Efficacy and safety of direct oral anticoagulants vs vitamin K antagonists in patients with atrial fibrillation and end-stage renal disease on hemodialysis: A systematic review and meta-analysis.

BACKGROUND: The prevalence of atrial fibrillation (AF) in individuals with end-stage renal disease (ESRD) on chronic hemodialysis is increasing. The optimal anticoagulant choice in this population is unclear since these patients were excluded from the pivotal randomized controlled trials (RCTs) of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) in the general AF population. We aimed to assess the efficacy and safety of DOACs vs. VKAs in patients with AF and ESRD on chronic hemodialysis through a systematic review and meta-analysis of all available evidence. PATIENTS/METHODS: We performed a systematic search in MEDLINE and Scopus for RCTs or observational studies of patients with AF and ESRD on chronic hemodialysis who were treated with DOACs or VKAs. The outcomes of interest included ischemic stroke, the composite of ischemic stroke or systemic embolism, major bleeding, gastrointestinal bleeding, minor bleeding events and all-cause mortality. RESULTS: Among 397 studies identified from the literature search, six studies (three RCTs and three observational studies) were included in the meta-analysis. Compared with VKA-treated patients, those treated with DOACs had similar risk of ischemic stroke (RR:0.76, 95% CI:0.41-1.41), ischemic stroke or systemic embolism (RR:0.65, 95% CI:0.38-1.10), major bleeding (RR:0.79, 95% CI:0.49-1.28) and all-cause death (RR:0.79, 95% CI:0.56-1.12). The risk of gastrointestinal bleeding was lower in DOAC- vs VKA-treated patients in three eligible observational studies (RR:0.73, 95% CI: 0.54-0.99, I2 = 79%) but this was not confirmed in two eligible RCTs (RR:0.69, 95% CI: 0.33-1.43, I2 = 0%). CONCLUSIONS: Among AF patients with ESRD on chronic hemodialysis, the risk of ischemic stroke, ischemic stroke or systemic embolism, minor bleeding, major bleeding, and all-cause mortality is similar in patients treated with DOACs compared to VKAs. Given that the meta-analysis of RCTs on gastrointestinal bleeding did not confirm the results of the meta-analysis of the observational studies, it cannot be concluded that gastrointestinal bleeding is lower among DOAC-treated patients. PROTOCOL REGISTRATION: PROSPERO CRD42023391966.

The use of vitamin K for coagulopathy in critically ill children.

OBJECTIVES: Coagulopathy is associated with increased mortality in children in the intensive care unit (ICU). Recommended management of vitamin K-deficient coagulopathy is vitamin K administration. The goal of this study was to evaluate vitamin K administration for coagulopathy in critically ill children and determine a relationship between vitamin K dose and change in prothrombin time (PT) and international normalized ratio (INR). METHODS: This retrospective cohort study reviewed electronic medical records of patients ≤17 years who received vitamin K for acute coagulopathy in the pediatric ICU from January 2013 to January 2021. Patients receiving vitamin K antagonists were excluded. Effectiveness data included change in PT/INR after vitamin K administration. Safety data included incidence of hypersensitivity or anaphylaxis. RESULTS: A total of 310 patients (median age 6.8 years, range 22 days-17.7 years) received vitamin K. A median of three doses (range 1-8) and 0.14 mg/kg per dose (range 0.09-0.22 mg/kg) were given, most frequently intravenously (892/949, 94%). Most patients (304/310, 98%) had at least one risk factor for vitamin K deficiency. Mean PT/INR was 21.5/2.1 prior to vitamin K administration, which decreased by 4.4 (SD = 9.0, 95% CI 16.011 to 18.015, p < 0.001) and 0.5 (SD = 1.0, 95% CI 1.490 to 1.705, p < 0.001) to means of 17.0 and 1.6, respectively, after the first vitamin K dose. No linear relationship was found between vitamin K dose and change in PT/INR. No hypersensitivity or anaphylaxis occurred following vitamin K administration; 27% (84/310) of patients died. CONCLUSIONS: Administration of vitamin K is effective and safe for the management of vitamin K-deficient coagulopathy in critically ill pediatric patients. Further study is needed to determine a relationship between vitamin K dose and change in PT/INR.

Vitamin E-induced coagulopathy in a young patient: a case report.

BACKGROUND: High-dose vitamin E intake is known to inhibit vitamin K-derived coagulation factor synthesis, which can cause serious bleeding events such as gastrointestinal bleeding and intracranial hemorrhage. We report a case of coagulopathy induced by marginally increased levels of vitamin E. CASE PRESENTATION: A 31-year-old Indian man presented with oral bleeding, black tarry stools, and bruising over his back. He had been taking non-steroidal anti-inflammatory drugs for low backache and vitamin E for hair loss. He had mild anemia with normal platelet count, thrombin time, and prolonged bleeding time, activated partial thromboplastin time, and prothrombin time. Serum fibrinogen was slightly raised. Mixing studies with pooled normal plasma, aged plasma, and adsorbed plasma were suggestive of deficiency of multiple coagulation factors due to acquired vitamin K deficiency. Serum phylloquinone was normal, while prothrombin induced by vitamin K absence-II level was increased. Serum alpha-tocopherol was slightly raised. Upper gastrointestinal endoscopy showed multiple gastroduodenal erosions. A final diagnosis of vitamin E toxicity-related coagulopathy was made. The patient responded well to pantoprazole, vitamin K supplementation, multiple fresh frozen plasma transfusions, and other supportive treatments besides the discontinuation of vitamin E supplementation. The coagulation parameters normalized, and the patient was discharged with complete resolution of symptoms and remained asymptomatic during the follow-up for 6 months. CONCLUSIONS: Vitamin E-related inhibition of vitamin K-dependent factors with coagulopathy may occur even at marginally increased levels of serum vitamin E. This risk becomes significant in patients receiving other drugs that may increase the risk of bleeding.

Research progress of nephrotic syndrome accompanied by thromboembolism.

Thromboembolism (TE) is a common and serious complication of nephrotic syndrome (NS). NS is associated with hypercoagulability, which may be induced by changes in coagulation, anticoagulant, and fibrinolytic factors. Moreover, accumulating evidence supports the hypothesis that the complex interactions between genetic and acquired risk factors in TE should be considered and that genetic susceptibility should not be ignored. Extracellular vesicles (EVs) also play unique roles. Further research on EVs may provide new insights into the discovery and treatment of TE associated with NS. The occurrence of NS accompanied by TE may be associated with various risk factors. Preventive anticoagulant therapy can not only reduce the risk of TE in patients but also aggravate the risk of bleeding. Heparin and vitamin K antagonists (VKAs), traditional anticoagulant drugs, have been extensively applied in the prevention and treatment of thromboembolic diseases, and emerging direct oral anticoagulants (DOACs) also provide an alternative choice. Owing to the particularity of NS, the safe application of DOACs still needs to be addressed. This review aimed to comprehensively describe the pathophysiology of TE in NS, as well as analyze the associated risk factors, the opportunity for preventive anticoagulation, and current anticoagulant information.

Methods to Correct Drug-Induced Coagulopathy in Bleeding Emergencies: A Comparative Review.

OBJECTIVE: Anticoagulant and antiplatelet therapy have become increasingly popular. The goal of therapy is to prevent venous thromboembolism and platelet aggregation, respectively. Traditional anticoagulant and antiplatelet drugs are quickly being replaced with novel medications with more predictable pharmacokinetics. Unfortunately, these drugs carry the risk of uncontrolled hemorrhage because of drug-induced coagulopathy. Uncontrolled hemorrhage continues to be a major cause of preventable death: hemorrhage accounts for approximately 30% of trauma-related deaths, second to brain injury. Controlling hemorrhage while dealing with comorbidities remains a challenge to clinicians. There are many gaps in care and knowledge that contribute to the struggle of treating this patient population. METHODS: This literature review is focused on the most effective ways to achieve hemostasis in a patient with drug-induced coagulopathy. The antiplatelet therapies aspirin, clopidogrel, ticlopidine, pasugrel, and ticagrelor are analyzed. Anticoagulant therapies are also reviewed, including warfarin, rivaroxaban, apixaban, edoxaban, and dabigatran. In addition, viscoelastic testing and platelet function assays are reviewed for their ability to monitor drug effectiveness and to accurately depict the patient's ability to clot. This review focuses on articles from the past 10 years. However, there are limitations to the 10-year restriction, including no new research posted within the 10-year timeline on particular subjects. The most recent article was then used where current literature did not exist (within 10 years). RESULTS: Traditional anticoagulants have unpredictable pharmacokinetics and can be difficult to correct in bleeding emergencies. Vitamin K has been proven to reliably and effectively reverse the effect of vitamin K antagonists (VKAs) while having a lower anaphylactoid risk than frozen plasma. Prothrombin complex concentrates should be used when there is risk of loss of life or limb. Frozen plasma is not recommended as a first-line treatment for the reversal of VKAs. Novel anticoagulants have specific reversal agents such as idarucizumab for dabigatran and andexxa alfa for factor Xa (FXa) inhibitors. Although reliable, these drugs carry a large price tag. As with traditional anticoagulants, cheaper alternative therapies are available such as prothrombin complex concentrates. Finally, static coagulation testing works well for routine therapeutic drug monitoring but may not be appropriate during bleeding emergencies. Viscoelastic testing such as thromboelastography and rotational thromboelastometry depict in vivo hemostatic properties more accurately than static coagulation assays. Adding viscoelastic testing into resuscitation protocols may guide blood product usage more efficiently. CONCLUSION: This review is intended to be used as a guide. The topics covered in this review should be used as a reference for treating the conditions described. This review article also covers laboratory testing and is meant as a guide for physicians on best practices. These findings illustrate recommended testing and reversal techniques based off evidence-based medicine and literature.

Direct oral anticoagulants versus vitamin K antagonists in epistaxis patients: A systematic review and meta-analysis.

OBJECTIVE: Epistaxis is the most common otolaryngological emergency and up to one third of patients in treated on an inpatient basis take oral anticoagulants (OAC). Direct oral anticoagulants (DOAC), an OAC subgroup, have been on the market since 2010 and are being increasingly prescribed due to the cardiological and haematological guidelines that favour them over vitamin K antagonists (VKA), the older of the OAC subgroups. The present study aims to investigate which subgroup of epistaxis patients taking OACs has a more favourable outcome. DESIGN/SETTING: A systematic review and meta-analysis were performed according to the PRISMA 2020 statement using the PubMed and Cochrane Library databases. Continuous data were analysed and standardised mean difference (SMD) was calculated according to Hedges' g. Dichotomous data were analysed, and the Mantel-Haenszel method was applied to establish the odds ratio (OR). Heterogeneity was assessed according to the I2  statistics. MAIN OUTCOME/RESULTS: A total of eight reports covering 1390 patients were included in the final synthesis. The pooled analysis demonstrated significantly shorter hospital stays in the DOAC group (SMD = -0.22, 95% CI-0.42 to -0.02, p = .03) and a significantly higher rate of posterior bleeding in the VKA group (OR = .39, 95% CI 0.23 to 0.68, p = .001). No statistically significant differences with regard to recurrence rates, admission rates, the need for transfusion or surgical intervention (p = .57, .12, .57 and .38 respectively) were found. CONCLUSION: According to this meta-analysis, epistaxis patients taking DOACs have a more favourable outcome than patients taking VKAs.

Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis.

OBJECTIVES: Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP. METHODS: We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association. RESULTS: Acenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94-3.20), both for knee (OR=2.34, 95% CI=1.67-3.22) and hip OA (OR=2.74, 95% CI=1.82-4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69-6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78-1.33). CONCLUSIONS: These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

A retrospective evaluation of vitamin K for hemoptysis in adult cystic fibrosis patients.

OBJECTIVES: Hemoptysis is a complication in cystic fibrosis (CF) patients, and is associated with pulmonary exacerbations and hospitalizations. Pancreatic insufficiency is common in CF patients, and therefore these patients may benefit from the use of vitamin K therapy. METHODS: This was an observational study conducted in adult CF patients aiming to describe the utilization of vitamin K therapy in the setting of hemoptysis during an acute CF pulmonary exacerbation. An evaluation of hospital length of stay, time until the next pulmonary exacerbation, and 30-day re-admission rates were evaluated in CF patients who presented with hemoptysis and received vitamin K therapy. RESULTS: The average dose of vitamin K therapy was 10 mg for an average duration of 4.9 ± 0.55 days for 38 adult CF patients included in this cohort. The median length of stay among patients who received vitamin K therapy was 8 days (IQR: 6-12 days). The median time until next hospital admission was 127 days (95% CI: 71.4 to 182.6 days), and the 30-day readmission rates were 7.89%. Two patients developed a thromboembolism after receiving vitamin K therapy. CONCLUSIONS: Evidence for the use of vitamin K therapy in the setting of CF-related hemoptysis remains unclear, and warrants further safety and efficacy evaluation. Further prospective studies are needed to determine the appropriateness of dosing and duration of vitamin K therapy, as well as determining its role in the setting of the varying levels of hemoptysis during a pulmonary CF exacerbation.

Direct Current Cardioversion in Atrial Fibrillation Patients on Edoxaban Therapy Versus Vitamin K Antagonists: a Real-world Propensity Score-Matched Study.

PURPOSE: The purpose of the present study was to compare the long-term effectiveness and safety of newly initiated anticoagulation with edoxaban (EDO) versus uninterrupted vitamin K antagonist (VKA) therapy in patients with atrial fibrillation (AF) scheduled for transesophageal echocardiogram (TEE)-guided direct electrical current cardioversion (DCC). METHODS: A propensity score-matched cohort observational study was performed comparing the safety and effectiveness of edoxaban versus well-controlled VKA therapy among a cohort of consecutive non-valvular AF patients scheduled for DCC. The primary safety outcome was major bleeding. The primary efficacy outcome was the composite of stroke, transient ischemic attack (TIA), and systemic embolism (SE). FINDINGS: A total of 130 AF patients receiving edoxaban 60-mg (EDO) treatment were compared with the same number of VKA recipients. The cumulative incidence of major bleedings was 1.54% in the EDO group and 3.08% in the VKA group (P = 0.4). The cumulative incidence of thromboembolic events was 1.54% in the EDO group and 2.31% in the VKA group (P = 0.9). A non-significant trend in improved adherence was observed between the EDO and VKA groups with a total anticoagulant therapy discontinuation rate of 4.62% (6/130) vs 6.15% (8/130), respectively (P = 0.06). IMPLICATIONS: Our study provides the evidence of a safe and effective use of edoxaban in this clinical setting, justified by no significant difference in major bleedings and thromboembolic events between edoxaban and well-controlled VKA treatments.

Vitamin K for the Treatment of Cardiovascular Disease in End-Stage Renal Disease Patients: Is there Hope?

In Chronic Kidney Disease, vascular calcification (VC) is highly prevalent even at early stages and is gradually enhanced, along with disease progression to End-Stage Renal Disease (ESRD). The calcification pattern in uremia includes all types of mineralization and contributes to the heavy cardiovascular (CV) burden that is common in these patients. Ectopic mineralization is the result of the imbalance between inhibitors and promoters of vascular calcification, with the latter overwhelming the former. The most powerful, natural inhibitor of calcification is Matrix Gla Protein (MGP), a small vitamin K dependent protein, secreted by chondrocytes and vascular smooth muscle cells. In uremia, MGP was reported as the only molecule able to reverse VC by "sweeping" calcium and hydroxyapatite crystals away from the arterial wall. To become biologically active, this protein needs to undergo carboxylation and phosphorylation, reactions highly dependent on vitamin K status. The inactive form of MGP reflects the deficiency of vitamin K and has been associated with CV events and mortality in ESRD patients. During the past decade, vitamin K status has emerged as a novel risk factor for vascular calcification and CV disease in various populations, including dialysis patients. This review presents evidence regarding the association between vitamin K and CV disease in ESRD patients, which are prone to atherosclerosis and atheromatosis.

Vitamin K antagonists vs. direct oral anticoagulants after transcatheter aortic valve implantation in atrial fibrillation.

AIMS: To examine the risk of arterial thromboembolism, bleeding, and all-cause mortality in atrial fibrillation (AF) patients treated with direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: In this nationwide observational cohort study, 735 patients undergoing TAVI from 1 January 2012 to 30 June 2017 with a history of AF and who were treated with oral anticoagulants were identified using data from Danish nationwide registries. Of these, 219 (29.8%) and 516 (70.2%) patients were treated with DOACs and VKAs, respectively. The DOAC group was characterized by a higher prevalence of previous arterial thromboembolism and a lower prevalence of chronic kidney disease compared with the VKA group. The distribution of age, sex, CHA2DS2-VASc and HAS-BLED scores, and concomitant antiplatelet therapy was similar between groups. Compared with VKA, treatment with DOACs was not associated with a significantly different 3-year absolute risk of arterial thromboembolism [9.6% (95% confidence interval, CI 4.7-16.5%) vs. 7.4% (95% CI 4.9-10.5%) in the DOAC and VKA group, respectively], bleeding [14.3% (95% CI 7.6-22.9%) vs. 13.3% (95% CI 9.9-17.1%)], or all-cause mortality [32.7% (95% CI 21.8-44.0%) vs. 32.0% (95% CI 26.8-37.3%)]. In adjusted analyses, treatment with DOACs, when compared with VKAs, was not associated with a significantly different rate of arterial thromboembolism [hazard ratio (HR) 1.23 (95% CI 0.58-2.59)], bleeding [HR 1.14 (95% CI 0.63-2.06)], or all-cause mortality [HR 0.93 (95% CI 0.61-1.40)]. CONCLUSION: In patients with AF undergoing TAVI, treatment with DOACs was not associated with a significantly different risk of arterial thromboembolism, bleeding, or all-cause mortality compared with VKA.

Particulate Matter and Temperature: Increased Risk of Adverse Clinical Outcomes in Patients With Atrial Fibrillation.

OBJECTIVE: To test the hypothesis that particulate matter with an aerodynamic diameter of less than 10 µm (PM10) and temperature are associated with an increased risk of adverse clinical outcomes in patients with atrial fibrillation (AF) taking vitamin K antagonists (VKAs). PATIENTS AND METHODS: We included patients with AF whose condition was stable while taking VKAs (international normalized ratio, 2.0 to 3.0) for 6 months seen in a tertiary hospital (recruitment from May 1, 2007, to December 1, 2007). During a median follow-up of 6.5 years (interquartile range, 4.3 to 7.9 years), ischemic strokes, major bleeding, adverse cardiovascular events, and mortality were recorded. From 2007 to 2016, data on average temperature and PM10 were compared with clinical outcomes. RESULTS: The study group included 1361 patients (663 [48.7%] male; median age, 76 years [interquartile range, 71 to 81 years]). High PM10 and low temperatures were associated with higher risk of major bleeding (adjusted hazard ratio [aHR], 1.44; 95% CI, 1.22 to 1.70 and aHR, 1.03; 95% CI, 1.01 to 1.05, respectively) and mortality (aHR, 1.50; 95% CI, 1.34 to 1.69 and aHR, 1.04; 95% CI, 1.02 to 1.06, respectively); PM10 was also associated with ischemic stroke and temperature with cardiovascular events. The relative risk (RR) for cardiovascular events and mortality increased in months in the lower quartile of temperature (RR, 1.12; 95% CI, 1.04 to 1.21 and RR, 1.41; 95% CI, 1.15 to 1.74, respectively). Comparing seasons, there were higher risks of cardiovascular events in spring, autumn, and winter than in summer, whereas the risk of mortality increased only in winter. CONCLUSION: In patients with AF taking VKAs, high PM10 and low temperature were associated with increased risk of ischemic stroke and cardiovascular events, respectively. Both factors increased major bleeding and mortality risks, which were higher during colder months and seasons.

Vitamin K for kidney transplant organ recipients: investigating vessel stiffness (ViKTORIES): study rationale and protocol of a randomised controlled trial.

BACKGROUND: Renal transplant recipients (RTRs) exhibit increased vascular stiffness and calcification; these parameters are associated with increased cardiovascular risk. Activity of endogenous calcification inhibitors such as matrix gla protein (MGP) is dependent on vitamin K. RTRs commonly have subclinical vitamin K deficiency. The Vitamin K in kidney Transplant Organ Recipients: Investigating vEssel Stiffness (ViKTORIES) study assesses whether vitamin K supplementation reduces vascular stiffness and calcification in a diverse population of RTR. METHODS AND ANALYSIS: ViKTORIES (ISRCTN22012044) is a single-centre, phase II, parallel-group, randomised, double-blind, placebo-controlled trial of the effect of vitamin K supplementation in 90 prevalent RTR. Participants are eligible if they have a functioning renal transplant for >1 year. Those on warfarin, with atrial fibrillation, estimated glomerular filtration rate <15 mL/min/1.73 m2 or contraindications to MRI are excluded. Treatment is with vitamin K (menadiol diphosphate) 5 mg three times per week for 1 year or matching placebo. All participants have primary and secondary endpoint measures at 0 and 12 months. The primary endpoint is ascending aortic distensibility on cardiac MR imaging. Secondary endpoints include vascular calcification (coronary artery calcium score by CT), cardiac structure and function on MR, carotid-femoral pulse wave velocity, serum uncarboxylated MGP, transplant function, proteinuria and quality of life. The study is powered to detect 1.0×10-3 mm Hg-1 improvement in ascending aortic distensibility in the vitamin K group relative to placebo at 12 months. Analyses will be conducted as between-group differences at 12 months by intention to treat. DISCUSSION: This trial may identify a novel, inexpensive and low-risk treatment to improve surrogate markers of cardiovascular risk in RTR.

A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle.

Drug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K-dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.

Minor bleeding affects the level of knowledge in patients with atrial fibrillation on oral anticoagulant therapy.

BACKGROUND: Anticoagulant therapy in patients with atrial fibrillation (AF) increases the risk of minor bleeding, which is mostly accepted by patients. We aimed to assess whether continuation of anticoagulation despite minor bleeding is associated with a higher level of knowledge on AF and anticoagulation. METHODS AND RESULTS: In 1525 patients with AF on oral anticoagulation who completed the Jessa AF Knowledge Questionnaire (JAKQ) (median age: 72 years [range, 65-79 years]; men: 54.6%), persistent self-reported minor bleeding was recorded. Minor bleeding was observed in 567 patients (37.2%) including 224 patients (39.5%) on vitamin K antagonists (VKAs) and 343 (60.5%) on non-vitamin K antagonist oral anticoagulants (NOACs). The risk of minor bleeding was lower among patients on NOACs than on VKAs (33.5% vs 44.6%; P < .0001). Multiple logistic regression showed that minor bleeding was associated with the use of NOACs (odds ratio [OR] 0.75; 95% CI 0.59-0.97), female gender (OR 2.19; 95% CI, 1.74-2.75; P < .0001), history of major bleeding (OR 2.85; 95% CI, 1.96-4.14; P < .0001), time since AF diagnosis (OR 1.04; 95% CI, 1.01-1.06; P < .0001), concomitant vascular disease (OR 1.43; 95% CI, 1.10-1.87; P = .0008) and diabetes mellitus (OR 1.3; 95% CI, 1.02-1.65, P = .03). Patients with minor bleeding, compared with the remaining subjects scored higher on the JAKQ (median, 62.5% vs 56.2%, respectively, P < .0001). The former group knew more about the purpose of anticoagulant therapy (71.8% vs 65.7%, P = .01) and bleeding as its key side effect (66.1% vs 52.7%, P < .0001), and were better informed on the safest painkillers to use in combination with anticoagulation (48% vs 35%, P < .0001). CONCLUSION: This study suggests that AF patients who accept persistent minor bleeding have better knowledge on the disease and anticoagulation therapy compared with those free of these side effects.

Clinical profile of direct oral anticoagulants versus vitamin K anticoagulants in octogenarians with atrial fibrillation: a multicentre propensity score matched real-world cohort study.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and its prevalence increases with age. Few data are available about the clinical performance of direct oral anticoagulant (DOACs) in patients aged ≥ 80 years with AF. The aim of our propensity score matched cohort study was to compare the safety and efficacy of DOACs versus well-controlled VKA therapy among octogenarians with AF in real life setting. Data for this study were sourced from the multicenter prospectively maintained Atrial Fibrillation Research Database (NCT03760874), which includes all AF patients followed by the participating centers, through outpatient visits every 3 to 6 months. The database was queried for AF patients aged ≥ 80 years who received DOACs or VKAs treatment. The primary effectiveness endpoint was the occurrence of thromboembolic events (a composite of stroke, transient ischemic attack, systemic embolism); the primary safety endpoint was the occurrence of major bleeding; the secondary endpoint was all-cause mortality. The database query identified 774 AF patients aged ≥ 80 years treated with VKAs and 279 with DOACs. Propensity score (2:1) matching selected 252 DOAC and 504 VKA recipients. The mean follow-up was 31.07 ± 14.09 months. The incidence rate of thromboembolic events was 13.79 per 1000 person-years [14.80 in DOAC vs 13.34 in VKA group, Hazard Ratio 1.10; 95% confidence interval (CI) 0.49 to 2.45; P = 0.823]. The incidence rate of intracranial hemorrhage (ICH) was 8.06 per 1000 person-years (3.25 in DOAC vs 10.23 in VKA group, HR 0.33; 95% CI 0.07 to 1.45; P = 0.600). Through these incidence rates, we found a positive net clinical benefit (NCB) of DOACs over VKAs, equal to + 9.01. The incidence rate of all-cause mortality was 105.05 per 1000 person-years (74.67 in DOAC vs 118.67 in VKA group, Hazard Ratio 0.65; 95% CI 0.47 to 0.90; P = 0.010). The concomitant use of antiinflammatory drugs (HR 7.90; P < 0.001) were found to be independent predictor of major bleeding. Moreover, age (HR 1.17; P < 0.002) and chronic kidney disease (HR 0.34; P = 0.019) were found to be independently associated with thromboembolic events. In our study no significant difference in terms of both thromboembolic and major bleeding events, but a significant lower incidence of all-cause mortality, was detected in AF patients aged ≥ 80 years treated with DOACs vs VKAs.

Successful switch to oral tacrolimus in a patient with hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus: A case report.

INTRODUCTION: Calcineurin inhibitors are widely used for the prevention and treatment of graft versus host disease in patients undergoing allogeneic hematopoietic stem cell transplantation, and successful treatment with calcineurin inhibitors is very important for the management of these cases. CASE REPORT: A 19-year-old man with thalassemia major experienced hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus before hematopoietic stem cell transplantation. All three episodes of reaction appeared a few minutes after administration of offended drugs and cause systemic signs and symptoms of anaphylaxis, i.e. itching, flushing, difficulty in breathing, and hypotension. MANAGEMENT AND OUTCOME: Hypersensitivity reaction was fully controlled by immediately discontinuing the drug and administering hydrocortisone, chlorpheniramine, epinephrine, and intravenous fluids. During hospitalization, the patient tolerated oral tacrolimus without any complication. DISCUSSION: It appears that Cremophor EL (polyoxyethylated castor oil) which acts as a carrier, solubilizer, and emulsifier in intravenous calcineurin inhibitors is responsible for the occurrence of anaphylactic reaction (anaphylaxis); therefore, it is suggested that the administration of cremophor-containing drug should be avoided in patients with a previous history of hypersensitivity reaction to one of these drugs.

Association of mortality among trauma patients taking preinjury direct oral anticoagulants versus vitamin K antagonists.

BACKGROUND: The population of patients on anticoagulant or antiplatelet therapy for medical conditions is increasing. The objective of this study was to investigate the effects of preinjury anticoagulation or antiplatelet therapy on outcomes after trauma. METHODS: This cohort study analyzed data from the Michigan Trauma Quality Improvement Program from 2012 to 2017 and included trauma patients age ≥16 years with an Injury Severity Score ≥5 treated at 29 hospitals. The primary outcome was in-hospital mortality. RESULTS: Of 115,042 trauma patients, 44.2% were women and 78.2% were white with a mean age (standard deviation) of 59.1 (23.2) years. A total of 23,196 patients were on antiplatelet therapy, 3,855 on warfarin, 1,893 on warfarin + antiplatelet agent, 1,306 on a direct oral anticoagulant, and 717 patients on direct oral anticoagulant + antiplatelet therapy. We observed an increased risk of mortality in patients on preinjury antiplatelet (odds ratio [OR] 1.17; 95% confidence interval [CI] 1.02-1.33), warfarin (OR 1.32; 95% CI 1.05-1.65), or warfarin + antiplatelet therapy (OR 1.59; 95% CI 1.18-2.14). Patients on a direct oral anticoagulant only were not at statistically increased risk for mortality. CONCLUSION: Preinjury antiplatelet and/or warfarin use was associated with an increased risk of mortality after traumatic injury. Preinjury direct oral anticoagulant use was not associated with a statistically increased risk of adverse outcomes.