Direct oral anticoagulant (DOAC) agents are established as the anticoagulation strategy of choice for a variety of clinical risks. Despite this, uncertainty still exists with regard to their efficacy and safety for the prevention of stroke and systemic embolism in some patient populations; most notably those with low body weight (LBW) (<60 kg or body mass index [BMI] <18 kg/m2). Currently, there is a paucity of trial and non-trial data to support a prescriptive recommendation for their use in these patient cohorts. We have carried out a pooled systematic review of the most up to date published data of patients stabilized on various DOAC analogs with the view to ascertaining the exact matrices of their efficacy and safety in these cohorts of patients.

We initially carried out a comprehensive search of databases from inception to June 2023 for eligible studies exploring the efficacy and safety of various analogs of direct oral anticoagulants in patients with atrial fibrillation who had low body weight. Databases accessed include PubMed, EMBASE, the Science Citation Index, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effectiveness. We carried out a weighted comparison of derived pooled odd ratios (with their corresponding confidence intervals) of mortality outcomes between various DOACs using the random effects model.

Thirteen studies (n = 165,205 patients) were included in our meta-analysis. DOAC analogs were associated with increased stroke-related events, composite outcome, and mortality in low body weight patients compared to non-low body weight patients (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.17-1.92), (OR 1.55, 95% CI 1.29-1.86), (OR 2.92, 95% CI 1.87-4.58), respectively. There was no significant difference in the safety outcome (major bleeding events) between the DOAC analogs (OR 1.19, 95% CI 0.93-1.52).

In this meta-analytical review comprising both real-world and randomized controlled studies, the use of DOAC analogs in low body weight patients (body weight of <60 kg or BMI<18 kg/m2) with atrial fibrillation was associated with increased risks of stroke-related events, composite outcomes, and mortality compared to non-low body weight cohorts patients. At the same time, there was no significant difference in terms of major bleeding events. This finding has provided the first resolution of pervading uncertainty surrounding the use of DOAC analogs in these patient cohorts and suggests the need for follow-up confirmatory systematic studies in this group of patients.

Oral anticoagulants (OACs) are commonly used to prevent and treat thromboembolism and stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). Vitamin K antagonist (VKAs) and direct oral anticoagulant (DOACs) therapies are challenging because of the possible risk of bleeding. Patient education by pharmacists could be beneficial for reducing the risk of adverse effects and improving therapeutic outcomes.

This scoping review aimed to investigate the outcomes of pharmacist-led patient education interventions regarding VKAs and DOACs therapies.

Three databases (PubMed, Web of Science, and Scopus) were used following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines to identify articles published between January 1, 2008, and December 31, 2024. The data were synthesized using Rayyan AI.

A total of 1102 records were identified. After title and abstract screening, 77 studies were selected for full-text review, and 57 articles were ultimately included. The percentages of studies that examined VKAs, DOACs, and both (OACs) were 66.7 %, 19.3 %, and 14.0 %, respectively. At least one statistically significant outcome was detected in 81.6 % (31 out of 38) of the studies on VKAs, 36.4 % (4 out of 11) of the studies on DOACs and 50 % (4 out of 8) of the studies on OACs.

This review revealed that pharmacist-led patient education was particularly effective in cases of VKAs, while the outcomes in cases of DOACs were modest. Moreover, while the role of pharmacists in patient education on VKAs has been widely studied, limited research has focused on the effect of pharmacist-led education on DOACs.

Scandinavian evaluation of laboratory equipment for point of care testing (SKUP) provides objective and supplier-independent information about analytical quality and user-friendliness of point-of-care (POC) measuring systems. The evaluation reports are freely available online and are valuable tools when selecting fit-for-purpose POC equipment. In this study, we present an overview of the performance of four POC measuring systems for monitoring prothrombin time international normalized ratio (INR) assessed against updated analytical performance specifications (APSs).

Primary healthcare centres (PHCCs) in Sweden and Norway did the practical work under real-life conditions. In each evaluation, 2-4 PHCCs participated with at least 40 patients on Warfarin treatment per site. Capillary samples were measured on the POC INR systems (qLabs Q3 Plus PT-INR Owren, Xprecia Stride, microINR or ProTime InRhythm), with venous samples analysed at hospital laboratories for comparison (STA-R Evolution or Sysmex CS5100). In the current study, APSs from SKUP, ISO 17593:2022, and CLSI POCT14-Ed2 were used. User-friendliness was assessed by addressing operational facilities, user-manual, time factors, and quality control.

Only microINR coagulometer met the APS for accuracy, while qLabs Q3 Plus PT-INR Owren and ProTime InRhythm met the repeatability criteria. Xprecia Stride scored highest on user-friendliness, whereas the other systems faced challenges with sample application and unclear error messages on the devices.

This study highlights the potential for improvements in POC INR measuring systems and underscores the importance of performing objective evaluations under real-life conditions.

Left atrial appendage occlusion (LAAO) is an alternative to chronic oral anticoagulation (OAT) for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients with contraindications to OAT. Postprocedure antithrombotic therapy (ATT) is essential to reduce the risk of device-related thrombosis (DRT), but the optimal regimen remains uncertain.

This study aims to compare the safety and efficacy of low-dose direct oral anticoagulants (DOACs) versus dual antiplatelet therapy (DAPT) following LAAO.

A comprehensive search of PubMed, Scopus, Cochrane, and Web of Science was conducted in August 2024. Studies comparing low-dose DOACs and DAPT post-LAAO were included. The primary outcomes were a composite efficacy endpoint (DRT, strokes, and systemic embolism [SE]) and major bleeding events as the safety endpoint. Secondary outcomes included all bleeding events, all-cause mortality, and a composite of efficacy and safety endpoints.

Four studies with 727 patients were included. Low-dose DOACs were associated with lower rates of the primary composite efficacy endpoint compared to DAPT (OR = 0.36; 95% CI [0.16, 0.85], p = 0.01). No significant difference in major bleeding events was observed (OR = 0.36; 95% CI [0.11, 1.18]; p = 0.091; I² = 0%). Compared to DAPT, low-dose DOACs were also associated with lower rates of DRT events (OR = 0.36; 95% CI [0.16, 0.79], p = 0.011).

Low-dose DOACs effectively reduce thromboembolic events post-LAAO without increasing bleeding risk. These findings support their use as a viable ATT option, but larger trials are needed to confirm optimal regimens.

Acute gastrointestinal (GI) hemorrhage is a common cause for hospital admission that requires prompt diagnosis and multidisciplinary management to optimize clinical outcomes. Acute gastrointestinal bleeding (GIB) includes both upper and lower GI tract sources with an extensive list of differential pathologies. This review provides a systematic approach to both upper and lower GIB management, emphasizing initial resuscitation, stabilization, diagnostic evaluation to identify the source, and treatment modalities. Endoscopy remains the cornerstone for diagnostic and interventional purposes, significantly reducing the need for surgical procedures. However, lower GIB and severe or refractory cases may necessitate additional imaging and interventions, including surgical management. Integrating clinical guidelines, evidence-based strategies, and individualized care, this review delineates what you need to know to diagnose and manage acute GI hemorrhage.

Therapeutic/Care Management; Level III.

This study highlights the importance of evaluating warfarin dosing in diabetic patients, who require careful anticoagulation management. With rising rates of diabetes and cardiovascular diseases, understanding the factors influencing warfarin therapy is vital for improving patient outcomes and reducing adverse events. Data was sourced from the IWPC dataset, examining characteristics such as age, gender, diabetes status, indication for warfarin, weight, and height. We utilized the Bidirectional Encoder Representations from Transformers (BERT) model to analyze therapeutic doses, leveraging its ability to understand contextual relationships in the data. A machine learning approach was essential for predicting appropriate warfarin dosages, employing algorithms like Random Forest, KNN, MLP, Linear Regression, and SVM classification. We allocated 20 % of the data for testing and 80 % for training. Results showed that Linear Regression performed less effectively than MLP, KNN, SVM, and Random Forest in both training and testing. Notably, Random Forest's training MAE was significantly lower, while the other models showed similar performance in predicting warfarin dosages. This study emphasizes the importance of personalized anticoagulation management for diabetic patients on warfarin. The application of the BERT model alongside machine learning algorithms, particularly Random Forest, demonstrated effectiveness in predicting appropriate dosages. These findings suggest that integrating these advanced models into clinical practice can enhance decision-making, optimize patient outcomes, and reduce adverse events.

Several real-world studies have been done in patients with nonvalvular atrial fibrillation (NVAF); however, information on its safety profile in patients with renal impairment is limited. XARENAL, a real-world study, aimed to prospectively investigate the safety profile of rivaroxaban in patients with NVAF with renal impairment (creatinine clearance [CrCl], 15-49 mL/min).

XARENAL is an observational single-arm cohort study in renal impairment NVAF patients. Patients were followed up approximately every 3 months for 1 year or until 30 days following early discontinuation. The primary endpoint was major bleeding events. All adverse events, symptomatic thromboembolic events, treatment duration, and renal function change from baseline were the secondary endpoints.

XARENAL included 888 patients from 29 study sites. Overall, 713 (80.3%) had moderate renal impairment (CrCl, 30-49 mL/min), and 175 (19.7%) had severe renal impairment (CrCl, 15-29 mL/min) with a mean estimated glomerular filtration rate (eGFR) of 45.2±13.0 mL/min/1.73 m². The mean risk scores were 3.3±1.4 and 1.7±0.9 for CHA₂DS₂-VASc score and HAS-BLED score, respectively. An incidence proportion of 5.6% (6.2 events per 100 patient-years) developed major bleeding; however, fatal bleeding occurred in 0.5% (0.5 events per 100 patient-years). The mean change in the eGFR was 2.22±26.47 mL/min/1.73 m² per year.

XARENAL observed no meaningful differences in major bleeding events from other previous findings as well as renal function changes in rivaroxaban-treated NVAF patients with renal impairment, which is considered to be acceptable in clinical practice.

ClinicalTrials.gov Identifier: NCT03746301.

Warfarin is used as anticoagulation for children for a wide range of cardiac indications but carries the disadvantage of requiring international normalised ratio monitoring and dose adjustment. Management of warfarin therapy is challenging due to its narrow therapeutic window and is further complicated in children by dietary changes, frequent illnesses, and developing systems of metabolism and haemostasis.A retrospective review was performed of patients' medical records to assess the indication for warfarin use, percentage of international normalised ratio values in target range (%ITR), and frequency of phlebotomy.Twenty-six patients were identified. The most common indication for warfarin use was in patients post-total cavo-pulmonary connection (n = 19, 73%). We demonstrated a variability in duration of warfarin therapy following total cavo-pulmonary connection (median of 11.1 months). Nineteen (73%) patients had used the CoaguChek machine for home measurement of international normalised ratio. The median frequency of phlebotomy for all indications was once every 10 days, and the median %ITR was 55.4 % (29.7-86.4%). Of note, the percentage under target range in the patients with mechanical mitral (n = 2) and aortic valves (n = 1) was found to be 23% and 33%, respectively.These data demonstrate a high frequency of international normalised ratio values outside of the target range as seen in previous studies of warfarin in children. This necessitates frequent phlebotomy and dose changes, which can have a significant effect on the quality of life of these patients and their families highlighting the need to focus on quality improvement in the area of anticoagulation in paediatric cardiac patients.

The elevated health burden of thromboembolic events necessitates development of blood-based risk monitoring tools.

We explored the potential of mass spectrometry-based plasma proteomics to provide insights into underlying plasma protein signatures associated with treatment and occurrence of thromboembolic events.

Utilizing a high-throughput, data-independent acquisition, discovery-based proteomics workflow, we analyzed 434 plasma proteomes from different groups of individuals with elevated risk of thromboembolic events, including individuals I) on vitamin K antagonists (VKAs; n = 130), II) with a prior venous thromboembolism (n = 10), III) with acute cerebral venous sinus thrombosis (n = 10, and IV) with SARS-CoV-2 infection (n = 67). Plasma protein levels measured with mass spectrometry were correlated with international normalized ratio and conventional clinical laboratory measurements. Plasma profile differences between different groups were assessed using principal component analysis, moderated t-test, and clustering analysis.

Plasma protein levels were in agreement with conventional clinical laboratory parameters, including albumin and fibrinogen. Levels of vitamin K-dependent proteins inversely correlated with international normalized ratio. In the individual studies, we found decreased levels of vitamin K-dependent coagulation proteins in patients on VKAs, alterations in inflammatory signatures among CVST patients and a distinctive signature indicative of SARS-CoV-2 infection. However, no protein signature associated with a thromboembolic event could be identified neither in individual nor combined studies.

Although VKA treatment-specific and disease-specific signatures were captured, our study highlights that the challenges of discovering biomarkers in patients at risk of thromboembolic events lie in the heterogeneity of individual plasma profiles in relation to treatment and etiology.

Hemorrhagic complications associated with regional anesthesia are extremely rare. The fifth edition of the American Society of Regional Anesthesia and Pain Medicine's Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy reviews the published evidence since 2018 and provides guidance to help avoid this potentially catastrophic complication.The fifth edition of the American Society of Regional Anesthesia and Pain Medicine's Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy uses similar methodology as previous editions but is reorganized and significantly condensed. Therefore, the clinicians are encouraged to review the earlier texts for more detailed descriptions of methods, clinical trials, case series and pharmacology. It is impossible to perform large, randomized controlled trials evaluating a complication this rare; therefore, where the evidence is limited, the authors continue to maintain an 'antihemorrhagic' approach focused on patient safety and have proposed conservative times for the interruption of therapy prior to neural blockade. In previous versions, the anticoagulant doses were described as prophylactic and therapeutic. In this version, we will be using 'low dose' and 'high dose,' which will allow us to be consistent with other published guidelines and more accurately describe the dose in the setting of specific patient characteristics and indications. For example, the same 'high' dose may be used in one patient as a treatment for deep venous thrombosis (DVT) and in another patient as prophylaxis for recurrent DVT. Due to the increasing ability to obtain drug-specific assays, we have included suggestions for when ordering these tests may be helpful and guide practice. Like previous editions, at the end of each recommendation the authors have clearly noted how the recommendation has changed from previous editions.

Here, a zirconium-based metal organic framework-dispersive solid phase extraction method was established as an efficient, robust, and accurate approach for quantifying apixabanin human plasma samples prior to capillary electrophoresis with diode array detection. Various types of metal organic frameworks based on UiO-66-NH2 were synthesized by altering modulators and solvents and applied as sorbents in the extraction procedure. Among the tested sorbents, UiO-66-NH2 prepared in dimethylformamide in the presence of acetic acid was found to be the best sorbent in this method for the extraction of apixaban with high extraction efficiency comparable to other types of UiO-66-NH2 metal organic frameworks. The extraction and preconcentration of apixaban were carried out by adding 5 mg of synthesized sorbent to a 5 mL sample solution, followed by vortexing for 3 min. After discarding the supernatant, the adsorbed analyte was eluted from the sorbent surface using 60 µL acetonitrile under vortexing for 2 min. The effective parameters of the offered method were optimized and validated using a one-parameter-at-a- time strategy. The detection and quantification limits of the method were 9.9 and 32 ng mL-1 in plasma and 1.5 and 4.9 ng mL-1 in deionized water, respectively. The method was linear ranging from 4.9 to 1000 ng mL-1 in deionized water and from 32 to 500 ng mL-1 in plasma, respectively. The enrichment factor and extraction recovery values were 44 % and 53 %, respectively. The relative standard deviations were ≤6.2 % for intra- and inter-day precisions. Finally, the proposed method was successfully employed to quantify apixaban in human plasma samples.

Atrial fibrillation (AF) prevalence increases in older patients which also show a high thromboembolic risk. Oral anticoagulants (OACs) are recommended to prevent cardioembolic events and direct oral anticoagulants (DOACs) improved anti-thrombotic treatment. However, the benefits/risks of anticoagulant in older patients still need to be completely defined. This retrospective observational study aimed to describe the treatment with OACs in older AF hospitalized patients, and to identify factors influencing OAC therapy or discontinuation using the REgistro Politerapie SIMI. Univariate and multivariate logistic regression models were applied to identify predictors of OACs treatment and discontinuation. Cox proportional hazards models were performed to evaluate one-year mortality by treatment groups. AF patients were 1,128(26.5 %) at discharge and 1,098(97.3 %) required OAC treatment; about half of them (N = 528;48.1 %) were no-OACs users; 236(21.5 %) and 334(30.4 %) used DOACs and VKA, respectively. Increasing DOACs use was observed during the study period. Predictors of OACs treatment were: BMI (OR:1.04; 95 %CI:1.01-1.07), Barthel index (OR:1.01; 95 %CI:1.01-1.02), medications number (OR:1.07; 95 %CI:1.01-1.13). Conversely, a lower probability was found in patients with a high CIR.S (OR:0.59; 95 %CI:0.36-0.97) and neoplasm (OR:0.57; 95 %CI:0.37-0.88). Hospital stay (OR:1.02; 95 %CI:1.01-1.05), neoplasm (OR:2.25; 95 %CI:1.07-4.70) and INR (OR:1.21; 95 %CI:1.05-1.40) increased OACs discontinuation. A lower discontinuation was observed in dyslipidemic patients (OR:0.18; 95 %CI:0.04-0.82) and heart failure (OR:0.38; 95 %CI:0.21-0.70). Among AF patients, 157(14.3 %) died during the follow-up year. Age (HR = 1.05; 95 %CI = 1.03-1.08) and CIR.S (HR = 2.54; 95 %CI = 1.53-4.21) were associated with a greater mortality risk. In conclusion, critical issues related to the underuse and discontinuation of OACs therapy in hospitalized older patients were highlighted.

Interactive artificial intelligence tools such as ChatGPT have gained popularity, yet little is known about their reliability as a reference tool for healthcare-related information for healthcare providers and trainees. The objective of this study was to assess the consistency, quality, and accuracy of the responses generated by ChatGPT on healthcare-related inquiries.

A total of 18 open-ended questions including six questions in three defined clinical areas (2 each to address "what", "why", and "how", respectively) were submitted to ChatGPT v3.5 based on real-world usage experience. The experiment was conducted in duplicate using 2 computers. Five investigators independently ranked each response using a 4-point scale to rate the quality of the bot's responses. The Delphi method was used to compare each investigator's score with the goal of reaching at least 80% consistency. The accuracy of the responses was checked using established professional references and resources. When the responses were in question, the bot was asked to provide reference material used for the investigators to determine the accuracy and quality. The investigators determined the consistency, accuracy, and quality by establishing a consensus.

The speech pattern and length of the responses were consistent within the same user but different between users. Occasionally, ChatGPT provided 2 completely different responses to the same question. Overall, ChatGPT provided more accurate responses (8 out of 12) to the "what" questions with less reliable performance to the "why" and "how" questions. We identified errors in calculation, unit of measurement, and misuse of protocols by ChatGPT. Some of these errors could result in clinical decisions leading to harm. We also identified citations and references shown by ChatGPT that did not exist in the literature.

ChatGPT is not ready to take on the coaching role for either healthcare learners or healthcare professionals. The lack of consistency in the responses to the same question is problematic for both learners and decision-makers. The intrinsic assumptions made by the chatbot could lead to erroneous clinical decisions. The unreliability in providing valid references is a serious flaw in using ChatGPT to drive clinical decision making.

The aim of this bibliometric analysis was to highlight potential future areas for the practical application of research on rheumatic heart disease (RHD), considering past and current research efforts.

A systematic search was conducted in the WoSCC to find articles and reviews focused on RHD published between 2013 and 2024. Microsoft Excel 2019 was used to chart the annual productivity of research relevant to RHD, while ArcGIS (version 10.8) was employed to visualize the global distribution of publications. Analysis tools such as CiteSpace (version 6.1.R6) and VOSviewer (version 1.6.18) were utilized to identify the most prolific countries or regions, authors, journals, and resource-, intellectual-, and knowledge-sharing in RHD research, and to perform co-citation analysis of references and keywords. Additionally, the Bibliometrix R Package was used to analyze topic dynamics.

From the search, a total of 2,428 publications were retrieved. In terms of countries or regions, the United States was the most productive country (566, 23.31%). As for institutions, most publications have been contributed by the University of Cape Town (149, 6.14%). Regarding authors, Jonathan R. Carapetis produced the most published works, and he received the most co-citations. The most prolific journal was identified as the International Journal of Cardiology (70, 2.88%). The study published in Circulation received the most co-citations. Keywords with ongoing strong citation bursts included "surgical treatment" and "valvular heart disease".

Despite the rapid advancements in the field of RHD research, future efforts should prioritize strengthening collaboration among national institutions to facilitate information dissemination. Current research on RHD mainly focuses on prognosis of patients. While, the emerging research trends in RHD encompass treatment strategies for complications, including atrial fibrillation (AF), heart failure (HF), and infective endocarditis, as well as screening strategies for RHD and surgical interventions for patients with rheumatic mitral valve disease.

This study describes the management of patients on oral anticoagulation (OAC) undergoing endoscopic endonasal transsphenoidal surgery (EETS) and analyzes the risk of postoperative hematoma and epistaxis following treatment of pituitary adenoma (PA).

Patients with OAC prior to EETS for PA were analyzed in a single center retrospective case series of consecutive patients with PA, who were treated between December 2008 and July 2022. Patient data (age, sex, clinical, endocrinology, tumor histology) were entered into a SPSS® database. The rate of postoperative hemorrhage (intracranial and epistaxis) and other perioperative complications were assessed.

Of 305 patients, 20 patients were on OAC prior to EETS for PA. Indications included non-valvular atrial fibrillation (AF) in 10 patients and previous venous thromboembolic event (VTE) in 8 patients, in 2 patients had overlapping indications. Twelve patients on direct oral anticoagulants (DOAC) paused medication 1-3 days (43.6 ± 23.6 h) before surgery, while phenprocoumon was paused 234 ± 123.55 h (min 6, max 22 days) before surgery. Baseline characteristics such as age, sex, tumor growth direction, tumor volume, and largest diameter showed no significant differences. No significant increase in postoperative hemorrhage was observed in patients with OAC compared to those without. One patient on apixaban paused 48 h before surgery experienced postoperative epistaxis. Among patients without OAC, one experienced intracranial hemorrhage and seven experienced epistaxis.

Patients with OAC prior to EETS for PA have no increased risk for postoperative hematoma when OAC is paused based on individual risk assessment and recent general recommendations.

Critically ill patients in the intensive care unit (ICU) are often immobilized and on mechanical ventilation, placing them at increased risk for thromboembolic diseases, particularly deep vein thrombosis (DVT) and, to a lesser extent, pulmonary embolism (PE). While these conditions are frequently encountered in the emergency department, managing them in the ICU presents unique challenges. Although existing guidelines are comprehensive and effective, they are primarily designed for patients presenting with PE in the emergency department and do not fully address the complexities of managing critically ill patients in the ICU. This review aims to summarize the available data on these challenging cases, offering a practical approach to the prevention, diagnosis, and treatment of PE, particularly when it is acquired in the ICU.

The optimal approach for anticoagulation in patients with bioprosthetic valves and atrial fibrillation (AF) remains a subject of debate. A meta-analysis using updated evidence to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKAs) in patients with AF and bioprosthetic valves to address this controversy.

A comprehensive search was conducted in multiple databases, including PubMed, Scopus, Web of Science, ProQuest, and the Cochrane Central Register of Controlled Trials, up until March 2023. The search aimed to identify relevant randomized controlled trials (RCTs) that examined the efficacy and safety outcomes of both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with bioprosthetic valves and atrial fibrillation. The primary outcomes of interest were major bleeding and all-cause mortality.

Our study demonstrated that despite the difference was not significant, the hazard of all-cause mortality was 2.5% higher in the DOAC group (HR = 1.03, 95% CI = [0.88, 1.19], p-value = .75). Similarly, the hazard of stroke (HR = 1.03, 95% CI = [0.87, 1.32], p-value = .71) and major bleeding (HR = 1.11, 95% CI = [0.89, 1.38], p-value = .36) were found to be respectively 3.2 and 10.7% higher in the DOAC group, although the difference was not significant. However, the hazard of intracranial hemorrhage was found to be 28.8 lower in the DOAC treatment group (HR = 0.71, 95% CI = [0.39, 1.31], p-value = .27), which again was not statistically significant.

Our meta-analysis demonstrates that in patients undergoing bioprosthetic valve surgery and presenting with AF afterward, DOAC and VKA are similar regarding life-threatening and all-cause mortality outcomes, including major bleeding, stroke, and intracranial hemorrhage.

Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US.

Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization.

A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing.

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.

Thrombolytic therapy is effective method in the high-risk acute pulmonary embolism (PE) treatment. Reduced-dose thrombolysis (RDT) plus oral anticoagulation therapy is effective and safe method in the moderate and severe PE treatment. It is leading to good early and intermediate-term outcomes. In the RE-COVER and RE-COVER II studies, dabigatran showed similar effectiveness as warfarin in the treatment of acute PE. Dabigatran leads to fewer hemorrhagic complications and is not inferior in efficacy to warfarin in the prevention of PE after mechanical fragmentation and RDT (catheter-directed treatment [CDT]+RDT) in patients with high and intermediate to high PE risk. We sought to evaluate the efficacy and safety (incidence of clinically significant recurrence of venous thromboembolic complications and deaths) during a 6-month course of treatment with dabigatran or warfarin in patients with high and intermediate to high acute PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT).

The RE-SPIRE is a prospective, multicenter randomized double-arm study. Over a 5-year period, 66 consecutive patients with symptomatic high and intermediate to high PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT) were randomized into two groups within the next 48 hours. The first group continued treatment with dabigatran 150 mg twice a day for 6 months; the second group continued treatment with warfarin under the control of international normalized ratio (2.0-3.0) for 6 months. Both groups received low molecular weight heparins for 2 days after surgery. Then, group 1 continued to receive low molecular-weight-heparin for 5 to 7 days, followed by a switch to dabigatran at a dosage of 150 mg two times a day. Group 2 received both low-molecular-weight heparin and warfarin up to an international normalized ratio of >2.0, followed by heparin withdrawal. The follow-up period was 6 months.

There were 63 patients who completed the study (32 in the dabigatran group and 31 in the warfarin group). In both groups, there was a statistically significant decrease in the mean pulmonary artery pressure. The mean pulmonary artery pressure at the 6-month follow-up after surgery was 24 mm Hg (interquartile range, 20.3-29.25 mm Hg) in the dabigatran group and 23 mm Hg (interquartile range, 20.0-26.3 mm Hg) in the warfarin group. The groups did not differ statistically in the deep vein thrombosis dynamics. Partial recanalization occurred in 52.0% vs 73.1% in the dabigatran and warfarin groups, respectively (P = .15). Complete recanalization occurred in 28.0% vs 19.2% in the dabigatran and warfarin groups, respectively (P = .56). The groups did not differ in the frequency of major bleeding events according to the International Society for Thrombosis and Hemostasis (0% vs 3.2% in the dabigatran and warfarin groups, respectively; P = 1.00). However, there were more nonmajor bleeding events in the warfarin group than in the dabigatran group (16.1% vs 0%, respectively; P = .02).

The results of the study show that dabigatran is comparable in effectiveness to warfarin. Dabigatran has greater safety in comparison with warfarin in the occurrence of all cases of bleeding in the postoperative and long-term periods. Thus, dabigatran may be recommended for the treatment and prevention of PE after CDT with RDT in patients with high and intermediate to high PE risk.

There are important pharmacological differences between direct oral anticoagulants (DOAC) and a deeper knowledge of how they influence different aspects of hemostasis in patients on treatment is desirable.

Blood samples from patients on dabigatran (n = 23), rivaroxaban (n = 26), or apixaban (n = 20) were analyzed with a fibrin network permeability assay, a turbidimetric clotting and lysis assay, the calibrated automated thrombogram (CAT), plasma levels of thrombin-antithrombin complex (TAT) and D-dimer, as well as DOAC concentrations, PT-INR and aPTT. As a comparison, we also analyzed samples from 27 patients on treatment with warfarin.

Patients on dabigatran had a more permeable fibrin network, longer lag time (CAT and turbidimetric assay), and lower levels of D-dimer in plasma, compared with patients on rivaroxaban- and apixaban treatment, and a more permeable fibrin network than patients on warfarin. Clot lysis time was slightly longer in patients on dabigatran than in patients on rivaroxaban. Warfarin patients formed a more permeable fibrin network than patients on apixaban, had longer lag time than patients on rivaroxaban (CAT assay), and lower peak thrombin and ETP compared to patients on treatment with both FXa-inhibitors.

Results from this study indicate dabigatran treatment is a more potent anticoagulant than apixaban and rivaroxaban. However, as these results are not supported by clinical data, they are probably more related to the assays used and highlight the difficulty of measuring and comparing the effect of anticoagulants.

This study aims to visualize publications related to venous thromboembolism (VTE) and lower limb joint arthroplasty to identify research frontiers and hotspots, providing references and guidance for further research. We retrieved original articles published from 1985 to 2022 and their recorded information from the Web of Science Core Collection. The search strategy used terms related to knee or hip arthroplasty and thromboembolic events. Microsoft Excel was used to analyze the annual publications and citations of the included literature. The rest of the data were analyzed using the VOSviewer, citespace and R and produced visualizations of these collaborative networks. We retrieved 3543 original articles and the results showed an overall upward trend in annual publications. The United States of America had the most significant number of publications (Np) and collaborative links with other countries. McMaster University had the greatest Np. Papers published by Geerts WH in 2008 had the highest total link strength. Journal of Arthroplasty published the most articles on the research of VTE associated with lower limb joint arthroplasty. The latest research trend mainly involved "general anesthesia" "revision" and "tranexamic acid." This bibliometric study revealed that the research on VTE after lower limb joint arthroplasty is developing rapidly. The United States of America leads in terms of both quantity and quality of publications, while European and Canadian institutions and authors also make significant contributions. Recent research focused on the use of tranexamic acid, anesthesia selection, and the VTE risk in revision surgeries.

Patients aged ≥65 years not only account for the majority of patients with atrial fibrillation (AF) and venous thromboembolism (VTE), they are also at a higher risk of morbidity, mortality, and undertreatment than younger patients. Several age-related physiological changes with effects on drug pharmacokinetics/-dynamics and blood vessel fragility as well as the higher prevalence of geriatric conditions such as frailty, multimorbidity, polypharmacy, fall risk, dementia, and malnutrition make older persons more vulnerable to disease- and anticoagulation-related complications. Moreover, because older patients with AF/VTE are underrepresented in oral anticoagulation (OAC) trials, evidence on OAC in older adults with AF/VTE is mainly based on subgroup analyses from clinical trials and observational studies. A growing body of such limited evidence suggests that direct oral anticoagulants (DOACs) may be superior in terms of efficacy and safety compared to vitamin K antagonists in older persons with AF/VTE and that specific DOACs may have a differing risk-benefit profile. In this narrative review, we summarize the evidence on epidemiology of AF/VTE, impact of age-related physiological changes, efficacy/safety of OAC, specifically considering individuals with common geriatric conditions, and review OAC guideline recommendations for older adults with AF/VTE. We also propose a research agenda to improve the evidence basis on OAC older individuals with AF/VTE, including the conduct of advanced age-specific and pragmatic studies using less restrictive eligibility criteria and patient-reported health outcomes, in order to compare the effectiveness and safety of different DOACs, and investigate lower-dose regimens and optimal OAC durations in older patients.

Warfarin, a widely utilized anticoagulant, is paramount for preventing thromboembolic events in patients with mechanical heart valve replacements. However, its narrow therapeutic index can lead to over-anticoagulation and overdose, resulting in serious health risks. This study examines the efficacy of human prothrombin complex concentrate (PCC) in managing warfarin overdose, in comparison with traditional treatments. A retrospective analysis was conducted on 162 adults who presented with warfarin overdose (INR > 5.0) at a tertiary care hospital between 2016 and 2020. Participants were divided into 2 groups-those treated with PCC (n = 57) and those treated with conventional methods (n = 105), including vitamin K and fresh frozen plasma. The primary outcome was the rate of reaching the target (International Normalized Ratio) INR within 24 hours. Secondary outcomes included transfusion requirements, thromboembolic events, adverse reactions, 30-day mortality, and length of hospital stay. PCC demonstrated significant efficacy, with 89.5% of patients achieving the target INR within 24 hours, compared to 64.8% in the control group (P < .05). The PCC group also had reduced transfusion requirements and a shorter average hospital stay. There was no significant difference in thromboembolic events or adverse reactions between the 2 groups, and the reduced 30-day mortality in the PCC group was not statistically significant. Human prothrombin complex concentrate is associated with rapid reaching the target INR, decreased transfusion needs, and shortened hospitalization, making it a promising option for warfarin overdose management. While the results are encouraging, larger, multicenter, randomized controlled trials are necessary to further validate these findings and optimize PCC administration protocols.

Cannabis-drug interactions have caused significant concerns, mainly due to their role in the cytochrome P450 (CYP) enzyme-mediated metabolic pathway of numerous medications. A systematic review was conducted to gain an overview of the potential interactions of cannabis with different drug classes by extracting pertinent information from published study data. From the inception of the study to October 1, 2023, we performed a systematic search of PubMed, Scopus, clinicaltrials.gov, and Web of Science. We included 54 out of 464 articles, and a total of 20 drug classes were identified to have interactions with medicinal cannabis. The cannabis-drug interactions were assessed and classified according to their probability and severity. The analysis revealed that antiepileptics had the most evidence of interaction with cannabis, followed by clobazam (CLB), warfarin, and tacrolimus. Generally, cannabis-drug interactions result in pharmacokinetic (PK) or pharmacodynamic (PD) changes. Therefore, careful monitoring should be performed to detect any unusual elevations in plasma levels. In addition, dose titrations or treatment withdrawal could help mitigate the adverse effects attributed to cannabis-drug interactions. Nevertheless, novel drugs are constantly emerging, and more research is needed to further identify potential interactions with cannabis.

Home INR testing (patient self-testing) is feasible and effective for warfarin patients but little is known about real-world differences in outcomes for patients using PST versus laboratory-based INR monitoring.

To compare the safety/efficacy of patient self-testing of real-world warfarin therapy versus office/lab-based monitoring of therapy.

A retrospective claims-based analysis of warfarin patients enrolled in the MarketScan® Commercial Claims and Encounters and Medicare databases between January 1, 2013, and March 30, 2020. Stratification was based on INR testing method: patient self-testing versus testing at physicians' offices/local laboratory. The probability of adverse events in each cohort was determined after adjusting for demographic and baseline clinical characteristics using a repeated measures analysis.

Rates of all adverse events: deep venous thrombosis, pulmonary embolism, bleeding, and stroke. A secondary outcome of interest was emergency department visits.

A total of 37,837 patients were included in the analysis: 1592 patients in the patient self-testing group and 36,245 in the office-based therapy group. After adjusting for demographic and baseline clinical characteristics, patients in the office-based group had statistically significantly higher rates of all adverse events (incidence rate ratio [IRR]=2.07, 95% CI [1.82, 2.36]), and specific adverse events including thromboembolism (IRR=4.38, 95% CI [3.29, 5.84]), major bleed (IRR=1.45, 95% CI [1.28, 1.64]), and stroke (IRR=1.30, 95% CI [1.05, 1.61]) than patients in the patient self-testing group. Office-based patients also had a statistically significant higher rate of emergency department visits than patient self-testing patients (IRR = 1.65, 95% CI [1.47, 1.84]).

This analysis of real-world claims data shows lower rates of stroke, thromboembolism, and major bleeding, as well as fewer emergency department visits, with patient self-testing compared to office-based/lab INR monitoring. Our finding that PST is safe and effective among current users suggests that more patients may benefit from its use.

Atrial fibrillation (AF) is 1 of the most common types of arrhythmias. At present, the treatment for patients with AF mainly includes oral anticoagulants (OACs). Studies have shown that OACs are associated with cognitive decline in patients with atrial fibrillation; however, there is a lack of relevant evidence. This study used Bayesian network meta-analysis (NMA) to investigate the effects of different oral anticoagulants on cognitive decline in patients with AF.

We systematically searched for clinical studies on oral anticoagulants in patients with AF in PubMed, Web of Science, Embase, and the Cochrane Library as of July 3, 2023. Cochrane's randomized controlled trial bias risk assessment tool and the Newcastle-Ottawa Scale were used to assess the bias risk of the included studies. The main outcome measure was decreased cognitive functioning.

Ten studies were included, including 2 RCTs and 7 RCSs, including 882,847 patients with AF. Five oral anticoagulants and 2 anticoagulants were included: VKAs (especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel. The results of the mesh meta-analysis showed that VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF (OR = -1.19, 95% CI (-2.35, -0.06), P < .05) (Table 5). The top 3 drugs in terms of the probability of reducing the incidence of cognitive impairment in patients with AF with different oral anticoagulants were VKAs (87%), rivaroxaban (62.2%), and dabigatran (60.8%).

Based on the results of this study, VKAs may be the best intervention measure for reducing the risk of cognitive decline in patients with AF. Owing to the limitations of this study, more high-quality randomized controlled trials with large sample sizes and multiple centers are required to provide more evidence.

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.

In cardiology, acetylsalicylic acid (ASA) and warfarin are among the most commonly used prophylactic therapies against thromboembolic events. Drug-drug interactions are generally well-known. Less known are the drug-nutrient interactions (DNIs), impeding drug absorption and altering micronutritional status. ASA and warfarin might influence the micronutritional status of patients through different mechanisms such as binding or modification of binding properties of ligands, absorption, transport, cellular use or concentration, or excretion. Our article reviews the drug-nutrient interactions that alter micronutritional status. Some of these mechanisms could be investigated with the aim to potentiate the drug effects. DNIs are seen occasionally in ASA and warfarin and could be managed through simple strategies such as risk stratification of DNIs on an individual patient basis; micronutritional status assessment as part of the medical history; extensive use of the drug-interaction probability scale to reference little-known interactions, and application of a personal, predictive, and preventive medical model using omics.

Spontaneous gastric intramural haematoma is an uncommon complication associated with anticoagulant therapy. A patient receiving chronic warfarin for paroxysmal atrial fibrillation was admitted due to atrial fibrillation with rapid ventricular response (RVR). An incidental intra-abdominal mass was detected on a CT scan. Following the initiation of the amiodarone infusion, the patient experienced bleeding attributed to warfarin-amiodarone-induced coagulopathy, with no identifiable bleeding source. Subsequent CT scans revealed an enlargement of the intra-abdominal mass, suggesting gastric intramural haematoma. After coagulopathy reversal, the haematoma is managed conservatively. Our case underscores the potential for incidental bleeding even when the international normalised ratio is within the normal range in patients on chronic warfarin therapy. When managing such patients with atrial fibrillation with RVR, physicians should maintain a high index of suspicion for bleeding, emphasising the importance of prompt coagulopathy reversal.

Several observational studies have suggested that oral anticoagulants (OACs) might reduce the risk of dementia in the elderly, but the evidence is inconclusive. And the consistency of this relationship across different OAC classes and dementia subtypes is still uncertain.

To comprehensively evaluate this association, we applied Mendelian randomization (MR) combined with pharmacovigilance analysis. MR was used to assess the associations between genetic proxies for three target genes of OACs (VKORC1, F2, and F10) and dementia, including Alzheimer's disease (AD) and vascular dementia (VaD). This genetic analysis was supplemented with real-world pharmacovigilance data, employing disproportionality analysis for more reliable causal inference.

Increased expression of the VKORC1 gene was strongly associated with increased risk of dementia, especially for AD (OR = 1.28, 95% CI = 1.14-1.43; p value < 0.001). Based on pharmacovigilance data, vitamin K antagonists (VKAs, inhibitors targeting VKORC1) exhibited a protective effect against dementia risk (ROR = 0.43, 95% CI = 0.28-0.67). Additional sensitivity analyses, including different MR models and cohorts, supported these results. Conversely, no strong causal associations of genetically proxied F2 and F10 target genes with dementia and its subtypes were found.

This study reveals that the inhibition of genetically proxied VKORC1 expression or VKAs exposure is associated with a reduced risk of Alzheimer's dementia. However, there is little evidence to support similar associations with direct oral anticoagulants (F2 inhibitors and F10 inhibitors). Further research is warranted to clinically validate our findings.

Warfarin is extensively used for venous thromboembolism and other coagulopathies. In clinical settings, warfarin is administered as a mixture of S-warfarin and R-warfarin, and both enantiomers are metabolized by multiple cytochrome P450 enzymes into many hydroxylation metabolites. Validation of analysis method and estimation of warfarin plasma levels are important, especially in narrow-index drugs such as warfarin.

This study aimed to obtain a validated method for analyzing warfarin in patient plasma according to the European Medicines Agency (EMA) guidelines.

A total of 77 patients were enrolled in this study. Five millimeters of venous blood was collected using sodium ethylenediaminetetraacetic acid (EDTA) tubes for pharmacokinetic analysis. Samples were prepared by the protein precipitation technique using acetonitrile. The optimum conditions for the analysis of warfarin in human plasma were tested using fluorescence detector (FLD) high-performance liquid chromatography (HPLC) with Chiralcel OD-RH column (4.6 × 150 mm i.d., 5 μm), Chiralcel OD-RH guard column (4.0 × 10 mm, 5 μm), and a column temperature of 45°C. The mobile phase used was acetonitrile: phosphate buffer pH 2 (40:60), with an isocratic flow rate of 1 ml/min and an injection volume of 20 μl. Excitation and emission wavelengths were 310 and 350 nm (warfarin) and 300 and 400 nm (griseofulvin). The retention time of griseofulvin was 6-7.5 minutes; R-warfarin was 10-11.5 minutes; and S-warfarin was 14-16 minutes.

The result of this validation obtained the optimum conditions. This method yielded the limit of detection (LOD) values of 0.0674 ppm (R-warfarin) and 0.0897 ppm (S-warfarin). The limit of quantification (LOQ) values were 0.225 ppm (R-warfarin) and 0.298 ppm (S-warfarin). Linearity existed at concentrations of 0.2-3 ppm with the line equation y = 0.0705x + 0.0704 with R² = 0.978 for R-warfarin and y = 0.0513x + 0.0297 with R² = 0.9924 for S-warfarin. At least 75% of the seven concentrations met the reverse concentration requirements, which were below ± 15%. This method met the requirements of accuracy and precision within and between runs, selectivity, and carryover where the %RSD and %diff values were below ± 15%. The mean plasma concentrations of R-warfarin and S-warfarin were found to be 0.76 ± 1.87 (SD) μg/ml and 0.59 ± 0.81 (SD) μg/ml, respectively. The mean standard dose group plasma concentration from the analysis of 77 samples was 0.68 ± 0.61 μg/mL for R-warfarin and 0.52 ± 0.42 μg/mL for S-warfarin.

Based on these results, this analytical method can be declared valid and can be used for sample measurement in warfarin pharmacokinetic studies.

Warfarin is a popular anticoagulant with high global demand. However, studies have underlined serious safety issues when warfarin is consumed concomitantly with herbs or its formulations. This review aimed to highlight the mechanisms behind herb-warfarin interactions while laying special emphasis on its PKPD interactions and evidence on Herb-Warfarin Interaction (HWI) with regards to three different scenarios, such as when warfarin is consumed with herbs, taken as foods or prescribed as medicine, or when used in special situations. A targeted literature methodology involving different scientific databases was adopted for acquiring information on the subject of HWIs. Results of the present study revealed some of the fatal consequences of HWI, including post-operative bleeding, thrombosis, subarachnoid hemorrhage, and subdural hematomas occurring as a result of interactions between warfarin and herbs or commonly associated food products from Hypericum perforatum, Zingiber officinale, Vaccinium oxycoccos, Citrus paradisi, and Punica granatum. In terms of PK-PD parameters, herbs, such as Coptis chinensis Franch. and Phellodendron amurense Rupr., were found to compete with warfarin for binding with plasma proteins, leading to an increase in free warfarin levels in the bloodstream, resulting in its augmented antithrombic effect. Besides, HWIs were also found to decrease International Normalised Ratio (INR) levels following the consumption of Persea americana or avocado. Therefore, there is an urgent need for an up-to-date interaction database to educate patients and healthcare providers on these interactions, besides promoting the adoption of novel technologies, such as natural language processing, by healthcare professionals to guide them in making informed decisions to avoid HWIs.

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

This systematic review evaluates the extent to which the effect of anticoagulants may be altered in the presence of cannabinoids. The following databases were searched: EMBASE, PubMed, Web of Science, Scopus, PscycINFO, and CINAHL from database inception through May 2023. Search terms included cannabis AND anticoagulant AND drug interactions and related keywords. The major outcome was hemorrhage or thrombosis and if available the relative change in quantitative intensity of anticoagulation after cannabinoid exposure. The search generated 959 citations. After the removal of 440 duplicates, 519 citations were screened. Overall, with the exception of warfarin, evidence supporting an interaction between cannabinoids and anticoagulants is non-existent. Seven case reports evaluating an interaction with warfarin were reported. Cannabis doses involved were either extremely high (e.g., >260 mg/day of delta-9-tetrahydrocannabidiol [THC] or >600 mg/day of cannabidiol [CBD]) or were not known. Hemorrhage was identified in 14.2% (1/7) of reports and thrombosis in 0%. Quantitative anticoagulation levels were increased in patients on warfarin (elevated International Normalized Ratio [INR]) in six of seven cases. A maximum INR change was available in five of seven reports, ranging from +0.4 to +9.61. One report found no change in INR after 4 days of medical cannabis exposure. Another report outlined two separate episodes of INR elevation associated with bleeding requiring hospitalization and reversal after marijuana smoking. Four cases involved reduction in weekly warfarin dose ranging from 22% to 31%. The Drug Information Probability Score was calculated in six cases, with a score of probable for five cases and possible for one. Very low-quality data support a potential drug-drug interaction with warfarin and both THC and CBD. Clinician recognition of this potential interaction is important. Available evidence supports the need to conduct a drug interaction study between cannabinoids and warfarin to clarify the existence of an interaction.

The left ventricular assist device (LVAD) is a mechanical circulatory support device that supports the heart failure patient as a bridge to transplant (BTT) or as a destination therapy for those who have other medical comorbidities or complications that disqualify them from meeting transplant criteria. In patients with severe heart failure, LVAD use has extended survival and improved signs and symptoms of cardiac congestion and low cardiac output, such as dyspnea, fatigue, and exercise intolerance. However, these devices are associated with specific hematologic and thrombotic complications. In this manuscript, we review the common hematologic complications of LVADs.

Percutaneous transcatheter left atrial appendage (LAA) closure (LAAC) is an effective approach for preventing ischemic stroke in nonvalvular atrial fibrillation patients. Intracardiac echocardiography (ICE), a new imaging modality, is a promising strategy for guiding LAAC. This review highlights the various strategies for ICE-guided-LAAC as an option for clinical policy.

A comprehensive literature search was conducted of PubMed, ScienceDirect, Ovid Web of Science, SpringerLink, and other notable databases to identify recent peer-reviewed clinical trials, reviews, and research articles related to ICE and its application in the guidance of LAAC.

Various methods are used to evaluate the spatial structure and dimensions of the LAA. The main techniques for guiding LAAC are transesophageal echocardiography (TEE), cardiac computed tomography (CTA), and ICE. Among these techniques, the advantages of ICE typically include (1) multiangle and real-time assessment of intracardiac structure, (2) a reduction in procedural fluoroscopy, (3) reduced operation time and improved workflow in the catheterization laboratory, and (4) the avoidance of general anesthesia and the early detection of complications.

ICE is a promising strategy for the guidance of LAAC. Among the most advanced and recent technological innovations in cardiovascular imaging in general and volume imaging in particular, ICE offers greater efficacy and safety.

This study aims to investigate the influence of MEF2A and SLC22A3-LPAL2-LPA polymorphisms on cardiovascular disease susceptibility and responsiveness to warfarin medication in Jordanian patients, during the initiation and maintenance phases of treatment.

Several candidate genes have been reported to be involved in warfarin metabolism and studying such genes may help in finding an accurate way to determine the needed warfarin dose to lower the risk of adverse drug effects, resulting in more safe anticoagulant therapy.

The study population included 212 cardiovascular patients and 213 healthy controls. Genotyping of MEF2A and SLC22A3-LPAL2-LPA polymorphisms was conducted to examine their effects on warfarin efficiency and cardiovascular disease susceptibility using PCR-based methods.

One SNP (SLC22A3-LPAL2-LPA rs10455872) has been associated with cardiovascular disease in the Jordanian population, whereas the other SNPs in the MEF2A gene and SLC22A3-LPAL2-LPA gene cluster did not have any significant differences between cardiovascular patients and healthy individuals. Moreover, SLC22A3-LPAL2-LPA rs10455872 was correlated with moderate warfarin sensitivity, the other SNPs examined in the current study have not shown any significant associations with warfarin sensitivity and responsiveness.

Our data refer to a lack of correlation between the MEF2A polymorphism and the efficacy of warfarin treatment in both phases of treatment, the initiation, and maintenance phases. However, only rs10455872 SNP was associated with sensitivity to warfarin during the initiation phase. Furthermore, rs3125050 has been found to be associated with the international normalized number treatment outcomes in the maintenance phase.

Demonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by venous thrombosis (VT) or arterial thrombosis (AT) and/or pregnancy morbidity and the presence of antiphospholipid antibodies. Direct oral anticoagulants (DOACs) hold several advantages to vitamin K antagonists (VKAs) for prevention of thrombosis and we wish to evaluate DOACs compared with VKAs in secondary prevention of thromboembolic events in patients with APS.

We conducted searches of the published literature using relevant data sources (MEDLINE, Embase and Cochrane CENTRAL), and of trial registers for unpublished data and ongoing trials. We included randomised trials examining individuals >18 years with APS classified according to the criteria valid when the trial was carried out. Randomised controlled trials had to examine any DOAC agent compared with any comparable drug. We tabulated all occurrences of events from all eligible randomised trials. Due to few events, ORs and 95% CIs were calculated using the Peto method.

5 randomised trials comprising 624 patients met the predefined eligibility criteria. The primary outcome measure was new thrombotic events, a composite endpoint of any VT or AT, during the VKA-controlled phase of treatment. According to the I2 inconsistency index, there was evidence of statistical heterogeneity across the studies (I2=60%). Across trials, 29 and 10 thrombotic events were observed in 305 and 319 patients with APS treated with DOAC and VKA, respectively, corresponding to a combined Peto OR of 3.01 (95% CI 1.56 to 5.78, p=0.001). There was a significantly increased risk of AT while treated with DOACs compared with VKA (OR 5.5 (2.5, 12.1) p<0.0001), but no difference in the risk of VT (p=0.87). We found no significant difference in risk of bleeding.

DOACs were associated with a significant increase in the risk of a new thrombotic event, especially AT, favouring standard prophylaxis with warfarin.

CRD42019126720.