Cirrhosis is associated with a procoagulant state that may worsen disease evolution. Anticoagulation could be of particular interest in these patients. However, evidence on the use of direct oral anticoagulants (DOAC) in patients with cirrhosis is limited.

Our aim was to explore the in vitro effect of DOAC on thrombin generation (TG) in plasma from patients with cirrhosis compared to plasma from healthy controls.

Platelet-poor-plasma was obtained from patients with cirrhosis (n = 87; Child-Turcotte-Pugh class: A, n = 68; B, n = 14; C, n = 5) and controls (n = 17). TG was assessed with ST-Genesia analyzer. Plasma from patients with cirrhosis and thrombomodulin-mediated inhibition of endogenous thrombin potential <20% (ThromboScreen) were defined as "highly procoagulant" (n = 36), ≥20% to 50% as "procoagulant" (n = 31), and >50% as "nonprocoagulant" (n = 20). Plasma samples were spiked with apixaban, edoxaban, rivaroxaban, or dabigatran at final concentrations of 50 and 150 ng/mL. TG was measured (DrugScreen) in plasma samples without and with DOAC.

Apixaban, edoxaban, and rivaroxaban demonstrated significantly reduced inhibition of in vitro TG parameters in highly procoagulant plasma from patients with cirrhosis compared to plasma from controls, whereas possibly artifactual results were observed with dabigatran.

The anticoagulant potency of DOAC differs according to the individual procoagulant potential. Highly procoagulant plasma from patients with cirrhosis is less sensitive to the anticoagulant action of apixaban, edoxaban, and rivaroxaban than control plasma. These results, if confirmed in vivo, would support the concept of personalizing anticoagulant treatment in patients with a highly procoagulant state.

Direct oral anticoagulants (DOACs) are the standard treatment for stroke prevention in AF. However, high-quality head-to-head comparisons of DOACs are lacking. This study compared oral anticoagulants in patients with AF.

Data were retrieved from eligible randomised controlled trials (RCTs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA) and the frequentist random effects model was applied. Efficacy outcomes included stroke, systemic embolism, MI, and all-cause mortality; the safety outcome was major bleeding. A composite outcome of efficacy and net clinical benefit was also evaluated.

From 23,152 records, 11 eligible RCTs were identified and included in the study. Rivaroxaban was superior to vitamin K antagonists (VKA) in net clinical benefit (RR 0.75; 95% CI [0.59-0.94]; p=0.0133), but there were no significant differences between other DOACs and VKA or among the DOACs themselves. Rivaroxaban reduced the risk of the composite outcome of efficacy compared with dabigatran (RR 0.85; 95% CI [0.75-0.98]; p=0.02) and edoxaban (RR 0.84; 95% CI [0.75-0.95]; p=0.0051), but not apixaban (RR 0.89; 95% CI [0.89-1.02]; p=0.087). All DOACs showed superiority over VKA in efficacy, without an increased risk of major bleeding. Based on the SUCRA, rivaroxaban showed a favourable risk-benefit profile compared with the other anticoagulants.

This study showed that DOACs are superior to VKA in efficacy without increasing major bleeding risk, with rivaroxaban demonstrating the most balanced risk-benefit profile. Well-designed RCTs are needed to validate these findings.

Ischemic stroke(IS) is the second leading cause of mortality and disability worldwide and neuroimmunity plays an important role in its occurrence and development. The pathogenesis of IS is associated with various metabolic disorders. Yet reports on the amelioration of neuroinflammation by modulating metabolic disorders in clinical practice are scarce. By screening drugs targeting the inflammatory cytokine pro IL-1β in the metabolism-related compound library, we first found that clofibrate, an antihyperlipidemic drug, has an anti-neuroinflammatory effect. However, the role of clofibrate in exerting anti-inflammatory effects in IS and its underlying mechanisms remain unclear. To further investigate the role of clofibrate, we administered clofibrate in an LPS-stimulated microglial cell model and in mice with transient middle cerebral artery occlusion. Notably, clofibrate lowered IL-1β expression, both in vivo and in vitro. Simultaneously, clofibrate reduced infarct volume after ischemia and reperfusion. Moreover, clofibrate affected IS by regulating the expression of NF-κB p65 and NLRP3, thus suppressing the expression of inflammatory factors. These findings suggest that clofibrate could be a prospective medication to alleviate neuroinflammation in IS.

Venous thromboembolism (VTE) is a leading cause of cardiovascular-related deaths. Non-vitamin K antagonist oral anticoagulants (NOACs) offer effective therapy without injections or blood monitoring. This bibliometric analysis explores the research on NOACs for preventing VTE and pulmonary embolism.

Literature up to July 20, 2024, was searched in Web of Science Core Collection. Citespace software was used for screening and analysis.

In this study, we analyzed 2124 articles and 767 reviews from 11,282 institutions across 528 countries and regions, encompassing 830 publications and 60 research directions. The USA led in publication count, followed by Germany and Canada. Cardiovascular System Cardiology, Hematology, and General Internal Medicine were the top research areas, while THROMBOSIS AND HAEMOSTASIS was the leading journal. From 2004 to 2024, we observed accelerated publication growth, particularly from 2008, highlighting the emergence of NOACs as a major research focus. Key contributors, including Bengt I. Eriksson, and major institutions like Harvard Medical School and University of Amsterdam, played pivotal roles in advancing anticoagulant research. Co-citation and keyword clustering analyses revealed research hotspots in NOACs, cancer-associated venous thromboembolism, stroke prevention, and COVID-19-related thrombotic events, reflecting a shift towards individualized anticoagulation therapy and the growing importance of NOACs in various clinical contexts.

The development of NOACs has progressed rapidly, with an increasing number of publications, indicating the lead research in the United States and other Western nations. Comparative studies on the safety and efficacy of NOACs have become a significant focus, shifting from traditional anticoagulants. Pharmacogenetics-guided use of NOACS shows new hope of precision medicine.

Bridging with low-molecular-weight heparin (LMWH) is recommended in continuous-flow left ventricular assist device (CF-LVAD) patients during subtherapeutic international normalized ratios (INRs). We aimed to assess the risk of adverse events during bridging in patients implanted at Leiden University Medical Center between 2010 and 2024. Incidence rates and hazard ratios of major bleeding, thromboembolic events, neurologic complications, and death with 95% confidence intervals (95% CI) were estimated by time-dependent Cox regression. Using a regression discontinuity design, we mimicked a trial by comparing patients during LMWH treatment due to a subtherapeutic INR to patients during INRs just in target range and no LMWH, considering INRs ±0.1, ±0.2, ±0.3, ±0.4, and ±0.5 around the lower INR target range. Ninety-two patients were included, with a median age of 63 years, 73 (79%) were male and 43 (47%) had Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 3. Major bleeding rates were increased during bridging in all analyses. Bridging had 3.7-fold (95% CI, 1.6-8.7) increased major bleeding risk compared with no bridging considering INRs ±0.1, and 2.8-fold (95% CI, 1.4-5.5) considering INRs ±0.5. Thromboembolic events were infrequent and not different between the two groups. Neurologic complications occurred more frequently during bridging. Moreover, the risk of mortality was 25.0-fold (95% CI, 3.6-173.1) increased during versus no bridging. Therefore, bridging should be considered with caution in CF-LVAD patients.

The objective of this study was to validate the PredictAI models for predicting major bleeding (MB) in patients with active cancer and venous thromboembolism (VTE) with anticoagulant (ACO) therapy, within 6 months after primary VTE, using an independent cohort of patients from the TESEO database.

This study conducted an external validation of the PredictAI models using the international, prospective TESEO registry from July 2018 until October 2021. Data from 40 Spanish and Portuguese hospitals recruiting consecutive cases of cancer-associated thrombosis under anticoagulant treatment and without missing values regarding the model outcome or predictors were used. Patients with baseline MB or unknown MB status during follow-up were excluded for the validation analysis. Logistic regression (LR), decision tree (DT), and random forest (RF) approaches were used to validate the models.

Included patients from the TESEO cohort (2179 patients) had similar key demographics and clinical characteristics to the PredictAI cohort (21,227 patients). During the 6-month follow-up period, 10.9% (n = 2314) and 5.9% (n = 129) of patients experienced at least one MB event in the PredictAI and TESEO cohorts, respectively. Hemoglobin, metastasis, age, platelets, leukocytes, and serum creatinine were described as predictors for MB in PredictAI; the external validation results in TESEO showed statistical significance by LR and RF approaches, with ROC-AUC values of 0.59 and 0.56, respectively (both p < 0.05).

PredictAI models for predicting MB in anticoagulant-treated cancer patients within the first 6 months following VTE diagnosis have been externally validated. These models may be considered as a tool to guide objective decisions regarding the indication or extension of anticoagulant therapy in this population.

Warfarin therapy is commonly used to prevent thromboembolic events and cardiovascular disorders, but its effectiveness can be influenced by interactions with drugs and foods. Nurses play a crucial role in managing warfarin therapy and counseling patients on these interactions. This study aimed to assess the predictors of nurses' knowledge regarding warfarin-nutrient and drug interactions and their competence in counseling patients on warfarin therapy.

A cross-sectional study design was used to evaluate nurses' knowledge and counseling practices related to warfarin therapy across various healthcare institutions in Amman, Jordan. Participants included 176 registered nurses with at least one year of experience, recruited through convenience sampling from governmental, private, and educational hospitals. Data were collected through a self-administered questionnaire that assessed demographic characteristics, work-related factors, exposure to health education, and knowledge of warfarin-drug and food interactions, as well as counseling practices.

The study found that most participants were female (58.6%) and held a bachelor's degree (72.7%). Nurses demonstrated moderate knowledge of warfarin-drug interactions, with a mean score of 8.76 ± 2.26 out of 26. Knowledge was better for cardiac agents like atenolol (53.4%) and gastrointestinal agents (53.4%), but gaps were observed for anti-inflammatory and CNS drugs. The mean score for knowledge of warfarin-food interactions (out of 18) was 12.27 ± 3.84, with strong knowledge of non-interfering foods, but gaps in understanding foods like leafy greens, high in vitamin K. Nurses' knowledge of counseling practices for warfarin therapy was moderate, with a mean score of 8.07 ± 2.31 out of 15. While knowledgeable about diet and adherence, gaps existed in counseling patients on missed doses and dietary restrictions. Regression analysis identified key predictors of knowledge, including education, work experience, direct patient care, self-confidence, exposure to health education, and anticoagulant training, explaining 35% of the variance in knowledge scores. A postgraduate degree, work experience, and confidence in warfarin care positively impacted knowledge, while demographic factors like age, gender, and job position had no significant effect. The findings highlight the need for educational programs and confidence-building initiatives.

The study highlights significant gaps in nurses' knowledge of warfarin interactions, particularly with certain drugs and foods, and underscores the need for targeted education and training. However, the study is limited by its reliance on self-reported data and a convenience sampling approach, which may impact generalizability. Strengthening nurses' understanding of warfarin management, especially regarding high-risk interactions, is essential for improving patient safety and the efficacy of anticoagulant therapy. Future initiatives should focus on structured educational programs, introducing interactive e-learning modules, regular workshops, and case-based training, as well as promoting multidisciplinary teamwork to enhance nurses' competency in warfarin counseling and patient care.

Background/Objectives: Oral anticoagulant (OA) therapy (OAT) may be prescribed to patients for a variety of reasons, with several agent classes currently available as well as emerging. The classical oral anticoagulants are represented by vitamin K antagonists (VKAs), including warfarin, and the more modern alternatives comprise the direct oral anticoagulants (DOACs). We aimed to assess usage of OAs over time in Australia, especially focusing on the period of the coronavirus disease 2019 (COVID-19) pandemic and its transition to an endemic phase, to assess for any trends. Methods: Using data from the pharmaceutical benefits scheme (PBS), Medicare and other online sites, we specifically assessed for changes in OA prescription and cost patterns over the period 1992-2024, but focusing especially on the period 2020-2024 inclusive. Results: Apixaban is now the most prescribed OA in Australia. Costs of OAT prescriptions have steadily increased over the data capture period, reaching half a billion dollars in 2023. Interestingly, costs have started to fall, seemingly driven by the release of DOAC generics and PBS pricing adjustments. We could identify no clear signals related to COVID-19-related changes in prescription trends, contrary to previous reports in other locations. Conclusions: We provide Australian data on both OA usage as well as costs. Despite an ongoing trend to increasing use of DOACs over VKAs, we could not identify any specific COVID-19-related changes.

In patients with mechanical heart valves, low-molecular-weight heparin (LMWH) and unfractionated heparin are commonly used as bridging anticoagulation therapies to reduce the risk of thromboembolic events and major adverse cardiac events; however, the efficacy and safety of these therapies remain debatable. The aim of this study was to compare the safety and outcomes of LMWH and unfractionated heparin in patients with mechanical heart valve replacement undergoing non-cardiac surgery. This systematic literature review was conducted from January to June 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to search for related studies through PubMed, ScienceDirect, and Cochrane Library. Categorical variables were analyzed using a Mantel-Haenszel random-effects model, with relative risk (RR) as the effect size. Higgins I2 was used to measure the heterogeneity and publication bias was assessed through funnel plots. Out of 814 potential studies, six studies (one randomized control trial and five prospective studies) were included. The analysis revealed no significant differences in thromboembolic event or valvular thrombosis (RR: 0.61; 95%CI: 0.36-1.04; p=0.07; χ2=1.96; I 2=0%), all-cause mortality (RR: 0.73; 95%CI: 0.40-1.35; p=0.32; χ2=0.97; I 2=0%), major bleeding (RR: 0.81; 95%CI: 0.53-1.23; p=0.33; χ2=4.14; I 2=0%), minor bleeding (RR: 1.18; 95%CI: 0.86-1.62; p=0.31; χ2=4.50; I 2=11%), and thrombocytopenia (RR: 0.56; 95%CI: 0.20-1.59; p=0.27; χ2=0.85; I 2=0%). The study highlights that LMWH and unfractionated heparin did not differ significantly when used as bridging anticoagulant therapy for non-cardiac surgery in mechanical heart valve patients.

Perioperative management of antithrombotic agents requires practical and medical considerations. Discontinuing antithrombotic therapies increases the risk of thrombotic adverse events including cerebrovascular accidents, myocardial infarction, pulmonary embolism, deep vein thrombosis, and retinal artery occlusion. Conversely, continuation of antithrombotic therapy during surgical procedures has associated bleeding risks. Currently, no guidelines exist regarding management of antithrombotic agents in the perioperative period for cutaneous surgeries and practice differs by surgeon. Here, we review the data on antithrombotic medications in patients undergoing cutaneous surgery including medication-specific surgical and postoperative bleeding risk if the medications are continued, and thromboembolic risk if the medications are interrupted. Specifically, we focus on vitamin K antagonist (warfarin), direct-acting oral anticoagulants (rivaroxaban, apixaban, edoxaban, dabigatran), antiplatelet medications (aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole), unfractionated heparin, low molecular weight heparin (enoxaparin and dalteparin), fondaparinux, bruton tyrosine kinase inhibitors (ibrutinib, acalabrutinib), and dietary supplements (ie, garlic, ginger, gingko).

To assess the knowledge level of physicians on anticoagulation management and identify their training needs to ensure the safety and efficacy of warfarin therapy among patients.

This project adopted convenient sampling and collected survey questionnaires online to investigate physicians' management level in aspects such as basic anticoagulation knowledge, routine adjustment of warfarin dosage, and management of warfarin complications and special situations after mechanical valve replacement.

Among the 232 participants in this survey, 158 were male (68.10%), and 74 were female (31.90%); Grade III hospitals accounted for 61.21%; cardiovascular medicine department accounted for 65.09%; primary, intermediate, and advanced title holders each accounted for about one-third. The respondents had a good foundation in warfarin anticoagulation knowledge, and most physicians could guide patients in anticoagulation treatment. However, there were still many respondents who answered incorrectly on some basic questions. Using the chi-square test, the analysis of the impact of gender, age, hospital level, department, education, and title on the knowledge level of warfarin anticoagulation found that gender had no statistical significance in all items; age, department, and title had statistically significant differences in the impact on the knowledge level of anticoagulation in the respondent (P < 0.05).

The respondents have good anticoagulation knowledge on basic items, but some healthcare professionals have insufficient understanding of some items, such as the approximate time required for INR to reach a stable value and the use of warfarin in pregnant women, posing significant risks in clinical work. Relevant healthcare professional training should be strengthened on extended knowledge on warfarin.

Atrial fibrillation (AF) poses significant thromboembolism and bleeding risks, especially in older adults. Warfarin continues to be a primary treatment option, and maintaining the Time in Therapeutic Range (TTR) is critical for ensuring its effectiveness. However, suboptimal TTR is associated with increased risks of stroke, bleeding, and mortality. Despite its importance, there is limited data on warfarin management in Ethiopian older adults with AF. Therefore, this study aimed to determine the TTR, bleeding events, and their determinants, in older patients with AF in Ethiopia receiving warfarin therapy.

In this study, older patients with AF who were treated with warfarin and had follow-up visits between May 2021 and May 2024, and met the inclusion criteria, were included. Patients were categorized based on TTR into two groups: poor anticoagulation (TTR < 65%) and good anticoagulation quality (TTR ≥ 65%). Bivariate and Multivariate Logistic regression was performed to predict determinants of a TTR < 65% and bleeding events. Odds ratios with 95% confidence intervals (CIs) were calculated, and statistical significance was set at P < 0.05.

In this study, 384 patients with AF were included. Of this 53.4% were female. Of these 71% of patients had a TTR below 65%, 29% achieved ≥65%, with a median TTR of 45%. Bleeding events were reported by 13.5% of patients. Poor TTR was significantly associated with age (AOR = 1.199, 95% CI: 1.109-1.297), chronic kidney disease (AOR = 27.809, 95% CI: 7.57-101.76), and infrequent INR monitoring at 31-90-day intervals (AOR = 0.15, 95% CI: 0.004-0.051). Regarding determinants of bleeding events, Patients with diabetes mellitus had a 2.6-fold higher bleeding risk (AOR = 2.585, 95% CI: 1.069-6.250), and a CHA2DS2-VASc score ≥3 significantly increased bleeding risk compared to scores ≤2 (AOR = 7.562, 95% CI: 2.770-20.640).

This study highlights suboptimal warfarin therapy among older Ethiopian patients with AF. Poor anticoagulation was associated with advanced age, chronic kidney disease, and infrequent INR monitoring, while diabetes mellitus and high CHA₂DS₂-VASc scores increased bleeding risks. Close monitoring and frequent INR checks are essential to improving outcomes.

Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) are at high risk of thrombosis. However, bleeding-related complications during antithrombotic therapy remain a major barrier to effective treatment and can often lead to adverse outcomes. This meta-analysis aimed to determine the efficacy and safety of bivalirudin and heparin in patients with ACS after PCI.

Randomized controlled trials (RCTs) on the efficacy and safety of bivalirudin versus heparin in patients with ACS after PCI were identified from the PubMed, Embase, Cochrane Library, CBM, CNKI, WanFang, and VIP database until August 2024. The outcomes included all-cause mortality, major adverse cardiovascular events (MACEs), incidence of recurrent myocardial infarction, stent thrombosis, short-term bleeding, revascularization, and retransfusion. Meta-analysis was performed using RevMan 5.3 and Stata 12.0 softwares. The included studies were assessed for risk of bias using the Cochrane risk-of-bias assessment tool.

A total of 70,199 patients from 27 randomized controlled trials (RCTs) were analyzed in this review. There were no significant differences between the bivalirudin and heparin groups in terms of all-cause mortality, major adverse cardiovascular events (MACEs), recurrent myocardial infarction, stent thrombosis within 30 days, or subacute stent thrombosis. Specifically, the incidence of short-term bleeding (P = 0.001) and retransfusion (P = 0.001) was significantly lower in the bivalirudin group compared to the heparin group. Conversely, the incidence of acute stent thrombosis (P < 0.0001) and revascularization (P = 0.009) was significantly higher in the bivalirudin group.

Compared with heparin, bivalirudin has definite anticoagulant effect in patients with acute myocardial infarction after PCI, and the risk of bleeding and the incidence of retransfusion were lower in the bivalirudin group. This review helps doctors in PCI management choose bivalirudin or heparin more precisely based on patients' conditions for better treatment and fewer adverse events.

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease. The use of conventional anticoagulants carries potential side effects, mainly bleeding. Drugs targeting Factor XI (FXI) have been investigated in randomized controlled trials as a new option with more favorable outcomes. A comprehensive literature search was conducted to identify relevant studies comparing FXI inhibitors to placebo or standard therapy. The primary outcomes were incidence of all bleeding events, major bleeding, and thromboembolism. Secondary outcomes included incidence of all adverse events (AE), serious AE, and all-cause mortality. A total of 11 studies involving 10,536 patients were included. FXI inhibitors were associated with a trend toward reduction of bleeding events and incidence of thromboembolism compared to the control group (placebo/standard therapy). There was no statistically significant difference between both groups in terms of adverse events and all-cause mortality. When compared to enoxaparin, FXI inhibitors significantly reduced the risk of bleeding events (RR = 0.42, 95% CI: 0.23-0.76, P = 0.004) and thromboembolism (RR = 0.59, 95% CI: 0.44-0.77, P = 0.001). On the other hand, when compared to DOACs, FXI inhibitors were associated with a significant reduction in bleeding events but not thromboembolism. Whereas, compared to placebo, FXI inhibitors did not increase the risk of bleeding events, adverse events, or all-cause mortality (P > 0.05). FXI inhibitors could be a safer and more potent option for prevention of thromboembolism than conventional therapy.

Anticoagulants, including warfarin and direct oral anticoagulants (DOACs), are used to prevent and treat venous thromboembolism (VTE) which is common in patients with obesity. Guidance statements regarding use of DOACs for VTE treatment in this patient population have been updated.

Examine DOAC prescribing trends in patients with obesity and VTE.

We performed a retrospective, single-site cross-sequential study of DOAC prescribing trends in adult patients with obesity (BMI ≥30) and objectively confirmed VTE diagnosis between 2014 and 2022. The primary outcome of interest was the proportion of patients with obesity prescribed DOACs.

A total of 1826 patients were included in our analysis. Most patients were of White race (85.8 %) and approximately half were female. Pulmonary embolism was the most common VTE type (62.2 %). A total of 1018 patients were prescribed DOAC therapy (55.8 %), 524 warfarin therapy (28.7 %), and 284 enoxaparin (15.6 %). Logistic regression analysis revealed that the utilization of DOACs exhibited a significant upward trend from 2017 to 2022 (odds ratio [OR] 1.85 to 14.08 compared to 2014), but not from 2015 to 2016 (OR 1.30 to 1.52). Patients with BMI ≥ 40 and ≥ 50 were twice and 4-times as likely to be prescribed warfarin than DOACs, respectively.

Between 2017 and 2022, the proportion of patients with obesity prescribed DOACs for the treatment of VTE increased significantly. This suggests an increasing likelihood to prescribe DOACs in this patient population despite the lack of safety and efficacy data from randomized controlled trials except for very heavy patients.

Heart failure (HF) is a common condition and one of the main morbidity and mortality factors in elderly patients. The incidence of HF progressively increases with age, reaching >10% in those aged 70 years or over. In the elderly population, both the diagnosis and the management of HF prove challenging, often requiring specialized care and a multidisciplinary approach. In seniors, atypical presentation of HF is much more common than in younger patients; thus, a holistic assessment with biomarkers related to HF allows for early diagnosis and accurate risk stratification in this group of patients. This article reviews the clinical and diagnostic differences in elderly patients with HF, highlighting the presence of comorbidities, frailty, cognitive impairment, and polypharmacy, as well as discussing potential biomarkers that may have clinical application in this population.

To identify the impact of CYP2C9*2, *3, VKORC1-1639 G>A and CYP4F2*3 on warfarin dose in an Arab population. To compare the accuracy of a clinical warfarin dosing (CWD) versus genetic warfarin dosing algorithms (GWD) during warfarin initiation.

A cohort of Arab patients newly starting on warfarin had their dose calculated using CWD published in www.warfarindosing.org and were followed for 1 month. Each patient provided a saliva sample. DNA was extracted, purified and genotyped for VKORC-1639 G>A, CYP2C9*2, CYP2C9*3 and CYP4F2*3. After reaching warfarin maintenance dose, the dose was recalculated using the GWD and median absolute error (MAE) and the percentage of warfarin doses within 20% of the actual dose were calculated and compared for the two algorithms.

The study enrolled 130 patients from 12 Arabian countries. Compared to those with wild type, carriers of reduced function alleles in CYP2C9 required significantly lower median (IQR) warfarin weekly dose [24.5 (15.3) vs. 35 (29.8) mg/week, p=0.006]. With regards to VKORC, patients with AA genotype had a significantly lower median (IQR) weekly warfarin dose compared to AG and GG [21(10.5) vs 29.4 (21), p<0.001 for AA vs AG, p<0.001 for AA vs GG]. The MAE (IQR) for the weekly dose of the GWD was significantly lower compared to CWD [8.1 (10.5) vs 12.4 (12.6) (p<0.001)].

CYP2C9 and VKORC1 variants are important determinants of warfarin dose in the Arab population. The use of the genetic and clinical factors led to better warfarin dose estimation when compared to clinical factors alone.

Over the last decade, the advent of direct oral anticoagulants (DOACs) has rapidly changed the landscape of anticoagulation. In the early 2010s, DOACs became widely available for stroke prevention in atrial fibrillation and the treatment of venous thromboembolism. About 10 years later, approximately two-thirds of patients requiring oral anticoagulant treatment were receiving a DOAC. The results of several post-marketing studies consistently confirmed the findings of phase 3 clinical trials, and research has focused on new areas of development, with heterogeneous results. A role for DOACs has emerged for patients with peripheral artery disease and other challenging conditions, such as cancer-associated thrombosis, unusual-site venous thromboembolism, and end-stage renal disease. Conversely, clinical trials showed that DOACs were not efficacious in patients with valvular atrial fibrillation, mechanical heart valves, embolic strokes of undetermined source, or antiphospholipid syndrome. In this Review, we discuss the impact of DOACs in clinical practice over the last decade, new areas under development, and practical issues in the management of these drugs.

Factor XIIa (FXIIa) is a plasma serine protease within the contact activation pathway. Inhibiting FXIIa could offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks that accompany the use of existing anticoagulants. Therefore, we investigated the anticoagulant properties of an amidine-containing molecule (inhibitor 1) to identify a potential lead molecule for subsequent development of FXIIa inhibitors. Results indicated that inhibitor 1 primarily inhibits human FXIIa with an IC50 value of ~30 µM. The inhibitor demonstrated variable selectivity against thrombin, factor IXa, factor Xa, factor XIa, and activated protein C. Michaelis-Menten kinetics indicated that the molecule is an active site inhibitor of FXIIa. Molecular modeling studies revealed that the molecule recognizes residues His57, Asp189, and Ala190 in FXIIa's active site. The inhibitor selectively and concentration-dependently prolonged the clotting time of human plasma under activated partial thromboplastin time assay conditions. The inhibitor did not exhibit significant cytotoxicity in human HEK293 cells and the in silico pharmacokinetics and toxicology data were comparable to known anticoagulants. This study introduces inhibitor 1 as a lead platform for further development as an anticoagulant to provide a more effective and safer approach to preventing and treating thromboembolic diseases.

Factor XIa (FXIa), a key component of the intrinsic coagulation pathway, has recently been recognized as a safe and effective target for antithrombotic therapy. Research indicates that FXIa inhibitors can lower bleeding risk compared to novel oral anticoagulants. In this study, we designed and synthesized a series of novel FXIa inhibitors based on the structure of Asundexian, with a particular focus on optimizing the P2' region to enhance binding to the S2' subsite of FXIa. This strategy led to the discovery of compound F47, which demonstrated significantly greater FXIa inhibition (IC50 = 2.0 nM) compared to Asundexian (IC50 = 5.0 nM). F47 also showed excellent anticoagulant activity in the aPTT assay (EC2x = 0.4 μM), with strong efficacy and minimal impact on the extrinsic coagulation pathway. Additionally, F47 exhibited inhibitory activity against plasma kallikrein (PKal), with selectivity comparable to that of Asundexian. The compound also displayed acceptable stability in human liver microsomal stability assays. Molecular modeling revealed that F47 binds tightly to the S1, S1', and S2' pockets of FXIa while maintaining key interactions; notably, its P2' moiety forms two additional π-π stacking interactions with the crucial amino acid TYR143. Further studies demonstrated that F47 exhibits dose-dependent antithrombotic efficacy in a rat FeCl3-induced thrombosis model. Ongoing research aims to further elucidate the potential of compound F47 as a promising lead in antithrombotic therapy.

The transition to or from direct oral anticoagulants (DOACs) is common in clinical practice.

A literature search was conducted on PubMed, Google Scholar, and UpToDate up to March 2024 for conditions and approaches for transitioning from one agent to the other. No randomized clinical trials were retrieved except for two studies regarding switching to DOAC in well-conducted vitamin K antagonist (VKA) therapy. A narrative review was conducted addressing the conditions for switching from one agent to the other, such as thromboembolic events and major bleeding during anticoagulation, development or worsening of kidney or liver failure, initiation of interfering drugs, adverse events such as allergic reactions, frailty, patients' preferences, and affordability. During transitions from one anticoagulant to the other, the risk of both thromboembolic and bleeding complications should be minimized. The current approaches for such transitions are derived from those employed in clinical trials evaluating DOAC and from product information.

Many uncertainties remain regarding those circumstances requiring a change in anticoagulant strategies, as they lack evidence-based guidance. It can be envisaged that the problem of switching to and from DOAC will need additional studies especially addressing the conditions and the best approach to such transitions.

Due to their very wide range of indications, anticoagulants are one of the most commonly used drug groups. Although these drugs are characterized by different mechanisms of action, the most common complication of their use is still bleeding episodes, the frequency of which depends largely on the clinical condition of the patient using such therapy. For this reason, to this day, the best method of preventing bleeding complications remains the assessment of bleeding risk using scales such as HAS-BLED. There are many reports in the literature assessing the occurrence of this type of complication after the use of drugs affecting the coagulation process, as well as many reports comparing individual groups of drugs with different mechanisms of action. However, there are still no clear guidelines that would indicate which group of anticoagulants should be preferred in particular groups of patients. The aim of our article is to summarize the data collected so far regarding the safety of using specific groups of anticoagulants and the frequency of bleeding complications after their use.

Rivaroxaban and dabigatran are approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF). However, the clinical benefits of rivaroxaban and dabigatran in people with high bleeding risk are unclear.

A retrospective study was conducted on NVAF patients admitted to the First Affiliated Hospital of Zhengzhou University from May 31, 2016 to May 31, 2019. These patients had a high risk of bleeding and were taking at least one study medication. The aim of the study was to evaluate clinical benefits by comparing the efficacy and safety risks of these two medications.

A total of 1,301 patients with high bleeding risk were enrolled, including 787 patients in the rivaroxaban group and 514 patients in the dabigatran group. Results of the primary efficacy benefit endpoint were obtained from 104 patients (13.21%) in the rivaroxaban group and 81 (15.76%) patients in the dabigatran group [hazard ratio (HR): 0.860; 95% confidence interval (CI): 0.637-1.162; P = 0.327], this indicates that there was no significant difference between dabigatran and rivaroxaban in preventing stroke and systemic embolism in patients with high bleeding risk NVAF. The principal safety end points were observed in 49 (6.23%) patients in the rivaroxaban group and in 36 (7.00%) patients in the dabigatran group (HR: 0.801 in the rivaroxaban group; 95% CI: 0.512-1.255; P = 0.333), this indicates that there was no a significant difference in reducing fatal bleeding and critical organ bleeding. With respect to secondary efficacy and benefit endpoints, 28 (3.56%) patients in the rivaroxaban group and 26 (5.06%) patients in the dabigatran group died, with an HR of 0.725 (95% CI: 0.425-1.238; P = 0.239); 32 (4.07%) patients in the rivaroxaban group; and 31 (6.03%) patients in the dabigatran group had myocardial infarction (MI), with an HR of 0.668 (95% CI: 0.405-1.102, P = 0.114) in the rivaroxaban group, this indicates that there was no significant difference between dabigatran and rivaroxaban in preventing all-cause death and MI.

In NVAF patients with high bleeding risk, there was no significant difference between dabigatran and rivaroxaban in preventing stroke and systemic embolism. There was also no significant difference between dabigatran and rivaroxaban in reducing fatal and critical organ bleeding.

Chinese Clinical Trials Registry, identifier ChiCTR2100052454.

Current drug-drug interaction (DDI) detection methods often miss the aspect of temporal plausibility, leading to false-positive disproportionality signals in spontaneous reporting system (SRS) databases.

This study aims to develop a method for detecting and prioritizing temporally plausible disproportionality signals of DDIs in SRS databases by incorporating co-exposure time in disproportionality analysis.

The method was tested in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The CRESCENDDI dataset of positive controls served as the primary source of true-positive DDIs. Disproportionality analysis was performed considering the time of co-exposure. Temporal plausibility was assessed using the flex point of cumulative reporting of disproportionality signals. Potential confounders were identified using a machine learning method (i.e. Lasso regression).

Disproportionality analysis was conducted on 122 triplets with more than three cases, resulting in the prioritization of 61 disproportionality signals (50.0%) involving 13 adverse events, with 61.5% of these included in the European Medicine Agency's (EMA's) Important Medical Event (IME) list. A total of 27 signals (44.3%) had at least ten cases reporting the triplet of interest, and most of them (n = 19; 70.4%) were temporally plausible. The retrieved confounders were mainly other concomitant drugs.

Our method was able to prioritize disproportionality signals with temporal plausibility. This finding suggests a potential for our method in pinpointing signals that are more likely to be furtherly validated.

We previously conducted a prospective, observational post-marketing surveillance study to assess the safety and effectiveness of four-factor prothrombin complex concentrate (4F-PCC) for rapid vitamin K antagonist (VKA) reversal in Japanese patients.

This subgroup analysis compared the safety, especially thromboembolic events (TEEs), and effectiveness of 4F-PCC by stratifying patients into two subgroups according to baseline international normalized ratio (INR) levels with < 2.0 and ≥ 2.0.

Of 1271 eligible patients, 215 (17.9%) had INR < 2.0 and 987 (82.1%) had INR ≥ 2.0. Overall baseline characteristics were similar between groups; age (74.0 years vs 74.0 years), body mass index (22.1 kg/m2 vs 21.9 kg/m2), ratio of inpatients (90.2% vs 88.7%), manifested atrial fibrillation (46.0% vs 48.8%). Median INRs at baseline were 1.72 (minimum 0.92, maximum 1.99) in the INR < 2.0 group and 2.95 (2.00, 27.11) in the INR ≥ 2.0 group. The most common reason for 4F-PCC administration was intracranial hemorrhage (67.0% vs 59.5%), and lesser gastrointestinal bleeding (0.9% vs 7.5%). After 4F-PCC administration (average doses 24.5 IU/kg [INR < 2.0 group] and 29.2 IU/kg [INR ≥ 2.0 group]), INRs were significantly reduced to 1.21 (- 28%) and 1.31 (- 68%), respectively, and resulted in hemostasis in a similarly rapid manner. The incidences of adverse drug reactions were 3.7% in each group. TEEs occurred in 4 (1.9%) patients in the INR < 2.0 group and 11 (1.1%) patients in the INR ≥ 2.0 group and were predominantly composed of stroke, while similar rates (67.0% vs 62.9%) of bleeding events post-anticoagulant resumption were observed between groups.

This study supports the favorable tolerability and efficacy of 4F-PCC regardless of baseline INR (< 2.0 or ≥ 2.0), with a prompt reduction of INR and substantial hemostatic effectiveness in the real-world setting for patients requiring urgent VKA reversal, although no indicated 4F-PCC dose for VKA reversal exists for INR < 2.0 to date.

Various pharmacokinetic changes have been reported in experimental hyperlipidemic (HL) animal models. To evaluate whether P-glycoprotein (P-gp) activity was affected in HL rats, we assessed the pharmacokinetics of dabigatran after oral administration of dabigatran etexilate (DABE); this is a dabigatran prodrug and a well-known P-gp substrate.HL and control rats exhibited similar area under the plasma concentration-time curve (AUC), total body clearance (CL), and steady state volume of distribution (Vss) values following intravenous administration of dabigatran (1 mg/kg). This suggested that the distribution and elimination of dabigatran were similar in control and HL rats.The hepatic and intestinal P-gp protein levels did not differ significantly between control and HL rats. The dabigatran AUC and extent of absolute oral bioavailability (F) values were similar in control and HL rats following oral administration of DABE (10 mg/kg as dabigatran). Therefore, there was no apparent change in intestinal P-gp activity in HL rats compared to control rats.This study revealed no significant change in P-gp expression or activity in the intestine or liver of HL rats, and similar pharmacokinetics of dabigatran. Hyperlipidaemia may not directly affect the oral absorption of P-gp substrate drugs.

The management of warfarin therapy presents clinical challenges due to its narrow therapeutic index. We aimed to evaluate the comparative effectiveness of different management strategies in patients using warfarin.

PubMed, Embase, Cochrane CENTRAL, CINAHL, and EBSCO Open Dissertation were searched from inception to 8 May 2024. Randomized controlled trials that compared the following interventions: patient self-management (PSM), patient self-testing (PST), anticoagulation management services (AMS), and usual care in patients prescribed warfarin for any indication were included. Risk ratios (RR) with 95% confidence interval (CI) were estimated using a random-effects model. Surface under the cumulative ranking curves (SUCRA) were used to rank different interventions. The certainty of evidence was assessed using the Confidence in Network Meta-Analysis (CINeMA) online platform. This study is registered with PROSPERO (CRD42023491978).

Twenty-eight trials involving 8100 participants were included, with follow-up periods of 1-24 months. Mean warfarin dosages were 4.9-7.2 mg/day. Only PSM showed a significant reduction of major TE risk compared with usual care (RR = 0.41; 95% CI: 0.24, 0.71; I2 = 0.0%) with moderate certainty of evidence. The 97.6% SUCRA also supported the beneficial effects of PSM over other interventions. The combined direct and indirect evidence showed significantly higher TTR in PSM compared with usual care (MD = 7.39; 95% CI: 2.39, 12.39), with very low certainty. However, direct evidence showed non-significant TTR improvement (MD = 6.49; 95% CI: -3.09, 16.07, I2 = 96.1%). No differences across various strategies were observed in all-cause mortality, major bleeding, stroke, transient ischemic attack, and hospitalization.

PSM reduces the risk of major TE events compared with usual care, tends to improve anticoagulation control, and should be considered where appropriate.

Agency for Healthcare Research and Quality (grant ID 5R18HS027960).

Millions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding.

To evaluate the hemostatic noninferiority of an investigational 4-factor prothrombin complex concentrate (4F-PCC) to a control 4F-PCC for rapid VKA reversal before urgent surgery.

This phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) was conducted in 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, through November 8, 2021; the study was stopped in February 2022. Participants were adult patients taking VKA who had an international normalized ratio (INR) of 2 or higher and needed urgent surgery with a substantial bleeding risk (≥50 mL). Patients were randomized 1:1 to a single infusion of either the investigational 4F-PCC or the control 4F-PCC. Data analysis followed intention-to-treat and per-protocol approaches.

Single intravenous infusion was dosed by body weight and baseline INR. A dose of 25, 35, or 50 IU/kg of investigational 4F-PCC or control 4F-PCC was administered for baseline INR of 2 to less than 4, 4 to 6, or over 6, respectively.

The primary end point was hemostatic efficacy at surgery end. An independent adjudication board, blinded to the 4F-PCC treatment allocation, assessed hemostatic efficacy using an objective 4-point scale.

A total of 208 patients (median [range] age, 67.5 [31-92] years; 118 males [56.7%]) received the investigational (n = 105) or the control (n = 103) 4F-PCC. The median (range) dose was 25 (16-50) IU/kg in the investigational group and 25 (15-50) IU/kg in the control group, with a median (range) infusion time of 12 (8-50) minutes and 13 (7-30) minutes and a median (range) time from infusion to surgery start of 1.42 (0.25-15.25) hours and 1.50 (0.42-18.50) hours, respectively. Baseline median (range) INR was 3.05 (1.97-21.10) in the investigational group and 3.00 (2.00-11.30) in the control group. In the intention-to-treat analysis, the investigational 4F-PCC was noninferior to the control 4F-PCC, resulting in effective hemostasis in 94.3% of patients vs 94.2% of patients (proportion difference, 0.001; 95% CI, -0.080 to 0.082; P < .001), meeting the prespecified noninferiority margin of 0.15. An INR of 1.5 or lower at 30 minutes after infusion occurred in 78.1% of patients in the investigational group vs 71.8% of patients in the control group (proportion difference, 0.063; 95% CI, -0.056 to 0.181). Thrombotic events (2.9% vs 0%, respectively) and mortality (4.8% vs 1.0%, respectively) were no different than expected for 4F-PCC use. One patient in each treatment group discontinued due to adverse events (cardiac disorders unrelated to 4F-PCC).

This randomized clinical trial found that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for rapid VKA reversal in patients needing urgent surgery with considerable bleeding risk; the safety profile of these two 4F-PCCs was similar. These results support the investigational 4F-PCC as a therapeutic option for surgical patients requiring rapid VKA reversal.

ClinicalTrials.gov Identifier: NCT02740335.

Life expectancy of patients with a durable, continuous-flow left ventricular assist device (CF-LVAD) continues to increase. Despite significant improvements in the delivery of care for patients with these devices, hemocompatability-related adverse events (HRAEs) are still a concern and contribute to significant morbility and mortality when they occur. As such, dissemination of current best evidence and practices is of critical importance. This ISHLT Consensus Statement is a summative assessment of the current literature on prevention and management of HRAEs through optimal management of oral anticoagulant and antiplatelet medications, parenteral anticoagulant medications, management of patients at high risk for HRAEs and those experiencing thrombotic or bleeding events, and device management outside of antithrombotic medications. This document is intended to assist clinicians caring for patients with a CF-LVAD provide the best care possible with respect to prevention and management of these events.

This review examines recent advancements in interventional treatments and nursing care for lower extremity deep vein thrombosis (DVT), highlighting significant innovations and their clinical applications. It discusses the transition to novel anticoagulants such as Direct Oral Anticoagulants, which offer a safer profile and simplified management compared to traditional therapies. Mechanical interventions, including balloon angioplasty and venous stenting, are detailed for their roles in improving immediate and long-term vascular function in acute DVT cases. Furthermore, the use of image-guided techniques is presented as essential for enhancing the accuracy and safety of DVT interventions. Additionally, this study outlines advances in nursing care strategies, emphasizing comprehensive preoperative and postoperative evaluations to optimize patient outcomes. These evaluations facilitate tailored treatment plans, crucial for managing the complex needs of DVT patients. Long-term care strategies are also discussed, with a focus on patient education to ensure adherence to treatment protocols and to prevent recurrence. The synthesis aims to inform healthcare professionals about cutting-edge practices in DVT management, promoting a deeper understanding of how these advancements can be integrated into clinical practice. It also underscores the necessity for ongoing research to address challenges such as cost-effectiveness and patient compliance, ensuring that future treatments are both accessible and effective.

Factor XIIIa (FXIIIa) is a cysteine transglutaminase that catalyzes the last step in the coagulation process. An anion-binding site inhibition of FXIIIa is a paradigm-shifting strategy that may offer key advantages of controlled inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We previously reported a flavonoid trimer-based allosteric inhibitor of FXIIIa with moderate potency and selectivity. To further advance this approach, we evaluated a series of 27 variably sulfonated heparin mimetics against human FXIIIa. Only 13 molecules exhibited inhibitory activity at the highest concentration tested with IC50 values of 2-286 μM. Specifically, inhibitor 16 demonstrated an IC50 value of 2.4 ± 0.5 μM in a bisubstrate, fluorescence-based trans-glutamination assay. It also demonstrated a significant selectivity over other clotting factors including thrombin, factor Xa, and factor XIa as well as other cysteine enzymes including papain and tissue transglutaminase 2. Inhibitor 16 did not affect the viability of three human cell lines at a concentration that is 5-fold its FXIIIa-IC50. The molecule had a very weak effect on the activated partial thromboplastin time of human plasma at a concentration of >700 μM, further supporting its functional selectivity. Importantly, molecule 16 inhibited FXIIIa-mediated polymerization of fibrin(ogen) in a concentration-dependent manner as shown by the gel electrophoresis experiment. Michaelis-Menten kinetics revealed that the molecule competes with the Gln-donor protein substrate, i.e., dimethylcasein, but not with the Lys-donor small substrate, i.e., dansylcadaverine. Molecular modeling studies revealed that this type of molecule likely binds to an anion-binding site comprising the basic amino acids of Lys54, Lys61, Lys73, Lys156, and Arg244 among others. Overall, our work puts forward a new anion-binding site, selective, nontoxic, sulfonated heparin mimetic FXIIIa inhibitor 16 for further development as an effective and safer anticoagulant.

This meta-analysis aimed to assess the outcomes of patients with atrial fibrillation undergoing chronic hemodialysis, comparing the effectiveness of direct oral anticoagulants (DOACs) and vitamin K antagonists. A systematic search was conducted across various databases including PubMed, Embase, and Google Scholar. Efficacy outcomes focused on the risk of stroke and mortality, whereas safety outcomes assessed the risk of bleeding. Review Manager generated forest plots for data synthesis. Statistical significance was set at P < 0.05, and random-effects models were used. Subgroup analysis identified the sources of heterogeneity. Nine studies met the inclusion criteria for the final analysis. The risk of all-cause stroke [risk ratio (RR): 0.64; 95% confidence interval (CI): 0.51-0.81; P = 0.0001; I2 = 0%], ischemic stroke (RR: 0.53; 95% CI: 0.29-0.96; P = 0.04; I2 = 0%), all-cause mortality (RR: 0.73; 95% CI: 0.60-0.88; P = 0.001; I2 = 71%), major bleeding (RR: 0.63; 95% CI: 0.52-0.76; P < 0.00001; I2 = 44%), gastrointestinal bleeding (RR: 0.67; 95% CI: 0.53-0.85; P = 0.0009; I2 = 36%), intracranial hemorrhage (RR: 0.57; 95% CI: 0.38-0.84; P = 0.004; I2 = 0%) were lower in the DOAC group compared with the vitamin K antagonist group. The risk of cardiovascular-related death (RR: 1.34; 95% CI: 0.69-2.60; P = 0.39; I2 = 0%), clinically relevant nonmajor bleeding (RR: 0.90; 95% CI: 0.75-1.08; P = 0.26; I2 = 28%), and hemorrhagic stroke (RR: 0.36; 95% CI: 0.06-2.24; P = 0.28; I2 = 10%) showed no significant differences. In conclusion, the risks of all-cause stroke, ischemic stroke, all-cause mortality, major bleeding, gastrointestinal bleeding, and intracranial hemorrhage in patients with atrial fibrillation undergoing chronic hemodialysis were lower in the DOAC group.

Clinical practice shows that a critical unmet need in the field of thrombosis prevention is the availability of anticoagulant therapy without bleeding risk. Inhibitors against FXIa or FXIIa have been extensively studied because of their low bleeding risk. However, whether these compounds produce synergistic effects has not yet been explored. In this study, analyses of activated partial thromboplastin time in combination with the FXIa inhibitor PN2KPI and the FXIIa inhibitor Infestin4 at different proportions were performed using the SynergyFinder tool identifying synergistic anticoagulation effects. Both an FeCl 3 -induced carotid artery thrombosis mouse model and a transient occlusion of the middle cerebral artery mouse model showed that the combination of PN2KPI and Infestin4, which are 28.57% and 6.25% of the effective dose, respectively, significantly prevents coagulation, and furthermore, dual inhibition does not cause bleeding risk.

Different dosing strategies exist to initiate warfarin, most commonly fixed warfarin dosing (FWD), clinical warfarin dosing (CWD), and genetic-guided warfarin dosing (GWD). Landmark trials have shown GWD to be superior when compared to FWD in the EU-PACT trial or CWD in the GIFT trial. COAG trial did not show differences between GWD and CWD. We aim to compare the anticoagulation quality outcomes of CWD and FWD. This is a prospective cohort study with a retrospective comparator. Recruited subjects in the CWD (prospective) arm were initiated on warfarin according to the clinical dosing component of the algorithm published in www.warfarindosing.org. The primary efficacy outcome was the percentage time in the therapeutic range (PTTR) from day 3 to 6 till day 28 to 35. The study enrolled 122 and 123 patients in the CWD and FWD, respectively. The PTTR did not differ statistically between CWD and FWD (62.2 ± 26.2% vs. 58 ± 25.4%, p = 0.2). There was also no difference between both arms in the percentage of visits with extreme subtherapeutic international normalized ratio (INR) (<1.5; 15 ± 18.3% vs. 16.8 ± 19.1%, p = 0.44) or extreme supratherapeutic INR (>4; 7.7 ± 14.7% vs. 7.5 ± 12.4%, p = 0.92). We conclude that CWD did not improve the anticoagulation quality parameters compared to the FWD method.

Patients with atrial fibrillation and concurrent liver cirrhosis have been excluded from major clinical trials evaluating direct oral anticoagulants (DOACs) due to safety concerns. This has led to uncertainty regarding the optimal anticoagulant therapy in this population at high risk of thromboembolic events. We conducted a systematic review and meta-analysis to compare the effectiveness and safety of DOACs versus vitamin K antagonists (VKAs) in patients with atrial fibrillation and liver cirrhosis. Databases including Embase, MEDLINE/PubMed, and Web of Science were searched for relevant studies. The primary effectiveness outcome was stroke or systemic embolism, and the safety outcome was major bleeding events. A total of 10 studies were included in the meta-analysis. Compared to VKAs, the use of DOACs was associated with a significantly lower risk of stroke or systemic embolism (RR: 0.78, 95% CI: 0.65-0.92, p=0.005). The risk of all-cause mortality was comparable between the two groups (RR: 0.89, 95% CI: 0.74-1.07, p=0.23). Notably, DOACs demonstrated a significantly lower risk of major bleeding events (RR: 0.67, 95% CI: 0.61-0.73, p<0.01) compared to VKAs. This meta-analysis suggests that DOACs may be a favorable alternative to VKAs for the prevention of thromboembolic events in patients with atrial fibrillation and liver cirrhosis, with a lower risk of stroke or systemic embolism and major bleeding. However, further research is needed to establish optimal dosing strategies and assess the safety and efficacy of DOACs in patients with advanced liver disease.

Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.

To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1).

A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.

Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).

CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

The aim of this study was to evaluate whether direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA) increase the risk of postoperative bleeding after dentoalveolar surgery. Patients were classified into two groups: one taking DOAC and the other taking VKA with a therapeutic INR range. The control group comprised non-anticoagulated subjects. Participants were matched regarding dentoalveolar procedure. The primary predictor was anticoagulant status. The primary outcome was postoperative bleeding. The DOAC group comprised 77 patients, while the VKA group and control group each consisted of 103 participants. In each group, 103 dentoalveolar surgical procedures were conducted. Postoperative bleeding was recorded in 3/103 (2.9%), 5/103 (4.8%), and 1/103 (0.97%) occasions in the DOAC, VKA, and control groups, respectively, without significant difference (χ2; p = 0.54). The fully adjusted odds ratio for postoperative bleeding was 0.14 (CI 0.01-1.61; p = 0.05) for patients taking DOAC and 0.19 (CI 0.02-1.65; p = 0.285) for those taking VKA compared with non-anticoagulated controls. In conclusion, there was no increase in risk for clinically significant postoperative bleeding after dentoalveolar surgery in patients taking DOAC or VKA compared with non-anticoagulated subjects. Dentoalveolar surgery in patients taking DOAC and VKA can be performed safely without therapy cessation. The study was registered at Clinicaltrials.gov (NCT04505475).