Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR.

BACKGROUND: The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS: We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS: A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS: In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

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.

Anticoagulant rodenticide exposure and toxicosis in bald eagles (Haliaeetus leucocephalus) and golden eagles (Aquila chrysaetos) in the United States.

Raptors, including eagles, are geographically widespread and sit atop the food chain, thereby serving an important role in maintaining ecosystem balance. After facing population declines associated with exposure to organochlorine insecticides such as dichlorodiphenyltrichloroethane (DDT), bald eagles (Haliaeetus leucocephalus) have recovered from the brink of extinction. However, both bald and golden eagles (Aquila chrysaetos) are exposed to a variety of other toxic compounds in the environment that could have population impacts. Few studies have focused on anticoagulant rodenticide (AR) exposure in eagles. Therefore, the purpose of this study was to determine the types of ARs that eagles are exposed to in the USA and better define the extent of toxicosis (i.e., fatal illness due to compound exposure). Diagnostic case records from bald and golden eagles submitted to the Southeastern Cooperative Wildlife Disease Study (University of Georgia) 2014 through 2018 were reviewed. Overall, 303 eagles were examined, and the livers from 116 bald eagles and 17 golden eagles were tested for ARs. The percentage of AR exposure (i.e., detectable levels but not associated with mortality) in eagles was high; ARs were detected in 109 (82%) eagles, including 96 (83%) bald eagles and 13 (77%) golden eagles. Anticoagulant rodenticide toxicosis was determined to be the cause of mortality in 12 (4%) of the 303 eagles examined, including 11 bald eagles and 1 golden eagle. Six different AR compounds were detected in these eagles, with brodifacoum and bromadiolone most frequently detected (81% and 25% of eagles tested, respectively). These results suggest that some ARs, most notably brodifacoum, are widespread in the environment and are commonly consumed by eagles. This highlights the need for research to understand the pathways of AR exposure in eagles, which may help inform policy and regulatory actions to mitigate AR exposure risk.

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.

Bromadiolone poisoning leading to subarachnoid haemorrhage: A case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVE: Many cases of rodenticide poisoning have been reported. Bromadiolone, often called a super-warfarin, is a second-generation dicoumarin rodenticide with long half-life. The main clinical manifestations of bromadiolone poisoning are excessive or inappropriate bleeding of skin mucosa, digestive tract and urinary tract. However, the phenomenon of central nervous system (CNS) toxicity is an uncommon medical emergency. We present a case of SAH and intracerebral haematoma mediated by bromadiolone intoxication, revealing that bromadiolone poisoning might cause intracerebral haematoma. CASE DESCRIPTION: A 44-year-old woman presented with skin mucosa haemorrhage and haematuresis initially. The patient developed lethargy, headache, nausea and vomiting. The toxicology test result revealed that the presence of bromadiolone in her blood. Coagulation test results showed a longer prothrombin time (PT), activated partial thromboplastin time (APTT) and a high international normalized ratio (INR). SAH, frontal lobe haematoma, midline shift and brain oedema were discovered by skull CT examination. The coagulation disorders were addressed after the treatment of vitamin K and fresh frozen plasma. The intracranial symptoms were relieved after surgery and the treatment with mannitol. WHAT IS NEW AND CONCLUSION: This case suggests that bromadiolone poisoning should be diagnosed and treated as early as possible. Bromadiolone poisoning might cause SAH and intracerebral haematoma, which is rare but potentially lethal. It is important to strengthen the diagnosis and post-treatment monitoring.

Hemorrhagic Soft Tissue Upper Airway Obstruction From Brodifacoum-Contaminated Synthetic Cannabinoid.

BACKGROUND: More than 60 types of cannabinoids are found in nature; the remaining are chemically synthesized analogs of natural cannabinoids. Synthetic cannabinoids were first reported in the United States in 2008. These compounds are usually smoked by users and are sold under various names. Synthesized products have clinical effects that are similar to the effects of cannabis, which include tachycardia, conjunctival injection, nystagmus, vomiting, and ataxia. In cases of acute overdose, hyperthermia, acute kidney injury, seizures, and rhabdomyolysis can occur. CASE REPORT: Deaths and life-threatening coagulopathies caused by brodifacoum (BDF) adulteration of synthetic cannabinoids have been reported in Illinois and other regions of the United States. BDF is a long-acting vitamin K-dependent antagonist that is often used as rat poison and that can cause massive hemorrhage. BDF is sometimes referred to as "superwarfarin" because the anticoagulant effect is 100 times greater than warfarin on a molar basis and its half-life is 20-130 days, which markedly exceeds that of warfarin. The rationale for lacing synthetic cannabinoids with BDF may be associated with attempts to enhance psychoactive effect of the drug, keeping the user high for a longer period of time because of lipid storage, hepatic metabolism, and slow release. We present the case of a healthy 27-year-old man who developed severe soft tissue hemorrhage and airway obstruction after use of a cannabinoid laced with BDF. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: To date there have been no case reports documenting severe soft tissue hemorrhage leading to airway obstruction and respiratory failure from synthetic cannabinoid use, whether or not the synthetic cannabinoid has been adulterated. Severe complications can arise from use, and treatment includes vitamin K and supportive therapy because the resulting coagulopathy can take days to weeks to resolve.

Coagulopathic hemorrhage with use of synthetic cannabinoids.

Synthetic cannabinoids contain many different chemicals and compounds, which pose new health risks to the population using these drugs. In May of 2018 the Center for Disease Control issued a health alert providing information on a multistate outbreak of coagulopathy from exposure to synthetic cannabinoid products containing a Vitamin K-dependent antagonistic agent such as brodifacoum. Recognizing signs, symptoms and imaging findings related to this outbreak is essential for clinicians caring for patients with a history or suspicion of using synthetic cannabinoids. To our knowledge, there are no studies that report the imaging findings demonstrating the coagulopathic complications associated with these synthetic compounds.

Evaluation of patients' knowledge on their vitamin K antagonist treatment.

INTRODUCTION: Vitamin K antagonists (VKA) are currently the most prescribed oral anticoagulant treatment in Tunisia. Despite the standardization of biological monitoring and the better definition of therapeutic objectives, their side effects are a frequent reason for hospitalization. AIM: To evaluate patients' knowledge about their VKA treatment. METHODS: We realized a cross-sectional descriptive study in the Cardiology Department of HabibThameur Hospital from September to October 2016. A questionnaire consisting of 14 items was used in a semi-directed interview in order to assess patients' knowledge on their VKA treatment. RESULTS: Our study included one hundred patients. Mean age was 61 ± 12 years and sex ratio of 1.8. Forty-eight per cent were illiterate. The median duration of AVK intake was 5 years. Atrial fibrillation (AF) was the most frequent indication (57%). Eighty percent of patients had more than five correct answers on the eight items of knowledge: VKA's name (96%), tablet description (93%), dose (99%), time (94%), VKA's effect (70%), INR (56%), treatment's risk (49%) and the target INR (20%). Twenty-two percent had more than four correct answers on the 6 items of know-how: what to do in case of haemorrhage (70%), what to do in case of oblivion (45%), interactions precautions to be observed with food (13%), activities advised against (49%) and medical procedures advised against (27%). In multivariate analysis, only prior VKA information was significantly associated with a better knowledge of VKA (p = 0.027). CONCLUSION: Our patients' knowledge on their VKA treatment was insufficient to ensure the safety and efficacy of treatment. The creation of a therapeutic education program on is therefore necessary to reduce the iatrogenic risk of this treatment.

An Outbreak of Synthetic Cannabinoid-Associated Coagulopathy in Illinois.

BACKGROUND: In March and April 2018, more than 150 patients presented to hospitals in Illinois with coagulopathy and bleeding diathesis. Area physicians and public health organizations identified an association between coagulopathy and synthetic cannabinoid use. Preliminary tests of patient serum samples and drug samples revealed that brodifacoum, an anticoagulant, was the likely adulterant. METHODS: We reviewed physician-reported data from patients admitted to Saint Francis Medical Center in Peoria, Illinois, between March 28 and April 21, 2018, and included in a case series adult patients who met the criteria used to diagnose synthetic cannabinoid-associated coagulopathy. A confirmatory anticoagulant poisoning panel was ordered at the discretion of the treating physician. RESULTS: A total of 34 patients were identified as having synthetic cannabinoid-associated coagulopathy during 45 hospitalizations. Confirmatory anticoagulant testing was performed in 15 of the 34 patients, and superwarfarin poisoning was confirmed in the 15 patients tested. Anticoagulant tests were positive for brodifacoum in 15 patients (100%), difenacoum in 5 (33%), bromadiolone in 2 (13%), and warfarin in 1 (7%). Common symptoms at presentation included gross hematuria in 19 patients (56%) and abdominal pain in 16 (47%). Computed tomography was performed to evaluate abdominal pain and revealed renal abnormalities in 12 patients. Vitamin K1 (phytonadione) was administered orally in all 34 patients and was also administered intravenously in 23 (68%). Red-cell transfusion was performed in 5 patients (15%), and fresh-frozen plasma infusion in 19 (56%). Four-factor prothrombin complex concentrate was used in 1 patient. One patient died from complications of spontaneous intracranial hemorrhage. CONCLUSIONS: Our data indicate that superwarfarin adulterants of synthetic cannabinoids can lead to clinically significant coagulopathy. In our series, in most of the cases in which the patient presented with bleeding diathesis, symptoms were controlled with the use of vitamin K1 replacement therapy. The specific synthetic cannabinoid compounds are not known.

[Educational and information needs of patients under vitamin K antagonist therapy]. / Quels besoins d'information et d'éducation des patients traités par les anti-vitamines K ?

BACKGROUND: Adverse events related to vitamin K antagonists (VKA) represent a major public health problem. Informative tools and educative program contributes to the reduction of iatrogenic risk. The purpose of our study is to assess representations and information needs of patients under VKA therapy in order to develop a suitable therapeutic education program. METHODS: Individual semi-structured interviews were conducted among both long term VKA therapy patient and patients initiating VKA. The thematic analysis allowed us to explore patient's speech qualitatively and semi-quantitatively. RESULTS: The main needs in information concerned the modalities of treatment (27.6%), side effects (24.1%), precautions and management of VKA treatment (24.1%). Origin of the disease (P=0.022) and drug mechanism of action (0.012) were specially asked about by patients initiating their treatment. CONCLUSION: Patients under VKA therapy reported needs for information on both their pathology and their anticoagulant therapy. The therapeutic education approach will enable us to adapt the educational tools and messages to the needs of patients under VKA therapy.

[Vitamine K antagonists overdose: Physician adherence to the French guidelines]. / Surdosages en antivitamines K : audit de la prise en charge hospitalière.

INTRODUCTION: Vitamin K antagonists (VKA) are drugs with a major risk of side effect. Guidelines have been published in 2008 by the Haute Autorité de santé (HAS) concerning the management of an excessively elevated INR ratio. Our research aimed to assess physicians' adherence to those guidelines. METHODS: We realized a retrospective, multicentric study. One hundred and ten cases of excessively elevated INR ratio were identified and analyzed. RESULTS: Overall physicians adherence was 58%. However, patients with the most elevated INR, i.e., INR>6, were treated according to guidelines in only 33% of the cases. The use of vitamin K was the major source of mistakes. The rate of mortality was 20%. CONCLUSION: Adherence to HAS guidelines seems finally limited. It is necessary to put in place procedures to secure the behavior of physicians.

[Vitamin K antagonist-induced necrotic leg ulcer, without protein C and S deficiencies]. / Ulcères nécrotiques sous antivitamine K, sans déficit en protéine C et S associé.

INTRODUCTION: Patients treated by vitamin K antagonists (VKA) represent 1% of the population in France. We report a case of atypical necrotic leg ulcers induced by VKA. CASE REPORT: A 84-year-old woman was referred to our dermatology department because of necrotic leg ulcers that developed for the past 5weeks, and appeared spontaneously after the introduction of a VKA, fluindione. The etiological assessment was non contributive, in particular the search for thrombophilic factors. The skin biopsy found an aspect compatible with pyoderma gangrenosum. The outcome was favorable after discontinuing the fluindione and the switch to apixaban. A complete healing was obtained in 5months. CONCLUSION: We report an original case of necrotic leg ulcers induced by VKA without deficit of protein C or S, with a pyoderma like histology. Reported cases of ulcers induced by VKA are uncommon and the physiopathology is not well known. The involvement of VKA should be evoked in case of necrotic leg ulcer without specific etiology found.

Recovery of brodifacoum in vomitus following induction of emesis in dogs that had ingested rodenticide bait.

AIM: To assess the benefit of inducing emesis in dogs that have ingested rodenticide bait containing brodifacoum (BDF), by determining the amount of BDF in bait recovered from the vomitus relative to the estimated amount consumed. METHODS: Between 2014 and 2015 samples of vomitus from seven dogs that ingested rodenticide baits containing BDF were submitted by veterinarians in New Zealand. All seven dogs had been given apomorphine by the veterinarian and vomited within 1 hour of ingesting the bait. Some or all of the bait particles were retrieved from each sample and were analysed for concentrations of BDF using HPLC. Based on estimations of the mass of bait consumed, the concentration of BDF stated on the product label, and the estimated mass of bait in the vomitus of each dog, the amount of BDF in the vomited bait was calculated as a percentage of the amount ingested. RESULTS: For five dogs an estimation of the mass of bait ingested was provided by the submitting veterinarian. For these dogs the estimated percentage of BDF in the bait retrieved from the vomitus was between 10-77%. All dogs were well after discharge but only one dog returned for further testing. This dog had a normal prothrombin time 3 days after ingestion. CONCLUSIONS AND CLINICAL RELEVANCE: The induction of emesis within 1 hour of ingestion can be a useful tool in reducing the exposure of dogs to a toxic dose of BDF. The BDF was not fully absorbed within 1 hour of ingestion suggesting that the early induction of emesis can remove bait containing BDF before it can be fully absorbed.

Massive neonatal intracranial hemorrhage caused by bromadiolone: A case report.

RATIONALE: Bromadiolone, often called a super-warfarin, is a potent rodenticide with long half-life. Skin and mucosal bleeding is the most common clinical manifestations of its intoxication. Bromadiolone intoxications in adults and children have been reported, but this phenomenon is rarely seen in fetuses. This paper presents a case of neonate with massive intracranial hemorrhage mediated by bromadiolone intoxication, highlighting that the bromadiolone is potentially lethal to the fetus. PATIENT CONCERNS: The male neonate presented with poor respiratory effort, decreased muscle tone, and pallor at birth. He developed generalized seizures on day 1 of life. His mother suffered from bleeding of oral mucosa and the subsequent lab screening for toxicants showed a bromadiolone level of 126 ng/mL. DIAGNOSES: Laboratory tests revealed that prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT). A computed tomography (CT) of his head revealed a severe subdural hematoma, which lead to midline shift, bilateral intraventricular hemorrhage, and subarachnoid hemorrhage. Serum from cord blood was collected and screened for toxicants. The result returned with a bromadiolone level of 94 ng/mL. INTERVENTIONS: The neonate was treated with vitamin K, fresh-frozen plasma, and red blood cells. OUTCOMES: His parents required termination of all treatments, and the neonate unfortunately died shortly after. LESSONS: Through clinical experience from this case, we believe that bromadiolone can be passed down to the fetus via placenta. Neonatal intracranial hemorrhage caused by bromadiolone is rare but potentially lethal. Pregnant women should be informed of the serious side effects of bromadiolone and this poisonous reagent should be avoided in any period during pregnancy.

A negative association between bromadiolone exposure and nestling body condition in common kestrels: management implications for vole outbreaks.

BACKGROUND: Vole outbreaks have been extensively described, along with their impacts on humans, particularly in agricultural areas. The use of rodenticides is a common legal practice to minimise crop damage induced by high vole density for biocidal use. However, rodenticides can have negative direct and indirect impacts on non-target species that feed on voles. We studied whether the use of a second-generation anticoagulant rodenticide (SGAR), bromadiolone, can be detected in the blood of fledglings of wild common kestrels Falco tinnunculus in two areas of central Spain, exploring its possible indirect effects. RESULTS: We found that 16.9% of fledglings had a detectable concentration of bromadiolone in their blood, with an average concentration of 0.248 ± 0.023 ng mL-1 . Fledglings with bromadiolone in their blood, regardless of the concentration, had 6.7% lower body mass than those without detectable bromadiolone. CONCLUSION: The use of bromadiolone was detectable in the blood of alive non-target species. Detected bromadiolone in blood may reduce the body condition of nestlings, potentially reducing their fitness. The source of bromadiolone found in nestlings needs to be determined in future studies to derive accurate management advice. However, we urge the discontinuation of official SGAR distribution to farmers and their use in agrarian lands to minimise damage of voles on crops, particularly where common kestrels breed, and encourage the use of alternative effective practices. © 2016 Society of Chemical Industry.