Warfarin Administration Research Articles

Warfarin pharmacokinetics and pharmacodynamics are not affected byconcomitant administration of the long-acting GLP-1 receptor agonist polyethylene glycol loxenatide.

To evaluate potential drug-drug interactions between polyethylene glycol loxenatide (PEX-168) and warfarin. This was an open-label, single-arm, two-treatment, sequential study. 16 healthy male subjects were administered warfarin (5 mg) alone on day 1 and received PEX-168 subcutaneously 200 µg once a week during days 14 - 42, with warfarin (5 mg) on day 44. Pharmacokinetics of R- and S-warfarin, as well as pharmacodynamics of warfarin, as measured by prothrombin time (PT) and international normalized ratio (INR), were assessed. The geometric mean ratios (GMRs) of area under the curve from time zero to the time of the last quantifiable concentration (AUC0-t) for PEX-168 + warfarin vs. warfarin were 0.950 (90% CI: 0.898, 1.006) for R-warfarin and 0.989 (90% CI: 0.946, 1.033) for S-warfarin. The GMRs of maximum observed plasma concentration (Cmax) values were 0.965 (90% CI: 0.893, 1.043) for R-warfarin and 0.983 (90% CI: 0.899, 1.075) for S-warfarin, both of which were contained in the interval 0.80 - 1.25. PEX-168 had no effect on the area under the effect-time curve from time 0 to 168 hours of INR and PT, as demonstrated by the GMRs of 0.987 (90% CI: 0.974, 1.000) and 0.990 (90% CI: 0.979, 1.002), respectively. Concomitant administration of PEX-168 and single-dose warfarin was well tolerated. PEX-168 had no effect on the pharmacokinetics or pharmacodynamics of warfarin.

Molecular Docking of Nigella Sativa L. with PXR Receptors and the Effect of Thymoquinone on PXR Expression in HepG2 Cells

ABSTRACT. The interaction between herbal remedies and drugs is a fascinating phenomenon that might cause therapeutic complications in patients. Warfarin is an anticoagulant drug that provides anti-blood-clotting effects by inhibiting the formation of vitamin K-dependent coagulation factors, and warfarin interacts with the nuclear receptor PXR, subsequently modulating cytochrome P450 during the metabolism process. St. John's wort, an herbal medicine with antidepressant effects, can alter the pharmacokinetics of warfarin. Thymoquinone is one of the active compounds in N. sativa and has pharmacological activities such as anticoagulant, antidiabetic, diuretic, antidepressant, and anti-inflammatory effects. In this study, we investigated the compounds in Nigella sativa (N. sativa) against pregnane X receptor (PXR) and evaluated the impact of thymoquinone (TQ) administration on PXR expression in HepG2 cells. The molecular docking analysis was conducted utilizing the Molecular Operating Environment (MOE) with the PXR (PDB ID: 7AXJ). At the same time, the PXR gene expression was measured using RT-PCR instruments. The RMSD value in docking represents the deviation criteria between the native ligand position and the redocking position result, indicating the capability of MOE and PDB qualification for performing molecular docking. The docking analysis showed that warfarin had the strongest binding energy (7AXJ -6.0507) by forming hydrogen binding type on Arg410. Despite TQ being the major component, it also displayed a high affinity for the two PDB IDs (7AXJ -4.5962). Furthermore, the concurrent administration of warfarin and TQ (19.27 μM) in HepG2 cells showed a significant reduction in the relative mRNA expression of the PXR gene. Given the above-mentioned findings, our study adequately enables us to predict the mechanism behind herb-drug interactions (HDIs) implicating N. sativa, specifically the TQ compound to warfarin metabolism via the activation of the PXR receptor. Keywords: Thymoquinone, expression mRNA, PXR, molecular docking, HepG2 cells.

Construction of warfarin population pharmacokinetics and pharmacodynamics model in Han population based on Bayesian method

The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.

Efficacy and Safety of Edoxaban in Anticoagulant Therapy Early After Surgical Bioprosthetic Valve Replacement: Rationale and Design of the ENBALV Trial.

Anticoagulant therapy with vitamin K antagonists is recommended within 3 to 6 months after bioprosthetic valve replacement to prevent thromboembolic events. However, data regarding whether direct oral anticoagulants can be an alternative to warfarin in such patients are limited. The purpose of this study is to compare the efficacy and safety of edoxaban versus warfarin within 3 months after bioprosthetic valve replacement. The ENBALV trial is an investigator-initiated, phase 3, randomized, open-label, multicenter study. It involves patients aged 18 to 85 years undergoing bioprosthetic valve replacement at the aortic and/or mitral position. They are randomized 1:1 to receive either edoxaban or warfarin. Administration of edoxaban or warfarin is to be continued for 12 weeks after surgery. The primary outcome is the occurrence rate of stroke or systemic embolism at 12 weeks after surgery. The net clinical outcome is a composite of stroke, systemic embolism, or major bleeding, which is included in the secondary outcomes. The ENBALV trial demonstrates the efficacy and safety of edoxaban compared with warfarin in patients early after bioprosthetic valve replacement, including patients with sinus rhythm, which will bring a significant benefit to patients in clinical practice. Japan Registry of Clinical Trials (jRCT) 2051210209. 30 Mar 2022 https://jrct.niph.go.jp/latest-detail/jRCT2051210209 .

Evaluation of the use and efficacy of prothrombin complex concentrates in patients presenting to the emergency department with warfarin

Aims: Warfarin administration has been a standard treatment for preventing thromboembolism in patients with atrial fibrillation prosthetic heart valves for many years. It is one of the leading drugs implicated in emergency room visits for adverse drug reactions. Because of a narrow therapeutic window, as many as 3% to 7% of patients taking warfarin are at risk of significant, life-threatening bleeding, and it is generally considered that this requires rapid and complete warfarin reversal. Although there are treatments such as vitamin K and fresh frozen plasma to reverse the effects of warfarin, the most effective method involves using prothrombin complex concentrates (PCC). This study aims to evaluate the use and efficacy of PCC in patients with warfarin-induced bleeding in the emergency department. Methods: The patients receiving PCC for warfarin reversal in the emergency department between January 1, 2019 – April 1, 2021, were identified from the hospital's electronic database. Demographic data, reasons for warfarin use, PCC indications, INR values before and after PCC, and mortality of the patients were evaluated. The four-factor PCC dose was determined according to the patient's body weight, admission INR level, and target INR level. The study was conducted with 73 patients. Results: The mean age of the patients was 69.3 ± 15.5 years. The female/male ratio was 1/1.5. The most common PCC indications were gastrointestinal bleeding (32.9%), urogenital bleeding (23.3%), epistaxis (12.3%), and urgent surgical need (12.3%), respectively. The median international normalized ratio (INR) before and after treatment with PCC was 9.2 (min-max 2.1-11.8) and 1.8 (min-max 1.0-4.6). The mean dose of PCC was 1500 IU (min-max 750-3250 IU). In addition to PCC, all patients received vitamin K; 17.8% received erythrocyte suspension, and 10.9% received fresh frozen plasma. There were no PCC-related complications in the emergency department. While 38.4% of the patients consulted the inpatient services after the emergency department, 5.5% were referred to an external center, and 56.2% were discharged from the emergency department after successful treatment. 26% of the patients were followed in the intensive care unit. No patient died in the emergency department. However, in-hospital mortality was 5.5%. Conclusion: Four-factor PCC is an effective and safe treatment for reversing warfarin-associated bleeding.

Effects of Salvianolate Injection on the Pharmacodynamics and Pharmacokinetics of Warfarin in Rats In vivo

Background:: Both Salvianolate Injection and warfarin are widely prescribed in patients with cardiovascular diseases, but the interaction between them is unknown and needs to be investigated. Objective:: This research aims to study the effects and mechanism of Salvianolate Injection on the pharmacodynamics and pharmacokinetics of warfarin in rats. Methods:: Male Wistar rats were intraperitoneally injected Salvianolate Injection (18 mg/kg) with or without oral administration of warfarin (0.2 mg/kg). A coagulation analyzer evaluated prothrombin time (PT) and activated partial thromboplastin time (APTT). International normalized ratio (INR) was calculated based on PT. UPLC-MS/MS combined with a chiral column was used to separate and measure the plasma concentration of R-warfarin and S-warfarin. Agilent SB-C18 column (1.8 μm, 2.1 mm × 50 mm) was used for separation, column temperature at 20°C. The isocratic mobile phase was acetonitrile-aqueous ammonium acetate (5 mM, pH 4) at a flow rate of 0.2 mL/min and 11.5 min for each injection. Pharmacokinetic parameters were calculated using DAS 2.0 software. Results:: Salvianolate Injection increased PT and INR (p < 0.05), while APTT was unaffected (p > 0.05). Compared with the warfarin group, the co-administration of Salvianolate Injection and singledose warfarin enlarged PT and INR (p < 0.05). Similar increases in pharmacokinetic parameters of R-warfarin and S-warfarin, including Cmax, AUC0-t, AUC0-∞, t1/2, and CL/F (p < 0.05), were observed in the co-administration group. A steady-state study of warfarin indicated that PT and INR in the coadministration group are longer than those in the warfarin group (p < 0.05). On days 7th and 8th of warfarin treatment (two and three days after Salvianolate Injection treatment), the plasma concentration of R-warfarin increased by 47.22% and 50.16% (p < 0.05), and plasma concentration of Swarfarin increased by 32.39% and 45.99% (p < 0.05), respectively. Conclusion:: Salvianolate Injection exhibits an anticoagulation effect in rats. Salvianolate Injection can enhance the anticoagulant effect of warfarin by slowing metabolism and increasing the concentration of both enantiomers. These results suggest that the combination of Salvianolate Injection and warfarin should be avoided or closely monitored in case of increasing bleeding risk.

Tracheal Calcification Following Warfarin Administration: A Case Report

Warfarin ought to be utilized for an extended duration in individuals with a predisposition to thromboembolism, such as those with atrial fibrillation or aortic valve replacement. While the primary complication of long-term warfarin usage is the potential for bleeding, there are also infrequent complications like vascular and tracheal calcification. We present a case of a patient who experienced diffuse tracheal calcification as a result of long-term warfarin usage.
 A 74-year-old female patient, who had been receiving chronic warfarin treatment for atrial fibrillation, required intubation and was admitted to the intensive care unit due to aspiration pneumonia. As the patient was unable to be extubated during the hospital stay, she became a candidate for Percutaneous dilution tracheostomy (PDT). It was discovered during the PDT procedure that all available spaces of the trachea above the sternum were calcified, preventing the passage of the trach needle. The presence of tracheal calcification was confirmed by both a radiologist and ultrasound examination.
 Currently, individuals are compelled to employ oral anticoagulants, like warfarin, in order to avert thromboembolic diseases. Nevertheless, the protracted utilization of warfarin is linked with infrequent adverse outcomes, such as disseminated calcification. Consequently, meticulous scrutiny of these side effects is requisite for patients with enduring warfarin consumption.

Protein kinase C delta enhances the diagnostic performance of hepatocellular carcinoma

Background The conventional markers for hepatocellular carcinoma (HCC), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), have several limitations; both have low sensitivity in patients with early-stage HCC; low sensitivity for AFP with HCC after eliminating hepatitis C virus (HCV); low specificity for DCP in patients with non-viral HCC, which is increasing worldwide; low specificity for AFP in patients with liver injury; and low specificity for DCP in patients treated with warfarin. To overcome these issues, the identification of novel biomarkers is an unmet need. Objective This study aimed to assess the usefulness of serum protein kinase C delta (PKCδ) for detecting these HCCs. Methods PKCδ levels were measured using a sandwich enzyme-linked immunosorbent assay in 363 chronic liver disease (CLD) patients with and without HCC. Results In both viral and non-viral CLD, PKCδ can detect HCCs with high sensitivity and specificity, particularly in the very early stages. Notably, the value and sensitivity of PKCδ were not modified by HCV elimination status. Liver injury and warfarin administration, which are known to cause false-positive results for conventional markers, did not modify PKCδ levels. Conclusions PKCδ is an enhanced biomarker for the diagnosis of HCC that compensates for the drawbacks of conventional markers.

Homonymous hemianopia due to cerebral venous thrombosis: A case report

Rationale: Diagnosing cerebral venous thrombosis (CVT) can be difficult because of nonspecific symptoms, such as headache and homonymous hemianopia (HH). Herein, we present a case of delayed CVT diagnosis due to nonspecific neurological symptoms and nonprominent lesions in a patient with HH. Patient concern: A 65-year-old woman presented with a sudden onset headache accompanied by right HH that lasted for 1 day. Brain computed tomography and magnetic resonance imaging were initially performed due to suspicion of ischemic lesions or hemorrhage in the left postchiasmal visual pathway; however, no remarkable acute brain lesions were detected. Ophthalmological examinations revealed no notable findings, except for a definite field defect in the Humphrey visual field test. The headaches then waxed and waned but recurred 3 days after the initial symptom. A repeat brain magnetic resonance imaging was performed, which revealed left sectoral gyral swelling and vascular enhancement in the occipital lobe. To further evaluate venous drainage, additional 3-dimensional cerebral computed tomography angiography and 4-vessel angiography were conducted, revealing a partial filling defect in the left transverse sinus and superior venous drainage impairment. These findings suggested the presence of venous thrombosis in the left transverse sinus. Diagnosis: The patient was diagnosed with thrombosis of the left transverse sinus, which subsequently caused the right HH. Intervention: Anticoagulation therapy with parenteral heparin was started as soon as the diagnosis of CVT was confirmed. Eventually, the patient was solely managed with oral warfarin administration. Outcomes: Following 3 days of treatment, her headache resolved, and a subsequent visual field testing conducted 2 weeks later revealed a definite improvement in the field defect. Lessons: Despite its favorable prognosis, CVT can be challenging to diagnose. CVT should be considered as a differential diagnosis when diagnosing patients who present with headaches accompanied by HH without prominent brain lesions.

Stroke and Bleeding Risks of Endocardial Ablation for Ventricular Arrhythmias

BackgroundRisks of radiofrequency catheter ablation for ventricular arrhythmias include emboli and bleeding complications but data on antithrombotic regimens are limited and guidelines do not specify a systematic approach. ObjectivesThis study sought to assess embolic and bleeding complications in relation to pre-periprocedure and post-periprocedure antithrombotic regimens. MethodsProspective assessment for complications was performed for 663 endocardial radiofrequency catheter ablation procedures in 616 consecutive patients (median age 64 years [Q1-Q3: 54-73 years], 70.3% men, 71.6% with cardiomyopathy, 44.5% with sustained ventricular tachycardia). ResultsThere were 2 strokes (0.3%; 95% CI: 0.0%-0.8%), 1 transient ischemic attack (0.15%), and 2 pulmonary emboli (0.3%). There were 39 bleeding complications (5.9%) including 11 pericardial effusions (1.7%), and 28 related to vascular access (4.2%). Consistent with the prevalence of coronary artery disease (47.5%), atrial fibrillation (30.0%), and prior stroke (10.6%), preprocedure, 464 patients (70.0%) were taking antithrombotic agents including 220 (33.2%) taking aspirin alone (ASA), and 163 (24.6%) taking warfarin or a direct acting oral anticoagulant (DOAC). Preprocedure non-ASA antiplatelet use (OR: 2.846; P = 0.011) and DOAC use (OR: 2.585; P = 0.032) were associated with risk of bleeding complications. Following ablation, 49.8% of patients were treated with ASA 325 mg/d and 30.3% received DOACs or warfarin. New DOAC or warfarin administration was initiated in only 6.6% of patients. Overall, 39.7% of patients continued the same preprocedure antithrombotic regimen. ConclusionsStroke is a rare complication of radiofrequency catheter ablation for ventricular arrhythmia using ASA 325 mg/d as a minimal postprocedure regimen with more potent regimens for selected patients.

Evaluation of anticoagulant rodenticide sensitivity by examining in vivo and in vitro responses in avian species, focusing on raptors

Anticoagulant rodenticides (ARs) are used to control pest rodent species but can result in secondary poisoning of non-target animals, especially raptors. In the present study, differences in AR sensitivity among avian species were evaluated by comparing in vivo warfarin pharmacokinetics and effects, measuring cytochrome P450s (CYPs) expression involved in AR metabolism, and conducting in vitro inhibition assays of the AR target enzyme Vitamin K 2,3-epoxide reductase (VKOR). Oral administration of warfarin at 4 mg/kg body weight did not prolong prothrombin time in chickens (Gallus gallus), rock pigeons (Columba livia), or Eastern buzzards (Buteo japonicus). Rock pigeons and buzzards exhibited shorter plasma half-life of warfarin compared to chickens. For the metabolite analysis, 4′-hydroxywarfarin was predominantly detected in all birds, while 10-hydroxywarfarin was only found in pigeons and raptors, indicating interspecific differences in AR metabolism among birds likely due to differential expression of CYP enzymes involved in the metabolism of ARs and variation of VKOR activities among these avian species. The present findings, and results of our earlier investigations, demonstrate pronounced differences in AR sensitivity and pharmacokinetics among bird species, and in particular raptors. While ecological risk assessment and mitigation efforts for ARs have been extensive, AR exposure and adverse effects in predatory and scavenging wildlife continues. Toxicokinetic and toxicodynamic data will assist in such risk assessments and mitigation efforts.

Healing effect of warfarin in the course of cerulein-induced acute pancreatitis in rats.

Acute pancreatitis (AP) is the most common gastrointestinal disease leading to hospitalizations and unexpected deaths. The development of AP leads to damage of the pancreatic microcirculation with a cascade of subsequent events resulting, among others, in coagulopathy. Previous research showed that anticoagulants can be important therapeutic agents. Heparin and acenocoumarol can alleviate the course of AP, as well as accelerate healing and post-inflammatory regeneration of the pancreas. The aim of this study was to determine whether warfarin, a drug with more stable effects than acenocoumarol, affects the healing and regeneration of the pancreas in the cerulein-induced AP. AP was evoked in Wistar male rats by intraperitoneal administration of cerulein. The first dose of warfarin (45, 90 or 180 μg/kg) was administered 24 hours after the first dose of cerulein and the doses of warfarin were repeated once a day in subsequent 10 days. The severity of AP was assessed immediately after the last dose of cerulein, as well as at days 1, 2, 3, 5, and 10 after AP induction. Treatment with warfarin dose-dependently increased international normalized ratio (INR) and attenuated the severity of pancreatitis in histological examination and accelerated pancreatic recovery. These effects were accompanied with a faster reduction in the AP-evoked increase in serum activity of amylase and lipase, the serum concentration of pro-inflammatory interleukin-1β, and the plasma level of D-Dimer. In addition, treatment with warfarin decreased pancreatic weight (an index of pancreatic edema) and improved pancreatic blood flow in rats with AP. The therapeutic effect was particularly pronounced after the administration of warfarin at a dose of 90 μg/kg. We conclude that treatment with warfarin accelerated regeneration of the pancreas and recovery in the course of cerulein-induced mild-edematous acute pancreatitis.

Warfarin and Antibiotics: Drug Interactions and Clinical Considerations.

Warfarin administration poses a notable challenge in clinical practice due to the increased susceptibility of patients to major bleeding, particularly when co-administered with other medications capable of modulating its metabolic pathways. Among these medications, antibiotics have been recognized as potential agents that can either induce or inhibit cytochrome P450-2C9, thereby impacting the effects of warfarin. A wealth of evidence from numerous studies consistently supports an elevated risk of serious bleeding in patients concurrently receiving antibiotics and warfarin therapy. This narrative review elucidates the intricate interactions between warfarin and various antibiotic classes. Notably, significant increases in the International Normalized Ratio (INR) were observed among warfarin-treated patients receiving penicillin derivatives, fluoroquinolones, TMP-SMX, and macrolides. Conversely, investigations have also demonstrated a reduction in INR levels in patients on warfarin when exposed to rifampin, a potent inducer of cytochrome P-450. Intriguingly, cephalosporin antibiotics and amoxicillin/clavulanate, despite not interfering with the cytochrome P450 system, exhibited a positive association with increased INR values. The findings of this narrative review underscore the importance of diligent monitoring in patients on warfarin requiring concomitant antibiotic therapy, as this surveillance strategy proves pivotal in mitigating the risk of major bleeding complications. Additionally, for patients necessitating cytochrome P450 inhibitors such as penicillin derivatives, fluoroquinolones, TMP-SMX, and macrolides, the consideration of dose reduction in warfarin therapy may confer substantial benefits in reducing the occurrence of major bleeding events. Similarly, patients who are co-administered rifampin alongside warfarin necessitate vigilant monitoring, with a potential need for escalating warfarin doses to counteract the risk of a hypercoagulable state.

Optimisation of warfarin-dosing algorithms for Han Chinese patients with CYP2C9*13 variants.

Existing pharmacogenetic algorithms cannot fully explain warfarin dose variability in allpatients. CYP2C9*13 is an important allelic variant in the Han Chinese population. However, adjustment of warfarin dosing in CYP2C9*13 variant carriers remains unclear. To the best of our knowledge, this study is the first to assess the effects of adjusting warfarin dosages in Han Chinese patients harbouring CYP2C9*13 variants. In total, 971 warfarin-treated Han Chinese patients with atrial fibrillation were enrolled in this study. Clinical data were collected, and CYP2C9*2, *3, *13 and VKORC1-1639 G > A variants were genotyped. We quantitatively analysed the effect of CYP2C9*13 on warfarin maintenance dose and provided multiplicative adjustments for CYP2C9*13 using validated pharmacogenetic algorithms. Approximately 0.6% of the Han Chinese population carried CYP2C9*13 variant, and the genotype frequency was between those of CYP2C9*2 and CYP2C9*3. The warfarin maintenance doses were significantly reduced in CYP2C9*13 carriers. When CYP2C9*13 variants were not considered, the pharmacogenetic algorithms overestimated warfarin maintenance doses by 1.03-1.16mg/d on average. The actual warfarin dose in CYP2C9*13 variant carriers was approximately 40% lower than the algorithm-predicted dose. Adjusting the warfarin-dosing algorithm according to the CYP2C9*13 allele could reduce the dose prediction error. Our study showed that the algorithm-predicted doses should be lowered for CYP2C9*13 carriers. Inclusion of the CYP2C9*13 variant in the warfarin-dosing algorithm tends to predict the warfarin maintenance dose more accurately and improves the efficacy and safety of warfarin administration in Han Chinese patients.

Impact of glycated hemoglobin on 2-year clinical outcomes in elderly patients with atrial fibrillation: sub-analysis of ANAFIE Registry, a large observational study

BackgroundThis ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM).MethodsThe ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%).ResultsOf 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA2DS2-VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11–1.93]) and net clinical outcome (aHR 1.33 [1.05–1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs.ConclusionsAmong elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level.Trial registrationUMIN000024006; date of registration: September 12, 2016.

Postoperative Atrial Fibrillation After Surgical Aortic Valve Replacement: Amiodarone and Warfarin Use

IntroductionThe association between amiodarone treatment for postoperative atrial fibrillation (POAF) after surgical aortic valve replacement (SAVR) and both the return to normal sinus rhythm (NSR) and anticoagulation use at discharge has not been extensively studied. MethodsWe retrospectively identified all patients who underwent biological SAVR with or without concomitant coronary artery bypass grafting (CABG) at a Veterans Affairs Medical Center (2005-2015). We reviewed new-onset POAF, amiodarone use, return to NSR, and anticoagulation use with warfarin. Discharge rhythm and warfarin administration were compared among patients with POAF who were treated with amiodarone and patients who did not receive amiodarone. ResultsOf the 395 patients (186 AVR/coronary artery bypass grafting; 209 AVR) studied, POAF developed in 191 patients (48.0%); 80.1% (153/191) of these patients received amiodarone. Among patients treated with amiodarone, 70.6% (108/153) were in SR at the time of discharge versus 65.8% (25/38) of POAF patients who were not treated with amiodarone (P = 0.57). Among amiodarone-treated patients, 30.7% (47/153) were discharged with warfarin; among patients not treated with amiodarone, 31.6% (12/38) were discharged with warfarin (P = 0.92). Among amiodarone-treated patients discharged in NSR, 89.9% (97/108 patients) were not discharged with warfarin; among patients not treated with amiodarone who were discharged in NSR, 92% (23/25) were not discharged with warfarin (P = 0.74). ConclusionsPOAF after SAVR appears common. Although amiodarone is often used for POAF patients, its use does not appear to be associated with surgeons' decision to anticoagulate patients. Surgeons’ preferences for using rhythm control and antithrombotic therapy for POAF after SAVR warrant further exploration.

Administration of Warfarin Inhibits the Development of Cerulein-Induced Edematous Acute Pancreatitis in Rats.

Acute pancreatitis (AP) is a severe disease with high morbidity and mortality in which inflammation and coagulation play crucial roles. The development of inflammation leads to vascular injury, endothelium and leukocytes stimulation, and an increased level of tissue factor, which results in the activation of the coagulation process. For this reason, anticoagulants may be considered as a therapeutic option in AP. Previous studies have shown that pretreatment with heparin, low-molecular-weight heparin (LMWH), or acenocoumarol inhibits the development of AP. The aim of the present study was to check if pretreatment with warfarin affects the development of edematous pancreatitis evoked by cerulein. Warfarin (90, 180, or 270 µg/kg/dose) or saline were administered intragastrically once a day for 7 days consecutively before the induction of AP. AP was evoked by the intraperitoneal administration of cerulein. The pre-administration of warfarin at doses of 90 or 180 µg/kg/dose reduced the histological signs of pancreatic damage in animals with the induction of AP. Additionally, other parameters of AP, such as an increase in the serum activity of lipase and amylase, the plasma concentration of D-dimer, and interleukin-1β, were decreased. In addition, pretreatment with warfarin administered at doses of 90 or 180 µg/kg/dose reversed the limitation of pancreatic blood flow evoked by AP development. Warfarin administered at a dose of 270 µg/kg/dose did not exhibit a preventive effect in cerulein-induced AP. Conclusion: Pretreatment with low doses of warfarin inhibits the development of AP evoked by the intraperitoneal administration of cerulein.

Effects of changing the timing of warfarin administration in combination with fluconazole on prolongation of the PT-INR: a case report

BackgroundFluconazole (FLCZ) inhibits cytochrome P450 (CYP) 2C9, 2C19, and 3A4 and has a drug-drug interaction that potentiates the effects of warfarin and prolong the prothrombin time-international normalized ratio (PT-INR). Although a drug-drug interaction have been reported between FLCZ and warfarin, the effects of the timing of their administration on this interaction have not yet been investigated.Case presentationA female patient in her 30s with Marfan syndrome had undergone the Bentall procedure with a mechanical valve and total arch replacement for acute aortic dissection Stanford A type and rupture of the ascending aorta. Warfarin was administered to prevent thromboembolism. She was hospitalized 1 year ago for graft infection caused by Candida albicans, and treatment with FLCZ was initiated. She received FLCZ 200 mg once a day in the morning and warfarin 1.75 mg once a day in the evening, and the PT-INR remained stable at approximately 2.0 and within the therapeutic range. However, 42 days after changing the timing of administration of warfarin from evening to morning, the PT-INR was prolonged by approximately 3-fold to 6.25. The PT-INR then decreased to the previous level by changing the timing of administration of warfarin from morning to evening.ConclusionsThe timing of administration of FLCZ and warfarin may affect the magnitude of drug-drug interaction.

Pharmacogenetics of warfarin dosing in Chinese adults with nonvalvular atrial fibrillation.

The guide for the use of genotype-guided warfarin dosing in patients for the treatment of non-valvular atrial fibrillation (AF) is still lacking. We aimed to evaluate whether genotype-guided warfarin dosing is superior to conventional clinical dosing for the outcomes of interest in Chinese patients. Our study consisted of 508 newly recruited and 471 existing Chinese AF patients. Among the total 979 patients, 585 patients received their dose of warfarin determined by a genetic and clinical factor (gene group), while the remaining 394 patients whose dosing was determined empirically in control group. We incorporated CYP2C9 and VKORC1 genotypes into the gene group. The international normalized ratio (INR) measurement and standard protocols were used for further dose adjustment in both groups. The primary outcomes were the percentage of time in the therapeutic range (%TTR) and INR during 12-month follow-up. Secondary safety outcome included bleeding and thrombotic events. Compared with the control group, the average TTR of the gene group was higher [68.4 ± 20.6% vs 48.5 ± 21.6%, P < 0.001]. The average INR monitoring times to reach the therapeutic time in the gene group was lower (P < 0.001). The risk ratios (RR) for cumulative incidence of total bleeding events, minor bleeding events, gastrointestinal bleeding, and intracerebral bleeding events were not significantly different between the two groups (P > 0.05). Comparing to the analysis using existing 471 patients, the analysis using total 979 patients showed that the gene group experienced a lower (RR 0.4 (95% CI 0.2 to 0.8), P = 0.008) incidence of cumulative ischemic stroke. Genotype-guided warfarin administration increases the average TTR, reaches higher TTR levels in the early anticoagulant phase, and significantly reduces the risk of ischemic stroke events.

Comparative study of predisposition to thrombosis with administration of known systemic hemostatic agents and fibrin monomer in the experiment

Aim. To compare predisposition to thrombosis caused by administration of known systemic hemostatic agents and fibrin monomer under the conditions of normal coagulation versus drug-induced hypocoagulation in the experiment.Materials and methods. The prothrombotic effect of intravenous (IV) administration of various systemic hemostatic agents was compared in a series of in vivo experiments. These agents included fibrin monomer (FM) (0.25 mg / kg), prothrombin complex concentrate (PCC) (40 IU / kg) or recombinant factor VIIa (rFVIIa) (270 mcg / kg). The studies were conducted under the conditions of hypocoagulation induced by the administration of warfarin (per os at a dose of 0.4–0.5 mg / kg / day for 14 days) or dabigatran etexilate (per os at a single dose of 15–20 mg / kg). Hemostatic system parameters were evaluated using thromboelastometry and calibrated automated thrombography.Results. It was found that PCC reversed anticoagulant effects and led to an overcompensated increase in the density characteristics of the blood clot along with an excessive increase in thrombin generation in the groups of animals with warfarin-induced coagulopathy. The use of PCC and rFVIIa in the groups of animals with dabigatran-induced hypocoagulation also resulted in an increase in blood thrombogenic properties. In the administration of PCC, it was manifested though an increased D-dimer level and in administration of rFVIIa – through an increase in the clot density characteristics. At the same time, replacement of these hemostatic agents with FM did not affect the hemostatic system parameters.Conclusion. FM at a dose of 0.25 mg / kg, as opposed to PCC and rFVIIa, is safer in terms of the risk of thrombosis.