Warfarin Research Articles

A-161 Diagnosis of Lupus Anticoagulant Cases using Deep Neural Networks

Abstract Background Laboratory identification of lupus anticoagulant (LAC) is critical for diagnosing antiphospholipid antibody syndrome, a common cause of unprovoked thromboembolic events and pregnancy morbidity. Commonly used clot-based assays for LAC include the dilute Russell’s viper venom time (DRVVT) and activated partial thromboplastin time (APTT), but these are susceptible to anticoagulant interferences. Despite standardization efforts, LAC interpretation remains challenging due to pre- and post-analytical complexity and limited expertise. This study explored the use of deep neural networks (DNN) to facilitate LAC diagnosis. Methods Retrospective data for LAC profiling with 13 features performed at Mayo Clinic between 2021 and 2022 was collected. The profiles of 7,202 patients were randomly divided into training (n=4608), validation (n=1153), and test cohorts (n=1441). Diagnostic outputs including LAC positivity (determined by DRVVT or APTT) and the presence of warfarin (WAR) and heparin (HEP), were confirmed by expert assessment. Three DNN architectures were developed and evaluated (Figure 1): (1) four single output DNN models with a domain knowledge driven selection of input features, (2) four single output DNN models using the same 13 inputs across all models, and (3) a multi-output DNN model. Model performance was evaluated using the F1 score and the index of balanced accuracy (IBA) for each output label. Results Architecture 1 achieved high diagnostic accuracy with IBA values of 0.989-1.000 for all four outputs and F1 scores of 0.945-0.991. Architecture 2 exhibited F1 scores of 0.902-0.973 and IBA values of 0.935-0.992. Architecture 3 achieved F1 scores of 0.933-0.967 and IBA values of 0.941-0.983. Conclusions All three architectures accurately classify LAC and common anticoagulation effects. The comparable performance of architectures 1 and 2 suggests that manual feature extraction is unnecessary. Given its relative simplicity and versatility, architecture 3 is the preferred choice for implementation in a clinical laboratory to standardize LAC diagnosis.

Efficacy of prophylactic clip closure in reducing the risk of delayed bleeding after colorectal endoscopic submucosal dissection in patients on anticoagulant therapy: Multicenter prospective study.

The high rate of delayed bleeding after colorectal endoscopic submucosal dissection (ESD) in patients undergoing anticoagulant therapy remains a problem. Whether prophylactic clip closure reduces the rate of delayed bleeding in these patients is unclear. This study aimed to evaluate the efficacy of prophylactic clip closure in patients receiving anticoagulants. This multicenter prospective interventional trial was conducted at nine referral centers in Japan. Patients regularly taking anticoagulants, including warfarin potassium or direct oral anticoagulants, and undergoing ESD for colorectal neoplasms were enrolled. The discontinuation of anticoagulants was minimized according to recent guidelines. After the ESD, post-ESD ulcers were prophylactically closed using endoclips. The primary end-point was the incidence of delayed bleeding. The sample size was 45 lesions, and prophylactic clip closurewas considered effective when the upper limit of the 90% confidence interval (CI) for delayed bleeding did not exceed 20%. Forty-five lesions were used, and three were excluded. Complete closure was achieved in 41/42 lesions (97.6%). The overall delayed bleeding rate was low, at 4.9% (2/41; 90% [CI] 0.8-14.5), which was significantly lower than that at the prespecified threshold of 20% (P = 0.007). The median closure procedure time was 17 min, and the median number of clips was nine. No massive delayed bleeding requiring transfusion, interventional radiology, or surgery was observed, and no thromboembolic events were observed. Prophylactic clip closure may reduce the risk of delayed bleeding following colorectal ESD in patients receiving anticoagulants. UMIN Clinical Trial Registry (UMIN000036734).

Rapid Qualitative and Quantitative Detection of Warfarin Sodium Based on Terahertz Spectroscopy

Rapid Qualitative and Quantitative Detection of Warfarin Sodium Based on Terahertz Spectroscopy

Influence of Quercetin Pretreatment on Pharmacokinetics of Warfarin in Rats.

Warfarin (WAR) is an anticoagulant with a narrow therapeutic index and is principally metabolized by CYP3A4 and CYP2C9 enzymes. The inhibitors of these enzymes may alter the systemic exposure to WAR. Quercetin (QUE), a bioflavonoid, may modify the bioavailability of drugs used concurrently by inhibiting CYP3A4, CYP2C8, CYP2C9, CYP1A2, and Pglycoprotein (P-gp). The current study scrutinized the influence of QUE on WAR pharmacokinetics in rats. QUE was orally administered to animals for 14 consecutive days, followed by WAR as a single oral dose on the 15th day in the pre-treatment group. The co-administration group received a single dose of QUE and WAR concomitantly. Only carboxymethylcellulose (CMC) 0.5% was administered as a vehicle to control group. In the pre-treated group, WAR's Cmax was increased by 30.43%, AUC0-∞ by 62.94%, and t1/2 by 10.54%, while Cl decreased by 41.35%, relative to control. In co-administered animals, WAR's Cmax increased by 10.98%, AUC0-∞ by 20.20%, and t1/2 by 8.87%, while Cl declined by 16.40%. QUE alters the pharmacokinetics of WAR, warranting possibly WAR dose adjustment after confirmatory clinical investigations, specifically in patients with thrombotic disorders and a pre-treatment history of QUE or its product.

Determining the effect of drug "Warfarin sodium" on toxicity indicators in an acute experiment

The drug "Warfarin sodium" refers to anticoagulants of indirect action. It contains only one substance - warfarin sodium, the toxicological indicator of which have been studied in many countries. Therefore, the range of indicators for DL50 of warfarin sodium is very large. However, warfarin sodium has not yet been studied in Ukraine, its maximum permissible concentration in the air of the work area has not been established. Significant volumes of production and use of the drug “Warfarin sodium” on the territory of Ukraine necessitate the clarification of its main toxicological indicators and the establishment of the maximum allowable concentration in the air of the working area, which includes several stages. The first of them is the purpose of this work, namely: to establish DL50 upon intragastric administration of the drug "Warfarin sodium" to two species of animals in the conditions of an acute experiment. Experimental animals (60 non-linear white rats and 70 non-linear white mice) were divided into 9 groups. Six groups were injected with the drug "Warfarin sodium" in different doses: the first group (female rats) – 58 mg/kg per animal, the second (also female rats) – 29 mg/kg, the third (male rats) – 323 mg/kg, the fourth (also male rats) – 161.5 mg/kg, the fifth (mice of both sexes) – 374 mg/kg, the sixth (also mice of both sexes) – 187 mg/kg. Three control groups (the first – 6 male rats, the second – 6 female rats, the third – 14 mice) received distilled water. As a result, the mortality rates of experimental animals were obtained, on the basis of which, using the probit analysis method, the toxicity indicator of DL50 was determined: for female rats – 15.85 mg/kg, male rats – 398.11 mg/kg and mice –645.65 mg/kg. The established DL50 for male rats after intragastric administration of the drug "Warfarin sodium" may indicate an increase in their resistance to the drug, and this determines the expediency of periodic repeated acute experiments in order to verify the relevance of previously established DL50 of sodium warfarin. According to DL50 upon intragastric administration to female rats, which are the most sensitive species of animals to it, warfarin sodium belongs to highly hazardous substances.

The fluorescence signal of albumin-bound bilirubin to monitor drug-induced bilirubin displacement from human serum albumin

Bilirubin (BR) binding to human serum albumin (HSA) may be affected by drugs, which may cause hyperbilirubinemia. A new method is proposed to investigate BR displacement from HSA using the characteristic fluorescence signal of albumin-bound BR at 533 nm upon 460 nm excitation. Any decrease in the fluorescence intensity at 533 nm upon drug addiction is direct evidence of BR displacement. Drug-induced BR displacement was tested using the well-known drug markers, warfarin (WFN) for Site I, ketoprofen (KTN) for Site II and hemin (HMN) for Site III of HSA. The maximum quenching (93%) and the highest Ka value (1.13 × 105 M1), obtained with HMN, suggested a common binding site of BR and HMN. Relatively lower BR displacement by WFN and KTN and lowered Ka values can be attributed to allosteric phenomena. These results showed the importance of the albumin-bound BR fluorescence signal in testing BR displacement from albumin.

Predicting bioequivalence and developing dissolution bioequivalence safe space in vitro for warfarin using a Physiologically-Based pharmacokinetic absorption model

ObjectiveBioequivalence (BE) studies support the approval and clinical use of both new and generic drug products. Narrow therapeutic index (NTI) drugs have relatively high costs and low success rates of BE evaluation clinical trials as high-risk drugs. A physiologically-based pharmacokinetic (PBPK) model can be used to evaluate the BE of two preparations. MethodsThis study inputs the basic physical and chemical property parameters of warfarin sodium available at the present stage into GastroPlus™ software, and combined it with the Advanced Compartmental Absorption and Transit (ACAT™) model built into the software. The PBPK model of Chinese individuals taking 2.5 mg of warfarin sodium orally while fasted condition was developed using the disposal parameters calculated from the clinically measured PK data of the reference preparations. The model was tested using the PK data of other reference preparations and tested preparations from different domestic manufacturers. ResultsThe results revealed that at least 30% of drugs are released in 30 min under a pH of 4.5 condition, and at least 80% are released in 30 min under a pH of 6.8 condition, which can be used as bioequivalent dissolution limits under fasted conditions. The risk of BE failure in the fed condition will be significantly reduced for the clinical study on the BE of warfarin sodium, which is a NTI drug if the fasted condition is bioequivalent. ConclusionThe results revealed that the PBPK models were successfully developed for 2.5 mg of warfarin sodium tablets in Chinese individuals. Developing a PBPK model for NTI drugs based on in vitro dissolution data in software is a promising method for BE evaluation, which can provide great help for developing new drugs and the clinical trial research of BE of generic drugs.

In silico evaluation of pharmacokinetic parameters, delivery, distribution and anticoagulative effects of new 4,7-dihydroxycoumarin derivative

In this study, pharmacological profiling and investigation of the anticoagulant activity of the newly synthesized coumarin derivative: (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (L) were performed. The obtained results were compared with the parameters obtained for Warfarin (WF), which is a standard good oral anticoagulant. The estimated high binding affinity of L toward plasma proteins (PPS% value is > 90%) justifies the investigation of binding affinity and comparative analysis of L and WF to Human Serum Albumin (HSA) using the spectrofluorimetric method (296, 303 and 310 K) as well as molecular docking and molecular dynamics simulations. Compound L shows a very good binding affinity especially to the active site of WF (the active site I -subdomain IIA), quenching HSA fluorescence by a static process. Also, the finite element smeared model (Kojic Transport Model, KTM), which includes blood vessels and tissue, was implemented to compute the convective-diffusion transport of L and WF within the liver. Finally, compound L shows a high degree of inhibitory activity toward the VKOR receptor comparable to the inhibitory activity of WF. Stabilization and limited flexibility of amino acid residues in the active site of the VKOR after binding of L and WF indicates a very good inhibitory potential of compound L. The high affinity of the L for the VKOR enzyme (Vitamin K antagonist), as well as the structural similarity to commercial anticoagulants (WF), provide a basis for further studies and potential application in the treatment of venous thrombosis, pulmonary embolism and ischemic heart disease. Communicated by Ramaswamy H. Sarma

Validation and Uncertainty Calculation of Rodenticide Analysis Methods in a Simulated Gastric Content Matrix – Uncertainty of Rodenticide Analysis Methods

Warfarin (WAR), brodifacoum (BDF) and bromadiolone (BDL) are compounds present in rodenticides, highly toxic to rats, humans and other animals. These compounds can be detected in complex matrices, such as stomach contents, by liquid chromatography techniques (HPLC) with mass spectrometry (MS) or fluorescence detection (FLD). However, no validated method showed determination of uncertainty in the quantification of these compounds. In this study, we compare the validation parameters of two analytical methods, HPLC FLD and ultra high performance liquid chromatography (UHPLC – MS), with uncertainty estimation for the three cited compounds. The results showed that UHPLC-MS outperformed HPLC FLD, however both methods were considered adequate for detection of WAR, BDF or BDL in samples of simulated human stomach contents, especially in cases of suspected contamination.

Evaluation of a compact composite sensor array for concentration monitoring of solutions and suspensions via multivariate analysis

Compact composite probes were identified as a priority to alleviate space constraints in miniaturized unit operations and pharmaceutical manufacturing platforms. Therefore, in this proof of principle study, a compact composite sensor array (CCSA) combining ultraviolet and near infrared features at four different wavelengths (280, 340, 600, 860 nm) in a 380 × 30 mm housing (length x diameter, 7 mm diameter at the probe head), was evaluated for its capabilities to monitor in situ concentration of solutions and suspensions via multivariate analysis using partial least squares (PLS) regression models. Four model active pharmaceutical ingredients (APIs): warfarin sodium isopropanol solvate (WS), lidocaine hydrochloride monohydrate (LID), 6-mercaptopurine monohydrate (6-MP), and acetaminophen (ACM) in their aqueous solution and suspension formulation were used for the assessment. The results demonstrate that PLS models can be applied for the CCSA prototype to measure the API concentrations with similar accuracy (validation samples within the United States Pharmacopeia (USP) limits), compared to univariate CCSA models and multivariate models for an established Raman spectrometer. Specifically, the multivariate CCSA models applied to the suspensions of 6-MP and ACM demonstrate improved accuracy of 63% and 31%, respectively, compared to the univariate CCSA models [1]. On the other hand, the PLS models for the solutions WS and LID showed a reduced accuracy compared to the univariate models [1].

Investigation of the separate and simultaneous bindings of warfarin and fenofibrate to bovine serum albumin

Lipid-lowering drugs are often taken with anticoagulant drugs in hyperlipidemia patients. Fenofibrate (FNBT) and warfarin (WAR) are common clinical lipid-lowering drugs and anticoagulant drugs, respectively. A study of binding affinity, binding force, binding distance, and binding sites was performed to determine the interaction mechanism between drugs and carrier proteins (bovine serum albumin, BSA), as well as their effects on BSA conformation. Both FNBT and WAR can form complexes with BSA by van der Waals force and hydrogen bonds. WAR had a stronger fluorescence quenching effect on BSA, a stronger binding affinity, and greater effects on BSA conformation than FNBT. According to fluorescence spectroscopy and cyclic voltammetry, co-administration of drugs decreased one drug's binding constant to BSA and increased its binding distance. This suggested that each drug's binding to BSA was disturbed by each other, as well as each drug's binding ability to BSA was altered by the other. It was demonstrated that co-administration of drugs had greater effects on the secondary structure of BSA and microenvironment polarity surrounding amino acid residues, using multiple spectroscopy techniques, such as ultraviolet spectroscopy, Fourier transform infrared spectroscopy, and synchronous fluorescence spectroscopy.

UPPER AIRWAY OBSTRUCTION: DELAYED COMPLICATION OF WARFARIN THERAPY

AIM- Report an unusual presentation of delayed complication of warfarin therapy leading to airway compromise. Warfarin is a BACKGROUNDwell-known oral anticoagulant and its major adverse side effect is bleeding (1-10%).Spontaneous hematoma of the sublingual and lingual space is an extremely rare and life threatening complication of warfarin sodium use and can lead to upper airway obstruction from elevation of the oor of mouth and tongue. -The case of a 40 year old male with complaints of swelling be CASE DESCRIPTION low chin and oor of mouth pushing the tongue backwards since 2 days and difculty speaking and swallowing since 1 day and difculty breathing since the past few hours is reported here. History revealed prolonged warfarin therapy. It was managed conservatively with withdrawal of warfarin and administration of Vitamin K and FFP. Prolonged warfarin therapy can lead to hematoma formation in the oor of mouth a CONCLUSION- nd neck swelling which can mimic Ludwig angina. The case can be managed conservatively with careful observation to avoid sudden upper airway obstruction.CLINICAL SIGNIFICANCE- Reporting of such case is warranted due to the need to create awareness of this life threatening complication of warfarin therapy, to preclude any diagnostic dilemma and to share our management of this dreaded complication.

Hem coagulase induced cerebral venous sinus thrombosis in patients with uterine fibroids surgery.

Cerebral venous sinus thrombosis (CVST) is a rare, high-risk, and easily misdiagnosed disease. Currently, there are case reports of hem coagulase-induced thrombotic events, but no reports of CVST being associated with hem coagulase. A 35-years-old woman presented to the outpatient clinic with a severe headache and sudden memory loss with intravenous hem coagulase for postoperative bleeding after uterine fibroids surgery. Abnormal neurological signs included slowed reactions, poor memory, and decreased numeracy. Magnetic resonance imaging and computed tomography scan showed multiple cerebral infarcts, and the infarct area was non-arterial. Brain magnetic resonance venography showed obstruction of the left sigmoid sinus. High-resolution magnetic resonance imaging of the left sigmoid sinus showed abnormally high signal. The patient was treated with a subcutaneous Low-Molecular-Weight Heparin Sodium injection 0.4 ml, twice a day (7 days), and oral Warfarin Sodium 3 mg, once a day, while monitoring the international normalized ratio, adjust the warfarin sodium dosage according to the international normalized ratio level. One month later, the patient had no neurological symptoms and her cognitive function returned to normal. hem coagulase may be a contributing factor to CVST in patients undergoing uterine fibroids surgery and should be administered intravenously with caution.

Medications mostly associated with hematuria: assessment of the EudraVigilance and Food and Drug Administration pharmacovigilance databases entries.

Drugs may have a direct causative role in triggering hematuria. The range of medications which may be responsible for hematuria is wide, but little is known on those which are most frequently involved. The aim of our study was to identify and compare drugs mostly related with hematuria. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and the EudraVigilance (EV) database were queried to identify the drugs which were associated the most with hematuria individual reports till 30 September 2021. Rivaroxaban, aspirin, warfarin sodium, clopidogrel bisulfate, dabigatran etexilate mesylate, apixaban, warfarin, cyclophosphamide, lansoprazole, enoxaparin sodium, and ibuprofen were analyzed. Analysis per gender, age and severity was performed. Disproportional analysis was performed to compare drugs. Overall, 15,687 reports of hematuria were recorded in the FDA database and 15 007 in the EV database. Rivaroxaban and Warfarin appear to be the most dangerous medications in terms of hematuria when compared to the other medications (PRR>1, P<0.05) while apixaban is the safest one (PRR<1, P<0.05) when compared to the other medications. In terms of severity only 162/15 007 (1.08%) were fatal. Between the drugs analyzed cyclophosphamide 7.2%, enoxaparin (3%) and dabigatran (2.5%) presented a higher number of fatal hematuria episodes when compared to the other drugs (<1%). Anticoagulants and antiplatelets are more frequently related to hematuria episodes however some differences exist between them. Particularly warfarin and rivaroxaban should be prescribed with caution in patients at increased risk of hematuria. Prescribers should inform those treated with these medications about the risk of hematuria and its sequelae.

A case of thromboembolic events as first manifestation of membranous nephropathy

We present a case of idiopathic membranous glomerulonephritis that presented with venous thromboembolism and was successfully managed with corticosteroid, cyclosporin, appropriate anticoagulant therapy. A 59-year old male patient was referred to our nephrology department who had an outpatient history of swelling in the feet and flank pain was detected proteinuria and thrombosis in the inferior vena cava. Warfarin sodium treatment was started when thrombus was detected in the femoral vein, renal vein and inferior vena cava in the imaging. The patient had 12 g/day proteinuria, hypoalbuminemia, hyperlipidemia and antiphospholipase A2 receptor antibody positivity and treatment was started with the diagnosis of idiopathic membranous nephropathy. The patient who was discharged with oral steroid, cyclosporine and warfarin sodium, but warfarin sodium was changed to rivaroxaban in another clinic due to incompatibility problems, was presented again with dsypnea. Pulmonary embolism was detected. Rivaroxaban was discontinued and low molecular weight heparin treatment was started. There was a very high risk of morbidity and mortality and with appropriate treatment, clinical status and renal function were stabilized. In conclusion, although thromboembolism can be seen in nephrotic syndrome, it may rarely be encountered as the first presentation of nephrotic syndrome. This situation should not be overlooked, appropriate treatments should be provided without delay.

VALIDATION OF WARFARIN ANALYSIS METHOD IN HUMAN BLOOD PLASMA USING HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH FLUORESCENCE DETECTION

Objective: Validation of analysis method is important, especially in analyzing narrow-index drugs such as warfarin (WF). This study aimed to obtain a validated method of analyzing warfarin in human plasma according to European Medicine Agency guidelines.&#x0D; Methods: The optimum conditions for the analysis of warfarin in human plasma using fluorescence detector HPLC with Chiralcel OD-RH column (4.6 x 150 mm i.d., 5μm); Chiralcel OD-RH guard column (4.0 x 10 mm, 5μm), column temperature 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 min; R-warfarin was 10-11.5 min; S-warfarin was 14-16 min.&#x0D; Results: The result of this validation obtained the optimum condition. This method yielded LOD values of 0.0674 ppm (R-warfarin) and 0.0897 ppm (S-warfarin). LOQ values were 0.225 ppm (R-warfarin) and 0.298 ppm (S-warfarin). Linearity 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. 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%&#x0D; Conclusion: This analytical method can be declared valid and can be used for sample measurement in warfarin pharmacokinetic studies.

Platelet and coagulation hemostasis status in patients with atrial fibrillation depending on warfarin dosing method

The aim. To evaluate indicators of induced platelet aggregation and D-dimer level in patients with atrial fibrillation (AF) depending on the method of warfarin (WF) dosing. Materials and methods. The study involved 110 patients with AF (mean age 68.72 ± 0.79; men – 57, women – 53). Patients with AF were divided into two groups: the main group – 50 patients with AF and genotype-guided dosing method, the control group – 60 patients with AF and traditional dosing method. CYP2C9, CYP4F2, VKORC1 genetic polymorphisms were determined using multiplex real time polymerase chain reaction, D-dimer concentration – by the method of solid-phase enzyme immunoassay; ADP- and epinephrine-induced aggregation indicators – by the method of G. Born. Results. The percentage (by 24 %), time (by 3 min 6 s) and rate in 30 s (by 19.5 %/min) of ADP-induced platelet aggregation were significantly lower in patients with AF and genotype-guided WF dosing method. D-dimer concentration in patients of the main and control groups did not differ significantly. However, significantly fewer patients with elevated D-dimer values were registered in the group with genotype-guided WF dosing method compared to the group with traditional dosing method: 0 (0.00 %) vs. 7 (11.67 %) at 500 ng FEU/ml cut-off (χ2 = 4.43, P &lt; 0.05), 1 (2.00 %) vs. 9 (15.00 %) at 390 ng FEU/ml cut-off (χ2 = 4.16, P &lt; 0.05), 0 (0.00 %) vs. 7 (11.67 %) at age-adjusted cut-off (χ2 = 4.43, P &lt; 0.05). Conclusions. The obtained results may indicate a potentially lower risk of thrombotic events in patients with AF and genotype-guided WF dosing method compared to the group with traditional dosing method, which confirms the benefit of the widespread use of the pharmacogenetic testing in clinical practice.

Acute middle cerebral artery occlusion caused by spontaneous thrombosis of a small internal carotid artery aneurysm: illustrative case

Spontaneous thrombosis of a saccular, unruptured, intracranial aneurysm is rare in nongiant aneurysms. Herein, the authors present a case of acute middle cerebral artery occlusion (MCO) caused by spontaneous thrombus of a small internal carotid artery (ICA) aneurysm. A 68-year-old woman presented with increased somnolence, right-sided hemiplegia, hemispatial neglect, and total aphagia. Left MCO and a small left ICA aneurysm were suspected based on magnetic resonance angiography (MRA). The authors detected early ischemic lesions from diffusion-weighted imaging (DWI). The DWI-Alberta Stroke Program Early Computed Tomography Score was 6. T2*-weighted imaging (T2*WI) showed a thrombus, the so-called susceptibility vessel sign, at the left MCO site. Another suspected thrombus was also found in the ipsilateral ICA aneurysm. The authors treated acute phase MCO with mechanical thrombectomy (MT), after which secondary stroke prophylaxis consisting of warfarin potassium was started. Since follow-up T2*WI showed the thrombus had disappeared from the left ICA aneurysm and the whole aneurysm was clarified by MRA, coil embolization was performed. After coil embolization, there was no ischemic recurrence. Aneurysms are infrequently found proximal to occlusion sites during MT. If the proximal aneurysm is a potential embolic source, treatment of the said aneurysm may prevent stroke.

Echocardiographic parameters of left atrial structure and function in elderly patients with atrial fibrillation, and clinical outcomes at 2 years: the ANAFIE echocardiographic substudy

Abstract Background Previous studies have shown an association between echocardiographic parameters of cardiac structure and function and prognosis in patients with atrial fibrillation (AF). However, only limited data are available for elderly patients (age, ≥75 years). Purpose The All Nippon Atrial Fibrillation In the Elderly (ANAFIE) Registry (UMIN000024006) was a prospective, multicenter, observational study which collected real-world data on the clinical status and prognosis of 33,062 Japanese patients aged ≥75 years and with non-valvular AF (NVAF). A prospective substudy of 1,474 patients who underwent transthoracic echocardiography at baseline was conducted to investigate relations between echocardiographic parameters of left atrial structure and function and clinical outcomes at 2 years. Methods Cumulative incidences and adjusted hazard ratios (HRs) of clinical outcomes were calculated using Kaplan–Meier analysis and the Cox proportional-hazards model, respectively. The data were analysed by left atrial volume index (LAVi) category, left atrial emptying fraction (LAEF) category, and direct oral anticoagulant (DOAC) use vs warfarin (WF) use. Cardiovascular (CV) events was a composite of stroke, myocardial infarction (MI), cardiac interventions, heart failure (HF) hospitalization, CV death. Cardiac events was a composite of MI, cardiac intervention, HF hospitalization, and CV death. Results Baseline characteristics were mean age of 80.7 years; male, 59.2%; paroxysmal AF, 45.9%; mean CHA2DS2-VASc score, 4.3; mean HAS-BLED score, 1.9; median LAVi, 48.7 mL/m2; median LAEF, 26.6%; comorbidity or history of HF, 32.2%; oral anticoagulant use, 92.7%; DOAC use, 68.7%; and WF use, 24.0%. Incidences (/100 patient-years) and HRs (95% CIs) for each clinical outcome according to LAVi and LAEF category are summarized in Table. Compared with patients with LAEF &amp;gt;45.0% (n=224), those with LAEF ≤45.0% (n=1,213) were at higher risk of CV events (2.19 [1.13–4.27], p=0.021) and HF hospitalization (2.25 [1.02–4.96], p=0.045). Risk of all-cause death was higher in patients with LAVi &amp;gt;48.0 mL/m2 (n=656) than in those with LAVi ≤48.0 mL/m2 (n=621) (1.69 [1.00–2.83], p=0.048). In the subgroups with LAEF ≤45.0% or LAVi &amp;gt;48.0 mL/m2, patients receiving a DOAC had significantly lower risk of cardiac events, CV events, and HF hospitalization than patients receiving warfarin. Conclusion In elderly Japanese patients with NVAF, those with LAEF ≤45.0% are at higher risk of CV events and HF hospitalization, and those with LAVi &amp;gt;48.0 mL/m2 are at higher risk of all-cause death. Thus, the higher risk differs between patients with LAEF ≤45.0% and those with LAVi &amp;gt;48.0 mL/m2. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Co., Ltd.

Efficacy and safety of warfarin therapy in patients with atrial fibrillation using genotype-guided dosing method

The aim. To evaluate the efficacy and safety of warfarin (WF) therapy in patients with atrial fibrillation (AF) using pharmacogenetic dosing method at an anticoagulant monitoring office according to the results of a one-year prospective follow-up. Materials and methods. The study involved 110 patients with AF (mean age 68.72 ± 0.79; men – 57, women – 53). By the method of stratified randomization, the patients with AF were divided into two groups: the main group – 50 patients with AF and genotype-guided dosing method, the control group – 60 patients with AF and clinical dosing method. The outcomes were examined after the one-year follow-up: excessive hypocoagulation episodes (INR &gt; 4) and bleeding. CYP2C9, CYP4F2, VKORC1 gene polymorphisms were determined using multiplex real time polymerase chain reaction; INR was controlled monthly; CHA2DS2-VASC, HAS-BLED, SAMe-TT2R2 scale scores were evaluated; TTR was calculated using the Rosendaal method. Results. The distribution of CYP2C9, CYP4F2, VKORC1 genotypes in the main and control groups were in accordance with the Hardy–Weinberg equilibrium. In patients with AF and genotype-guided dosing, the frequency and risk of excessive hypocoagulation episodes (χ2 = 5.11; P &lt; 0.05; RR = 0.50 (CI 0.27; 0.94)) and bleeding (χ2 = 9.57; P &lt; 0.05; RR = 0.41 (CI 0.22; 0.77)) were significantly lower. However, the groups did not differ in TTR. The validity of genetic-guided dosing was confirmed by the comparability of the medians and the direct correlation between the calculated and therapeutic WF doses (r = +0.57; P &lt; 0.05). There were no relationships between TTR, excessive hypocoagulation episodes, hemorrhagic complications and clinical and genetic factors in the main group. Conclusions. In patients with AF, the use of genotype-guided dosing method in the anticoagulant monitoring office helped to reduce the frequency and risk of excessive hypocoagulation episodes and bleeding as well as eliminate the influence of endogenous and exogenous factors in the personalized management of patients.