis in patients with thrombotic antiphospholipid syndrome.

Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis, and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation, and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lack of need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a triple positivity for antiphospholipid antibodies. No differences were observed in the incidence of venous thromboembolism between both groups. Major bleeding was similar in patients treated with DOACs or VKAs. Several observational studies have reported similar results. This review aims to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention in patients with APS.

Anticoagulation strategy for patients presenting with ischemic strokes while using a direct oral anticoagulant: A systematic review and meta-analysis.

BACKGROUND: While direct-acting oral anticoagulants (DOACs) have established efficacy in reducing the risk of ischemic stroke, they still leave a residual risk of stroke, which may be greater in practice (0.7-2.3%) than in controlled clinical trial settings. This meta-analysis examines four therapeutic approaches following a stroke in patients already on DOACs: continuing with the same DOAC, changing to a different DOAC, increasing the current DOAC dosage, or switching to a vitamin K antagonist (VKA), such as warfarin. METHODS: Systematic review of literature from the MEDLINE, Embase, and Cochrane databases, was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The analysis focused on six studies with varied patient demographics, examining as outcomes as recurrent ischemic stroke, intracranial hemorrhage, other bleeding events, and mortality. RESULTS: Six studies comprising 12,159 patients were included, all of them were observational. Patients who remained on their initial DOAC regimen had a lower risk of experiencing ischemic strokes (risk ratio (RR) 0.55; 95% confidence interval (CI) 0.43-0.70; p < 0.001; I2 = 0%), intracranial hemorrhage (RR 0.37; 95% CI 0.25-0.55; p < 0.001; I2 = 0%), and hemorrhagic events (RR 0.44; 95% CI 0.30-0.63; p < 0.001; I2 = 6%) compared to those who were switched to warfarin, with an increase in mortality rates (hazard ratio (HR) 1.85; 95% CI 1.06-3.24; p = 0.03; I2 = 84%). In contrast, neither changing to a different DOAC nor adjusting the dose proved to be more effective than the original regimen. CONCLUSION: Post-stroke adjustments to anticoagulation therapy-whether altering the drug or its dosage-do not yield additional benefits. In addition, the results suggest that warfarin may be less effective than DOACs for preventing stroke recurrence, bleeding complications, and death in this patient population.

Effective application of a direct-acting oral anticoagulants reversal agent in acute type A aortic dissection repair: A case report.

There are insufficient reports on the use of andexanet alfa in cardiac surgery. A 67-year-old man was diagnosed with type A aortic dissection and performed emergent surgery. His medical history included atrial fibrillation treated with Edoxaban. We performed total arch replacement. Despite administration of enough protamine, fresh frozen plasma, and platelet administration, controlling bleeding was difficult. Thus, Andexanet Alfa was initiated after CPB withdrawal. Surgical bleeding was dramatically controlled after its administration. There were no findings suggestive of an embolic event. In conclusion, administration of Andexanet Alfa is safe after cardiopulmonary bypass withdrawal.

Evaluation of the Hemocompatibility of the Direct Oral Anticoagulant Apixaban in Left Ventricular Assist Devices: The DOAC LVAD Study.

BACKGROUND: Patients receiving left ventricular assist device (LVAD) support require long-term anticoagulation to reduce the risk of thromboembolic complications. Apixaban is a direct oral anticoagulant that has become first-line therapy; however, its safety in LVAD recipients has not been well described. OBJECTIVES: This study sought to investigate whether, in patients with a fully magnetically levitated LVAD, treatment with apixaban would be feasible and comparable with respect to safety and freedom from the primary composite outcome of death or major hemocompatibility-related adverse events (HRAEs) (stroke, device thrombosis, major bleeding, aortic root thrombus, and arterial non-central nervous system thromboembolism) as compared with treatment with warfarin. METHODS: The DOAC LVAD (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices) trial was a phase 2, open label trial of LVAD recipients randomized 1:1 to either apixaban 5 mg twice daily or warfarin therapy. All patients were required to take low-dose aspirin. Patients were followed up for 24 weeks to evaluate the primary composite outcome. RESULTS: A total of 30 patients were randomized: 14 patients to warfarin and 16 patients to apixaban. The median patient age was 60 years (Q1-Q3: 52-71 years), and 47% were Black patients. The median time from LVAD implantation to randomization was 115 days (Q1-Q3: 56-859 days). At 24 weeks, the primary composite outcome occurred in no patients receiving apixaban and in 2 patients (14%) receiving warfarin (P = 0.12); these 2 patients experienced major bleeding from gastrointestinal sources. CONCLUSIONS: Anticoagulation with apixaban was feasible in patients with an LVAD without an excess of HRAEs or deaths. This study informs future pivotal clinical trials evaluating the safety and efficacy of apixaban in LVAD recipients. (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices [DOAC LVAD]; NCT04865978).

Does in vitro hemolysis affect measurements of plasma apixaban concentration by UPLC-MS and anti-Xa assay?

INTRODUCTION: Hemolytic interference may impact various laboratory tests, including coagulation analyses. Apixaban is the most commonly used direct oral anticoagulant in Norway, and there is lacking knowledge on how apixaban concentration measurements might be influenced by hemolysis. Moreover, hemolysis-induced alterations in apixaban levels could potentially impact the risk of bleeding in specific clinical scenarios. We wanted to study whether hemolysis would increase apixaban concentration and investigate the impact of hemolytic interference on apixaban concentration measurements. METHODS: Blood samples from 20 apixaban-treated patients and 8 healthy controls were hemolyzed in vitro by a freeze method. The degree of hemolysis was measured with plasma free hemoglobin (PfHb) at baseline and two levels of hemolysis. Apixaban concentration was measured in plasma using both the chromogenic anti-Xa method and the ultraperformance liquid chromatography mass spectrometry (UPLC-MS). Thrombin generation assay was performed to assess coagulability. RESULTS: UPLC-MS measurements showed a mean concentration change of -1.66% (±3.2%, p = 0.005) and anti-Xa assay showed a mean concentration change of 3.37% (±6.5%, p = 0.09) with increasing hemolysis. Thrombin generation lagtime decreased, and endogenous thrombin potential and peak thrombin increased with increasing hemolysis in both the control group and the apixaban group. CONCLUSION: Apixaban concentration measurements by anti-Xa assay and UPLC-MS were not affected by hemolysis to a clinically relevant extent. Furthermore, hemolysis did not lead to hypocoagulability when assessed by thrombin generation.

Use of direct-acting anticoagulants (DOACs) delays surgery and is associated with increased mortality in hip fracture patients.

PURPOSE: Treatment with direct-acting oral anticoagulants (DOACs) is increasing among hip-fracture patients, with accompanying safety concerns regarding spinal anesthesia (SA). The aim of this study was to investigate if DOAC use is associated with increased waiting time before surgery, increased mortality, or other adverse events. METHODS: Registry data on surgically treated hip-fracture cases at a single hospital between 2015 and 2021 were analyzed. Multivariable regression analyses were performed with DOAC-status and choice of anesthesia as exposures, and waiting time, length of stay, transfusion, and mortality as outcomes. RESULTS: 2885 cases were included, 467 patients (16%) were using DOACs. DOAC users were older (86.3 vs. 82.2 years, p < 0.001), had a higher Charlson Comorbidity Index (2.1 vs. 1.5, p < 0.001) and had longer median time to surgery than non-DOAC cases (36 h vs 17 h, p < 0.001). General anesthesia (GA) was used in 19.3% of DOAC patients and in 3.0% of non-DOAC patients. DOAC-patients had an increased risk of one-month mortality (Adjusted Odds Ratio (AOR) 1.6 (1.1-2.3)) and one-year mortality (AOR 1.4 (1.1-1.8)). There were no differences in risk of blood transfusion. Patients on DOAC operated under GA had a lower risk of one-year mortality (AOR 0.5 (0.3-0.9)), but a similar one-month mortality to DOAC-patients operated under SA. CONCLUSION: DOAC users had a longer waiting time to surgery, indicating postponement of surgery due to concerns of the safety of SA. The clinical practice should be changed to allow earlier surgery for DOAC patients.

Effectiveness of edoxaban in portal vein thrombosis associated with liver cirrhosis.

Portal vein thrombosis (PVT) worsens the long-term prognosis of patients with cirrhosis; however, the optimal treatment remains to be determined. Reports on the efficacy of direct oral anticoagulants are increasing, and further evidence is needed. Therefore, we investigated the effectiveness of treatment with edoxaban in patients with PVT. We retrospectively reviewed the outcomes of edoxaban and warfarin as antithrombotic therapies for PVT. The median overall survival time was 4.2 years in patients with PVT, with a 1-year survival rate of 70.7% and a 5-year survival rate of 47.9%. The leading cause of death was hepatocellular carcinoma. The overall response rate for thrombolysis in the edoxaban group was 76.7% compared to 29.4% in the warfarin group, and edoxaban significantly improved PVT compared to warfarin. In addition, edoxaban provided long-term improvement of PVT. Warfarin, on the other hand, was temporarily effective but did not provide long-term benefits. The Child-Pugh and albumin-bilirubin scores did not change after edoxaban or warfarin use. No deaths occurred due to adverse events associated with edoxaban or warfarin. Edoxaban as a single agent can achieve long-term recanalization without compromising the hepatic reserves. Edoxaban is easy to initiate, even in an outpatient setting, and could become a major therapeutic agent for the treatment of PVT.

Comparison of Effectiveness and Safety of Direct-Acting Oral Anticoagulants and Vitamin K Agonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease: A Systematic Review and Meta-Analysis.

The objective of the study is mentioned, but it could be further clarified by explicitly stating the aim to compare the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) specifically in patients with atrial fibrillation (AF) and end-stage renal disease (ESRD). We conducted a thorough electronic search of the literature, encompassing databases such as PubMed, EMBASE, Cochrane Library, and Web of Science from their inception up to March 5, 2024. Furthermore, we meticulously examined the bibliographies of included studies to identify additional relevant literature. The reporting of this meta-analysis adhered to the guidelines outlined in the Preferred Reporting of Systematic Review and Meta-analysis guidelines. The endpoints evaluated in this meta-analysis included all-cause mortality, stroke or systemic embolism, and major bleeding. Data analysis was carried out utilizing RevMan Version 5.4 (Cochrane, London, United Kingdom). Dichotomous outcomes, including all-cause mortality, stroke or systemic embolism, and major bleeding, were presented as risk ratios (RRs) with corresponding 95% confidence intervals (CI). A total of 11 studies were incorporated in this meta-analysis, comprising a pooled sample size of 44,863 participants with AF. The pooled analysis revealed no significant disparity between DOACs and VKAs concerning stroke or systemic embolism (RR: 0.93, 95% CI: 0.77 to 1.14) and all-cause mortality (RR: 0.86, 95% CI: 0.74 to 1.00). However, there was a noteworthy reduction in the risk of major bleeding events associated with DOACs compared to VKAs (RR: 0.84, 95% CI: 0.73 to 0.96). Consequently, DOACs may be considered a viable alternative to warfarin in patients with ESRD. However, we need further larger clinical trials to validate these findings.

Equivalent thrombotic risk with Warfarin, Dabigatran, or Enoxaparin after failure of initial direct oral anticoagulation (DOAC) therapy.

BACKGROUND: The direct oral anticoagulants (DOACs) are now commonly regarded as first line anticoagulants in most cases of venous thromboembolism (VTE). However, the optimal choice of subsequent anticoagulant in instances of first line DOAC failure is unclear. OBJECTIVES: To describe and compare outcomes with second line anticoagulants used after DOAC failure. METHODS: Patients seen at an urban hospital system for an episode of acute VTE initially treated with either apixaban or rivaroxaban who experienced a subsequent recurrent thrombosis while on anticoagulation (1st recurrent thrombosis) were included. RESULTS: In total, 166 patients after apixaban or rivaroxaban failure were included. Following DOAC failure (1st recurrent thrombosis), the subsequent anticoagulant was warfarin in 60 patients (36%), dabigatran in 42 patients (25%), and enoxaparin in 64 patients (39%). Enoxaparin was preferentially prescribed in patients with a malignancy-associated etiology for 1st recurrent thrombosis (p < 0.01). The median follow-up time in our cohort was 16 months. There was no difference in 2nd recurrent thrombosis-free survival (p = 0.72) or risk for major bleeding event (p = 0.30) among patients treated with dabigatran, warfarin, or enoxaparin. CONCLUSIONS: In this retrospective analysis of patients failing first line DOAC therapy, rates of 2nd recurrent thrombosis and bleeding did not differ among subsequently chosen anticoagulants. Our study provides evidence that the optimal 2nd anticoagulant is not clear, and the choice of 2nd anticoagulant should continue to balance patient preference, cost, and provider experience.

Evidence of the association between increased use of direct oral anticoagulants and a reduction in the rate of atrial fibrillation-related stroke and major bleeding at the population level (2012–2019) / Evidencia a nivel poblacional de la asociación entre el aumento del uso de anticoagulantes orales directos y una reducción de la incidencia de ictus y hemorragias mayores relacionados con fibrilación auricular (2012-2019)

Background: The introduction of direct-acting oral anticoagulants (DOACs) has shown to decrease atrial fibrillation (AF)-related stroke and bleeding rates in clinical studies, but there is no certain evidence about their effects at the population level. Our aim was to assess changes in AF-related stroke and major bleeding rates between 2012 and 2019 in Andalusia (Spain), and the association between DOACs use and events rates at the population level. Methods: All patients with an AF diagnosis from 2012 to 2019 were identified using the Andalusian Health Population Base, that provides clinical information on all Andalusian people. Annual ischemic and hemorrhagic stroke, major bleeding rates, and used antithrombotic treatments were determined. Marginal hazard ratios (HR) were calculated for each treatment. Results: A total of 95,085 patients with an AF diagnosis were identified. Mean age was 76.1±10.2 years (49.7% women). An increase in the use of DOACs was observed throughout the study period in both males and females (p<0.001). The annual rate of ischemic stroke decreased by one third, while that of hemorrhagic stroke and major bleeding decreased 2–3-fold from 2012 to 2019. Marginal HR was lower than 0.50 for DOACs compared to VKA for all ischemic or hemorrhagic events. Conclusions: In this contemporary population-based study using clinical and administrative databases in Andalusia, a significant reduction in the incidence of AF-related ischemic and hemorrhagic stroke and major bleeding was observed between 2012 and 2019. The increased use of DOACs seems to be associated with this reduction.(AU)

Introducción: La introducción de los anticoagulantes orales de acción directa (ACOD) ha demostrado disminuir las tasas de accidentes cerebrovasculares y hemorragias relacionados con fibrilación auricular (FA) en estudios clínicos, pero no hay tanta evidencia sobre sus efectos a nivel poblacional. Nuestro objetivo fue evaluar los cambios en la incidencia de ictus y hemorragias mayores relacionados con FA entre 2012 y 2019 en Andalucía (España), y estudiar la asociación entre el uso de ACOD y estos eventos a nivel poblacional. Métodos: Se incluyeron pacientes con diagnóstico de FA entre los años 2012 y 2019 en la Base de Población Sanitaria de Andalucía, que proporciona información clínica de todos los andaluces. Se determinaron los accidentes cerebrovasculares isquémicos y hemorrágicos anuales, las tasas de sangrado mayor y los tratamientos antitrombóticos utilizados. Se estimaron los hazard ratio para cada tratamiento. Resultados: Se identificaron un total de 95.085 pacientes con diagnóstico de FA. La edad media fue de 76,1±10,2 años (49,7% mujeres). Se observó un aumento en el uso de ACOD a lo largo del período de estudio, tanto en varones como en mujeres (p<0,001). La tasa anual de ictus isquémico disminuyó en un tercio, mientras que la de ictus hemorrágico y hemorragia mayor se redujo de 2 a 3 veces entre 2012 y 2019. Los hazard ratio fueron inferiores a 0,50 para los ACOD en comparación con los antivitamina K para todos los eventos isquémicos o hemorrágicos. Conclusiones: En este estudio poblacional contemporáneo, se observó, utilizando bases de datos clínicas y administrativas de Andalucía, una reducción significativa en la incidencia de ictus isquémico y hemorrágico, y hemorragia mayor relacionados con FA entre los años 2012 y 2019. El mayor uso de ACOD parece estar asociado con esta reducción.(AU)

Obesity: the perfect storm for heart failure.

Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi-imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost-effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium-glucose co-transporter-2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF.

High-Risk Aortic Plaque in Atrial Fibrillation: A Therapeutic Dilemma.

Atrial fibrillation (AF), a common cardiac arrhythmia, is often accompanied by aortic plaques that are associated with an increased risk of embolic events, including stroke. Evidence-based management in this population is lacking. We present a case of a 77-year-old female with new-onset AF who was found to have a high-risk aortic plaque at the level of the ascending aorta and ostium of the right coronary artery. Definitive treatment for AF, cardioversion, high-risk aortic plaque, and cardiothoracic surgery, could not be performed due to the elevated risk of ischemic stroke and embolic complications. Based on existing literature, the cardiologist and cardiothoracic surgeon collaboratively decided to treat both conditions with anticoagulation, statin, and periodic imaging surveillance of high-risk aortic plaque. The patient was successfully managed without any thromboembolic complications despite an elevated risk. This case report provides a comprehensive literature review of managing AF with high-risk aortic plaques. It delves into the integration of anticoagulation and antiplatelet agents in the dual challenge of stroke prevention in AF and mitigating embolic risks associated with aortic plaques. To date, there has been no consensus on managing AF and high-risk aortic plaques; thus, we aim to fill this gap.

Assessing the Safety and Efficacy of Rivaroxaban for Stroke Prevention in Patients With Atrial Fibrillation: A Systemic Review and Meta-Analysis.

An effective anticoagulation therapy is required for patients with atrial fibrillation because it presents a significant risk of stroke. The current study evaluates the relative safety as well as efficacy of rivaroxaban in patients who are diagnosed with atrial fibrillation. A thorough literature review of relevant databases was conducted, focusing on academic and clinical studies that were published from 2017 onward. Inclusion criteria comprised randomized controlled trials and other observational studies comparing the incidence of stroke and the safety index of rivaroxaban in atrial fibrillation. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) for data overview reporting and overview. A total of 21 studies were selected based on the inclusion criteria. A total of 19/21 studies advocated the adoption of rivaroxaban for minimizing stroke incidence. Rivaroxaban also showed superiority in achieving the therapeutic objectives, i.e., reduction in the incidence of stroke. The results for rivaroxaban against warfarin showed an improved safety index and effectiveness of rivaroxaban. The total effect size for the analysis was calculated to be Z=2.62 (p-value=0.009). The individual effect of all studies favored the "rivaroxaban" group. The heterogeneity in the study was as follows: tau2=0.10; chi2=110.10, df=6; I2=95%. The second analysis for risk reduction and incidence of stroke after rivaroxaban therapy also showed a bias towards rivaroxaban therapy. The combined effect for the analysis was found to be as follows: HR=0.73 ((95% CI: 0.50, 1.07). The total effect was calculated to be Z=1.61 (p-value= 0.10). The heterogeneity was found to be as follows: tau2= 0.20, chi2=89.97, df=6, I2=93%. Standard dosing of rivaroxaban emerges as a preferred strategy for stroke prevention, balancing efficacy and safety. Clinical decision-making should consider individual patient characteristics and future research should delve into specific subpopulations and long-term outcomes to further refine treatment guidelines.

Exploring the level of agreement among different drug-drug interaction checkers: a comparative study on direct oral anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) may be involved in drug-drug interactions (DDIs) potentially increasing the risk of adverse drug reactions. This study aimed to evaluate the level of agreement among interaction checkers (ICs) and DOACs' summary of product characteristics (SPCs), in listing DDIs and in attributing DDIs' severity. RESEARCH DESIGN AND METHODS: The level of agreement among five ICs (i.e. INTERCheck WEB, Micromedex, Lexicomp, Epocrates, and drugs.com) in identifying potential DDIs and in attributing severity categories was evaluated using Gwet's AC1 on all five ICs and by comparing groups of four- and two-pair sets of ICs. RESULTS: A total of 486 potentially interacting drugs with dabigatran, 556 for apixaban, 444 for edoxaban, and 561 for rivaroxaban were reported. The level of agreement among the ICs in identifying potential DDIs was poor (range: 0.12-0.16). Similarly, it was low in 4 and 2 sets analyses. The level of agreement among the ICs in classifying the severity of potential DDIs was poor (range: 0.32-0.34), also in 4 and 2 sets analyses. CONCLUSIONS: The heterogeneity among different ICs and SPCs underscores the need to standardize DDI datasets and to conduct real-world studies to generate evidence regarding the frequency and clinical relevance of potential DOAC-related DDIs.

Direct-Acting Oral Anticoagulants in patients at extremes of body weight: a review of pharmacological considerations and clinical implications.

Patients at extremes of body weight are underrepresented in randomized controlled trials of direct-acting oral anticoagulants (DOACs). Therefore, their optimal anticoagulant treatment remains a topic of debate. The aim of this narrative review is to summarize the evidence on the pharmacokinetic and pharmacodynamic profile of DOACs for treating patients at extremes of body weight in venous thromboembolism (VTE) and in the prevention of cardioembolic stroke in nonvalvular atrial fibrillation (NVAF). A literature search was conducted in the main bibliographic databases, and the most relevant reviews and original articles on the topic were selected. Although data in these patient groups are limited, apixaban and rivaroxaban show a favorable pharmacokinetic and pharmacodynamic profile in obese VTE treatment and NVAF patients and, in the case of apixaban, also in underweight patients. In particular, these drugs demonstrated comparable efficacy and safety to standard therapy. Very few data were available for dabigatran and edoxaban; the latter drug was safer at a lower dose, mainly in underweight patients. Our findings are in line with the last International Society of Haemostasis and Thrombosis position paper and European Heart Rhythm Association 2021 practical guide, suggesting the use of apixaban and rivaroxaban in morbidly obese patients (>120 kg or body mass index ≥40 kg/m 2 ) and the reduced dosage of edoxaban in low-weight patients. Future studies should focus on large populations of patients at extremes of body weights to acquire more clinical and pharmacokinetic evidence on all available DOACs, especially those currently less investigated.